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Sample records for melanoma xenografts treatment

  1. The Effect of Sunitinib Treatment in Human Melanoma Xenografts: Associations with Angiogenic Profiles.

    PubMed

    Gaustad, Jon-Vidar; Simonsen, Trude G; Andersen, Lise Mari K; Rofstad, Einar K

    2017-04-01

    The effect of antiangiogenic agents targeting the vascular endothelial growth factor A (VEGF-A) pathway has been reported to vary substantially in preclinical studies. The purpose of this study was to investigate the effect of sunitinib treatment on tumor vasculature and oxygenation in melanoma xenografts with different angiogenic profiles. A-07, U-25, D-12, or R-18 melanoma xenografts were grown in dorsal window chambers and given daily treatments of sunitinib (40 mg/kg) or vehicle. Morphologic parameters of tumor vascular networks were assessed from high-resolution transillumination images, and tumor blood supply times (BSTs) were assessed from first-pass imaging movies. Tumor hypoxia was assessed with immunohistochemistry by using pimonidazole as hypoxia marker, and the gene expression and the protein secretion rate of angiogenic factors were assessed by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The melanoma lines differed substantially in the expression of VEGF-A, VEGF-C, and platelet-derived growth factor A. Sunitinib treatment reduced vessel densities and induced hypoxia in all melanoma lines, and the magnitude of the effect was associated with the gene expression and protein secretion rate of VEGF-A. Sunitinib treatment also increased vessel segment lengths, reduced the number of small-diameter vessels, and inhibited growth-induced increases in the diameter of surviving vessels but did not change BST. In conclusion, sunitinib treatment did not improve vascular function but reduced vessel density and induced hypoxia in human melanoma xenografts. The magnitude of the treatment-induced effect was associated with the VEGF-A expression of the melanoma lines.

  2. Evaluation of Arginine Deiminase Treatment in Melanoma Xenografts Using 18F-FLT PET

    PubMed Central

    Stelter, Lars; Fuchs, Simon; Jungbluth, Achim A.; Ritter, Gerd; Longo, Valerie A.; Zanzonico, Pat; Raschzok, Nathanael; Sauer, Igor M.; Bomalaski, John S.; Larson, Steven M.

    2015-01-01

    Purpose This study aims to develop a molecular imaging strategy for response assessment of arginine deiminase (ADI) treatment in melanoma xenografts using 3′-[18F]fluoro-3′-deoxythymidine ([18F]-FLT) positron emission tomography (PET). Procedures F-FLT response to ADI therapy was studied in preclinical models of melanoma in vitro and in vivo. The molecular mechanism of response to ADI therapy was investigated, with a particular emphasis on biological pathways known to regulate 18F-FLT metabolism. Results Proliferation of SK-MEL-28 melanoma tumors was potently inhibited by ADI treatment. However, no metabolic response was observed in FLT PET, presumably based on the known ADI-induced degradation of PTEN, followed by instability of the tumor suppressor p53 and a relative overexpression of thymidine kinase 1, the enzyme mainly responsible for intracellular FLT processing. Conclusion The specific pharmacological properties of ADI preclude using 18F-FLT to evaluate clinical response in melanoma and argue for further studies to explore the use of other clinically applicable PET tracers in ADI treatment. PMID:23722880

  3. Dissection of stromal and cancer cell-derived signals in melanoma xenografts before and after treatment with DMXAA

    PubMed Central

    Henare, K; Wang, L; Wang, L-Cs; Thomsen, L; Tijono, S; Chen, C-Jj; Winkler, S; Dunbar, P R; Print, C; Ching, L-M

    2012-01-01

    Background: The non-malignant cells of the tumour stroma have a critical role in tumour biology. Studies dissecting the interplay between cancer cells and stromal cells are required to further our understanding of tumour progression and methods of intervention. For proof-of-principle of a multi-modal approach to dissect the differential effects of treatment on cancer cells and stromal cells, we analysed the effects of the stromal-targeting agent 5,6-dimethylxanthenone-4-acetic acid on melanoma xenografts. Methods: Flow cytometry and multi-colour immunofluorescence staining was used to analyse leukocyte numbers in xenografts. Murine-specific and human-specific multiplex cytokine panels were used to quantitate cytokines produced by stromal and melanoma cells, respectively. Human and mouse Affymetrix microarrays were used to separately identify melanoma cell-specific and stromal cell-specific gene expression. Results: 5,6-Dimethylxanthenone-4-acetic acid activated pro-inflammatory signalling pathways and cytokine expression from both stromal and cancer cells, leading to neutrophil accumulation and haemorrhagic necrosis and a delay in tumour re-growth of 26 days in A375 melanoma xenografts. Conclusion: 5,6-Dimethylxanthenone-4-acetic acid and related analogues may potentially have utility in the treatment of melanoma. The experimental platform used allowed distinction between cancer cells and stromal cells and can be applied to investigate other tumour models and anti-cancer agents. PMID:22415295

  4. sup 211 At-methylene blue for targeted radiotherapy of human melanoma xenografts: Treatment of micrometastases

    SciTech Connect

    Link, E.M.; Carpenter, R.N. )

    1990-05-15

    Treatment of micrometastases of HX34 human melanoma grown as xenografts in nude mice represents an advanced stage of preclinical investigations concerning targeted radiotherapy of this neoplasm using 3,7-(dimethylamino)phenazathionium chloride methylene blue (MTB) labeled with astatine-211 (211At) (alpha-particle emitter). The therapeutic effectiveness of 211At-MTB administered i.v. was determined by a lung colony assay combined with a search for metastases to organs other than the lungs. A single dose of 211At-MTB lowered the HX34 cell surviving fraction in lungs to below 10% almost independently of the time interval between cell inoculation and radioisotope injection and of 211At-MTB radioactivity within its investigated range. Radiation dose and the time of its administration did, however, influence the size of lung colonies. In contrast, the efficacy of 211At-MTB treatment as assessed by both surviving fraction and colony size was significantly dependent on a number of HX34 cells inoculated initially into mice. These results are explained by a short range of alpha-particles emitted by 211At and a mechanism of growth of lung colonies from tumor cells circulating with blood and blocking lung capillaries. Metastases in organs other than lungs and characteristic of control animals were not found in mice treated with 211At-MTB. The high therapeutic efficacy achieved proved that 211At-MTB is a very efficient scavenger of single melanoma cells distributed through blood and micrometastases with sizes below the limit of clinical detection.

  5. Sunitinib treatment does not improve blood supply but induces hypoxia in human melanoma xenografts

    PubMed Central

    2012-01-01

    Background Antiangiogenic agents that disrupt the vascular endothelial growth factor pathway have been demonstrated to normalize tumor vasculature and improve tumor oxygenation in some studies and to induce hypoxia in others. The aim of this preclinical study was to investigate the effect of sunitinib treatment on the morphology and function of tumor vasculature and on tumor oxygenation. Methods A-07-GFP and R-18-GFP human melanoma xenografts grown in dorsal window chambers were used as preclinical tumor models. Morphologic parameters of tumor vascular networks were assessed from high-resolution transillumination images, and tumor blood supply time was assessed from first-pass imaging movies recorded after a bolus of 155 kDa tetramethylrhodamine isothiocyanate-labeled dextran had been administered intravenously. Tumor hypoxia was assessed from immunohistochemical preparations of the imaged tissue by use of pimonidazole as a hypoxia marker. Results Sunitinib treatment reduced vessel densities, increased vessel segment lengths, did not affect blood supply times, and increased hypoxic area fractions. Conclusion Sunitinib treatment did not improve vascular function but induced hypoxia in A-07-GFP and R-18-GFP tumors. PMID:22947392

  6. Anti-Tumor Effect of Adipose Tissue Derived-Mesenchymal Stem Cells Expressing Interferon-β and Treatment with Cisplatin in a Xenograft Mouse Model for Canine Melanoma

    PubMed Central

    Ahn, Jin ok; Lee, Hee woo; Seo, Kyoung won; Kang, Sung keun; Ra, Jeong chan; Youn, Hwa young

    2013-01-01

    Adipose tissue-derived mesenchymal stem cells (AT-MSCs) are attractive cell-therapy vehicles for the delivery of anti-tumor molecules into the tumor microenvironment. The innate tropism of AT-MSCs for tumors has important implications for effective cellular delivery of anti-tumor molecules, including cytokines, interferon, and pro-drugs. The present study was designed to determine the possibility that the combination of stem cell-based gene therapy with low-dose cisplatin would improve therapeutic efficacy against canine melanoma. The IFN-β transduced canine AT-MSCs (cAT-MSC-IFN-β) inhibited the growth of LMeC canine melanoma cells in direct and indirect in vitro co-culture systems. In animal experiments using BALB/c nude mouse xenografts, which developed by injecting LMeC cells, the combination treatment of cAT-MSC-IFN-β and low-dose cisplatin significantly reduced tumor volume compared with the other treatment groups. Fluorescent microscopic analysis with a TUNEL (terminal deoxynucleotidyl transferase-mediated nick-end labeling) assay of tumor section provided evidence for homing of cAT-MSC-IFN-β to the tumor site and revealed that the combination treatment of cAT-MSC-IFN-β with low-dose cisplatin induced high levels of cell apoptosis. These findings may prove useful in further explorations of the application of these combined approaches to the treatment of malignant melanoma and other tumors. PMID:24040358

  7. Anti-tumor effect of adipose tissue derived-mesenchymal stem cells expressing interferon-β and treatment with cisplatin in a xenograft mouse model for canine melanoma.

    PubMed

    Ahn, Jin ok; Lee, Hee woo; Seo, Kyoung won; Kang, Sung keun; Ra, Jeong chan; Youn, Hwa young

    2013-01-01

    Adipose tissue-derived mesenchymal stem cells (AT-MSCs) are attractive cell-therapy vehicles for the delivery of anti-tumor molecules into the tumor microenvironment. The innate tropism of AT-MSCs for tumors has important implications for effective cellular delivery of anti-tumor molecules, including cytokines, interferon, and pro-drugs. The present study was designed to determine the possibility that the combination of stem cell-based gene therapy with low-dose cisplatin would improve therapeutic efficacy against canine melanoma. The IFN-β transduced canine AT-MSCs (cAT-MSC-IFN-β) inhibited the growth of LMeC canine melanoma cells in direct and indirect in vitro co-culture systems. In animal experiments using BALB/c nude mouse xenografts, which developed by injecting LMeC cells, the combination treatment of cAT-MSC-IFN-β and low-dose cisplatin significantly reduced tumor volume compared with the other treatment groups. Fluorescent microscopic analysis with a TUNEL (terminal deoxynucleotidyl transferase-mediated nick-end labeling) assay of tumor section provided evidence for homing of cAT-MSC-IFN-β to the tumor site and revealed that the combination treatment of cAT-MSC-IFN-β with low-dose cisplatin induced high levels of cell apoptosis. These findings may prove useful in further explorations of the application of these combined approaches to the treatment of malignant melanoma and other tumors.

  8. Application of Sequencing, Liquid Biopsies, and Patient-Derived Xenografts for Personalized Medicine in Melanoma.

    PubMed

    Girotti, Maria Romina; Gremel, Gabriela; Lee, Rebecca; Galvani, Elena; Rothwell, Dominic; Viros, Amaya; Mandal, Amit Kumar; Lim, Kok Haw Jonathan; Saturno, Grazia; Furney, Simon J; Baenke, Franziska; Pedersen, Malin; Rogan, Jane; Swan, Jacqueline; Smith, Matthew; Fusi, Alberto; Oudit, Deemesh; Dhomen, Nathalie; Brady, Ged; Lorigan, Paul; Dive, Caroline; Marais, Richard

    2016-03-01

    Targeted therapies and immunotherapies have transformed melanoma care, extending median survival from ∼9 to over 25 months, but nevertheless most patients still die of their disease. The aim of precision medicine is to tailor care for individual patients and improve outcomes. To this end, we developed protocols to facilitate individualized treatment decisions for patients with advanced melanoma, analyzing 364 samples from 214 patients. Whole exome sequencing (WES) and targeted sequencing of circulating tumor DNA (ctDNA) allowed us to monitor responses to therapy and to identify and then follow mechanisms of resistance. WES of tumors revealed potential hypothesis-driven therapeutic strategies for BRAF wild-type and inhibitor-resistant BRAF-mutant tumors, which were then validated in patient-derived xenografts (PDX). We also developed circulating tumor cell-derived xenografts (CDX) as an alternative to PDXs when tumors were inaccessible or difficult to biopsy. Thus, we describe a powerful technology platform for precision medicine in patients with melanoma. Although recent developments have revolutionized melanoma care, most patients still die of their disease. To improve melanoma outcomes further, we developed a powerful precision medicine platform to monitor patient responses and to identify and validate hypothesis-driven therapies for patients who do not respond, or who develop resistance to current treatments. ©2015 American Association for Cancer Research.

  9. Melanoma Treatment Costs

    PubMed Central

    Guy, Gery P.; Ekwueme, Donatus U.; Tangka, Florence K.; Richardson, Lisa C.

    2015-01-01

    Context Melanoma is the most deadly form of skin cancer and an important public health concern. Given the substantial health burden associated with melanoma, it is important to examine the economic costs associated with its treatment. The purpose of the current study was to systematically review the literature on the direct medical care costs of melanoma. Evidence acquisition A systematic review was performed using multiple databases including MEDLINE, Embase, CINAHL, and Econlit. Nineteen articles on the direct medical costs of melanoma were identified. Evidence synthesis Detailed information on the study population, study country/setting, study perspective, costing approach, disease severity (stage), and key study results were abstracted. The overall costs of melanoma were examined as well as per-patient costs, costs by phase of care, stage of diagnosis, and setting/type of care. Among studies examining all stages of melanoma, annual treatment costs ranged from $44.9 million among Medicare patients with existing cases to $932.5 million among newly diagnosed cases across all age groups. Conclusions Melanoma leads to substantial direct medical care costs, with estimates varying widely because of the heterogeneity across studies in terms of the study setting, populations studied, costing approach, and study methods. Melanoma treatment costs varied by phase of care and stage at diagnoses; costs were highest among patients diagnosed with late-stage disease and in the initial and terminal phases of care. Aggregate treatment costs were generally highest in the outpatient/office-based setting; per-patient/per-case treatment costs were highest in the hospital inpatient setting. Given the substantial costs of treating melanoma, public health strategies should include efforts to enhance both primary prevention (reduction of ultraviolet light exposure) and secondary prevention (earlier detection) of melanoma. PMID:23079178

  10. Intra- and inter-tumor heterogeneity in a vemurafenib-resistant melanoma patient and derived xenografts.

    PubMed

    Kemper, Kristel; Krijgsman, Oscar; Cornelissen-Steijger, Paulien; Shahrabi, Aida; Weeber, Fleur; Song, Ji-Ying; Kuilman, Thomas; Vis, Daniel J; Wessels, Lodewyk F; Voest, Emile E; Schumacher, Ton Nm; Blank, Christian U; Adams, David J; Haanen, John B; Peeper, Daniel S

    2015-09-01

    The development of targeted inhibitors, like vemurafenib, has greatly improved the clinical outcome of BRAF(V600E) metastatic melanoma. However, resistance to such compounds represents a formidable problem. Using whole-exome sequencing and functional analyses, we have investigated the nature and pleiotropy of vemurafenib resistance in a melanoma patient carrying multiple drug-resistant metastases. Resistance was caused by a plethora of mechanisms, all of which reactivated the MAPK pathway. In addition to three independent amplifications and an aberrant form of BRAF(V600E), we identified a new activating insertion in MEK1. This MEK1(T55delins) (RT) mutation could be traced back to a fraction of the pre-treatment lesion and not only provided protection against vemurafenib but also promoted local invasion of transplanted melanomas. Analysis of patient-derived xenografts (PDX) from therapy-refractory metastases revealed that multiple resistance mechanisms were present within one metastasis. This heterogeneity, both inter- and intra-tumorally, caused an incomplete capture in the PDX of the resistance mechanisms observed in the patient. In conclusion, vemurafenib resistance in a single patient can be established through distinct events, which may be preexisting. Furthermore, our results indicate that PDX may not harbor the full genetic heterogeneity seen in the patient's melanoma.

  11. Adjuvant Treatment of Melanoma

    PubMed Central

    Moreno Nogueira, J. A.; Valero Arbizu, M.; Pérez Temprano, R.

    2013-01-01

    Melanomas represent 4% of all malignant tumors of the skin, yet account for 80% of deaths from skin cancer.While in the early stages patients can be successfully treated with surgical resection, metastatic melanoma prognosis is dismal. Several oncogenes have been identified in melanoma as BRAF, NRAS, c-Kit, and GNA11 GNAQ, each capable of activating MAPK pathway that increases cell proliferation and promotes angiogenesis, although NRAS and c-Kit also activate PI3 kinase pathway, including being more commonly BRAF activated oncogene. The treatment of choice for localised primary cutaneous melanoma is surgery plus lymphadenectomy if regional lymph nodes are involved. The justification for treatment in addition to surgery is based on the poor prognosis for high risk melanomas with a relapse index of 50–80%. Patients included in the high risk group should be assessed for adjuvant treatment with high doses of Interferon-α2b, as it is the only treatment shown to significantly improve disease free and possibly global survival. In the future we will have to analyze all these therapeutic possibilities on specific targets, probably associated with chemotherapy and/or interferon in the adjuvant treatment, if we want to change the natural history of melanomas. PMID:23476798

  12. Optimising the combination dosing strategy of abemaciclib and vemurafenib in BRAF-mutated melanoma xenograft tumours

    PubMed Central

    Tate, Sonya C; Burke, Teresa F; Hartman, Daisy; Kulanthaivel, Palaniappan; Beckmann, Richard P; Cronier, Damien M

    2016-01-01

    Background: Resistance to BRAF inhibition is a major cause of treatment failure for BRAF-mutated metastatic melanoma patients. Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, overcomes this resistance in xenograft tumours and offers a promising drug combination. The present work aims to characterise the quantitative pharmacology of the abemaciclib/vemurafenib combination using a semimechanistic pharmacokinetic/pharmacodynamic modelling approach and to identify an optimum dosing regimen for potential clinical evaluation. Methods: A PK/biomarker model was developed to connect abemaciclib/vemurafenib concentrations to changes in MAPK and cell cycle pathway biomarkers in A375 BRAF-mutated melanoma xenografts. Resultant tumour growth inhibition was described by relating (i) MAPK pathway inhibition to apoptosis, (ii) mitotic cell density to tumour growth and, under resistant conditions, (iii) retinoblastoma protein inhibition to cell survival. Results: The model successfully described vemurafenib/abemaciclib-mediated changes in MAPK pathway and cell cycle biomarkers. Initial tumour shrinkage by vemurafenib, acquisition of resistance and subsequent abemaciclib-mediated efficacy were successfully captured and externally validated. Model simulations illustrate the benefit of intermittent vemurafenib therapy over continuous treatment, and indicate that continuous abemaciclib in combination with intermittent vemurafenib offers the potential for considerable tumour regression. Conclusions: The quantitative pharmacology of the abemaciclib/vemurafenib combination was successfully characterised and an optimised, clinically-relevant dosing strategy was identified. PMID:26978007

  13. Optimising the combination dosing strategy of abemaciclib and vemurafenib in BRAF-mutated melanoma xenograft tumours.

    PubMed

    Tate, Sonya C; Burke, Teresa F; Hartman, Daisy; Kulanthaivel, Palaniappan; Beckmann, Richard P; Cronier, Damien M

    2016-03-15

    Resistance to BRAF inhibition is a major cause of treatment failure for BRAF-mutated metastatic melanoma patients. Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, overcomes this resistance in xenograft tumours and offers a promising drug combination. The present work aims to characterise the quantitative pharmacology of the abemaciclib/vemurafenib combination using a semimechanistic pharmacokinetic/pharmacodynamic modelling approach and to identify an optimum dosing regimen for potential clinical evaluation. A PK/biomarker model was developed to connect abemaciclib/vemurafenib concentrations to changes in MAPK and cell cycle pathway biomarkers in A375 BRAF-mutated melanoma xenografts. Resultant tumour growth inhibition was described by relating (i) MAPK pathway inhibition to apoptosis, (ii) mitotic cell density to tumour growth and, under resistant conditions, (iii) retinoblastoma protein inhibition to cell survival. The model successfully described vemurafenib/abemaciclib-mediated changes in MAPK pathway and cell cycle biomarkers. Initial tumour shrinkage by vemurafenib, acquisition of resistance and subsequent abemaciclib-mediated efficacy were successfully captured and externally validated. Model simulations illustrate the benefit of intermittent vemurafenib therapy over continuous treatment, and indicate that continuous abemaciclib in combination with intermittent vemurafenib offers the potential for considerable tumour regression. The quantitative pharmacology of the abemaciclib/vemurafenib combination was successfully characterised and an optimised, clinically-relevant dosing strategy was identified.

  14. The embryonic morphogen, Nodal, is associated with channel-like structures in human malignant melanoma xenografts.

    PubMed

    McAllister, Josephine C; Zhan, Qian; Weishaupt, Carsten; Hsu, Mei-Yu; Murphy, George F

    2010-04-01

    Formation of channel-like structures, also termed vasculogenic mimicry (VM), describes the ability of aggressive melanoma cells to form PAS-positive anastomosing structures that correlate with tumor virulence. This phenomenon may indicate differentiation plasticity, a feature melanoma cells may share with stem cells in the developing embryo. Recent studies have indicated that VM and tumorigenicity of human malignant melanoma may depend on the signaling pathways of an embryonic morphogen, Nodal. However, given the secretory nature of Nodal protein and melanoma cell heterogeneity, it remains unclear whether the Nodal-expressing cells participate directly or indirectly in VM that is potentially related to tumorigenic growth. We have developed a humanized murine xenograft model in which developing human melanomas may be sequentially studied during early stages of tumorigenic growth within a physiological human dermal microenvironment. Nodal protein localized diffusely to melanoma cell membranes, with occasional foci of accentuated reactivity in patterns suggestive of channel formation. Similar findings were detected in a limited number of patient-derived tumors. In situ hybridization confirmed Nodal mRNA to be restricted to tumor cells within xenografts that formed arborizing networks in patterns consistent with VM. These data indicate that Nodal gene expression is associated with formation of VM-like structures in a physiologically relevant model of human melanoma tumorigenesis, and further support a key role for Nodal expression in the formation of channel-like structures. The humanized xenograft model should be useful in future studies to define the mechanistic pathways responsible for VM and melanoma progression.

  15. [Treatment of conjunctival melanoma].

    PubMed

    Salazar Méndez, R; Baamonde Arbaiza, B; de la Roz Martín, P; Parra Rodríguez, T

    2014-02-01

    The cases of an 86 year-old woman and a 61 year-old man with conjunctival pigmented tumors are presented. An excisional biopsy, conjunctival cryotherapy and amniotic membrane grafts were performed in both cases, along with the application of mitomycin-C in the postoperative period. The histology study confirmed the clinical suspicion of melanoma. Tolerance was good during the follow-up with no signs of recurrence in the last 12 and 6 months, respectively. The recommended treatment for conjunctival melanoma is surgical removal with adjunctive therapies such as cryotherapy or topical mitomycin-C. This is a well tolerated therapy and effective for preventing recurrences in the short-medium term. Copyright © 2011 Sociedad Española de Oftalmología. Published by Elsevier Espana. All rights reserved.

  16. Hypoxia-regulated gene expression explains differences between melanoma cell line-derived xenografts and patient-derived xenografts.

    PubMed

    Bhadury, Joydeep; Einarsdottir, Berglind O; Podraza, Agnieszka; Bagge, Roger Olofsson; Stierner, Ulrika; Ny, Lars; Dávila López, Marcela; Nilsson, Jonas A

    2016-04-26

    Cell line-derived xenografts (CDXs) are an integral part of drug efficacy testing during development of new pharmaceuticals against cancer but their accuracy in predicting clinical responses in patients have been debated. Patient-derived xenografts (PDXs) are thought to be more useful for predictive biomarker identification for targeted therapies, including in metastatic melanoma, due to their similarities to human disease. Here, tumor biopsies from fifteen patients and ten widely-used melanoma cell lines were transplanted into immunocompromised mice to generate PDXs and CDXs, respectively. Gene expression profiles generated from the tumors of these PDXs and CDXs clustered into distinct groups, despite similar mutational signatures. Hypoxia-induced gene signatures and overexpression of the hypoxia-regulated miRNA hsa-miR-210 characterized CDXs. Inhibition of hsa-miR-210 with decoys had little phenotypic effect in vitro but reduced sensitivity to MEK1/2 inhibition in vivo, suggesting down-regulation of this miRNA could result in development of resistance to MEK inhibitors.

  17. Hypoxia-regulated gene expression explains differences between melanoma cell line-derived xenografts and patient-derived xenografts

    PubMed Central

    Bhadury, Joydeep; Einarsdottir, Berglind O.; Podraza, Agnieszka; Bagge, Roger Olofsson; Stierner, Ulrika; Ny, Lars; López, Marcela Dávila; Nilsson, Jonas A.

    2016-01-01

    Cell line-derived xenografts (CDXs) are an integral part of drug efficacy testing during development of new pharmaceuticals against cancer but their accuracy in predicting clinical responses in patients have been debated. Patient-derived xenografts (PDXs) are thought to be more useful for predictive biomarker identification for targeted therapies, including in metastatic melanoma, due to their similarities to human disease. Here, tumor biopsies from fifteen patients and ten widely-used melanoma cell lines were transplanted into immunocompromised mice to generate PDXs and CDXs, respectively. Gene expression profiles generated from the tumors of these PDXs and CDXs clustered into distinct groups, despite similar mutational signatures. Hypoxia-induced gene signatures and overexpression of the hypoxia-regulated miRNA hsa-miR-210 characterized CDXs. Inhibition of hsa-miR-210 with decoys had little phenotypic effect in vitro but reduced sensitivity to MEK1/2 inhibition in vivo, suggesting down-regulation of this miRNA could result in development of resistance to MEK inhibitors. PMID:27009863

  18. Orthotopic xenografts of human melanoma and colonic and ovarian carcinoma in sheep to evaluate radioimmunotherapy.

    PubMed Central

    Turner, J. H.; Rose, A. H.; Glancy, R. J.; Penhale, W. J.

    1998-01-01

    Extrapolation to humans from experimental radioimmunotherapy in nude mouse xenograft models is confounded by large relative tumour size and small volume of distribution in mice allowing tumour uptake of radiolabelled antibodies unattainable in patients. Our large animal model of human tumours in cyclosporin-immunosuppressed sheep demonstrated tumour uptake of targeted radiolabelled monoclonal antibodies comparable with uptakes reported in clinical trials. Sheep immunosuppression with daily intravenous cyclosporin augmented by oral ketoconazole maintained trough blood levels of cyclosporin within the range 1000-1500 ng ml(-1). Human tumour cells were transplanted orthotopically by inoculation of 10(7) cells: SKMEL melanoma subcutaneously; LS174T and HT29 colon carcinoma into bowel, peritoneum and liver; and JAM ovarian carcinoma into ovary and peritoneum. Tumour xenografts grew at all sites within 3 weeks of inoculation, preserving characteristic morphology without evidence of necrosis or host rejection. Lymphatic metastasis was demonstrated in regional nodes draining xenografts of melanoma and ovarian carcinoma. Colonic LS1 74T xenografts produced mucin and carcinoembryonic antigen (CEA). The anti-CEA IgG1 monoclonal antibody A5B7 was radiolabelled with iodine-131 and administered intravenously to sheep. Peak uptake at 5 days in orthotopic human tumour transplants in gut was 0.027% DI g(-1) (percentage of injected dose per gram) and 0.034% DI g(-1) in hepatic metastases with tumour to blood ratios of 2-2.5. Non-specific tumour uptake in melanoma was 0.003% DI g(-1). Uptake of radiolabelled monoclonal antibody in human tumours in our large animal model is comparable with that observed in patients and may be more realistic than nude mice xenografts for prediction of clinical efficacy of radioimmunotherapy. Images Figure 1 Figure 2 Figure 3 PMID:9716032

  19. Properdistatin inhibits angiogenesis and improves vascular function in human melanoma xenografts with low thrombospondin-1 expression

    PubMed Central

    Gaustad, Jon-Vidar; Simonsen, Trude G.; Andersen, Lise Mari K.; Rofstad, Einar K.

    2016-01-01

    In this study, the effect of properdistatin, a novel peptide derived from the thrombospondin 1 (TSP-1) domain of properdin, was investigated in three melanoma xenograft models with different TSP-1 expression. The tumors were grown in dorsal window chambers and were treated with 80 mg/kg/day properdistatin or vehicle. Morphological parameters of the tumor vasculature were assessed from high resolution transillumination images. Blood supply time (i.e., the time required for arterial blood to flow from a supplying artery to downstream microvessels) and plasma velocities were assessed from first-pass imaging movies recorded after a bolus of fluorescence-labeled dextran had been administered intravenously. Gene and protein expression of TSP-1 were assessed with quantitative PCR and immunohistochemistry, respectively. Properdistatin treatment inhibited angiogenesis in low TSP-1 expressing tumors but did not alter the vasculature in high TSP-1 expressing tumors. In low TSP-1 expressing tumors, properdistatin selectively removed small-diameter capillaries, but did not change the morphology of tumor arterioles or tumor venules. Properdistatin also reduced blood supply times and increased plasma velocities, implying that the treatment reduced the geometric resistance to blood flow and improved vascular function. PMID:27756886

  20. BRAF(V600E) Kinase Domain Duplication Identified in Therapy-Refractory Melanoma Patient-Derived Xenografts.

    PubMed

    Kemper, Kristel; Krijgsman, Oscar; Kong, Xiangjun; Cornelissen-Steijger, Paulien; Shahrabi, Aida; Weeber, Fleur; van der Velden, Daphne L; Bleijerveld, Onno B; Kuilman, Thomas; Kluin, Roel J C; Sun, Chong; Voest, Emile E; Ju, Young Seok; Schumacher, Ton N M; Altelaar, A F Maarten; McDermott, Ultan; Adams, David J; Blank, Christian U; Haanen, John B; Peeper, Daniel S

    2016-06-28

    The therapeutic landscape of melanoma is improving rapidly. Targeted inhibitors show promising results, but drug resistance often limits durable clinical responses. There is a need for in vivo systems that allow for mechanistic drug resistance studies and (combinatorial) treatment optimization. Therefore, we established a large collection of patient-derived xenografts (PDXs), derived from BRAF(V600E), NRAS(Q61), or BRAF(WT)/NRAS(WT) melanoma metastases prior to treatment with BRAF inhibitor and after resistance had occurred. Taking advantage of PDXs as a limitless source, we screened tumor lysates for resistance mechanisms. We identified a BRAF(V600E) protein harboring a kinase domain duplication (BRAF(V600E/DK)) in ∼10% of the cases, both in PDXs and in an independent patient cohort. While BRAF(V600E/DK) depletion restored sensitivity to BRAF inhibition, a pan-RAF dimerization inhibitor effectively eliminated BRAF(V600E/DK)-expressing cells. These results illustrate the utility of this PDX platform and warrant clinical validation of BRAF dimerization inhibitors for this group of melanoma patients.

  1. Targeting Tumor Vasculature Endothelial Cells and Tumor Cells for Immunotherapy of Human Melanoma in a Mouse Xenograft Model

    NASA Astrophysics Data System (ADS)

    Hu, Zhiwei; Sun, Ying; Garen, Alan

    1999-07-01

    An immunotherapy treatment for cancer that targets both the tumor vasculature and tumor cells has shown promising results in a severe combined immunodeficient mouse xenograft model of human melanoma. The treatment involves systemic delivery of an immunoconjugate molecule composed of a tumor-targeting domain conjugated to the Fc effector domain of human IgG1. The effector domain induces a cytolytic immune response against the targeted cells by natural killer cells and complement. Two types of targeting domains were used. One targeting domain is a human single-chain Fv molecule that binds to a chondroitin sulfate proteoglycan expressed on the surface of most human melanoma cells. Another targeting domain is factor VII (fVII), a zymogen that binds with high specificity and affinity to the transmembrane receptor tissue factor (TF) to initiate the blood coagulation cascade. TF is expressed by endothelial cells lining the tumor vasculature but not the normal vasculature, and also by many types of tumor cells including melanoma. Because the binding of a fVII immunoconjugate to TF might cause disseminated intravascular coagulation, the active site of fVII was mutated to inhibit coagulation without affecting the affinity for TF. The immunoconjugates were encoded as secreted molecules in a replication-defective adenovirus vector, which was injected into the tail vein of severe combined immunodeficient mice. The results demonstrate that a mutated fVII immunoconjugate, administered separately or together with a single-chain Fv immunoconjugate that binds to the tumor cells, can inhibit the growth or cause regression of an established human tumor xenograft. This procedure could be effective in treating a broad spectrum of human solid tumors that express TF on vascular endothelial cells and tumor cells.

  2. Resveratrol Is Rapidly Metabolized in Athymic (Nu/Nu) Mice and Does Not Inhibit Human Melanoma Xenograft Tumor Growth1

    PubMed Central

    Niles, Richard M.; Cook, Carla P.; Meadows, Gary G.; Fu, Ya-Min; McLaughlin, Jerry L.; Rankin, Gary O.

    2006-01-01

    Resveratrol has been shown to have anticarcinogenic activity. We previously found that resveratrol inhibited growth and induced apoptosis in 2 human melanoma cell lines. In this study we determined whether resveratrol would inhibit human melanoma xenograft growth. Athymic mice received control diets or diets containing 110 μmol/L or 263 μmol/L resveratrol, 2 wk prior to subcutaneous injection of the tumor cells. Tumor growth was measured during a 3-wk period. Metabolism of resveratrol was assayed by bolus gavage of 75 mg/kg resveratrol in tumor-bearing and nontumor-bearing mice. Pellets containing 10–100 mg resveratrol were implanted into the mice, next to newly palpated tumors, and tumor growth determined. We also determined the effect of a major resveratrol metabolite, piceatannol, on experimental lung metastasis. Resveratrol, at any concentration tested, did not have a statistically significant effect on tumor growth. The higher levels of resveratrol tested (0.006% in food or 100 mg in slow-release pellets) tended to stimulate tumor growth (P = 0.08–0.09). Resveratrol and its major metabolites, resveratrol glucuronide and piceatannol, were found in serum, liver, skin, and tumor tissue. Piceatannol did not affect the in vitro growth of a murine melanoma cell line, but significantly stimulated the number of lung metastases when these melanoma cells were directly injected into the tail vein of the mouse. These results suggest that resveratrol is not likely to be useful in the treatment of melanoma and that the effects of phytochemicals on cell cultures may not translate to the whole animal system. PMID:16988123

  3. Step-down heating of human melanoma xenografts: effects of the tumour microenvironment.

    PubMed Central

    Rofstad, E. K.

    1994-01-01

    Thermosensitisation by step-down heating (SDH) has previously been demonstrated in experimental rodent tumours. The purpose of the study reported here was to investigate whether the SDH effect in tumours in part may be attributed to heat-induced alterations in the capillary network and/or the microenvironment. Two human melanoma xenograft lines differing substantially in vascular parameters were selected for the study. A thermostatically regulated water bath was used for heat treatment. The conditioning treatment (44.5 degrees C or 45.5 degrees C for 15 min) was given in vivo, whereas the test treatment (42.0 degrees C for 45, 90, 135 or 180 min) was given either in vitro or in vivo. Treatment response was measured in vitro using a cell clonogenicity assay. Fraction of occluded vessels following heat treatment was assessed by examination of histological sections from tumours whose vascular network was filled with a contrast agent. Tumour bioenergetic status and tumour pH were measured by 31P magnetic resonance spectroscopy. The conditioning heat treatments caused significant vessel occlusion, decreased tumour bioenergetic status and decreased tumour pH in both tumour lines. The SDH effect measured when the test treatment was given in vivo was significantly increased relative to that measured when the test treatment was given in vitro. The magnitude of the increase showed a close relationship to fraction of occluded vessels, tumour bioenergetic status and tumour pH measured 90 min after treatment with 44.5 degrees C or 45.5 degrees C for 15 min. The increased SDH effect in vivo was probably attributable to tumour cells that were heat sensitive owing to the induction of low nutritional status and pH during the conditioning treatment. Consequently, the SDH effect in some tumours may in part be due to heat-induced alterations in the microenvironment. This suggests that SDH may be exploited clinically to achieve increased cell inactivation in tumours relative to the

  4. pO{sub 2} Fluctuation Pattern and Cycling Hypoxia in Human Cervical Carcinoma and Melanoma Xenografts

    SciTech Connect

    Ellingsen, Christine; Ovrebo, Kirsti Marie; Galappathi, Kanthi; Mathiesen, Berit; Rofstad, Einar K.

    2012-07-15

    Purpose: Blood perfusion in tumors is spatially and temporally heterogeneous, resulting in local fluctuations in tissue oxygen tension (pO{sub 2}) and tissue regions showing cycling hypoxia. In this study, we investigated whether the pO{sub 2} fluctuation pattern and the extent of cycling hypoxia differ between tumor types showing high (e.g., cervical carcinoma xenograft) and low (e.g., melanoma xenograft) fractions of connective tissue-associated blood vessels. Methods and Materials: Two cervical carcinoma lines (CK-160 and TS-415) and two melanoma lines (A-07 and R-18) transplanted into BALB/c nu/nu mice were included in the study. Tissue pO{sub 2} was measured simultaneously in two positions in each tumor by using a two-channel OxyLite fiber-optic oxygen-sensing device. The extent of acute and chronic hypoxia was assessed by combining a radiobiological and a pimonidazole-based immunohistochemical assay of tumor hypoxia. Results: The proportion of tumor regions showing pO{sub 2} fluctuations, the pO{sub 2} fluctuation frequency in these regions, and the relative amplitude of the pO{sub 2} fluctuations were significantly higher in the melanoma xenografts than in the cervical carcinoma xenografts. Cervical carcinoma and melanoma xenografts did not differ significantly in the fraction of acutely hypoxic cells or the fraction of chronically hypoxic cells. However, the ratio between fraction of acutely hypoxic cells and fraction of chronically hypoxic cells was significantly higher in melanoma than in cervical carcinoma xenografts. Conclusions: Temporal heterogeneity in blood flow and tissue pO{sub 2} in tumors may depend on tumor histology. Connective tissue surrounding microvessels may stabilize blood flow and pO{sub 2} and, thus, protect tumor tissue from cycling hypoxia.

  5. Fluorescent peptide biosensor for monitoring CDK4/cyclin D kinase activity in melanoma cell extracts, mouse xenografts and skin biopsies.

    PubMed

    Prével, Camille; Pellerano, Morgan; González-Vera, Juan A; Henri, Pauline; Meunier, Laurent; Vollaire, Julien; Josserand, Véronique; Morris, May C

    2016-11-15

    Melanoma constitutes the most aggressive form of skin cancer, which further metastasizes into a deadly form of cancer. The p16(INK4a)-Cyclin D-CDK4/6-pRb pathway is dysregulated in 90% of melanomas. CDK4/Cyclin D kinase hyperactivation, associated with mutation of CDK4, amplification of Cyclin D or loss of p16(INK4a) leads to increased risk of developing melanoma. This kinase therefore constitutes a key biomarker in melanoma and an emerging pharmacological target, however there are no tools enabling direct detection or quantification of its activity. Here we report on the design and application of a fluorescent peptide biosensor to quantify CDK4 activity in melanoma cell extracts, skin biopsies and melanoma xenografts. This biosensor provides sensitive means of comparing CDK4 activity between different melanoma cell lines and further responds to CDK4 downregulation by siRNA or small-molecule inhibitors. By affording means of monitoring CDK4 hyperactivity consequent to cancer-associated molecular alterations in upstream signaling pathways that converge upon this kinase, this biosensor offers an alternative to immunological identification of melanoma-specific biomarkers, thereby constituting an attractive tool for diagnostic purposes, providing complementary functional information to histological analysis, of particular utility for detection of melanoma onset in precancerous lesions. This is indeed the first fluorescent peptide biosensor which has been successfully implemented to monitor kinase activity in skin samples and melanoma tumour xenografts. Moreover by enabling to monitor response to CDK4 inhibitors, this biosensor constitutes an attractive companion assay to identify compounds of therapeutic relevance for melanoma.

  6. Expression of galectin-3 in primary and metastatic melanoma: immunohistochemical studies on human lesions and nude mice xenograft tumors.

    PubMed

    Vereecken, Pierre; Debray, Charles; Petein, Michel; Awada, Ahmad; Lalmand, Marie-Claude; Laporte, Marianne; Van Den Heule, Bernard; Verhest, Alain; Pochet, Roland; Heenen, Michel

    2005-02-01

    Galectins are a large family of proteins which bind galactoside-containing glycans. Their role in cancer seems to be important since members of the family may mediate cell adhesion and modulate cell growth. Galectin-3 (Gal-3) is expressed in the nucleus, in the cytoplasm and on the cell surface, and can also be secreted into the extracellular matrix. A series of experimental and clinical data have been reported which indicate that Gal-3 may play a putative role in carcinogenesis, cancer progression and the process of metastasis. To study the possible correlation between Gal-3 expression and malignant potential in primary melanoma lesions, we conducted an immunohistochemical study with monoclonal anti-Gal-3 antibody in a series of primary and metastatic melanoma lesions as well as benign skin pigmented lesions. We also developed a xenograft melanoma model in nude mice with two melanoma cell lines (ATCC G-361 and ATCC HT-144) and assessed staining with the Gal-3 antibody in the xenografts and the metastases. The expression of anti-Gal-3 staining was determined semiquantitatively. The expression of Gal-3 was higher in thin primary melanoma lesions than in benign pigmented skin lesions or metastases and seemed to correlate inversely with the aggressiveness as estimated by the Breslow index which is recognized as the main prognostic factor in melanoma. We propose Gal-3 expression in melanoma as a diagnostic and/or a prognostic parameter and suggest that further studies of such a role for Gal-3 are warranted.

  7. Antibody Therapy Targeting CD47 and CD271 Effectively Suppresses Melanoma Metastasis in Patient-Derived Xenografts.

    PubMed

    Ngo, Michael; Han, Arum; Lakatos, Anita; Sahoo, Debashis; Hachey, Stephanie J; Weiskopf, Kipp; Beck, Andrew H; Weissman, Irving L; Boiko, Alexander D

    2016-08-09

    The high rate of metastasis and recurrence among melanoma patients indicates the existence of cells within melanoma that have the ability to both initiate metastatic programs and bypass immune recognition. Here, we identify CD47 as a regulator of melanoma tumor metastasis and immune evasion. Protein and gene expression analysis of clinical melanoma samples reveals that CD47, an anti-phagocytic signal, correlates with melanoma metastasis. Antibody-mediated blockade of CD47 coupled with targeting of CD271(+) melanoma cells strongly inhibits tumor metastasis in patient-derived xenografts. This therapeutic effect is mediated by drastic changes in the tumor and metastatic site immune microenvironments, both of whichwhich exhibit greatly increased density of differentiated macrophages and significantly fewer inflammatory monocytes, pro-metastatic macrophages (CCR2(+)/VEGFR1(+)), and neutrophils, all of which are associated with disease progression. Thus, antibody therapy that activates the innate immune response in combination with selective targeting of CD271(+) melanoma cells represents a powerful therapeutic approach against metastatic melanoma.

  8. Treatment Option Overview (Melanoma)

    MedlinePlus

    ... Treatment for more information.) Unusual moles, exposure to sunlight, and health history can affect the risk of ... Red or blond hair. Being exposed to natural sunlight or artificial sunlight (such as from tanning beds) ...

  9. Matrix metalloproteinases in human melanoma cell lines and xenografts: increased expression of activated matrix metalloproteinase-2 (MMP-2) correlates with melanoma progression

    PubMed Central

    Hofmann, U B; Westphal, J R; Waas, E T; Zendman, A J W; Cornelissen, I M H A; Ruiter, D J; Muijen, G N P van

    1999-01-01

    Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in tumour progression and metastasis. In this study, we investigated the in vitro and in vivo expression patterns of MMP-1, MMP-2, MMP-3, MMP-9, TIMP-1 and TIMP-2 mRNA and protein in a previously described human melanoma xenograft model. This model consists of eight human melanoma cell lines with different metastatic behaviour after subcutaneous (s.c.) injection into nude mice. MMP-1 mRNA was detectable in all cell lines by reverse transcription polymerase chain reaction (RT-PCR), but the expression was too low to be detected by Northern blot analysis. No MMP-1 protein could be found using Western blotting. MMP-2 mRNA and protein were present in all cell lines, with the highest expression of both latent and active MMP-2 in the highest metastatic cell lines MV3 and BLM. MMP-3 mRNA was expressed in MV3 and BLM, and in the non-metastatic cell line 530, whereas MMP-3 protein was detectable only in MV3 and BLM. None of the melanoma cell lines expressed MMP-9. TIMP-1 and TIMP-2 mRNA and protein, finally, were present in all cell lines. A correlation between TIMP expression level and metastatic capacity of cell lines, however, was lacking. MMP and TIMP mRNA and protein expression levels were also studied in s.c. xenograft lesions derived from a selection of these cell lines. RT-PCR analysis revealed that MMP-1 mRNA was present in MV3 and BLM xenografts, and to a lesser extent in 530. Positive staining for MMP-1 protein was found in xenograft lesions derived from both low and high metastatic cell lines, indicating an in vivo up-regulation of MMP-1. MMP-2 mRNA was detectable only in xenografts derived from the highly metastatic cell lines 1F6m, MV3 and BLM. In agreement with the in vitro results, the highest levels of both latent and activated MMP-2 protein were observed in MV3 and BLM xenografts. With the exception of MMP-9 mRNA expression in 530 xenografts, MMP-3, MMP-9, and TIMP-1 mRNA and

  10. Effects of hyperglycemia on lonidamine-induced acidification and de-energization of human melanoma xenografts and sensitization to melphalan

    PubMed Central

    Nath, Kavindra; Nelson, David S.; Heitjan, Daniel F.; Zhou, Rong; Leeper, Dennis B.; Glickson, Jerry D.

    2015-01-01

    We seek to exploit the natural tendency of melanomas and other tumors to convert glucose to lactate as a method for selective intracellular acidification of cancer cells and for potentiating the activity of N-mustard antineoplastic agents. We performed this study to evaluate whether induction of hyperglycemia (26 mM) could enhance the effects of lonidamine (LND, 100 mg/kg; i.p.) on inducing intracellular acidification, bioenergetic decline and potentiation of the activity of melphalan (LPAM) against DB-1 melanoma xenografts in mice. Intracellular pH (pHi), extracellular pH (pHe) and bioenergetics (βNTP/Pi) were reduced by 0.7 units (p<0.001), 0.3 units (p>0.05) and 51.4% (p<0.05), respectively. Therapeutic response to LPAM (7.5 mg/kg; i.v.) + LND (100 mg/kg; i.p.) was reduced by about a factor of 3 under hyperglycemic conditions compared to normoglycemia, producing a growth delay of 7.76 d (tumor doubling time = 5.31 d, cell kill = 64%) compared to LND alone of 1.70 d and LPAM alone of 0.29 d. Under normoglycemic conditions LND plus LPAM produced a growth delay of 17.75 d, corresponding to a cell kill of 90 % at the same doses for each of these agents. The decrease in tumor cell kill under hyperglycemic conditions correlates with an increase in tumor ATP levels resulting from increased glycolytic activity. However, hyperglycemia substantially increases lactic acid production in tumors by a factor of ~6 (p<0.05), but hyperglycemia did not increase the effects of LND on acidification of the tumor most likely because of the strong buffering action of carbon dioxide (the pKa of carbonic acid is 6.4). Therefore, this study demonstrates that addition of glucose during treatment with LND diminishes the activity of this agent. PMID:25702942

  11. Peginterferon Beta-1a Shows Antitumor Activity as a Single Agent and Enhances Efficacy of Standard of Care Cancer Therapeutics in Human Melanoma, Breast, Renal, and Colon Xenograft Models.

    PubMed

    Boccia, Antonio; Virata, Cyrus; Lindner, Daniel; English, Nicki; Pathan, Nuzhat; Brickelmaier, Margot; Hu, Xiao; Gardner, Jennifer L; Peng, Liaomin; Wang, Xinzhong; Zhang, Xiamei; Yang, Lu; Perron, Keli; Yco, Grace; Kelly, Rebecca; Gamez, James; Scripps, Thomas; Bennett, Donald; Joseph, Ingrid B; Baker, Darren P

    2017-01-01

    Because of its tumor-suppressive effect, interferon-based therapy has been used for the treatment of melanoma. However, limited data are available regarding the antitumor effects of pegylated interferons, either alone or in combination with approved anticancer drugs. We report that treatment of human WM-266-4 melanoma cells with peginterferon beta-1a induced apoptotic markers. Additionally, peginterferon beta-1a significantly inhibited the growth of human SK-MEL-1, A-375, and WM-266-4 melanoma xenografts established in immunocompromised mice. Peginterferon beta-1a regressed large, established WM-266-4 xenografts in nude mice. Treatment of SK-MEL-1 tumor-bearing mice with a combination of peginterferon beta-1a and the MEK inhibitor PD325901 ((R)-N-(2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide) significantly improved tumor growth inhibition compared with either agent alone. Examination of the antitumor activity of peginterferon beta-1a in combination with approved anticancer drugs in breast and renal carcinomas revealed improved antitumor activity in these preclinical xenograft models, as did the combination of peginterferon beta-1a and bevacizumab in a colon carcinoma xenograft model.

  12. Targeting Syndecan-1, a molecule implicated in the process of vasculogenic mimicry, enhances the therapeutic efficacy of the L19-IL2 immunocytokine in human melanoma xenografts

    PubMed Central

    Orecchia, Paola; Conte, Romana; Balza, Enrica; Pietra, Gabriella; Mingari, Maria Cristina; Carnemolla, Barbara

    2015-01-01

    Anti-angiogenic therapy of solid tumors has until now failed to produce the long lasting clinical benefits desired, possibly due to the complexity of the neoangiogenic process. Indeed, a prominent role is played by “vasculogenic” or “vascular” mimicry (VM), a phenomenon in which aggressive cancer cells form an alternative microvascular circulation, independently of endothelial cell angiogenesis. In this study we observed, in melanoma patient cell lines having vasculogenic/stem-cell like phenotype and in melanoma tumors, the syndecan-1 co-expression with VM markers, such as CD144 and VEGFR-2. We show that melanoma cells lose their ability to form tubule-like structures in vitro after blocking syndecan-1 activity by the specific human recombinant antibody, OC-46F2. Moreover, in a human melanoma xenograft model, the combined therapy using OC-46F2 and L19-IL2, an immunocytokine specific for the tumor angiogenic-associated B-fibronectin isoform(B-FN), led to a complete inhibition of tumor growth until day 90 from tumor implantation in 71% of treated mice, with statistically significant differences compared to groups treated with OC-46F2 or L19-IL2 as monotherapy. Furthermore, in the tumors recovered from mice treated with OC-46F2 either as monotherapy or in combination with L19-IL2, we observed a dramatic decrease of vascular density and loss of VM structures. These findings indicate for the first time a role of syndecan-1 in melanoma VM and that targeting syndecan-1, together with B-FN, could be promising in improving the treatment of metastatic melanoma. PMID:26460958

  13. Dextran-Conjugated Vascular Endothelial Growth Factor Receptor Antibody for In Vivo Melanoma Xenografted Mouse Imaging

    PubMed Central

    Kim, Eun-Mi; Jeong, Min-Hee; Lee, Chang-Moon; Cheong, Su-Jin; Kim, Dong Wook; Lim, Seok Tae; Sohn, Myung-Hee

    2012-01-01

    Abstract Intact immunoglobulin G antibody has a relatively large molecule size of approximately 150 kDa that remains in the bloodstream for many weeks, which is a considerable disadvantage when it is used to carry radioactive materials for imaging. To lower background activity and increase the contrast of images, we investigated antivascular endothelial growth factor (VEGF) receptor 2 antibody (DC101) conjugated dextran for VEGF receptor 2 imaging in tumor xenografted mice. DTPA-conjugated aminodextran was synthesized, reacted with sulfo-LC-SPDP, and then reacted with DC101. The binding affinity of DTPA-dextran-DC101 to Flk-1 was measured. The gamma imaging and biodistributions of 99mTc-DTPA-dextran-DC101, 99mTc-DTPA-DC101, and 125I-DC101 were studied in B16F10 melanoma xenografted mice. The dissociation values for DC101, DTPA-DC101, and DTPA-dextran-DC101 were 22.48, 3.05, and 14.74 pM, respectively. In gamma images, 99mTc-DTPA-dextran-DC101 showed weak liver uptake and rapid kidney elimination. In biodistribution results, the liver uptake of 99mTc-DTPA-dextran-DC101 was similar with that of 99mTc-DTPA-DC101 at each time point. However, the blood activity of 99mTc-DTPA-dextran-DC101 has shown significant differences, compared with 99mTc-DTPA-DC101 at all time points. The tumor accumulation of dextran-conjugated antibody was increased with time, whereas that of dextran nonconjugated antibody decreased. In particular, the pattern of tumor uptake of 99mTc-DTPA-dextran-DC101 was similar to that of 125I-DC101, so this was thought to reflect the kinetics of DC101, unlike the nonconjugated form. The results of this study suggested that introduction of dextran moiety to make 99mTc-radiolabeled DC101 imaging agent could provide better images with the impaired background and the steady increasing binding to the receptor. However, further studies are necessary to improve clinical pharmacokinetics, such as enhancement of tumor uptake and impaired renal uptake. PMID:22149589

  14. Uveal Melanoma Treatment and Prognostication.

    PubMed

    Dogrusöz, Mehmet; Jager, Martine J; Damato, Bertil

    2017-01-01

    Approximately 90% of uveal melanoma develop in the choroid, with the remainder arising in the ciliary body or the iris. The treatment of uveal melanoma is aimed at conserving the eye and useful vision, and, if possible, preventing metastatic disease. Enucleation is now reserved for tumors that are large and/or involve the optic disc, having largely been replaced by various forms of radiotherapy (plaque brachy-therapy, proton beam or stereotactic radiotherapy) and laser therapy. Whereas iridectomy and iridocyclectomy are widely performed, transscleral exoresection of choroidal tumors is performed only in a few centers because it requires special skills and hypotensive anesthesia. Transretinal endoresection using vitrectomy equipment is easier but controversial because of concerns about tumor seeding. Long-term postoperative surveillance is necessary to identify and treat local tumor recurrence and any other complications, such as radiation-induced morbidity, and to provide counseling to the patient. Factors predicting metastasis include older age, large tumor size, ciliary body involvement, extraocular spread, epithelioid cytomorphology, chromosome 3 loss and chromosome 8q gain, class 2 gene expression profile, loss of BRCA1-associated protein-1 (BAP1), and the presence of inflammation. Prognostication is enhanced by multi-variable analysis combining clinical, histologic, and genetic factors, also taking the patient's age and sex into account. As there is a lack of options for treating metastases, much research is focused on identifying potential therapeutic targets. Copyright 2017 Asia-Pacific Academy of Ophthalmology.

  15. Progression of cutaneous melanoma: implications for treatment

    PubMed Central

    Leong, Stanley P. L.; Mihm, Martin C.; Murphy, George F.; Hoon, Dave S. B.; Kashani-Sabet, Mohammed; Agarwala, Sanjiv S.; Zager, Jonathan S.; Hauschild, Axel; Sondak, Vernon K.; Guild, Valerie; Kirkwood, John M.

    2015-01-01

    The survival rates of melanoma, like any type of cancer, become worse with advancing stage. Spectrum theory is most consistent with the progression of melanoma from the primary site to the in-transit locations, regional or sentinel lymph nodes and beyond to the distant sites. Therefore, early diagnosis and surgical treatment before its spread is the most effective treatment. Recently, new approaches have revolutionized the diagnosis and treatment of melanoma. Genomic profiling and sequencing will form the basis for molecular taxonomy for more accurate subgrouping of melanoma patients in the future. New insights of molecular mechanisms of metastasis are summarized in this review article. Sentinel lymph node biopsy has become a standard of care for staging primary melanoma without the need for a more morbid complete regional lymph node dissection. With recent developments in molecular biology and genomics, novel molecular targeted therapy is being developed through clinical trials. PMID:22892755

  16. Dynamic Contrast-Enhanced Magnetic Resonance Imaging of the Metastatic Potential of Melanoma Xenografts

    SciTech Connect

    Ovrebo, Kirsti Marie; Ellingsen, Christine; Galappathi, Kanthi; Rofstad, Einar K.

    2012-05-01

    Purpose: Gadolinium diethylene-triamine penta-acetic acid (Gd-DTPA)-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been suggested as a useful noninvasive method for characterizing the physiologic microenvironment of tumors. In the present study, we investigated whether Gd-DTPA-based DCE-MRI has the potential to provide biomarkers for hypoxia-associated metastatic dissemination. Methods and Materials: C-10 and D-12 melanoma xenografts were used as experimental tumor models. Pimonidazole was used as a hypoxia marker. A total of 60 tumors were imaged, and parametric images of K{sup trans} (volume transfer constant of Gd-DTPA) and v{sub e} (fractional distribution volume of Gd-DTPA) were produced by pharmacokinetic analysis of the DCE-MRI series. The host mice were killed immediately after DCE-MRI, and the primary tumor and the lungs were resected and prepared for histologic assessment of the fraction of pimonidazole-positive hypoxic tissue and the presence of lung metastases, respectively. Results: Metastases were found in 11 of 26 mice with C-10 tumors and 14 of 34 mice with D-12 tumors. The primary tumors of the metastatic-positive mice had a greater fraction of hypoxic tissue (p = 0.00031, C-10; p < 0.00001, D-12), a lower median K{sup trans} (p = 0.0011, C-10; p < 0.00001, D-12), and a lower median v{sub e} (p = 0.014, C-10; p = 0.016, D-12) than the primary tumors of the metastatic-negative mice. Conclusions: These findings support the clinical attempts to establish DCE-MRI as a method for providing biomarkers for tumor aggressiveness and suggests that primary tumors characterized by low K{sup trans} and low v{sub e} values could have a high probability of hypoxia-associated metastatic spread.

  17. Efficacy of Tumor-Targeting Salmonella A1-R on a Melanoma Patient-Derived Orthotopic Xenograft (PDOX) Nude-Mouse Model

    PubMed Central

    Yamamoto, Mako; Zhao, Ming; Hiroshima, Yukihiko; Zhang, Yong; Shurell, Elizabeth; Eilber, Fritz C.; Bouvet, Michael; Noda, Makoto; Hoffman, Robert M.

    2016-01-01

    Tumor-targeting Salmonella enterica serovar Typhimurium A1-R (Salmonella A1-R) had strong efficacy on a melanoma patient-derived orthotopic xenograft (PDOX) nude-mouse model. GFP-expressing Salmonella A1-R highly and selectively colonized the PDOX melanoma and significantly suppressed tumor growth (p = 0.021). The combination of Salmonella A1-R and cisplatinum (CDDP), both at low-dose, also significantly suppressed the growth of the melanoma PDOX (P = 0.001). Salmonella A1-R has future clinical potential for combination chemotherapy with CDDP of melanoma, a highly-recalcitrant cancer. PMID:27500926

  18. The Sydney Melanoma Unit--a multidisciplinary melanoma treatment center.

    PubMed

    Thompson, John F; Shaw, Helen M; Stretch, Jonathan R; McCarthy, William H; Milton, Gerald W

    2003-04-01

    The undoubted success of the SMU as a specialist multidisciplinary melanoma treatment center has clearly been the result of many factors. Perhaps chief among these was the vision and commitment that led Dr. Milton to establish it in the first place, and the sharing of that vision and commitment by those who were associated with him and by those who joined the SMU later. Another vitally important element, however, has been the continuing sense of unity and purpose fostered by the weekly SMU clinical meetings, which are truly multidisciplinary, in which all staff are encouraged to participate, and at which the desirability of adherence to agreed, evidence-based treatment guidelines is emphasized. A further influential factor has been the SMU's strong commitment to clinical and basic research as a concomitant of high quality clinical care, with stimulation, encouragement, and advice provided at its monthly multidisciplinary research meetings, where all current and proposed clinical and laboratory studies are discussed. As a result of these activities, despite an ever-increasing number of people working within it, the SMU has been able to present to referring doctors, to patients, and to the community a unified commitment to the best possible patient care and to high quality clinical and laboratory research. These groups have responded by recognizing the SMU as the major referral center for melanoma in Australia, as evidenced by the steadily increasing number of patients referred to it for treatment each year. Melanoma is a more pressing health problem in Australia than elsewhere, because it is the third most common cancer in women (after breast cancer and colorectal cancer), and the fourth most common cancer in men (after prostate cancer, colorectal cancer, and lung cancer). Nevertheless the experiences of the SMU as a large multidisciplinary melanoma treatment center are likely to have relevance and application in other countries, where the incidence of melanoma is

  19. Personalized treatment of uveal melanoma

    PubMed Central

    Damato, B; Heimann, H

    2013-01-01

    Personalized treatment of uveal melanoma involves the tailoring of all aspects of care to the condition, needs, wishes, and fears of the patient, taking account of the individual's circumstances. When selecting between radiotherapy, surgical resection, and phototherapy, or when deciding how best to combine these different therapeutic modalities, it is necessary to understand the patients utilities, with respect to tumour control, visual conservation, and preservation of the eye, so as to prioritize outcomes accordingly. For example, such considerations would influence the width of the safety margins when administering radiotherapy, according to whether the patient considers it more important to conserve vision or to guarantee tumour control. With ‘suspicious naevi', the choice between observation, immediate treatment, and biopsy is complicated by the lack of adequate survival data on which to base rational decisions, making it necessary for both patient and doctor to accept uncertainty. Personalized care should involve close relatives, as appropriate. It must also adapt to changes in the patient's needs over time. Such personalized care demands the ability to respond to such needs and the sensitivity to identify these requirements in the first place. Personalized treatment enhances not only the patient's satisfaction but also the ‘job satisfaction' of all members of the multidisciplinary team, improving quality of care. PMID:23174751

  20. Effects of hyperglycemia on lonidamine-induced acidification and de-energization of human melanoma xenografts and sensitization to melphalan.

    PubMed

    Nath, Kavindra; Nelson, David S; Heitjan, Daniel F; Zhou, Rong; Leeper, Dennis B; Glickson, Jerry D

    2015-03-01

    We seek to exploit the natural tendency of melanomas and other tumors to convert glucose to lactate as a method for the selective intracellular acidification of cancer cells and for the potentiation of the activity of nitrogen-mustard antineoplastic agents. We performed this study to evaluate whether the induction of hyperglycemia (26 mM) could enhance the effects of lonidamine (LND, 100 mg/kg; intraperitoneally) on the induction of intracellular acidification, bioenergetic decline and potentiation of the activity of melphalan (LPAM) against DB-1 melanoma xenografts in mice. Intracellular pH (pHi ), extracellular pH (pHe ) and bioenergetics (β-nucleoside triphosphate to inorganic phosphate ratio, β-NTP/Pi) were reduced by 0.7 units (p < 0.001), 0.3 units (p > 0.05) and 51.4% (p < 0.05), respectively. The therapeutic response to LPAM (7.5 mg/kg; intravenously) + LND (100 mg/kg; intraperitoneally) was reduced by about a factor of three under hyperglycemic conditions relative to normoglycemia, producing a growth delay of 7.76 days (tumor doubling time, 5.31 days; cell kill, 64%) compared with LND alone of 1.70 days and LPAM alone of 0.29 days. Under normoglycemic conditions, LND plus LPAM produced a growth delay of 17.75 days, corresponding to a cell kill of 90% at the same dose for each of these agents. The decrease in tumor cell kill under hyperglycemic conditions correlates with an increase in tumor ATP levels resulting from increased glycolytic activity. However, hyperglycemia substantially increases lactic acid production in tumors by a factor of approximately six (p < 0.05), but hyperglycemia did not increase the effects of LND on acidification of the tumor, most probably because of the strong buffering action of carbon dioxide (the pKa of carbonic acid is 6.4). Therefore, this study demonstrates that the addition of glucose during treatment with LND diminishes the activity of this agent.

  1. Long-term efficiency of mesenchymal stromal cell-mediated CD-MSC/5FC therapy in human melanoma xenograft model.

    PubMed

    Kucerova, L; Skolekova, S; Demkova, L; Bohovic, R; Matuskova, M

    2014-10-01

    Mesenchymal stromal cells (MSC) can be exploited as cellular delivery vehicles for the enzymes converting non-toxic prodrugs to toxic substances. Because of their inherent chemoresistance, they exert potent bystander and antitumor effect. Here we show that the human adipose tissue-derived MSC expressing fusion yeast cytosine deaminase::uracil phosphoribosyltransferase (CD-MSC) in combination with 5-fluorocytosine (5FC) mediated a long-term tumor-free survival in the 83.3% of tumor-bearing animals. CD-MSC/5FC treatment induced cytotoxicity against model human melanoma cells EGFP-A375. Only 4% of the therapeutic CD-MSC cells eliminated >98.5% of the tumor cells in vitro. Long-term tumor-free survival was confirmed in 15 out of the 18 animals. However, repeatedly used CD-MSC/5FC therapeutic regimen generated more aggressive and metastatic variant of the melanoma cells EGFP-A375/Rel3. These cells derived from the refractory xenotransplants exhibited increased resistance to the CD-MSC/5FC treatment, altered cell adhesion, migration, tumorigenic and metastatic properties. However, long-term curative effect was achieved by the augmentation of the CD-MSC/5FC regimen along with the inhibition of c-Met/hepatocyte growth factor signaling axis in this aggressive melanoma derivative. In summary, the CD-MSC/5FC regimen can be regarded as a very effective antitumor approach to achieve long-term tumor-free survival as demonstrated on a mouse model of aggressive human melanoma xenografts.

  2. SHP2 phosphatase as a novel therapeutic target for melanoma treatment

    PubMed Central

    Zhang, Ruo-Yu; Yu, Zhi-Hong; Zeng, Lifan; Zhang, Sheng; Bai, Yunpeng; Miao, Jinmin; Chen, Lan; Xie, Jingwu; Zhang, Zhong-Yin

    2016-01-01

    Melanoma ranks among the most aggressive and deadly human cancers. Although a number of targeted therapies are available, they are effective only in a subset of patients and the emergence of drug resistance often reduces durable responses. Thus there is an urgent need to identify new therapeutic targets and develop more potent pharmacological agents for melanoma treatment. Herein we report that SHP2 levels are frequently elevated in melanoma, and high SHP2 expression is significantly associated with more metastatic phenotype and poorer prognosis. We show that SHP2 promotes melanoma cell viability, motility, and anchorage-independent growth, through activation of both ERK1/2 and AKT signaling pathways. We demonstrate that SHP2 inhibitor 11a-1 effectively blocks SHP2-mediated ERK1/2 and AKT activation and attenuates melanoma cell viability, migration and colony formation. Most importantly, SHP2 inhibitor 11a-1 suppresses xenografted melanoma tumor growth, as a result of reduced tumor cell proliferation and enhanced tumor cell apoptosis. Taken together, our data reveal SHP2 as a novel target for melanoma and suggest SHP2 inhibitors as potential novel therapeutic agents for melanoma treatment. PMID:27650545

  3. Intratumoral Approaches for the Treatment of Melanoma.

    PubMed

    Bommareddy, Praveen K; Silk, Ann W; Kaufman, Howard L

    There have been significant advances in the immunotherapy of melanoma over the last decade. The tumor microenvironment is now known to promote an immune-suppressive milieu that can block effective immune-mediated tumor rejection. Several novel strategies designed to overcome local immunosuppression hold promise for treatment of melanoma and other cancers. These approaches include oncolytic viruses, plasmid DNA delivery, Toll-like receptor agonists, inflammatory dyes, cytokines, checkpoint inhibitors, immunomodulatory agents, and host and pathogenic cell-based vectors. In addition, there are several novel methods for local drug delivery, including direct injection, image-guided, electroporation, and nanodelivery techniques under study. The approval of talimogene laherparepvec (Imlygic), an attenuated, recombinant oncolytic herpesvirus, for melanoma treatment is the first intratumoral agent to receive regulatory approval for the treatment of patients with melanoma. This review will focus on the rationale for intratumoral treatment in melanoma, describe the clinical and safety data for some of the agents in clinical development, and provide a perspective for future clinical investigation with intratumoral approaches. Melanoma has been a paradigm tumor for progress in targeted therapy and immunotherapy and will likely also be the tumor to establish the therapeutic role of intratumoral treatment for cancer.

  4. Recent developments in nanomedicine for melanoma treatment.

    PubMed

    Tang, Jian-Qin; Hou, Xiao-Yang; Yang, Chun-Sheng; Li, Ya-Xi; Xin, Yong; Guo, Wen-Wen; Wei, Zhi-Ping; Liu, Yan-Qun; Jiang, Guan

    2017-08-15

    Melanoma is a most aggressive skin cancer with limited therapeutic options and its incidence is increasing rapidly in recent years. The discovery and application of new targeted therapy agents have shown significant benefits. However, adverse side-effects and resistance to chemotherapy remain formidable challenges in the clinical treatment of malignant melanoma. Nanotherapeutics offers an important prospect of overcoming these drawbacks. The anti-tumoral applications of nanomedicine are varied, including those in chemotherapy, RNA interference, photothermal therapy, and photodynamic therapy. Furthermore, nanomedicine allows delivery of the effector structures into the tumor site via passive or active targeting, thereby allowing increased therapeutic specificity and reduced side effects. In this review, we summarize the latest developments in the application of nanocarrier-mediated targeted drug delivery to melanoma and nanomedicine-related clinical trials in melanoma treatment. We also discuss existing problems and opportunities for future developments, providing direction and new thoughts for further studies. © 2017 UICC.

  5. Genital melanoma: prognosis factors and treatment modality.

    PubMed

    Ferraioli, Domenico; Lamblin, Gery; Mathevet, Patrice; Hetu, Jessika; Berakdar, Isabelle; Beurrier, Frederic; Chopin, Nicolas

    2016-11-01

    Genital melanoma is a rare pathology. We present the experience of two comprehensive cancer centers in Lyon (France) in the management of genital melanoma in order to identify prognostic factors and optimal treatments. Between April 1992 and Mars 2014, 16 patients with a primary genital melanoma were referred to our department. Nine patients presented a vaginal melanoma, six vulvar melanomas and only one cervical melanoma. The median dimension of the lesion was 33.7 mm (5-100 mm). The AJCC stage ranged from IB to IIIC. 12 cases were the classic dark-blue flat melanoma and the other 4 cases were an atypical amelanotic tumor. Wide local surgery was performed in nine patients. A radical surgery was performed in six patients. In the large cervical melanoma, radiotherapy was performed as first-line treatment. In all the patients regional lymph node staging was performed. Adjuvant treatment was realized in nine patients. Two patients are alive without recurrence. Only one patient was lost to the first follow-up. The other 13 patients experienced a rapid recurrence. The median disease-free survival and the median overall survival were 11.8 months (2-49 m) and of 30.4 m (11-144 m), respectively. The disease-free survival and overall survival could be linked to a clinical presentation (Breslow thickness and morphology of lesion) associated to the early diagnosis. In our small series, the most important prognosis factor remains the tumor thickness. These rare lesions should be treated in experienced centers in order to improve their prognostic.

  6. Melanoma.

    PubMed

    Schadendorf, Dirk; Fisher, David E; Garbe, Claus; Gershenwald, Jeffrey E; Grob, Jean-Jacques; Halpern, Allan; Herlyn, Meenhard; Marchetti, Michael A; McArthur, Grant; Ribas, Antoni; Roesch, Alexander; Hauschild, Axel

    2015-04-23

    Melanoma is a common cancer in the Western world with an increasing incidence. Sun exposure is still considered to be the major risk factor for melanoma. The prognosis of patients with malignant (advanced-stage) melanoma differs widely between countries, but public campaigns advocating early detection have led to significant reductions in mortality rates. As well as sun exposure, distinct genetic alterations have been identified as associated with melanoma. For example, families with melanoma who have germline mutations in CDKN2A are well known, whereas the vast majority of sporadic melanomas have mutations in the mitogen-activated protein kinase cascade, which is the pathway with the highest oncogenic and therapeutic relevance for this disease. BRAF and NRAS mutations are typically found in cutaneous melanomas, whereas KIT mutations are predominantly observed in mucosal and acral melanomas. GNAQ and GNA11 mutations prevail in uveal melanomas. Additionally, the PI3K-AKT-PTEN pathway and the immune checkpoint pathways are important. The finding that programmed cell death protein 1 ligand 1 (PDL1) and PDL2 are expressed by melanoma cells, T cells, B cells and natural killer cells led to the recent development of programmed cell death protein 1 (PD1)-specific antibodies (for example, nivolumab and pembrolizumab). Alongside other new drugs - namely, BRAF inhibitors (vemurafenib and dabrafenib) and MEK inhibitors (trametinib and cobimetinib) - these agents are very promising and have been shown to significantly improve prognosis for patients with advanced-stage metastatic disease. Early signs are apparent that these new treatment modalities are also improving long-term clinical benefit and the quality of life of patients. This Primer summarizes the current understanding of melanoma, from mechanistic insights to clinical progress. For an illustrated summary of this Primer, visit: http://go.nature.com/vX2N9s.

  7. [Systemic treatment of inoperable metastasized malignant melanoma].

    PubMed

    Gutzmer, R; Rauschenberg, R; Meier, F

    2016-07-01

    The medical therapy of inoperable malignant melanoma has changed dramatically over the last few years. The purpose of this article is to summarize the current state of systemic medical treatment of malignant melanoma. Clinical studies and guidelines in the therapy of malignant melanoma are reviewed. Medical therapy of inoperable melanoma changed due to developments in immunotherapies (checkpoint inhibitors) and molecular-targeted therapies (BRAF and MEK inhibitors). Checkpoint inhibitors are antibodies administered as infusions every 2-3 weeks, blocking the checkpoints PD-1 or CTLA-4, thus, preventing downregulation of the immune system. BRAF and MEK inhibitors are small molecules, they are given orally and block a certain signaling pathway in tumor cells. The activation of this pathway has to be demonstrated by molecular analysis of tumor tissue first. This strategy is currently registered for 40-50 % of melanomas harboring a BRAF V600 mutation, while the combination of a BRAF plus MEK inhibitor has been proven more efficient than a BRAF inhibitor alone. A fascinating development has started in the melanoma field due to immunotherapeutic and molecular-targeted treatment strategies. The continuation of this development needs further clinical and translational studies. This includes particular clinical studies with the new substances in the adjuvant situation, and sequences and combinations in the metastatic setting. Translational studies are needed to develop biomarkers for response and side effects.

  8. Pembrolizumab for the treatment of advanced melanoma

    PubMed Central

    Burns, Michael C; O’Donnell, Aidan; Puzanov, Igor

    2016-01-01

    Introduction Since 2010 multiple targeted therapies and immunotherapies have been approved for the treatment of advanced melanoma. Pembrolizumab, a humanized monoclonal antibody directed against programed death receptor 1 has shown significant activity in advanced melanoma resulting in its approval first as post-ipilimumab and subsequently as frontline treatment. Areas Covered This article reviews the approved agents for the treatment of advanced melanoma with a focus on the preclinical and clinical evidence for the use of pembrolizumab in this setting. Primary emphasis is given to the clinical development of pembrolizumab, including phase I-III trials. Finally, we explore the role of pembrolizumab in combination with other therapies and ongoing investigations into its effectiveness in expanded patient populations. Expert Opinion Pembrolizumab provides durable responses and represents a major advancement in the treatment options for patients with advanced melanoma. Early studies of pembrolizumab in combination with other therapeutic agents have generated significant interest and further investigations including advanced clinical trials are warranted to evaluate safety and potential improved outcomes. Pembrolizumab and other immune checkpoint inhibitors are likely to play an expanded role in the treatment of advanced melanoma and other solid tumors over the next decade. PMID:27597930

  9. Cisplatin and 4-hexylresorcinol synergise to decrease metastasis and increase survival rate in an oral mucosal melanoma xenograft model: a preliminary study.

    PubMed

    Lee, Sang-Woon; Kim, Seong-Gon; Park, Young-Wook; Kweon, Haeyong; Kim, Jwa-Young; Rotaru, Horatiu

    2013-06-01

    The present study was undertaken to examine the effects of cisplatin plus 4-hexylresorcinol (4-HR) combination therapy on oral mucosal melanoma (OMM) using cultured primary OMM cells in a tumour xenograft model. Cultured primary OMM cells were used for the MTT assay and DNA microarray. OMM cells were implanted into the submandibular glands of nude mice. The mice were then treated with cisplatin only or cisplatin plus 4-HR. Tumour size changes, survival rate and tumour metastasis were compared between the two groups by observation, micro-positron emission tomography (PET) and histological examination. In the MTT assay, the cisplatin plus 4-HR group showed significantly higher inhibition of OMM cell growth compared to the other groups (p<0.05). DNA microarray results showed significant inhibition of matrix metalloproteinase (MMP)-2 gene expression upon 4-HR application. The necropsy and micro-PET results showed that the mice from the cisplatin-only group had more distant metastases than the mice from the cisplatin plus 4-HR combination group (p=0.002). MMP-2 expression was lower in the primary tumours in the cisplatin plus 4-HR combination group than in the cisplatin-only group (p<0.001). Overall survival was longer in mice from the cisplatin plus 4-HR combination group than in the cisplatin-only group (p=0.049). In conclusion, the combined effect of cisplatin and 4-HR resulted in fewer metastases and longer survival than cisplatin-only treatment in the OMM xenograft model.

  10. Cutaneous melanoma: new advances in treatment.

    PubMed

    Foletto, Michele Ceolin; Haas, Sandra Elisa

    2014-01-01

    Cutaneous melanoma is a challenge to treat. Over the last 30 years, no drug or combination of drugs demonstrated significant impact to improve patient survival. From 1995 to 2000, the use of cytokines such as interferon and interleukin become treatment options. In 2011, new drugs were approved by the U.S. Food and Drug Administration, including peginterferon alfa-2b for patients with stage III disease, vemurafenib for patients with metastatic melanoma with the BRAF V600E mutation, and ipilimumab, a monoclonal antibody directed to the CTLA-4 T lymphocyte receptor, to combat metastatic melanoma in patients who do not have the BRAF V600E mutation. Both ipilimumab and vemurafenib showed results in terms of overall survival. Other trials with inhibitors of other genes, such as the KIT gene and MEK, are underway in the search for new discoveries. The discovery of new treatments for advanced or metastatic disease aims to relieve symptoms and improve patient quality of life.

  11. Trametinib in the treatment of melanoma.

    PubMed

    Thota, Ramya; Johnson, Douglas B; Sosman, Jeffrey A

    2015-05-01

    Aberrant MAPK pathway signaling is a hallmark of melanoma. Mitogen/extracellular signal-regulated kinase (MEK) 1/2 are integral components of MAPK signaling. Several MEK inhibitors have demonstrated activity as single agents and in combination with other therapies. Trametinib was the first MEK inhibitor approved for use in treatment of advanced BRAF(V600) mutant melanoma as a single agent and in combination with BRAF inhibitor, dabrafenib. In this article, we discuss the underlying biology of MEK inhibition and its rationale in melanoma treatment with special emphasis on the clinical development of trametinib, from initial Phase I studies to randomized Phase II and III studies, both as monotherapy and in combination with other therapeutics. Furthermore, we briefly comment on trametinib for NRAS mutant and other non-BRAF mutant subsets of melanoma. Trametinib is a novel oral MEK inhibitor with clinical activity in BRAF(V600) mutant metastatic melanoma alone and in combination with dabrafenib. Trametinib is currently being explored in other genetic subsets as well, particularly those with NRAS mutations or atypical BRAF alterations. Furthermore, to maximize efficacy and overcome acquired resistance, studies evaluating the combination of trametinib with other targeted agents and immunotherapy are underway.

  12. Predictive biomarkers for dasatinib treatment in melanoma

    PubMed Central

    Eustace, Alex J.; Kennedy, Susan; Larkin, Anne-Marie; Mahgoub, Thamir; Tryfonopoulos, Dimitrios; O'Driscoll, Lorraine; Clynes, Martin; Crown, John; O'Donovan, Norma

    2014-01-01

    Dasatinib has anti-proliferative and anti-invasive effects in melanoma cell lines. However clinical trials have shown modest activity for dasatinib in metastatic melanoma. Although dasatinib targets SRC kinase, neither expression nor phosphorylation of SRC appears to predict response to dasatinib. Identification of predictive biomarkers for dasatinib may facilitate selection of melanoma patients who are more likely to respond to dasatinib. We correlated the anti-proliferative effects of dasatinib in 8 melanoma cell lines with expression of a previously identified 6-gene biomarker panel. We examined the relationship between response to dasatinib and expression of each gene at both the mRNA and protein level. Dasatinib inhibited growth in 3 of the 8 cell lines tested. mRNA expression of the panel of 6 biomarkers did not correlate with response, whilst elevated protein expression of ANXA1, CAV-1 and EphA2 correlated significantly with response to dasatinib in the panel of cell lines. Expression of ANXA1, CAV-1 and EphA2 were analysed in 124 melanoma samples by immunohistochemistry. ANXA1 protein was detected in 81 % (97/120) of tumours, CAV-1 in 44 % (54/122) of tumours and EphA2 in 74 % (90/121) of tumours. Thirty one % (35/113) of tumours tested expressed all three markers and 19 % (21/112) had moderate or strong expression of ANXA1, CAV-1 and EphA2. Seventeen percent (19/112) of melanoma samples were positive for SRC kinase expression, combined with high expression of ANXA1, CAV-1 and EphA2. This subgroup may represent a population of melanoma patients who would be more likely to derive clinical benefit from dasatinib treatment. PMID:25594008

  13. Discrepancy Between Tumor Antigen Distribution and Radiolabeled Antibody Binding in a Nude Mouse Xenograft Model of Human Melanoma.

    PubMed

    Kim, Yong-Il; Paeng, Jin Chul; Cheon, Gi Jeong; Kang, Keon Wook; Lee, Dong Soo; Chung, June-Key

    2017-04-01

    Biodistribution of antibodies is vital to successful immunoscintigraphy/immunotherapy, and it is assumed to be similar to antigen distribution. We measured and compared the binding pattern of radiolabeled antibody to tissue antigen distribution in a nude mouse xenograft model of human melanoma. We transplanted 10(7) FEM-XII human melanoma cells into the right flank of five nude mice. For the control, we transplanted 5 × 10(6) LS174T human colon cancer cells into the left flank. Two weeks later, 10 μCi of (131)I-labeled melanoma-associated 96.5 monoclonal antibody (targeting p97 antigen) was intravenously injected. Three days later, we sacrificed the mice and evaluated 96.5 antibody binding and concentration in the tumors by ex vivo quantitative autoradiography (QAR). Two months later, we incubated adjacent tumor tissue slices in various concentrations of (125)I-labeled 96.5 MoAb and evaluated the distribution/concentration of p97 antigen by in vitro QAR. p97 antigen distribution was homogeneous in the tumors (total antigen concentration [Bmax] = 17.36-38.36 pmol/g). In contrast, radiolabeled 96.5 antibody binding was heterogenous between location within the tumor (estimated bound antigen concentration = 0.7-6.6 pmol/g). No quantifiable parameters were found to be related with radiolabeled antibody binding and tumor antigen distribution. Antibody-bound tumor antigen to total antigen ratios ranged between 2% and 38%. Heterogeneous features of target antibody binding were observed in contrast to relatively homogenous feature of tumor antigen. We did not identify any correlations between p97 antigen distribution and 96.5 antibody binding in melanoma tissue. Radiolabeled 96.5 antibody binding patterns within melanoma cannot be predicted based on p97 antigen distribution in the tumor, which needs to be further studied with several other methods and more subjects in the future.

  14. The Treatment of Melanoma Brain Metastases.

    PubMed

    Kibbi, Nour; Kluger, Harriet

    2016-12-01

    Melanoma is the malignancy with the highest rate of dissemination to the central nervous system once it metastasizes. Until recently, the prognosis of patients with melanoma brain metastases (MBM) was poor. In recent years, however, the prognosis has improved due to high-resolution imaging that facilitates early detection of small asymptomatic brain metastases and early intervention with local modalities such as stereotactic radiosurgery. More recently, a number of systemic therapies have been approved by the Food and Drug Administration for metastatic melanoma, resulting in improved survival for many MBM patients. Registration trials for these newer therapies excluded patients with untreated brain metastases, and a number of studies specifically tailored to this population of patients have been conducted or are underway. Herein, we review contemporary locoregional and systemic therapies and describe the unique challenges posed by treatment of brain metastases, such as radionecrosis, cerebral edema, and pseudoprogression. Since the number of systemic and combined modality clinical trials has increased, we expect that the treatment landscape for patients with melanoma brain metastasis will change dramatically. In addition to ongoing clinical trials, which show great promise, we conclude that our understanding of intracranial metastasis remains quite limited. In addition to inter-disciplinary, multi-modality studies, bench-side work to better understand the process of cerebrotropism is needed to fuel more drug development and further improve outcomes.

  15. Nanolipolee-007, a novel nanoparticle based drug containing leelamine for the treatment of melanoma

    PubMed Central

    Gowda, Raghavendra; Madhunapantula, SubbaRao V.; Sharma, Arati; Kuzu, Omer F; Robertson, Gavin P.

    2015-01-01

    Malignant melanoma is a difficult cancer to treat due to the rapid development of resistance to drugs targeting single proteins. One response to this observation is to identify single pharmacological agents that due to a unique mechanism of action simultaneously target multiple key pathways involved in melanoma development. To develop a single nanoparticle-based agent targeting the PI3 kinase, STAT3 and MAP kinase signaling pathways, a natural product library was screened, identifying leelamine, as a potential inhibitor. To overcome the poor bioavailability of leelamine in animals and lethality when administered intravenously, a nanoliposomal-based delivery system has been developed called Nanolipolee-007, which stably loads 60% of the compound. The nanoparticle was as effective at killing melanoma cells as leelamine dissolved in DMSO and was 4.5-fold more effective at killing cultured melanoma cell survival compared to normal cells. Mechanistically, Nanolipolee-007 inhibited PI3K/Akt, STAT3 and MAPK signaling mediated through inhibition of cholesterol transport shutting down these key pathways. Nanolipolee-007 inhibited the growth of preexisting xenografted melanoma tumors by an average of 64% by decreasing cellular proliferation, reducing tumor vascularization, and increasing cellular apoptosis, with negligible toxicity. Thus, a unique clinical viable nanoparticle based drug has been developed containing leelamine for the treatment of melanoma that acts by inhibiting the activity of major signaling pathways regulating the development of this disease. PMID:25082958

  16. Efficient ferrocifen anticancer drug and Bcl-2 gene therapy using lipid nanocapsules on human melanoma xenograft in mouse.

    PubMed

    Resnier, Pauline; Galopin, Natacha; Sibiril, Yann; Clavreul, Anne; Cayon, Jérôme; Briganti, Alessandro; Legras, Pierre; Vessières, Anne; Montier, Tristan; Jaouen, Gérard; Benoit, Jean-Pierre; Passirani, Catherine

    2017-01-31

    Metastatic melanoma has been described as a highly aggressive cancer with low sensibility to chemotherapeutic agents. New types of drug, such as metal-based drugs (ferrocifens) have emerged and could represent an alternative for melanoma treatment since they show interesting anticancer potential. Furthermore, molecular analysis has evidenced the role of apoptosis in the low sensibility of melanomas and especially of the key regulator, Bcl-2. The objective of this study was to combine two strategies in the same lipid nanocapsules (LNCs): i) gene therapy to modulate anti-apoptotic proteins by the use of Bcl-2 siRNA, and ii) ferrocifens as a new type of anticancer agent. The efficient gene silencing with LNCs was verified by the specific extinction of Bcl-2 in melanoma cells. The cellular toxicity of ferrocifens (ferrociphenol (FcDiOH) or Ansa-FcDiOH) was demonstrated, showing higher efficacy than dacarbazine. Interestingly, the association of siBcl-2 LNCs with Ansa-FcDiOH demonstrated a significant effect on melanoma cell viability. Moreover, the co-encapsulation of siRNA and ferrocifens was successfully performed into LNCs for animal experiments. A reduction of tumor volume and mass was proved after siBcl-2 LNC treatment and Ansa-FcDiOH LNC treatment, individually (around 25%). Finally, the association of both components into the same LNCs increased the reduction of tumor volume to about 50% compared to the control group. In conclusion, LNCs appeared to provide a promising tool for the co-encapsulation of a metal-based drug and siRNA.

  17. Melanoma

    MedlinePlus

    Melanoma is the most serious type of skin cancer. Often the first sign of melanoma is a change in the size, shape, color, or feel of a mole. Most melanomas have a black or black-blue area. Melanoma ...

  18. The metastasis suppressor KISS1 lacks antimetastatic activity in the C8161.9 xenograft model of melanoma.

    PubMed

    Navenot, Jean-Marc; Evans, Barry; Oishi, Shinya; Setsuda, Shohei; Fujii, Nobutaka; Peiper, Stephen C

    2012-04-01

    The objective of this study was to use the established xenograft model of human melanoma (C8161.9) to test a pharmacological approach to the effect of the metastasis suppressor KISS1. A KISS1 analog was used to inhibit the metastatic development of C8161.9 cells in nude mice. Further experiments were performed to test the validity of the C8161.9 model and test the connection between KISS1 expression and loss of metastatic potential. New clones of C8161.9 cells were obtained, with or without KISS1 expression, and were tested for metastasis formation. The absence of benefit in survival with the KISS1 analog compared with PBS prompted us to revisit the C8161.9 model. We found that the cells expressing KISS1, used in the previous study and obtained by transfection and single-cell cloning, were defective for both formation of orthotopic tumors and metastases. In mixing experiments, these cells could not suppress orthotopic tumor growth of KISS1-negative C8161.9 cells, suggesting that the suppression of metastasis by C8161.9-KISS1 cells may be intrinsic to the selected clone rather than related to KISS1 expression. Isolation of clones from parental C8161.9 cells in soft agar yielded cell populations that phenotypically and genotypically mimicked the KISS1-positive clone. In addition, new clones expressing KISS1 did not show any decrease in metastatic growth. These data demonstrate the heterogeneity of cell types in the C8161.9 cell line and the high risk of artifact linked to single-cell selection. A different xenograft model will be necessary to evaluate the use of KISS1 analogs as antimetastatic therapy.

  19. Treatment of malignant melanoma by selective thermal neutron capture therapy using melanoma-seeking compound

    SciTech Connect

    Mishima, Y.; Ichihashi, M.; Tsuji, M.; Hatta, S.; Ueda, M.; Honda, C.; Suzuki, T.

    1989-05-01

    As pigment cells undergo melanoma genesis, accentuated melanogenesis concurrently occurs in principle. Subsequent to the understanding of intrinsic factors controlling both processes, we found our selective melanoma neutron capture therapy (NCT) using 10B-dopa (melanin substrate) analogue, 10B1-p-boronophenylalanine (10B1-BPA), followed by 10B(n, alpha)7Li reaction, induced by essentially harmless thermal neutrons, which releases energy of 2.33 MeV to 14 mu, the diameter of melanoma cells. In vitro/in vivo radiobiological analysis revealed the highly enhanced melanoma killing effect of 10B1-BPA. Chemical and prompt gamma ray spectrometry assays of 10B accumulated within melanoma cells after 10B1-BPA administration in vitro and in vivo show high affinity, e.g., 10B melanoma/blood ratio of 11.5. After successfully eradicating melanoma transplanted into hamsters with NCT, we advanced to preclinical studies using spontaneously occurring melanoma in Duroc pig skin. We cured three melanoma cases, 4.6 to 12 cm in diameter, by single neutron capture treatment. Complete disappearance of melanoma was obtained without substantial side effects. Acute and subacute toxicity as well as pharmacodynamics of 10B1-BPA have been studied in relation to therapeutic dosage requirements. Clinical radiation dosimetry using human phantom has been carried out. Further preclinical studies using human melanoma transplanted into nude mouse have been a useful model for obtaining optimal results for each melanoma type. We recently treated the first human melanoma patient with our NCT, using essentially the method for Duroc pig melanoma, and obtained similar regression time course leading to cure.

  20. Recent advances in uveal melanoma treatment.

    PubMed

    Álvarez-Rodríguez, Beatriz; Latorre, Alfonso; Posch, Christian; Somoza, Álvaro

    2017-07-31

    Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Recent advances in the understanding of molecular characteristics helped to determine which tumors are most likely to progress. About 50% of patients carrying genetic alterations such as chromosomal aberrations and mutations are at significant risk for metastatic disease of which the majority will succumb to UM within few months. Currently, there is no effective treatment for metastatic uveal melanoma, and we hope this review will encourage researchers and clinicians to work to find a better standard of care. In this article we provide a comprehensive overview of the molecular framework of UM, highlighting the most common mutations involved in this kind of cancer. It also covers the most recent treatments from basic research to clinical trials, including small molecules, nucleic acids or immunotherapy, among others. It is intended to serve as a key reference for clinicians and researchers working in this field. © 2017 Wiley Periodicals, Inc.

  1. [Systemic treatment of melanoma brain metastases].

    PubMed

    Le Rhun, É; Mateus, C; Mortier, L; Dhermain, F; Guillot, B; Grob, J-J; Lebbe, C; Thomas, M; Jouary, T; Leccia, M-T; Robert, C

    2015-02-01

    Melanomas have a high rate of brain metastases. Both the functional prognosis and the overall survival are poor in these patients. Until now, surgery and radiotherapy represented the two main modalities of treatment. Nevertheless, due to the improvement in the management of the extracerebral melanoma, the systemic treatment may be an option in patients with brain metastases. Immunotherapy with anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) - ipilimumab - or BRAF (serine/threonine-protein kinase B-raf) inhibitors - vemurafenib, dabrafenib - has shown efficacy in the management of brain metastases in a- or pauci-symptomatic patients. Studies are ongoing with anti-PD1 (programmed cell death 1) and combinations of targeted therapies associating anti-RAF (raf proto-oncogene, serine/threonine kinase) and anti-MEK (mitogen-activated protein kinase kinase).

  2. Melanoma.

    PubMed

    Gershenwald, J E

    2001-01-01

    The presentations at the American Society of Clinical Oncology 2001 meeting reported or updated the results of phase I, II, and III randomized trials and also reported important meta-analyses and retrospective studies impacting on the management of patients with melanoma. In the treatment of early stage melanoma, the prognostic significance of pathologic status of sentinel lymph nodes was affirmed. With respect to regional nodal involvement (American Joint Committee on Cancer [AJCC] stage III), investigators presented the interim results of the United Kingdom randomized low-dose interferon (IFN) trial, and up-to-date meta-analyses of several IFN trials including a pooled analysis of the Eastern Cooperative Oncology Group trials evaluating interferon in the adjuvant setting. In the advanced disease setting (AJCC stage IV), several studies elucidated the pros and cons of biochemotherapy in patients with metastatic melanoma, with an emphasis on seeking to improve response in the central nervous system and durability of response in general. Thought provoking was new data regarding the potential for lovastatin to act as a chemopreventive agent for melanoma. Translational studies were presented, one supporting the importance of HLA-typing in developing targeted vaccine therapy. Finally, the results of a novel experimental melanoma vaccine were presented using autologous tumor-derived heat-shock protein peptide complex-96 (HSPPC-96).

  3. 31P and 1H MRS of DB-1 Melanoma Xenografts: Lonidamine Selectively Decreases Tumor Intracellular pH and Energy Status and Sensitizes Tumors to Melphalan

    PubMed Central

    Nath, Kavindra; Nelson, David S.; Ho, Andrew; Lee, Seung-Cheol; Darpolor, Moses M.; Pickup, Stephen; Zhou, Rong; Heitjan, Daniel F.; Leeper, Dennis B.; Glickson, Jerry D.

    2012-01-01

    In vivo 31P MRS demonstrates that human melanoma xenografts in immunosuppressed mice treated with lonidamine (LND, 100 mg/kg, i.p.) exhibit a decrease in intracellular pH (pHi) from 6.90 ± 0.05 to 6.33 ± 0.10 (p < 0.001), a slight decrease in extracellular pH (pHe) from 7.00 ± 0.04 to 6.80 ± 0.07 (p > 0.05), and a monotonic decline in bioenergetics (NTP/Pi) by 66.8 ± 5.7% (p < 0.001) relative to the baseline level. Both bioenergetics and pHi decreases were sustained for at least 3 hr following LND treatment. Liver exhibited a transient intracellular acidification by 0.2 ± 0.1 pH units (p > 0.05) at 20 min post-LND with no significant change in pHe and a small transient decrease in bioenergetics, 32.9 ± 10.6 % (p > 0.05), at 40 min post-LND. No changes in pHi or ATP/Pi were detected in the brain (pHi, bioenergetics; p > 0.1) or skeletal muscle (pHi, pHe, bioenergetics; p > 0.1) for at least 120 min post-LND. Steady-state tumor lactate monitored by 1H MRS with a selective multiquantum pulse sequence with Hadamard localization increased ~3-fold (p = 0.009). Treatment with LND increased systemic melanoma response to melphalan (LPAM; 7.5 mg/kg, i.v.) producing a growth delay of 19.9 ± 2.0 d (tumor doubling time = 6.15 ± 0.31d, log10 cell-kill = 0.975 ± 0.110, cell-kill = 89.4 ± 2.2%) compared to LND alone of 1.1 ± 0.1 d and LPAM alone of 4.0 ± 0.0 d. The study demonstrates that the effects of LND on tumor pHi and bioenergetics may sensitize melanoma to pH-dependent therapeutics such as chemotherapy with alkylating agents or hyperthermia. PMID:22745015

  4. Cutaneous melanoma: new advances in treatment*

    PubMed Central

    Foletto, Michele Ceolin; Haas, Sandra Elisa

    2014-01-01

    Cutaneous melanoma is a challenge to treat. Over the last 30 years, no drug or combination of drugs demonstrated significant impact to improve patient survival. From 1995 to 2000, the use of cytokines such as interferon and interleukin become treatment options. In 2011, new drugs were approved by the U.S. Food and Drug Administration, including peginterferon alfa-2b for patients with stage III disease, vemurafenib for patients with metastatic melanoma with the BRAF V600E mutation, and ipilimumab, a monoclonal antibody directed to the CTLA-4 T lymphocyte receptor, to combat metastatic melanoma in patients who do not have the BRAF V600E mutation. Both ipilimumab and vemurafenib showed results in terms of overall survival. Other trials with inhibitors of other genes, such as the KIT gene and MEK, are underway in the search for new discoveries. The discovery of new treatments for advanced or metastatic disease aims to relieve symptoms and improve patient quality of life. PMID:24770508

  5. Metastatic disease from uveal melanoma: treatment options and future prospects

    PubMed Central

    Carvajal, Richard D; Schwartz, Gary K; Tezel, Tongalp; Marr, Brian; Francis, Jasmine H; Nathan, Paul D

    2017-01-01

    Uveal melanoma represents ∼85% of all ocular melanomas and up to 50% of patients develop metastatic disease. Metastases are most frequently localised to the liver and, as few patients are candidates for potentially curative surgery, this is associated with a poor prognosis. There is currently little published evidence for the optimal management and treatment of metastatic uveal melanoma and the lack of effective therapies in this setting has led to the widespread use of systemic treatments for patients with cutaneous melanoma. Uveal and cutaneous melanomas are intrinsically different diseases and so dedicated management strategies and therapies for uveal melanoma are much needed. This review explores the biology of uveal melanoma and how this relates to ongoing trials of targeted therapies in the metastatic disease setting. In addition, we consider the options to optimise patient management and care. PMID:27574175

  6. Metastatic melanoma treatment: Combining old and new therapies.

    PubMed

    Davey, Ryan J; van der Westhuizen, Andre; Bowden, Nikola A

    2016-02-01

    Metastatic melanoma is an aggressive form of cancer characterised by poor prognosis and a complex etiology. Until 2010, the treatment options for metastatic melanoma were very limited. Largely ineffective dacarbazine, temozolamide or fotemustine were the only agents in use for 35 years. In recent years, the development of molecularly targeted inhibitors in parallel with the development of checkpoint inhibition immunotherapies has rapidly improved the outcomes for metastatic melanoma patients. Despite these new therapies showing initial promise; resistance and poor duration of response have limited their effectiveness as monotherapies. Here we provide an overview of the history of melanoma treatment, as well as the current treatments in development. We also discuss the future of melanoma treatment as we go beyond monotherapies to a combinatorial approach. Combining older therapies with the new molecular and immunotherapies will be the most promising way forward for treatment of metastatic melanoma. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  7. Tumor-targeting Salmonella typhimurium A1-R combined with temozolomide regresses malignant melanoma with a BRAF-V600E mutation in a patient-derived orthotopic xenograft (PDOX) model

    PubMed Central

    Kawaguchi, Kei; Igarashi, Kentaro; Murakami, Takashi; Chmielowski, Bartosz; Kiyuna, Tasuku; Zhao, Ming; Zhang, Yong; Singh, Arun; Unno, Michiaki; Nelson, Scott D.; Russell, Tara A.; Dry, Sarah M.; Li, Yunfeng; Eilber, Fritz C.; Hoffman, Robert M.

    2016-01-01

    Melanoma is a recalcitrant disease in need of transformative therapuetics. The present study used a patient-derived orthotopic xenograft (PDOX) nude-mouse model of melanoma with a BRAF-V600E mutation to determine the efficacy of temozolomide (TEM) combined with tumor-targeting Salmonella typhimurium A1-R. A melanoma obtained from the right chest wall of a patient was grown orthotopically in the right chest wall of nude mice to establish a PDOX model. Two weeks after implantation, 40 PDOX nude mice were divided into 4 groups: G1, control without treatment (n = 10); G2, TEM (25 mg/kg, administrated orally daily for 14 consecutive days, n = 10); G3, S. typhimurium A1-R (5 × 107 CFU/100 μl, i.v., once a week for 2 weeks, n = 10); G4, TEM combined with S. typhimurium A1-R (25 mg/kg, administrated orally daily for 14 consecutive days and 5 × 107 CFU/100 μl, i.v., once a week for 2 weeks, respectively, n = 10). Tumor sizes were measured with calipers twice a week. On day 14 from initiation of treatment, all treatments significantly inhibited tumor growth compared to untreated control (TEM: p < 0.0001; S. typhimurium A1-R: p < 0.0001; TEM combined with S. typhimurium A1-R: p < 0.0001). TEM combined with S. typhimurium A1-R was significantly more effective than either S. typhimurium A1-R (p = 0.0004) alone or TEM alone (p = 0.0017). TEM combined with S. typhimurium A1-R could regress the melanoma in the PDOX model and has important future clinical potential for melanoma patients. PMID:27835903

  8. Treatment Options by Stage (Melanoma)

    MedlinePlus

    ... Treatment for more information.) Unusual moles, exposure to sunlight, and health history can affect the risk of ... Red or blond hair. Being exposed to natural sunlight or artificial sunlight (such as from tanning beds) ...

  9. Casticin Induced Apoptosis in A375.S2 Human Melanoma Cells through the Inhibition of NF-[Formula: see text]B and Mitochondria-Dependent Pathways In Vitro and Inhibited Human Melanoma Xenografts in a Mouse Model In Vivo.

    PubMed

    Shiue, Yin-Wen; Lu, Chi-Cheng; Hsiao, Yu-Ping; Liao, Ching-Lung; Lin, Jing-Pin; Lai, Kuang-Chi; Yu, Chien-Chih; Huang, Yi-Ping; Ho, Heng-Chien; Chung, Jing-Gung

    2016-01-01

    Casticin, a polymethoxyflavone occurring in natural plants, has been shown to have anticancer activities. In the present study, we aims to investigate the anti-skin cancer activity of casticin on melanoma cells in vitro and the antitumor effect of casticin on human melanoma xenografts in nu/nu mice in vivo. A flow cytometric assay was performed to detect expression of viable cells, cell cycles, reactive oxygen species production, levels of [Formula: see text] and caspase activity. A Western blotting assay and confocal laser microscope examination were performed to detect expression of protein levels. In the in vitro studies, we found that casticin induced morphological cell changes and DNA condensation and damage, decreased the total viable cells, and induced G2/M phase arrest. Casticin promoted reactive oxygen species (ROS) production, decreased the level of [Formula: see text], and promoted caspase-3 activities in A375.S2 cells. The induced G2/M phase arrest indicated by the Western blotting assay showed that casticin promoted the expression of p53, p21 and CHK-1 proteins and inhibited the protein levels of Cdc25c, CDK-1, Cyclin A and B. The casticin-induced apoptosis indicated that casticin promoted pro-apoptotic proteins but inhibited anti-apoptotic proteins. These findings also were confirmed by the fact that casticin promoted the release of AIF and Endo G from mitochondria to cytosol. An electrophoretic mobility shift assay (EMSA) assay showed that casticin inhibited the NF-[Formula: see text]B binding DNA and that these effects were time-dependent. In the in vivo studies, results from immuno-deficient nu/nu mice bearing the A375.S2 tumor xenograft indicated that casticin significantly suppressed tumor growth based on tumor size and weight decreases. Early G2/M arrest and mitochondria-dependent signaling contributed to the apoptotic A375.S2 cell demise induced by casticin. In in vivo experiments, A375.S2 also efficaciously suppressed tumor volume in a

  10. Novel Immunologic Approaches to Melanoma Treatment.

    PubMed

    Escandell, I; Martín, J M; Jordá, E

    2017-10-01

    Approaches to treating melanoma have changed radically since the introduction of immunotherapy, and survival figures are now higher than possible with earlier therapies. The immunomodulators currently available mainly block CTLA-4 (cytotoxicT lymphocyte-associated molecule-4) and PD-1 (programed cell death protein 1) translocated to the cell surface, where they inhibit the antitumor immune response. Treatments blocking these molecules are being more widely used. Research now seeks new molecular targets, the best combinations of available drugs, and biomarkers that can identify ideal candidates for each one. Copyright © 2017 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

  11. [Cutaneous Melanoma (CM): Current Diagnosis and Treatment].

    PubMed

    Gallegos Hernández, José Francisco; Nieweg, Omgo E

    2014-12-01

    Cutaneous melanoma (CM) is the third most common cancer of the skin, but it is the neoplasia with the greatest impact on mortality. Its etiology is multifactorial and it has been reported that its prevalence has increased in the last two decades. In Mexico, CM ranks seventh in frequency among all malignancies and 80% of cases are in locally advanced stages. The prognosis depends on the stage. The prognostic factors with greatest impact in survival are nodal status, tumor thickness or Breslow depth, ulceration, and in thin melanomas (< 1 mm thickness, without ulceration and Clarck level III), the mitotic index. The diagnostic approach is of great importance to achieve adequate treatment. Adherence to global guidelines of treatment allows us to obtain the best rates of locoregional control, which is the first target to be achieved in patients with CM. The goal of this manuscript is to provide a synthesis of the most important aspects in the diagnosis and treatment of CM, based on current evidence obtained in the literature.

  12. Topical phospho-sulindac (OXT-328) is effective in the treatment of non-melanoma skin cancer.

    PubMed

    Cheng, Ka Wing; Mattheolabakis, George; Wong, Chi C; Ouyang, Nengtai; Huang, Liqun; Constantinides, Panayiotis P; Rigas, Basil

    2012-10-01

    Phospho-sulindac (P-S, OXT-328), a novel sulindac derivative, has shown superior anticancer efficacy and safety compared to sulindac. In this study, we investigated the efficacy of topical P-S hydrogel in the treatment of non-melanoma skin cancer in preclinical models. P-S is a potent inhibitor of A431 epidermoid carcinoma in vitro and achieves this effect by inhibiting cell proliferation and inducing apoptosis. The anticancer efficacy of topical and oral P-S was further evaluated in mice bearing A431 intradermal xenografts. Compared to the controls, topical P-S hydrogel inhibited the A431 xenografts by 70.5% (p<0.01), while oral P-S inhibited it by 43.4% (p<0.05), being significantly less effective than topical P-S (p=0.017). Topical P-S hydrogel generated significant levels (>500 nmol/g tumor tissue) of intact P-S in the tumors, accounting for 92.5% of the total metabolites in the A431 xenografts. This local delivery of high levels of intact P-S to the A431 xenografts is an important contributor to the potent activity of topical P-S and no local or systemic side effects were noted in the treatment group. Thus, topical P-S is a promising treatment modality against non-melanoma skin cancer and merits further evaluation.

  13. Nanotechnology for the treatment of melanoma skin cancer.

    PubMed

    Naves, Lucas B; Dhand, Chetna; Venugopal, Jayarama Reddy; Rajamani, Lakshminarayanan; Ramakrishna, Seeram; Almeida, Luis

    2017-03-16

    Melanoma is the most aggressive type of skin cancer and has very high rates of mortality. An early stage melanoma can be surgically removed, with a survival rate of 99%. This literature review intends to elucidate the possibilities to treat melanoma skin cancer using hybrid nanofibers developed by advanced electrospinning process. In this review we have shown that the enhanced permeability and retention is the basis for using nanotechnology, aiming topical drug delivery. The importance of the detection of skin cancer in the early stages is directly related to non-metastatic effects and survival rates of melanoma cells. Inhibitors of protein kinase are already available in the market for melanoma treatment and are approved by the FDA; these agents are cobimetinib, dabrafenib, ipilimumab, nivolumab, trametinib, and vemurafenib. We also report a case study involving two different approaches for targeting melanoma skin cancer therapy, namely, magnetic-based core-shell particles and electrospun mats.

  14. ALDH1A3 is epigenetically regulated during melanocyte transformation and is a target for melanoma treatment.

    PubMed

    Pérez-Alea, M; McGrail, K; Sánchez-Redondo, S; Ferrer, B; Fournet, G; Cortés, J; Muñoz, E; Hernandez-Losa, J; Tenbaum, S; Martin, G; Costello, R; Ceylan, I; Garcia-Patos, V; Recio, J A

    2017-06-05

    Despite the promising targeted and immune-based interventions in melanoma treatment, long-lasting responses are limited. Melanoma cells present an aberrant redox state that leads to the production of toxic aldehydes that must be converted into less reactive molecules. Targeting the detoxification machinery constitutes a novel therapeutic avenue for melanoma. Here, using 56 cell lines representing nine different tumor types, we demonstrate that melanoma cells exhibit a strong correlation between reactive oxygen species amounts and aldehyde dehydrogenase 1 (ALDH1) activity. We found that ALDH1A3 is upregulated by epigenetic mechanisms in melanoma cells compared with normal melanocytes. Furthermore, it is highly expressed in a large percentage of human nevi and melanomas during melanocyte transformation, which is consistent with the data from the TCGA, CCLE and protein atlas databases. Melanoma treatment with the novel irreversible isoform-specific ALDH1 inhibitor [4-dimethylamino-4-methyl-pent-2-ynthioic acid-S methylester] di-methyl-ampal-thio-ester (DIMATE) or depletion of ALDH1A1 and/or ALDH1A3, promoted the accumulation of apoptogenic aldehydes leading to apoptosis and tumor growth inhibition in immunocompetent, immunosuppressed and patient-derived xenograft mouse models. Interestingly, DIMATE also targeted the slow cycling label-retaining tumor cell population containing the tumorigenic and chemoresistant cells. Our findings suggest that aldehyde detoxification is relevant metabolic mechanism in melanoma cells, which can be used as a novel approach for melanoma treatment.Oncogene advance online publication, 5 June 2017; doi:10.1038/onc.2017.160.

  15. [Melanoma: from molecular studies to the treatment breakthrough].

    PubMed

    Imianitov, E N

    2013-01-01

    Melanoma holds a leading position in the mortality from skin tumors. Standard treatment of metastatic melanoma allows tumor remission to be achieved only in a small subset of patients. Studies on melanoma molecular pathogenesis led to the identification of several causative genetic events and, consequently, to the development of novel targeted drugs. More than a half of melanomas contain amine acid substitutions in serine-threonine kinase BRAF. Clinical trials involving specific BRAF inhibitors--vemurafenib and dabrafenib--demonstrated high efficacy of these agents towards BRAF-mutated melanoma. MEK inhibitors may show activity against both BRAF--and NRAS-driven tumors. Mucosal and acral melanomas frequently contain mutation in KIT receptor and can be successfully treated by imatinib. There are novel therapeutic monoclonal antibodies targeted against immunosuppressive molecules CTLA4, PD-1 and PD-L1. In some instances these drugs allow to obtain exceptionally prolonged responses. Whole genome sequencing led to the identification of new melanoma genes, e.g. GRIN2A, TRRAP, PREX2, RAC1, STK19, PPP6C, etc. Molecular testing, especially BRAF mutation analysis, has become a mandatory part of melanoma diagnosis. Nevertheless, despite the revolution in melanoma treatment, the prevention of excessive ultraviolet exposure, cancer awareness and early diagnosis remain the main tools for the management of this disease.

  16. Local tumor control following single dose irradiation of human melanoma xenografts: Relationship to cellular radiosensitivity and influence of an immune response by the athymic mouse

    SciTech Connect

    Rofstad, E.K.

    1989-06-15

    The potential usefulness of untreated congenitally athymic adult mice as hosts for human tumors in radiocurability studies was investigated using five human melanoma xenograft lines (E.E., E.F., G.E., M.F., V.N.). The tumor radiocurability was found to differ considerably among the lines; the radiation doses required to achieve local control of 50% of the tumors irradiated (TCD50 values) ranged from 29.6 +/- 2.1 (SE) to 67.9 +/- 3.5 Gy. Since the clinical relevance of experimentally determined TCD50 values depends on to what extent they are modified by a host immune response, a possible immune reactivity against the melanomas was investigated by comparing the radiocurability data with cell survival data measured in vitro after irradiation in vivo and by performing quantitative tumor transplantability studies. The radiocurability and the cell survival data were found to agree well for the E.F., G.E., and M.F. melanomas. Moreover, the number of tumor cells required to achieve tumors in 50% of the inoculation sites (TD50 values) in untreated and in whole-body irradiated mice were similar, suggesting that the TCD50 values measured for these lines were not significantly influenced by a host immune response. On the other hand, the E.E. and V.N. melanomas showed significantly lower TCD50 values in vivo than predicted theoretically from the in vitro cell survival data and a significantly lower number of tumor cells required to achieve tumors in 50% of the inoculation sites in whole-body irradiated than in untreated mice, suggesting that the radiocurability of these two lines was enhanced due to an immune response by the host. Athymic mice may thus express a significant immune reactivity against some human tumor xenograft lines but not against others.

  17. Photodynamic therapy in treatment of cutaneous and choroidal melanoma.

    PubMed

    Kawczyk-Krupka, Aleksandra; Bugaj, Andrzej M; Latos, Wojciech; Zaremba, Katarzyna; Sieroń, Aleksander

    2013-12-01

    Melanoma is a malignant, the most aggressive and dreaded skin cancer. This form of cancer arises from melanocytes and may grow rapidly and metastasize. Melanoma predominantly occurs in skin, but could also be found in the mouth, iris and retina of the eye. Melanoma is the most dangerous form of skin cancer, with a steeply rising incidence and a poor prognosis in its advanced stages. It is highly resistant to traditional chemotherapy and radiotherapy, although modern biological therapies are showing some promise. Photodynamic therapy (PDT), as a novel effective modality of the treatment of skin cancers, opens up new possibilities in melanoma treatment also. Many experimental photodynamic therapy studies were performed. The results of many experiments indicate that that photodynamic therapy may be a promising tool for adjuvant treatment in advanced melanoma. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. Management and treatment of mucosal melanoma of the genital tract.

    PubMed

    Vaccari, Sabina; Barisani, Alessia; Dika, Emi; Fanti, Pier A; DE Iaco, Pierandrea; Gurioli, Carlotta; Tosti, Giulio

    2017-01-24

    Melanoma of the genital mucosa is a rare melanocytic neoplasm that affects both sexes. The diagnosis is often delayed; a useful diagnostic tool may be represented by videodermatoscopy, The treatment is complex and multidisciplinary. We report the main diagnostic features and therapeutic approaches for mucosal melanoma of the genital tract.

  19. Successful Treatment of Lower Eyelid Melanoma in Situ

    PubMed Central

    Yuan, Joyce; Koh, Justin; Miller, Timothy A.

    2014-01-01

    Summary: We present a brief literature review of the topical immune-modulating medication Imiquimod. The treatment of periorbital melanoma in situ typically requires surgical resection. Here we discuss a case of lower eyelid melanoma in situ successfully treated non-operatively with Imiquimod. PMID:25289347

  20. 5-Aminolevulinic acid-mediated sonodynamic therapy reverses macrophage and dendritic cell passivity in murine melanoma xenografts.

    PubMed

    Wang, Shan; Hu, Zheng; Wang, Xiaolong; Gu, Chuanwen; Gao, Zhongxiuzi; Cao, Wenwu; Zheng, Jinhua

    2014-09-01

    Sonodynamic therapy (SDT) uses a combination of sonosensitizing drugs and low-intensity therapeutic ultrasound to cause apoptosis and autophagy of tumor cells. However, its effects on the tumor microenvironment, especially on the immune state, remain unknown. In this study, we investigated the transformation of macrophages and dendritic cells (DCs) in the tumor microenvironment during 5-aminolevulinic acid (5-ALA)-mediated SDT in mice transplanted with B16F10 melanomas. Tumor growth and mouse weight were measured. Hematoxylin-eosin staining was used to evaluate tumor morphology to quantify the anti-tumor efficacy of 5-ALA-mediated SDT. We investigated anti-tumor immunity in the tumor microenvironment by immunocytochemical staining of CD68, CD163, CD80, CD86, tumor necrosis factor α (TNF-α), interleukin 10 (IL-10) and interferon γ (IFN-γ). Tumor growth was restrained by 5-ALA-mediated SDT in B16F10 melanoma-bearing mice. CD68 levels increased and CD163 decreased, indicating that M2 macrophages were converted to the M1 phenotype in the tumor. The increase in CD80 and CD86 showed that DCs in the tumor microenvironment tend to mature after SDT treatment. The cytokines INF-γ, TNF-α and IL-10 significantly increased in SDT. Application of low-intensity therapeutic ultrasound alone also led to similar trends in our study, but combined treatment with 5-ALA yielded a change. The original stabilized immune state in the tumor microenvironment can be interrupted by low-intensity therapeutic ultrasound combined with 5-ALA, which enhanced the pro-inflammatory response and reversed the passive properties of macrophages and dendritic cells.

  1. [Topical treatment of melanoma skin metastases with imiquimod].

    PubMed

    Sigüenza, Mercedes; Pizarro, Angel; Mayor, Matías; Vidaurrázaga, Carmen; Miralles, Lara; González-Beato, María; Casado, Mariano

    2005-03-01

    The treatment of skin metastases of melanoma can be difficult in many cases because of the patients age, as well as the number, size and location of the lesions. We present the case of an 82-year-old male with melanoma skin metastases on the scalp, which responded satisfactorily to treatment with 5 % imiquimod cream. Imiquimod is a topical immunomodulator with antiviral and antineoplastic action. This case, along with others that have recently been published, supports the usefulness of this treatment in selected cases of melanoma skin metastases, at least for palliative purposes.

  2. What's New in Research and Treatment of Melanoma Skin Cancer?

    MedlinePlus

    ... Melanoma Skin Cancer About Melanoma Skin Cancer What’s New in Melanoma Skin Cancer Research? Research into the ... Cancer? Key Statistics for Melanoma Skin Cancer What’s New in Melanoma Skin Cancer Research? More In Melanoma ...

  3. Emerging targeted therapies for melanoma treatment (review).

    PubMed

    Russo, Angela; Ficili, Bartolomea; Candido, Saverio; Pezzino, Franca Maria; Guarneri, Claudio; Biondi, Antonio; Travali, Salvatore; McCubrey, James A; Spandidos, Demetrios A; Libra, Massimo

    2014-08-01

    Cutaneous melanoma is an aggressive cancer with a poor prognosis for patients with advanced disease. The identification of several key molecular pathways implicated in the pathogenesis of melanoma has led to the development of novel therapies for this devastating disease. In melanoma, both the Ras/Raf/MEK/ERK (MAPK) and the PI3K/AKT (AKT) signalling pathways are constitutively activated through multiple mechanisms. Targeting various effectors of these pathways with pharmacologic inhibitors may inhibit melanoma cell growth and angiogenesis. Ongoing clinical trials provide hope to improve progression-free survival of patients with advanced melanoma. This review summarizes the most relevant studies focused on the specific action of these new molecular targeted agents. Mechanisms of resistance to therapy are also discussed.

  4. Emerging targeted therapies for melanoma treatment (Review)

    PubMed Central

    RUSSO, ANGELA; FICILI, BARTOLOMEA; CANDIDO, SAVERIO; PEZZINO, FRANCA MARIA; GUARNERI, CLAUDIO; BIONDI, ANTONIO; TRAVALI, SALVATORE; McCUBREY, JAMES A.; SPANDIDOS, DEMETRIOS A.; LIBRA, MASSIMO

    2014-01-01

    Cutaneous melanoma is an aggressive cancer with a poor prognosis for patients with advanced disease. The identification of several key molecular pathways implicated in the pathogenesis of melanoma has led to the development of novel therapies for this devastating disease. In melanoma, both the Ras/Raf/MEK/ERK (MAPK) and the PI3K/AKT (AKT) signalling pathways are constitutively activated through multiple mechanisms. Targeting various effectors of these pathways with pharmacologic inhibitors may inhibit melanoma cell growth and angiogenesis. Ongoing clinical trials provide hope to improve progression-free survival of patients with advanced melanoma. This review summarizes the most relevant studies focused on the specific action of these new molecular targeted agents. Mechanisms of resistance to therapy are also discussed. PMID:24899250

  5. Therapy response monitoring of the early effects of a new BRAF inhibitor on melanoma xenograft in mice: evaluation of (18) F-FDG-PET and (18) F-FLT-PET.

    PubMed

    Geven, Edwin J W; Evers, Stefan; Nayak, Tapan K; Bergström, Mats; Su, Fei; Gerrits, Danny; Franssen, Gerben M; Boerman, Otto C

    2015-01-01

    Inhibition of the V600E mutated BRAF kinase gene (BRAF(V600E) ) is an important and effective approach to treating melanomas. A new specific small molecule inhibitor of BRAF(V600E) , PLX3603, showed potent melanoma growth-inhibiting characteristics in preclinical studies and is currently under clinical investigation. In this study we investigated the feasibility of (18) F-FDG and (18) F-FLT-PET to monitor the early effects of the BRAF(V600E) inhibitor in mice with melanoma xenografts. SCID/beige mice with subcutaneous (s.c.) A375 melanoma xenografts, expressing BRAF(V600E) , received the BRAF(V600E) inhibitor twice daily orally (0, 25, 50 and 75 mg/kg). At 1, 3 and 7 days after start of therapy, the uptake of (18) F-FDG and (18) F-FLT in the tumor and normal tissues was determined in ex vivo tissue samples. Serial (18) F-FDG and (18) F-FLT-PET scans were acquired of animals at 1 day before and 1, 3 and 7 days after start of treatment with 75 mg/kg BRAF(V600E) inhibitor. A dose-dependent decrease in (18) F-FDG uptake in the A375 tumors was observed by ex vivo biodistribution analysis. Administration of 75 mg/kg BRAF inhibitor for 1, 3 and 7 days resulted in a significantly decreased (18) F-FDG uptake in A375 tumors (41, 35 and 51%, respectively). (18) F-FLT uptake in the A375 tumors was low at baseline and no significant changes in (18) F-FLT uptake were observed at any of the doses administered. These effects were corroborated by serial in vivo (18) F-FDG and (18) F-FLT-PET imaging. These data demonstrate that (18) F-FDG-PET can be used as an imaging biomarker to noninvasively evaluate the early effects of PLX3603.

  6. Melanoma: diagnosis, staging, and treatment. Consensus group recommendations.

    PubMed

    Berrocal, Alfonso; Cabañas, Luis; Espinosa, Enrique; Fernández-de-Misa, Ricardo; Martín-Algarra, Salvador; Martínez-Cedres, José Carlos; Ríos-Buceta, Luis; Rodríguez-Peralto, José Luis

    2014-09-01

    The incidence of malignant melanoma is increasing worldwide. In Spain, its incidence is increasing faster than any other cancer type, with a 5-year survival rate of about 85%. The impact and characteristics of malignant melanoma in the Spanish population can be ascertained from the national melanoma registry of the Academia Española de Dermatología y Venereología. This review presents consensus group recommendations for the diagnosis, staging and treatment of malignant melanoma in Spain. Incidence and mortality are discussed, as well as evaluation of various prevention and treatment strategies. Prognostic factors, such as BRAF and C-KIT mutations, which are expected to become routine staging procedures over the next few years, are outlined, especially in relation to treatment options. The use of recently approved targeted agents such as ipilimumab, a cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitor, and vemurafenib, a BRAF inhibitor, in metastatic disease are also discussed.

  7. Metastatic disease from uveal melanoma: treatment options and future prospects.

    PubMed

    Carvajal, Richard D; Schwartz, Gary K; Tezel, Tongalp; Marr, Brian; Francis, Jasmine H; Nathan, Paul D

    2017-01-01

    Uveal melanoma represents ∼85% of all ocular melanomas and up to 50% of patients develop metastatic disease. Metastases are most frequently localised to the liver and, as few patients are candidates for potentially curative surgery, this is associated with a poor prognosis. There is currently little published evidence for the optimal management and treatment of metastatic uveal melanoma and the lack of effective therapies in this setting has led to the widespread use of systemic treatments for patients with cutaneous melanoma. Uveal and cutaneous melanomas are intrinsically different diseases and so dedicated management strategies and therapies for uveal melanoma are much needed. This review explores the biology of uveal melanoma and how this relates to ongoing trials of targeted therapies in the metastatic disease setting. In addition, we consider the options to optimise patient management and care. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  8. Nivolumab-Based Treatments for Advanced Melanoma

    Cancer.gov

    A summary of results from an international, double-blind, randomized phase III trial testing the combination of nivolumab (Opdivo®) and ipilimumab (Yervoy®) against nivolumab alone and ipilimumab alone in patients with advanced melanoma.

  9. Novel therapeutics for the treatment of metastatic melanoma.

    PubMed

    Mansfield, Aaron S; Markovic, Svetomir N

    2009-05-01

    Metastatic malignant melanoma is an incurable disease with a median survival of 8.5 months and a probability of surviving 5 years after the diagnosis of less than 5%. To date, no systemic therapy has meaningfully changed these survival end points. Currently, in the USA the FDA has approved three agents for the treatment of metastatic melanoma: hydroxyurea, dacarbazine and interleukin-2. None of these have demonstrated a meaningfully prolonged survival of patients with metastatic melanoma. Therefore, a number of innovative therapeutic strategies have been pursued to improve outcomes, including immune therapy, tyrosine kinase inhibitors and angiogenesis inhibitors. Herein, we review some of the recent advances in novel therapeutic developments for the treatment of metastatic melanoma.

  10. Metastatic melanoma: Pathologic characterization, current treatment, and complications of therapy.

    PubMed

    Wick, Mark R; Gru, Alejandro A

    2016-07-01

    Metastatic melanoma (MM) has the potential to involve virtually any anatomical site, and it also has a wide spectrum of histological appearances. General clinicopathologic data pertaining to MM are presented in this review, together with a discussion of its differential diagnosis and therapy. "Biological" agents used in the treatment of melanoma are considered, along with the pathological features of the complications that they may cause. Copyright © 2016. Published by Elsevier Inc.

  11. Ipilimumab in the treatment of advanced melanoma - a clinical update.

    PubMed

    Kim, Dae Won; Trinh, Van Anh; Hwu, Wen-Jen

    2014-11-01

    Ipilimumab has become an important treatment option for patients with advanced melanoma; however, active research perseveres to resolve many clinical practice issues and to further improve the therapeutic index of this agent. This article aims to provide an update on long-term data, current challenge and recent progress relating to the clinical application of ipilimumab in the treatment of advanced melanoma. A literature search using PubMed database was conducted using search words ipilimumab, melanoma, treatment sequencing, adjuvant therapy, combination therapy, and biomarkers. Data were also obtained from meeting abstracts and clinical trial registries. Signal of clinical activity as adjuvant therapy in patients with resected high-risk melanoma begins to emerge, but longer follow-up is required for confirmation. Many issues, such as optimal dosing schedules and therapeutic sequences, remain unraveled. At present, treatment should be individualized based on patient- and disease-specific factors. Immunotherapy like ipilimumab still represents the best treatment option for durable remission; however, targeted therapies are more appropriate for patients with BRAF V600-mutated tumor who are symptomatic or have rapidly growing disease. With novel therapeutic options in the pipeline, the role of ipilimumab continues to evolve in the rapidly changing treatment landscape of advanced melanoma. Most likely, this agent will be utilized in combinatorial or sequential approach.

  12. Cancer stem cell as therapeutic target for melanoma treatment.

    PubMed

    Alamodi, Abdulhadi A; Eshaq, Abdulaziz M; Hassan, Sofie-Yasmin; Al Hmada, Youssef; El Jamal, Siraj M; Fothan, Ahmed M; Arain, Omair M; Hassan, Sarah-Lilly; Haikel, Youssef; Megahed, Mosaad; Hassan, Mohamed

    2016-12-01

    Human malignant melanoma is a highly aggressive skin tumor that is characterized by its extraordinary heterogeneity, propensity for dissemination to distant organs and resistance to cytotoxic agents. Although chemo- and immune-based therapies have been evaluated in clinical trials, most of these therapeutics do not show significant benefit for patients with advanced disease. Treatment failure in melanoma patients is attributed mainly to the development of tumor heterogeneity resulting from the formation of genetically divergent subpopulations. These subpopulations are composed of cancer stem-like cells (CSCs) as a small fraction and non-cancer stem cells that form the majority of the tumor mass. In recent years, CSCs gained more attention and suggested as valuable experimental model system for tumor study. In melanoma, intratumoral heterogeneity, progression and drug resistance result from the unique characteristics of melanoma stem cells (MSCs). These MSCs are characterized by their distinct protein signature and tumor growth-driving pathways, whose activation is mediated by driver mutation-dependent signal. The molecular features of MSCs are either in a causal or consequential relationship to melanoma progression, drug resistance and relapse. Here, we review the current scientific evidence that supports CSC hypothesis and the validity of MSCs-dependent pathways and their key molecules as potential therapeutic target for melanoma treatment.

  13. Bioelectric Applications for Treatment of Melanoma

    PubMed Central

    Beebe, Stephen J.; Schoenbach, Karl H.; Heller, Richard

    2010-01-01

    Two new cancer therapies apply bioelectric principles. These methods target tumor structures locally and function by applying millisecond electric fields to deliver plasmid DNA encoding cytokines using electrogene transfer (EGT) or by applying rapid rise-time nanosecond pulsed electric fields (nsPEFs). EGT has been used to locally deliver cytokines such as IL-12 to activate an immune response, resulting in bystander effects. NsPEFs locally induce apoptosis-like effects and affect vascular networks, both promoting tumor demise and restoration of normal vascular homeostasis. EGT with IL-12 is in melanoma clinical trials and nsPEFs are used in models with B16F10 melanoma in vitro and in mice. Applications of bioelectrics, using conventional electroporation and extensions of it, provide effective alternative therapies for melanoma. PMID:24281185

  14. The genetic basis of new treatment modalities in melanoma.

    PubMed

    Kunz, Manfred

    2015-01-01

    In recent years, intracellular signal transduction via RAS-RAF-MEK-ERK has been successfully targeted in new treatment approaches for melanoma using small molecule inhibitors against activated BRAF (V600E mutation) and activated MEK1/2. Also mutated c-KIT has been identified as a promising target. Meanwhile, evidence has been provided that combinations between BRAF inhibitors and MEK1/2 inhibitors are more promising than single-agent treatments. Moreover, new treatment algorithms favor sequential treatment using BRAF inhibitors and newly developed immunotherapies targeting common T lymphocyte antigen 4 (CTLA-4) or programmed cell death 1 (PD-1). In depth molecular analyses have uncovered new mechanisms of treatment resistance and recurrence, which may impact on future treatment decisions. Moreover, next-generation sequencing data have shown that recurrent lesions harbor specific genetic aberrations. At the same time, high throughput sequencing studies of melanoma unraveled a series of new treatment candidates for future treatment approaches such as ERBB4, GRIN2A, GRM3, and RAC1. More recent bioinformatic technologies provided genetic evidence for extensive tumor heterogeneity and tumor clonality of solid tumors, which might also be of relevance for melanoma. However, these technologies have not yet been applied to this tumor. In this review, an overview on the genetic basis of current treatment of melanoma, treatment resistance and recurrences including new treatment perspectives based on recent high-throughput sequencing data is provided. Moreover, future aspects of individualized treatment based on each patient's individual mutational landscape are discussed.

  15. Treatment of melanoma with a serotype 5/3 chimeric oncolytic adenovirus coding for GM-CSF: Results in vitro, in rodents and in humans.

    PubMed

    Bramante, Simona; Kaufmann, Johanna K; Veckman, Ville; Liikanen, Ilkka; Nettelbeck, Dirk M; Hemminki, Otto; Vassilev, Lotta; Cerullo, Vincenzo; Oksanen, Minna; Heiskanen, Raita; Joensuu, Timo; Kanerva, Anna; Pesonen, Sari; Matikainen, Sampsa; Vähä-Koskela, Markus; Koski, Anniina; Hemminki, Akseli

    2015-10-01

    Metastatic melanoma is refractory to irradiation and chemotherapy, but amenable to immunological approaches such as immune-checkpoint-inhibiting antibodies or adoptive cell therapies. Oncolytic virus replication is an immunogenic phenomenon, and viruses can be armed with immunostimulatory molecules. Therefore, oncolytic immuno-virotherapy of malignant melanoma is an appealing approach, which was recently validated by a positive phase 3 trial. We investigated the potency of oncolytic adenovirus Ad5/3-D24-GMCSF on a panel of melanoma cell lines and animal models, and summarized the melanoma-specific human data from the Advanced Therapy Access Program (ATAP). The virus effectively eradicated human melanoma cells in vitro and subcutaneous SK-MEL-28 melanoma xenografts in nude mice when combined with low-dose cyclophosphamide. Furthermore, virally-expressed granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulated the differentiation of human monocytes into macrophages. In contrast to human cells, RPMI 1846 hamster melanoma cells exhibited no response to oncolytic viruses and the chimeric 5/3 fiber failed to increase the efficacy of transduction, suggesting limited utility of the hamster model in the context of viruses with this capsid. In ATAP, treatments appeared safe and well-tolerated. Four out of nine melanoma patients treated were evaluable for possible therapy benefit with modified RECIST criteria: one patient had minor response, two had stable disease, and one had progressive disease. Two patients were alive at 559 and 2,149 days after treatment. Ad5/3-D24-GMCSF showed promising efficacy in preclinical studies and possible antitumor activity in melanoma patients refractory to other forms of therapy. This data supports continuing the clinical development of oncolytic adenoviruses for treatment of malignant melanoma.

  16. Prognostic significance of autoimmunity during treatment of melanoma with interferon.

    PubMed

    Krauze, Michal T; Tarhini, Ahmad; Gogas, Helen; Kirkwood, John M

    2011-07-01

    Since the pivotal cooperative group trials in the 1980's-90's,, high-dose interferon (HDI) has been the standard of adjuvant therapy. Despite multiple other trials evaluating potential new therapies in melanoma, HDI remains the only FDA-approved therapy for stage IIB and III melanoma. Initial reports from the more recent phase III international trials of modifications of the original HDI regimen linked the appearance of autoimmunity with improved outcomes of disease. Trials of high-dose interleukin-2, many years earlier, reported anecdotal observations that were consistent with the hypothesis that autoimmunity and clinical benefit of immunotherapies of melanoma are linked with one another. The only prospectively conducted study examining the appearance of clinical and laboratory evidence of autoimmunity during HDI therapy was published by Gogas and colleagues, demonstrating statistically significant impact on relapse-free survival and overall survival. Retrospectively conducted studies of different intermediate dosage regimens of interferon (IFN) have not fully confirmed the linkage of serological evidence of autoimmunity and improved survival outcomes. With the emergence of new immunotherapies in treatment of melanoma, this review highlights the importance of autoimmunity for future applications in melanoma and reviews significant differences of past studies evaluating the appearance of autoimmunity during IFN therapy in high-risk melanoma.

  17. Optimized Nanosecond Pulsed Electric Field Therapy Can Cause Murine Malignant Melanomas to Self-Destruct with a Single Treatment

    PubMed Central

    Nuccitelli, Richard; Tran, Kevin; Sheikh, Saleh; Athos, Brian; Kreis, Mark; Nuccitelli, Pamela

    2010-01-01

    We have identified a new, nanosecond pulsed electric field (nsPEF) therapy capable of eliminating murine melanomas located in the skin with a single treatment. When these optimized parameters are used, nsPEFs initiate apoptosis without hyperthermia. We have developed new suction electrodes that are compatible with human skin and have applied them to a xenograft nude mouse melanoma model system to identify the optimal field strength, pulse frequency and pulse number for the treatment of murine melanomas. A single treatment using the optimal pulse parameters (2000 pulses, 100 ns in duration, 30 kV/cm in amplitude at a pulse frequency of 5–7 pulses/s) eliminated all 17 melanomas treated with those parameters in 4 mice. This was the highest pulse frequency that we could use without raising the treated skin tumor temperature above 40 °C. We also demonstrate that the effects of nsPEF therapy are highly localized to only cells located between electrodes and results in very little scarring of the nsPEF-treated skin. PMID:20473857

  18. Isolation of tumorigenic circulating melanoma cells

    PubMed Central

    Ma, Jie; Lin, Jennifer Y.; Alloo, Allireza; Wilson, Brian J.; Schatton, Tobias; Zhan, Qian; Murphy, George F.; Waaga-Gasser, Ana-Maria; Gasser, Martin; Hodi, F. Stephen; Frank, Natasha Y.; Frank, Markus H.

    2010-01-01

    Circulating tumor cells (CTC) have been identified in several human malignancies, including malignant melanoma. However, whether melanoma CTC are tumorigenic and cause metastatic progression is currently unknown. Here we isolate for the first time viable tumorigenic melanoma CTC and demonstrate that this cell population is capable of metastasis formation in human-to-mouse xenotransplantation experiments. The presence of CTC among peripheral blood mononuclear cells (PBMC) of murine recipients of subcutaneous (s.c.) human melanoma xenografts could be detected based on mRNA expression for human GAPDH and/or ATP-binding cassette subfamily B member 5 (ABCB5), a marker of malignant melanoma-initiating cells previously shown to be associated with metastatic disease progression in human patients. ABCB5 expression could also be detected in PBMC preparations from human stage IV melanoma patients but not healthy controls. The detection of melanoma CTC in human-to-mouse s.c. tumor xenotransplantation models correlated significantly with pulmonary metastasis formation. Moreover, prospectively isolated CTC from murine recipients of s.c. melanoma xenografts were capable of primary tumor initiation and caused metastasis formation upon xenotransplantation to secondary murine NOD-scid IL2Rγnull recipients. Our results provide initial evidence that melanoma CTC are tumorigenic and demonstrate that CTC are capable of causing metastatic tumor progression. These findings suggest a need for CTC eradication to inhibit metastatic progression and provide a rationale for assessment of therapeutic responses of this tumorigenic cell population to promising emerging melanoma treatment modalities. PMID:20977885

  19. Upcoming strategies for the treatment of metastatic melanoma.

    PubMed

    Spagnolo, Francesco; Queirolo, Paola

    2012-04-01

    Prognosis for advanced and metastatic melanoma is poor, with a 5-year survival of 78, 59 and 40% for patients with stage IIIA, IIIB and IIIC, respectively, and a 1-year survival of 62% for M1a, 53% for M1b and 33% for M1c. The unsatisfactory results of actual standard therapies for metastatic melanoma highlight the need for effective new therapeutic strategies. Several drugs, including BRAF, KIT and MEK inhibitors, are currently being evaluated after promising data from Phase I and Phase II studies; Vemurafenib, a BRAF-inhibitor agent, has been approved by the Food and Drug Administration (FDA) for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation after a significant impact on both progression-free and overall survival was demonstrated compared with dacarbazine in a Phase III trial. Ipilimumab, an immunotherapeutic drug, has proven to be capable of inducing long-lasting responses and was approved for patients with advanced melanoma in first- and second-line treatment by the FDA and in second-line treatment by the European Medicines Agency. Furthermore, a significant survival benefit of the combination of ipilimumab with dacarbazine compared with dacarbazine alone for first-line treatment was reported. In the near future, patients with BRAF mutations could have the chance to benefit from treatment with BRAF inhibitors; patients harboring BRAF or NRAS mutations could be treated with MEK inhibitors; finally, the subgroup of patients with acral, mucosal or chronic sun-damaged melanoma harboring a KIT mutation could benefit from KIT inhibitors. Ipilimumab could become a standard treatment for metastatic melanoma, both as a single agent and in combination; its efficacy has been proven, and researchers should now address their efforts to understanding the predictive variables of response to treatment.

  20. Melanoma

    MedlinePlus

    ... flat or raised, large or small, light or dark, and can appear anywhere on our bodies. Sometimes, ... can still get melanoma even if they're dark skinned, young, and have no family history. Even ...

  1. Melanoma

    MedlinePlus

    ... the most important contributors to melanoma is ultraviolet (UV) sun damage. Cells that have been damaged — particularly ... red hair) multiple moles (typically, more than 25) UV exposure (whether from the sun or a tanning ...

  2. Melanoma

    MedlinePlus

    ... gls/pdf/melanoma.pdf . Accessed March 17, 2016. Review Date 1/31/2016 Updated by: Kevin Berman, ... PhD, Atlanta Center for Dermatologic Disease, Atlanta, GA. Review provided by VeriMed Healthcare Network. Also reviewed by ...

  3. Salmonella typhimurium A1-R targeting of a chemotherapy-resistant BRAF-V600E melanoma in a patient-derived orthotopic xenograft (PDOX) model is enhanced in combination with either vemurafenib or temozolomide.

    PubMed

    Kawaguchi, Kei; Igarashi, Kentaro; Murakami, Takashi; Kiyuna, Tasuku; Zhao, Ming; Zhang, Yong; Nelson, Scott D; Russell, Tara A; Dry, Sarah M; Singh, Arun S; Chmielowski, Bartosz; Li, Yunfeng; Unno, Michiaki; Eilber, Fritz C; Hoffman, Robert M

    2017-07-03

    A metastatic melanoma obtained from the right chest wall of a patient was previously established orthotopically in the right chest wall of nude mice as a patient-derived orthotopic xenograft (PDOX) model. We previously showed that the combination of tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) and chemotherapy was highly effective against the melanoma PDOX. In the present study, we investigated the mechanism of the high efficacy of this combination. Two weeks after implantation, 40 PDOX mouse models were randomized into 4 groups of 10 mice each: untreated control (n = 10); treated with S. typhimurium A1-R (5 × 10(7) CFU/100 μl, i.v., once a week for 2 weeks, n = 10); treated with temozolomide (TEM) (25 mg/kg, p.o. for 14 consecutive days) combined with S. typhimurium A1-R (5 × 10(7) CFU/100 μl, i.v., once a week for 2 weeks, n = 10); treated with vemurafenib (VEM) (30 mg/kg, p.o., for 14 consecutive days) combined with S. typhimurium A1-R (5 × 10(7) CFU/100 μl, i.v., once a week for 2 weeks) (n = 10). On day 14 from initiation, all treatments significantly inhibited tumor growth compared with untreated control (S. typhimurium A1-R: p < 0.01; TEM combined with S. typhimurium A1-R: p < 0.01; VEM combined with S. typhimurium A1-R: p < 0.01). Combination therapy with S. typhimurium A1-R was significantly more effective on tumor growth than S. typhimurium A1-R alone (with TEM: p < 0.01; with VEM: p < 0.01). Combination therapy significantly increased S. typhimurium A1-R tumor targeting alone (S. typhimurium A1-R + TEM: p < 0.01, S. typhimurium A1-R + VEM: p < 0.01), relative to S. typhimurium A1-R alone, respectively. In conclusion, chemotherapy drugs promoted targeting of S. typhimurium A1-R of melanoma, thereby enhancing efficacy against the melanoma PDOX.

  4. [Update on surgical treatment of primary and metastatic cutaneous melanoma].

    PubMed

    Zuluaga-Sepúlveda, María Alejandra; Arellano-Mendoza, Ivonne; Ocampo-Candiani, Jorge

    2016-01-01

    Melanoma is a common cutaneous tumour. It is of great importance due to its increasing incidence and aggressive behaviour, with metastasis to lymph nodes and internal organs. When suspecting melanoma, excisional biopsy should be performed to obtain complete histological information in order to determine the adverse factors such as ulceration, mitosis rate, and Breslow depth, which influence preoperative staging and provide data for sentinel lymph biopsy decision making. The indicated management for melanoma is wide local excision, observing recommended and well-established excision margins, depending on Breslow depth and anatomical location of the tumour. Therapeutic lymphadenectomy is recommended for patients with clinically or radiologically positive lymph nodes. This article reviews surgical treatment of melanoma, adverse histological factors, sentinel lymph node biopsy, and radical lymphadenectomy. Details are presented on special situations in which management of melanoma is different due to the anatomical location (plantar, subungual, lentigo maligna), or pregnancy. Copyright © 2015 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.

  5. First-line treatment of metastatic melanoma: role of nivolumab

    PubMed Central

    Force, Jeremy; Salama, April KS

    2017-01-01

    Historically, the median overall survival of metastatic melanoma patients was less than 1 year and long-term survivors were rare. Recent advances in therapies have dramatically shifted this landscape with increased survival rates and the real possibility that long-term disease control is achievable. Advances in immune modulators, including cytotoxic T-lymphocyte antigen-4 and programmed death-1 based treatments, have been an integral part of this success. In this article, we review previous and recent therapeutic developments for metastatic melanoma patients. We discuss advances in immunotherapy while focusing on the use of nivolumab alone and in combination with other agents, including ipilimumab in advanced melanoma. One major goal in melanoma research is to optimize combination strategies allowing for more patients to experience benefit while minimizing toxicity. A better understanding of the optimal sequencing, combinations, and mechanisms underlying the development of resistance may provide evidence for rational clinical trial designs of novel immunotherapy strategies in melanoma and other cancer subtypes. PMID:28243579

  6. Treatment of advanced melanoma with laser immunotherapy and ipilimumab.

    PubMed

    Naylor, Mark F; Zhou, Feifan; Geister, Brian V; Nordquist, Robert E; Li, Xiaosong; Chen, Wei R

    2017-05-01

    Immunotherapy has become a promising modality for melanoma, especially using checkpoint inhibitors, which revive suppressed T cells against the cancer. Such inhibitors should work better when combined with other treatments which could increase the number and quality of anti-tumor T cells. We treated one patient with advanced (stage IV) melanoma, using the combination of laser immunotherapy (LIT), a novel immunological approach for metastatic cancers that has been shown to stimulate adaptive immunity, and ipilimumab. The patient was treated with LIT, followed with one course of ipilimumab 3 months after the beginning of LIT. After LIT treatment, all treated cutaneous melanoma in head and neck cleared completely. After the application of ipilimumab, all the tumor nodules in the lungs decreased. The patient had remained tumor free for one year. While anecdotal, the responses seen in this patient support the hypothesis that laser immunotherapy increases the number and quality of anti-tumor T cells so that ipilimumab and other checkpoint inhibitors are more effective in enhancing the therapeutic effects. Picture: Schematic of treatment using laser immunotherapy and ipilimumab on a stage IV melanoma patient. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Uveal melanoma: From diagnosis to treatment and the science in between.

    PubMed

    Chattopadhyay, Chandrani; Kim, Dae Won; Gombos, Dan S; Oba, Junna; Qin, Yong; Williams, Michelle D; Esmaeli, Bita; Grimm, Elizabeth A; Wargo, Jennifer A; Woodman, Scott E; Patel, Sapna P

    2016-08-01

    Melanomas of the choroid, ciliary body, and iris of the eye are collectively known as uveal melanomas. These cancers represent 5% of all melanoma diagnoses in the United States, and their age-adjusted risk is 5 per 1 million population. These less frequent melanomas are dissimilar to their more common cutaneous melanoma relative, with differing risk factors, primary treatment, anatomic spread, molecular changes, and responses to systemic therapy. Once uveal melanoma becomes metastatic, therapy options are limited and are often extrapolated from cutaneous melanoma therapies despite the routine exclusion of patients with uveal melanoma from clinical trials. Clinical trials directed at uveal melanoma have been completed or are in progress, and data from these well designed investigations will help guide future directions in this orphan disease. Cancer 2016;122:2299-2312. © 2016 American Cancer Society. © 2016 American Cancer Society.

  8. Core Endoresection as Neoadjuvant Treatment of Uveal Melanoma

    PubMed Central

    Rospond-Kubiak, Iwona; Groenewald, Carl; Coupland, Sarah E.; Damato, Bertil

    2015-01-01

    Aim To present a case of neoadjuvant treatment of uveal melanoma with a limited core endoresection, which enabled ruthenium plaque radiotherapy to be administered. Material and Methods A 77-year-old woman presented in 2005 with a ciliochoroidal uveal melanoma measuring 7.2 by 6.5 mm basally with a thickness of 6.2 mm. The vision in the affected eye was 6/9. Because of diagnostic uncertainty, we performed a biopsy, which produced a copious sample. The biopsy serendipitously reduced the tumour thickness to 4.4 mm, making ruthenium plaque brachytherapy possible. Results Histopathological examination showed the tumour to be a melanoma predominantly of spindle cell type. Postoperative complications included a dense vitreous haemorrhage, which cleared spontaneously, and raised intraocular pressure, controlled with latanoprost. Seven years after brachytherapy, the vision was 6/5 and the thickness of the residual tumour was 2.5 mm. Nine years after treatment, there was no evidence of any intra- or extraocular seeding or distant metastases. Conclusions Core endoresection of a ciliochoroidal melanoma may reduce tumour thickness enough to allow subsequent ruthenium plaque radiotherapy. PMID:27171344

  9. Drug Combinations as the New Standard for Melanoma Treatment.

    PubMed

    Polkowska, Marta; Czepielewska, Edyta; Kozłowska-Wojciechowska, Małgorzata

    2016-12-01

    Advanced melanoma is related to a very grim prognosis and fast progression. Until recently, there has been no indicated treatment that would affect the disease's outcome. However, the progress in immunotherapy and molecular therapy has significantly changed the unfavourable prognosis of melanoma progression and its short survival rate. Both approaches have improved patients' outcomes and provided renewed hope for successful treatment. Moreover, in order to further enhance patients' outcomes and to avoid mechanisms of tumour resistance, investigators attempted a combined approach. Targeted therapy combinations allowed a better response rate and progression-free survival than monotherapy with one of the agents. Another promising combination, but with limiting toxicities, is a concurrent immuno- and molecular-targeted therapy. It is suspected that complimentary usage of these drugs may lead to synergism, providing robust and quick tumour responses as well as long-lasting effects. Results of currently ongoing clinical trials that investigate combination strategies in melanoma are expected to provide more mature data about the effectiveness and the safety profile of those therapies. Until more robust results of these studies occur, the best management of advanced and metastatic melanoma is immunotherapy with anti-PD1 drugs or targeted therapy with concomitant BRAF and MEK inhibitor. However, which of these two options should be used first is still under discussion.

  10. Transperitoneal laparoscopical iliac lymphadenectomy for treatment of malignant melanoma.

    PubMed

    Picciotto, F; Volpi, E; Zaccagna, A; Siatis, D

    2003-10-01

    Current treatment for melanoma of the lower limb includes excision of the primary tumor with ilioinguinal lymphadenectomy in the case of lymph node metastases. The standard surgical approach includes sectioning of the inguinal ligament to gain access to the iliac nodes. More recently, some authors have reported that extraperitoneal laparoscopically assisted ilioinguinal lymphadenectomy for the treatment of malignant melanoma is feasible and less aggressive than standard open surgery. So far, no publications have described transperitoneal laparoscopic iliac lymphadenectomy (TPLND). From November 2001 to June 2002, 13 patients with ilioinguinal node melanoma metastases underwent TPLND (stage IIIA in 1 case, IIIB in 5 cases, IIIC in 4 cases, and IV in 3 cases). In all 13 cases, the TPLND and groin dissection was performed correctly. Operative time, intra- and postoperative complications, number of lymph nodes retrieved, immediate morbidity, hospital stay, and feasibility of TPLND were evaluated. This study was conducted to evaluate the feasibility and the preliminary results of TPLND used to manage malignant melanoma of the lower limb. This approach has many advantages over the traditional procedure: less surgical trauma, no incision of the abdominal muscles or the inguinal ligament, and less postoperative pain. Moreover, as compared with extraperitoneal laparoscopically assisted ilioinguinal lymphoadenectomy, it provides an improved view of the operative area, dissection zone, and surrounding structures. Further research is needed to confirm these preliminary results regarding the potential applications of this method for treating malignant metastasis to the lower limb.

  11. Dabrafenib and its potential for the treatment of metastatic melanoma

    PubMed Central

    Menzies, Alexander M; Long, Georgina V; Murali, Rajmohan

    2012-01-01

    The purpose of this study is to review the development of BRAF inhibitors, with emphasis on the trials conducted with dabrafenib (GSK2118436) and the evolving role of dabrafenib in treatment for melanoma patients. Fifty percent of cutaneous melanomas have mutations in BRAF, resulting in elevated activity of the mitogen-activated protein kinase signaling pathway. Dabrafenib inhibits the mutant BRAF (BRAFmut) protein in melanomas with BRAFV600E and BRAFV600K genotypes. BRAFV600E metastatic melanoma patients who receive dabrafenib treatment exhibit high clinical response rates and compared with dacarbazine chemotherapy, progression-free survival. Efficacy has also been demonstrated in BRAFV600K patients and in those with brain metastases. Dabrafenib has a generally mild and manageable toxicity profile. Cutaneous squamous cell carcinomas and pyrexia are the most significant adverse effects. Dabrafenib appears similar to vemurafenib with regard to efficacy but it is associated with less toxicity. It is expected that new combinations of targeted drugs, such as the combination of dabrafenib and trametinib (GSK1120212, a MEK inhibitor), will provide higher response rates and more durable clinical benefit than dabrafenib monotherapy. PMID:23251089

  12. Carbon nanotubes in the diagnosis and treatment of malignant melanoma.

    PubMed

    Naderi, Naghmeh; Madani, Seyed Y; Ferguson, Elaine; Mosahebi, Afshin; Seifalian, Alexander M

    2013-01-01

    The potential role of carbon nanotubes (CNTs) in the diagnosis and treatment of malignant melanoma (MM) is still an emerging area of research. To date, there is strong evidence for the efficiency of CNTs in this therapeutic area, despite their unique physical, mechanical and biological properties. In this review, the application of CNTs in cancer diagnostics and treatment is reviewed, and consideration is given to the toxicity issues associated with their use.

  13. What Is New in Melanoma Genetics and Treatment?

    PubMed

    Ribero, Simone; Longo, Caterina; Glass, Dan; Nathan, Paul; Bataille, Veronique

    2016-01-01

    New therapies for advanced melanoma have led to major advances, which, for the first time, showed improved survival for patients with this very challenging neoplasm. These new treatments are based on gene-targeted therapies or stimulation of immune responses. However, these treatments are not without challenges in terms of resistance and toxicity. Physicians should be aware of these side effects as prompt treatment may save lives. Melanoma genetics is also unravelling new genetic risk factors involving telomere genes as well as new gene pathways at the somatic level which may soon become therapeutic targets. It is also shedding new light onto the pathology of this tumour with links to neural diseases and longevity. © 2016 S. Karger AG, Basel.

  14. Uveal Melanoma: From Diagnosis to Treatment and the Science in Between

    PubMed Central

    Chattopahdyay, Chandrani; Kim, Dae Won; Gombos, Dan; Oba, Junna; Qin, Yong; Williams, Michelle; Esmaeli, Bita; Grimm, Elizabeth; Wargo, Jennifer; Woodman, Scott; Patel, Sapna

    2017-01-01

    Melanomas of the choroid, ciliary body, and iris of the eye are collectively known as uveal melanomas. These cancers represent 5% of all melanoma diagnoses in the U.S., an age-adjusted risk of 5 per million. These less frequent melanomas are dissimilar to their more common cutaneous melanoma relative, with differing risk factors, primary treatment, anatomical spread, molecular changes, and responses to systemic therapy. Once metastatic, therapy options are limited, and often extrapolated from cutaneous melanoma therapies despite routine exclusion of uveal melanoma from clinical trials. Clinical trials directed at uveal melanoma have been completed or are in progress and data from these well-designed investigations will help guide future directions in this orphan disease. PMID:26991400

  15. Regional Treatment Strategies for In-transit Melanoma Metastasis

    PubMed Central

    Raymond, Amanda K.; Tyler, Douglas S.

    2010-01-01

    Synopsis For in-transit melanoma confined to the extremities, regional chemotherapy in the form of hyperthermic isolated limb perfusion and isolated limb infusion are effective treatment modalities carrying superior response rates to current standard systemic therapy. Despite high response rates, most patients will eventually recur, supporting the role for novel research aimed at improving durable responses and minimizing toxicity. Although the standard cytotoxic agent for regional chemotherapy is melphalan, alternative agents such as temozolomide are currently being tested with promising preliminary results. Current strategies for improving chemosensitivity to regional chemotherapy are aimed at overcoming classic resistance mechanisms such as drug metabolism and DNA repair, increasing drug delivery, inhibiting tumor-specific angiogenesis, and decreasing the apoptotic threshold of melanoma cells. Concurrent with development and testing of these agents, genomic profiling and biomolecular analysis of acquired tumor tissue may define patterns of tumor resistance and sensitivity from which personalized treatment may be tailored to optimize efficacy. Here, rational strategies for treatment of in-transit melanoma are outlined with special emphasis on current translational and clinical research efforts. PMID:21111960

  16. Highly efficient IL-21 and feeder cell-driven ex vivo expansion of human NK cells with therapeutic activity in a xenograft mouse model of melanoma.

    PubMed

    Granzin, Markus; Stojanovic, Ana; Miller, Matthias; Childs, Richard; Huppert, Volker; Cerwenka, Adelheid

    2016-01-01

    Natural killer (NK) cells are promising antitumor effector cells, but the generation of sufficient NK cell numbers for adoptive immunotherapy remains challenging. Therefore, we developed a method for highly efficient ex vivo expansion of human NK cells. Ex vivo expansion of NK cells in medium containing IL-2 and irradiated clinical-grade feeder cells (EBV-LCL) induced a 22-fold NK cell expansion after one week that was significantly increased to 53-fold by IL-21. Repeated stimulation with irradiated EBV-LCL and IL-2 and addition of IL-21 at the initiation of the culture allowed sustained NK cell proliferation with 10(11)-fold NK cell expansion after 6 weeks. Compared to naive NK cells, expanded NK cells upregulated TRAIL, NKG2D, and DNAM-1, had superior cytotoxicity against tumor cell lines in vitro and produced more IFNγ and TNF-α upon PMA/Iono stimulation. Most importantly, adoptive transfer of NK cells expanded using feeder cells, IL-2 and IL-21 led to significant inhibition of tumor growth in a melanoma xenograft mouse model, which was greater than with NK cells activated with IL-2 alone. Intriguingly, adoptively transferred NK cells maintained their enhanced production of IFNγ and TNF-α upon ex vivo restimulation, although they rapidly lost their capacity to degranulate and mediate tumor cytotoxicity after the in vivo transfer. In conclusion, we developed a protocol for ex vivo NK cell expansion that results in outstanding cell yields. The expanded NK cells possess potent antitumor activity in vitro and in vivo and could be utilized at high numbers for adoptive immunotherapy in the clinic.

  17. Highly efficient IL-21 and feeder cell-driven ex vivo expansion of human NK cells with therapeutic activity in a xenograft mouse model of melanoma

    PubMed Central

    Granzin, Markus; Stojanovic, Ana; Miller, Matthias; Childs, Richard; Huppert, Volker; Cerwenka, Adelheid

    2016-01-01

    ABSTRACT Natural killer (NK) cells are promising antitumor effector cells, but the generation of sufficient NK cell numbers for adoptive immunotherapy remains challenging. Therefore, we developed a method for highly efficient ex vivo expansion of human NK cells. Ex vivo expansion of NK cells in medium containing IL-2 and irradiated clinical-grade feeder cells (EBV-LCL) induced a 22-fold NK cell expansion after one week that was significantly increased to 53-fold by IL-21. Repeated stimulation with irradiated EBV-LCL and IL-2 and addition of IL-21 at the initiation of the culture allowed sustained NK cell proliferation with 1011-fold NK cell expansion after 6 weeks. Compared to naive NK cells, expanded NK cells upregulated TRAIL, NKG2D, and DNAM-1, had superior cytotoxicity against tumor cell lines in vitro and produced more IFNγ and TNF-α upon PMA/Iono stimulation. Most importantly, adoptive transfer of NK cells expanded using feeder cells, IL-2 and IL-21 led to significant inhibition of tumor growth in a melanoma xenograft mouse model, which was greater than with NK cells activated with IL-2 alone. Intriguingly, adoptively transferred NK cells maintained their enhanced production of IFNγ and TNF-α upon ex vivo restimulation, although they rapidly lost their capacity to degranulate and mediate tumor cytotoxicity after the in vivo transfer. In conclusion, we developed a protocol for ex vivo NK cell expansion that results in outstanding cell yields. The expanded NK cells possess potent antitumor activity in vitro and in vivo and could be utilized at high numbers for adoptive immunotherapy in the clinic. PMID:27757317

  18. Malignant melanoma: diagnosis, treatment and cancer stem cells.

    PubMed

    Kozovska, Z; Gabrisova, V; Kucerova, L

    2016-01-01

    Malignant melanoma represents a neoplasm stemming from melanocytes or the cells that develop from melanocytes. Melanocytes, pigment-producing cells, arise from the neural crest and migrate to their final destinations in the skin, uveal tract, meninges, and mucosa. Most melanocytes are found at the epidermal-dermal junction of the skin, and the vast majority of melanocytes arise from cutaneous sites. Cancerous growths develop when unrepaired DNA damage to skin cells (most often caused by ultraviolet radiation from sunshine or tanning beds) triggers mutations (genetic defects) that lead the skin cells to multiply rapidly and form malignant tumours. Malignant tumours consist of heterogeneous populations of tumour cells. Cancer stem cells (CSC) represent a population of cells within a tumour with highly tumorigenic and chemoresistant properties. These cells may be identified by the expression of CSC markers and also by functional assays as tumour-initiating properties in vivo, high aldehyde dehydrogenase activity tested by Aldefluor assay. There are several key stem cells markers specified for malignant melanoma: CD20, CD133, ABCB5, CD271 and ALDH1A. The review provides a detailed overview of risk factors, diagnosis, treatment possibilities and specific properties of cancer stem cells in malignant melanoma.

  19. The safety of nivolumab for the treatment of metastatic melanoma.

    PubMed

    O'Reilly, Aine; Larkin, James

    2017-08-01

    Nivolumab, a human IgG4 monoclonal antibody directed against PD-1, is a checkpoint inhibitor that is licenced in the treatment of metastatic melanoma either as a monotherapy or in combination with ipilimumab, a CTLA-4 inhibitor. The introduction of immune checkpoint inhibitors to the therapeutic landscape has dramatically altered outcomes in a proportion of patients with metastatic melanoma. Immune checkpoint inhibitors result in a toxicity profile that is distinct from that of chemotherapy or targeted therapy based on their immunomodulatory mechanism and similarly can result in patterns of response that are unique. Areas covered: Herein we will profile nivolumab's efficacy and safety both as a combination therapy and a monotherapy and discuss the results of relevant clinical trials in this respect. Expert opinion: The future of immunotherapy in melanoma will evolve around the development of biomarkers, the refinement of criteria to define patterns of response and toxicity and the combination of current immunotherapies with existing and novel agents to maximise responses.

  20. Dutch Melanoma Treatment Registry: Quality assurance in the care of patients with metastatic melanoma in the Netherlands.

    PubMed

    Jochems, Anouk; Schouwenburg, Maartje G; Leeneman, Brenda; Franken, Margreet G; van den Eertwegh, Alfons J M; Haanen, John B A G; Gelderblom, Hans; Uyl-de Groot, Carin A; Aarts, Maureen J B; van den Berkmortel, Franchette W P J; Blokx, Willeke A M; Cardous-Ubbink, Mathilde C; Groenewegen, Gerard; de Groot, Jan Willem B; Hospers, Geke A P; Kapiteijn, Ellen; Koornstra, Rutger H; Kruit, Wim H; Louwman, Marieke W; Piersma, Djura; van Rijn, Rozemarijn S; Ten Tije, Albert J; Vreugdenhil, Gerard; Wouters, Michel W J M; van der Hoeven, Jacobus J M

    2017-02-01

    In recent years, the treatment of metastatic melanoma has changed dramatically due to the development of immune checkpoint and mitogen-activated protein (MAP) kinase inhibitors. A population-based registry, the Dutch Melanoma Treatment Registry (DMTR), was set up in July 2013 to assure the safety and quality of melanoma care in the Netherlands. This article describes the design and objectives of the DMTR and presents some results of the first 2 years of registration. The DMTR documents detailed information on all Dutch patients with unresectable stage IIIc or IV melanoma. This includes tumour and patient characteristics, treatment patterns, clinical outcomes, quality of life, healthcare utilisation, informal care and productivity losses. These data are used for clinical auditing, increasing the transparency of melanoma care, providing insights into real-world cost-effectiveness and creating a platform for research. Within 1 year, all melanoma centres were participating in the DMTR. The quality performance indicators demonstrated that the BRAF inhibitors and ipilimumab have been safely introduced in the Netherlands with toxicity rates that were consistent with the phase III trials conducted. The median overall survival of patients treated with systemic therapy was 10.1 months (95% confidence interval [CI] 9.1-11.1) in the first registration year and 12.7 months (95% CI 11.6-13.7) in the second year. The DMTR is the first comprehensive multipurpose nationwide registry and its collaboration with all stakeholders involved in melanoma care reflects an integrative view of cancer management. In future, the DMTR will provide insights into challenging questions regarding the definition of possible subsets of patients who benefit most from the new drugs. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. A Formulation Study of 5-Aminolevulinic Encapsulated in DPPC Liposomes in Melanoma Treatment.

    PubMed

    Lin, Ming-Wei; Huang, Yaw-Bin; Chen, Chun-Lin; Wu, Pao-Chu; Chou, Chien-Ying; Wu, Ping-Ching; Hung, Shih-Ya

    2016-01-01

    Photodynamic therapy (PDT) is a widely used technique for epithelial skin cancer treatment. 5-aminolevulinic acid (5-ALA) is a drug currently used for PDT and is a hydrophilic molecule at its physiological pH, and this limits its capacity to cross the stratum corneum of skin. Since skin penetration is a key factor in the efficacy of topical 5-ALA-mediated PDT, numerous strategies have been proposed to improve skin penetration. Yet this problem is still ongoing. The results of a previous study showed a low rate of 5-ALA encapsulated in liposomes (5.7%) that were 400 nm in size. In the present study, we used 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes as vehicles and tested their delivery efficacy of 5-ALA-medicated PDT both in vitro and in vivo. Our data shows that 5-ALA encapsulated in 0.1 or 0.5% DPPC liposomes (5-ALA/DPPC) had a better encapsulated rate (15~16%) and were smaller in size (84~89 nm). We found the 5-ALA/DPPC formulation reduced cell viability, mitochondria membrane potential, and enhanced intracellular ROS accumulation as compared to 5-ALA alone in melanoma cells. Furthermore, the 5-ALA/DPPC formulation also had better skin penetration ability as compared to the 5-ALA in our ex vivo data by assaying 5-ALA converted into protoporphyrin IX (PpIX) in the skin of the mice that were experimented on. In melanoma xenograft models, 5-ALA/DPPC enhanced PpIX accumulation only in tumor tissue but not normal skin. In conclusion, we found DPPC liposomes to be good carriers for 5-ALA delivery and believe that they may prove useful in 5-ALA-mediated PDT in the future.

  2. A Formulation Study of 5-Aminolevulinic Encapsulated in DPPC Liposomes in Melanoma Treatment

    PubMed Central

    Lin, Ming-Wei; Huang, Yaw-Bin; Chen, Chun-Lin; Wu, Pao-Chu; Chou, Chien-Ying; Wu, Ping-Ching; Hung, Shih-Ya

    2016-01-01

    Photodynamic therapy (PDT) is a widely used technique for epithelial skin cancer treatment. 5-aminolevulinic acid (5-ALA) is a drug currently used for PDT and is a hydrophilic molecule at its physiological pH, and this limits its capacity to cross the stratum corneum of skin. Since skin penetration is a key factor in the efficacy of topical 5-ALA-mediated PDT, numerous strategies have been proposed to improve skin penetration. Yet this problem is still ongoing. The results of a previous study showed a low rate of 5-ALA encapsulated in liposomes (5.7%) that were 400 nm in size. In the present study, we used 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes as vehicles and tested their delivery efficacy of 5-ALA-medicated PDT both in vitro and in vivo. Our data shows that 5-ALA encapsulated in 0.1 or 0.5% DPPC liposomes (5-ALA/DPPC) had a better encapsulated rate (15~16%) and were smaller in size (84~89 nm). We found the 5-ALA/DPPC formulation reduced cell viability, mitochondria membrane potential, and enhanced intracellular ROS accumulation as compared to 5-ALA alone in melanoma cells. Furthermore, the 5-ALA/DPPC formulation also had better skin penetration ability as compared to the 5-ALA in our ex vivo data by assaying 5-ALA converted into protoporphyrin IX (PpIX) in the skin of the mice that were experimented on. In melanoma xenograft models, 5-ALA/DPPC enhanced PpIX accumulation only in tumor tissue but not normal skin. In conclusion, we found DPPC liposomes to be good carriers for 5-ALA delivery and believe that they may prove useful in 5-ALA-mediated PDT in the future. PMID:27429584

  3. Colony-stimulating factor-1 antisense treatment suppresses growth of human tumor xenografts in mice.

    PubMed

    Aharinejad, Seyedhossein; Abraham, Dietmar; Paulus, Patrick; Abri, Hojatollah; Hofmann, Michael; Grossschmidt, Karl; Schäfer, Romana; Stanley, E Richard; Hofbauer, Reinhold

    2002-09-15

    Matrix metalloproteinases (MMPs) foster cellular invasion by disrupting extracellular matrix barriers and thereby facilitate tumor development. MMPs are synthesized by both cancer cells and adjacent stromal cells, primarily macrophages. The production of macrophages is regulated by colony-stimulating factor-1 (CSF-1). Tissue CSF-1 expression increased significantly in embryonic and colon cancer xenografts. We, therefore, hypothesized that blocking CSF-1 may suppress tumor growth by decelerating macrophage-mediated extracellular matrix breakdown. Cells expressing CSF-1 and mice xenografted with CSF-1 receptor (c-fms)- and CSF-1-negative malignant human embryonic or colon cancer cells were treated with mouse CSF-1 antisense oligonucleotides. Two weeks of CSF-1 antisense treatment selectively down-regulated CSF-1 mRNA and protein tissue expression in tumor lysates. CSF-1 blockade suppressed the growth of embryonic tumors to dormant levels and the growth of the colon carcinoma by 50%. In addition, tumor vascularity and the expression of MMP-2 and angiogenic factors were reduced. Six-month survival was observed in colon carcinoma mice only after CSF-1 blockade, whereas controls were all dead at day 65. These results suggest that human embryonic and colon cancer cells up-regulate host CSF-1 and MMP-2 expression. Because the cancer cells used were CSF-1 negative, CSF-1 antisense targeted tumor stromal cell CSF-1 production. CSF-1 blockade could be a novel strategy in treatment of solid tumors.

  4. Bioinformatic Analysis of Gene Expression for Melanoma Treatment

    PubMed Central

    Kawakami, Akinori; Fisher, David E.

    2016-01-01

    Bioinformatic analysis of genome-wide gene expression allows us to characterize cells, including melanomas. Gene expression profiles have been generated in various stages of melanomas and analyzed by researchers in unique ways. Lauss et al. compared their melanoma subtypes with those of The Cancer Genome Atlas Network and found consistency between the two studies. PMID:27884291

  5. Immune Checkpoint Inhibitors for Treatment of Metastatic Melanoma of the Orbit and Ocular Adnexa.

    PubMed

    Ford, Joshua; Thuro, Bradley A; Thakar, Sudip; Hwu, Wen-Jen; Richani, Karina; Esmaeli, Bita

    Programmed cell death 1 (PD-1) inhibitors are members of a new class of drugs known as immune checkpoint inhibitors and have proven efficacy in the treatment of metastatic melanoma. Herein, the authors report the use of nivolumab and pembrolizumab, 2 recently Food and Drug Administration-approved PD-1 inhibitors, in 3 patients: 1 with metastatic conjunctival melanoma and 2 with metastatic cutaneous melanoma and orbital involvement. The patients' metastatic disease responded well to drug treatment. As of this writing, 2 patients have completed therapy and remain disease free at least 1 year after treatment completion; the other patient is still receiving treatment, and his orbital disease is responding. The authors herein describe the use of PD-1 inhibitors as a new alternative in the treatment of metastatic melanoma to the orbit or metastatic ocular adnexal melanomas in these clinical settings.

  6. Sox2 is not required for melanomagenesis, melanoma growth and melanoma metastasis in vivo.

    PubMed

    Cesarini, V; Guida, E; Todaro, F; Di Agostino, S; Tassinari, V; Nicolis, S; Favaro, R; Caporali, S; Lacal, P M; Botti, E; Costanzo, A; Rossi, P; Jannini, E A; Dolci, S

    2017-08-01

    Melanoma is a dangerous form of skin cancer derived from the malignant transformation of melanocytes. The transcription factor SOX2 is not expressed in melanocytes, however, it has been shown to be differentially expressed between benign nevi and malignant melanomas and to be essential for melanoma stem cell maintenance and expansion in vitro and in xenograft models. By using a mouse model in which BRaf(V600E) mutation cooperates with Pten loss to induce the development of metastatic melanoma, we investigated if Sox2 is required during the process of melanomagenesis, melanoma growth and metastasis and in the acquisition of resistance to BRAF inhibitors (BRAFi) treatments. We found that deletion of Sox2 specifically in Pten null and BRafV600E-expressing melanocytes did not prevent tumor formation and did not modify the temporal kinetics of melanoma occurrence compared to Sox2 wt mice. In addition, tumor growth was similar between Sox2 wt and Sox2 deleted (del) melanomas. By querying publicly available databases, we did not find statistically significant differences in SOX2 expression levels between benign nevi and melanomas, and analysis on two melanoma patient cohorts confirmed that Sox2 levels did not significantly change between primary and metastatic melanomas. Melanoma cell lines derived from both Sox2 genotypes showed a similar sensitivity to vemurafenib treatment and the same ability to develop vemurafenib resistance in long-term cultures. Development of vemurafenib resistance was not dependent on SOX2 expression also in human melanoma cell lines in vitro. Our findings exclude an oncogenic function for Sox2 during melanoma development and do not support a role for this transcription factor in the acquisition of resistance to BRAFi treatments.

  7. Current and emerging treatment options for uveal melanoma

    PubMed Central

    Pereira, Patricia Rusa; Odashiro, Alexandre Nakao; Lim, Li-Anne; Miyamoto, Cristina; Blanco, Paula L; Odashiro, Macanori; Maloney, Shawn; De Souza, Dominique F; Burnier, Miguel N

    2013-01-01

    Uveal melanoma (UM) is the most common primary malignant intraocular tumor in adults, with a 10-year cumulative metastatic rate of 34%. The most common site of metastasis is the liver (95%). Unfortunately, the current treatment of metastatic UM is limited by the lack of effective systemic therapy. Options for the management of the primary intraocular tumor include radical surgery as well as conservative treatments in order to preserve visual acuity. For metastatic disease, several approaches have been described with no standard method. Nevertheless, median survival after liver metastasis is poor, being around 4–6 months, with a 1-year survival of 10%–15%. In this review, the authors summarize current and promising new treatments for UM. PMID:24003303

  8. Diagnosis and treatment of in-transit melanoma metastases.

    PubMed

    Testori, A; Ribero, S; Bataille, V

    2017-03-01

    In transit metastases (ITM) from extremity or trunk melanomas are subcutaneous or cutaneous lymphatic deposits of melanoma cells, distant from the primary site but not reaching the draining nodal basin. Superficial ITM metastases develop in 5-10% of melanoma patients and are thought to be caused by cells spreading along lymphatics; ITM appear biologically different from distant cutaneous metastases, these probably due to a haematogenous dissemination. The diagnosis is usually clinical and by patients, but patients need to be adequately educated in the recognition of this clinical situation. Ultrasound or more sophisticated instrumental devices may be required if the disease develops more deeply in the soft tissues. According to AJCC 2009 staging classification, ITM are included in stages IIIb and IIIc, which are considered local advanced disease with quite poor 5-year survival rates and outcomes of 24-54% at 5 years.(2) Loco-regional recurrence is in fact an important risk factor for distant metastatic disease, either synchronous or metachronous. Therapy for this pattern of recurrence is less standardised then in most other clinical situations and options vary based on the volume and site of the disease. Definitive surgical resection remains the preferred therapeutic approach. However, when surgery cannot be performed with a reasonable cosmetic and functional outcome, other options must be utilized.(3-6) Treatment options are classified as local, regional or systemic. The choice of therapy depends on the number of lesions, their anatomic location, whether or not these are dermal or subcutaneous, the size and the presence or absence of extra-regional disease.

  9. In vitro and in vivo evaluation of resveratrol and 3,5-dihydroxy-4′-acetoxy-trans-stilbene in the treatment of human prostate carcinoma and melanoma

    PubMed Central

    Osmond, Gregory W.; Masko, Elizabeth M.; Tyler, Douglas S.; Freedland, Stephen J.; Pizzo, Salvatore

    2013-01-01

    Background Resveratrol (RESV) is a naturally occurring compound that may possess anti-cancer capabilities in both prostate carcinoma and melanoma. Methods The in vitro and in vivo cytotoxic activity of RESV and 3,5-dihydroxy-4′-acetoxy-trans-stilbene (4-ACE) was tested using cellular assays and a xenograft model. Five prostate carcinoma cell lines were used for in vitro evaluation. A melanoma cell line (Duke melanoma 738 [DM738]) and the prostate carcinoma line CWR22 were used for in vivo experiments. Mice were randomized to osmotic mini pumps with 200 μL of RESV (250 mg/mL), 4-ACE (335 mg/mL), or vehicle (50% dimethyl sulfoxide, 50% polyethylene glycol). Serum drug and metabolite levels were calculated by high-performance liquid chromatography with diode-array detection. Western blots were performed on treated tumors. Results were analyzed using a student’s t-test, analysis of variance, and the Mann–Whitney rank sum test. Results RESV and 4-ACE were cytotoxic in a time- and dose-dependent manner in all prostate carcinoma cell lines tested. Enhanced growth compared with controls was seen at the 24 h time point in four lines treated with RESV and two lines treated with 4-ACE (Ps < 0.048). In vivo, no difference in either tumor growth or postmortem tumor weight was detected in either DM738 (P = 0.555, P = 0.562) or CWR22 (P = 0.166, P = 0.811) xenografts treated with either drug. Serum drug levels did not correlate with tumor growth rates for any treatment group (all Ps > 0.11). Treated tumors demonstrated protein changes by western blot. Conclusion Although in vitro data were promising, RESV and 4-ACE have limited potential as single agents in the treatment of prostate carcinoma and melanoma. PMID:22482756

  10. Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug

    PubMed Central

    Sharpe, Martyn A.; Livingston, Andrew D.; Gist, Taylor L.; Ghosh, Pardip; Han, Junyan; Baskin, David S.

    2015-01-01

    The last major advance in the treatment of glioblastoma multiforme (GBM) was the introduction of temozolomide in 1999. Treatment with temozolomide following surgical debulking extends survival rate compared to radiotherapy and debulking alone. However, virtually all glioblastoma patients experience disease progression within 7 to 10 months. Although many salvage treatments, including bevacizumab, rechallenge with temozolomide, and other alkylating agents, have been evaluated, none of these clearly improves survival. Monoamine oxidase B (MAOB) is highly expressed in glioblastoma cell mitochondria, and mitochondrial function is intimately tied to treatment-resistant glioblastoma progression. These glioblastoma properties provide a strong rationale for pursuing a MAOB-selective pro-drug treatment approach that, upon drug activation, targets glioblastoma mitochondria, especially mitochondrial DNA. MP-MUS is the lead compound in a family of pro-drugs designed to treat GBM that is converted into the mature, mitochondria-targeting drug, P+-MUS, by MAOB. We show that MP-MUS can successfully kill primary gliomas in vitro and in vivo mouse xenograft models. PMID:26501110

  11. Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug.

    PubMed

    Sharpe, Martyn A; Livingston, Andrew D; Gist, Taylor L; Ghosh, Pardip; Han, Junyan; Baskin, David S

    2015-09-01

    The last major advance in the treatment of glioblastoma multiforme (GBM) was the introduction of temozolomide in 1999. Treatment with temozolomide following surgical debulking extends survival rate compared to radiotherapy and debulking alone. However, virtually all glioblastoma patients experience disease progression within 7 to 10 months. Although many salvage treatments, including bevacizumab, rechallenge with temozolomide, and other alkylating agents, have been evaluated, none of these clearly improves survival. Monoamine oxidase B (MAOB) is highly expressed in glioblastoma cell mitochondria, and mitochondrial function is intimately tied to treatment-resistant glioblastoma progression. These glioblastoma properties provide a strong rationale for pursuing a MAOB-selective pro-drug treatment approach that, upon drug activation, targets glioblastoma mitochondria, especially mitochondrial DNA. MP-MUS is the lead compound in a family of pro-drugs designed to treat GBM that is converted into the mature, mitochondria-targeting drug, P(+)-MUS, by MAOB. We show that MP-MUS can successfully kill primary gliomas in vitro and in vivo mouse xenograft models.

  12. Bioactive proanthocyanidins inhibit growth and induce apoptosis in human melanoma cells by decreasing the accumulation of β-catenin.

    PubMed

    Vaid, Mudit; Singh, Tripti; Prasad, Ram; Katiyar, Santosh K

    2016-02-01

    Melanoma is a highly aggressive form of skin cancer with poor survival rate. Aberrant activation of Wnt/β-catenin has been observed in nearly one-third of human melanoma cases thereby indicating that targeting Wnt/β-catenin signaling could be a promising strategy against melanoma development. In the present study, we determined chemotherapeutic effect of grape seed proanthocyanidins (GSPs) on the growth of melanoma cells and validated their protective effects in vivo using a xenograft mouse model, and assessed if β-catenin is the target of GSP chemotherapeutic effect. Our in vitro data show that treatment of A375 and Hs294t human melanoma cells with GSPs inhibit the growth of melanoma cells, which was associated with the reduction in the levels of β-catenin. Administration of dietary GSPs (0.2 and 0.5%, w/w) in supplementation with AIN76A control diet significantly inhibited the growth of melanoma tumor xenografts in nude mice. Furthermore, dietary GSPs inhibited the xenograft growth of Mel928 (β-catenin-activated), while did not inhibit the xenograft growth of Mel1011 (β-catenin-inactivated) cells. These observations were further verified by siRNA knockdown of β-catenin and forced overexpression of β-catenin in melanoma cells using a cell culture model.

  13. Mitotane effects in a H295R xenograft model of adjuvant treatment of adrenocortical cancer.

    PubMed

    Lindhe, O; Skogseid, B

    2010-09-01

    Adrenocortical cancer is one of the most aggressive endocrine malignancies. Growth through the capsule or accidental release of cancer cells during surgery frequently results in metastatic disease. We investigated the antitumoral effect of 2 adrenocorticolytic compounds, O, P'-DDD and MeSO2-DDE, in the adrenocortical cell line H295R both in vitro and as a xenograft model in vivo. H295R cells were injected s. c. in nude mice. O, P'-DDD, MeSO2-DDE, or oil (control) was administered i. p., either simultaneously with cell injection at day 0 (mimicking adjuvant treatment), or at day 48 (established tumors). Accumulation of PET tracers [ (11)C]methionine (MET), [ (11)C] metomidate (MTO), 2-deoxy-2-[ (18)F]fluoro-d-glucose (FDG), and [ (18)F]-l-tyrosine (FLT) in the aggregates were assessed +/- drug treatment in vitro. Tumor growth was significantly inhibited when O, P'-DDD was given at the same time as injection of tumor cells. No significant growth inhibition was observed after treatment with O, P'-DDD at day 48. A significant reduction in FLT uptake and an increased FDG uptake, compared to control, were observed following treatment with 15 microM O, P'-DDD (p<0.01) in vitro. MeSO2-DDE (15 microM) treatment gave rise to a reduced MET and an increased FLT uptake (p<0.01). Both compounds reduced the uptake of MTO compared to control (p<0.01). Treatment with O, P'-DDD simultaneously to inoculation of H295R cells in mice, imitating release of cells during surgery, gave a markedly better effect than treatment of established H295R tumors. We suggest that FLT may be a potential PET biomarker when assessing adrenocortical cancer treatment with O,P'-DDD. Further studies in humans are needed to investigate this.

  14. Alternative treatments for melanoma: targeting BCL-2 family members to de-bulk and kill cancer stem cells

    PubMed Central

    Mukherjee, Nabanita; Schwan, Josianna V.; Fujita, Mayumi; Norris, David A.; Shellman, Yiqun G.

    2015-01-01

    For the first time new treatments in melanoma have produced significant responses in advanced diseases, but 30–90% of melanoma patients do not respond or eventually relapse after the initial response to the current treatments. The resistance of these melanomas is likely due to tumor heterogeneity, which may be explained by models such as the stochastic, hierarchical, and phenotype-switching models. This review will discuss the recent advancements in targeting BCL-2 family members for cancer treatments, and how this approach can be applied as an alternative option to combat melanoma, and overcome melanoma relapse or resistance in current treatment regimens. PMID:25947358

  15. Review of melanoma antigens recognized by monoclonal antibodies (MAbs). Their functional significance and applications in diagnosis and treatment of melanoma.

    PubMed

    Hersey, P

    1985-04-01

    The introduction of monoclonal antibody techniques has led to a rapid advance in information concerning antigenic structures in melanoma cell membranes. These have been classified according to the extent of their expression on cells of other tissues, but it is evident that a more precise classification based on their biochemical nature is possible. Several monoclonal antibodies appear to define antigens restricted to melanoma cells and fetal tissues. Many antibodies recognize antigens shared with gliomas and nevi, whereas other groups can be defined which recognize antigens on melanocytes or other carcinomas. One of the commonly detected antigens was shown to be a high molecular weight (MW) proteoglycan which may be involved in reactions with other cells and the intercellular matrix. A second antigen was shown to be a ganglioside which may have receptor functions in cells. A third was shown to be a glycoprotein with iron transport functions. The latter antigen and the large MW proteoglycan have been a focus of attention for in vivo targeting studies in treatment and diagnosis. The ganglioside, large MW proteoglycan and a melanocarcinoma antigen may be detected in the circulation of patients and are being evaluated for monitoring of disease activity in patients with melanoma. Several monoclonals may be of value in histological evaluation of melanoma, e.g. diagnosis of preneoplastic lesions, metastatic lesions of unknown origin and identification of cell structures related to metastatic behaviour in the host. Further studies should help to define cellular structures recognized by the immune system in humans.

  16. Advances in the treatment of metastatic melanoma: new immunomodulatory agents.

    PubMed

    Sznol, Mario

    2012-04-01

    Antibodies targeting ligand-receptor interactions that control activation and function of immune cell subsets such as dendritic cells (DCs) and in particular T cells have shown substantial promise for the treatment of unresectable or metastatic melanoma. The furthest in development, the antagonist anti-CTLA-4 antibodies, which block a key negative regulator of T-cell activation, have been shown to produce durable clinical responses in a small subset of patients. One of these antibodies, ipilimumab, also prolonged overall survival in two randomized phase III studies, leading to regulatory approval for marketing by the US Food and Drug Administration (FDA). Consistent with its mechanism of action, the major adverse events from anti-CTLA4 stem from immune-mediated inflammatory reactions. Paradigms for the administration of anti-CTLA-4 and newer immunomodulatory agents have evolved to effectively manage the adverse events and also to consider unique patterns and kinetics of tumor response. Early clinical studies of another antagonist antibody, which blocks the co-inhibitory receptor PD-1 on activated T cells, also are showing promising activity in metastatic melanoma. The clinical efficacy of cancer vaccines, which in broad terms also includes intratumorally administered agents designed to increase tumor immunogenicity, is being investigated in ongoing phase III trials, and various new agents are in earlier development, including newer cytokines and T-cell or DC co-stimulatory antibodies, some of which have already demonstrated clinical activity in advanced disease. Current data suggest that focusing development on agents countering immune suppression in the tumor microenvironment or blocking regulatory checkpoints to T-cell activation may have the greatest clinical yield. Combinations of immunomodulatory agents also may improve clinical activity, although possibly at a cost of greater toxicity. A major challenge for the field will be to develop predictive biomarkers

  17. Optimal management and challenges in treatment of upper facial melanoma.

    PubMed

    Berdahl, John P; Pockaj, Barbara A; Gray, Richard J; Casey, William J; Woog, John J

    2006-12-01

    This study's purpose was to evaluate clinical and surgical outcomes in patients with upper facial melanoma. A sentinel lymph node (SLN) biopsy database review identified 43 patients receiving a diagnosis of upper facial melanoma between February 1997 and April 2005 at Mayo Clinic Arizona in Scottsdale. Patients underwent wide local excision (n = 40) or Mohs excision (n = 3) and SLN biopsy. Nine patients (21%) had positive margins requiring reexcision. SLN mapping identified the SLN in 39 patients (91%) and drainage to bilateral lymph node basins in 8 (21%). The SLN was positive for melanoma in 2 patients (5%). Recurrence in 33 patients with more than 1 year of follow-up (local in 5 [15%] and regional in 1 [3%]) was treated with salvage surgery; 1 patient developed metastatic disease. Two patients (5%) died, one of an unknown cause and the other of metastatic melanoma. We concluded that oncologic surgery can result in good local disease control in patients with upper facial melanoma.

  18. Precision, high dose radiotherapy: helium ion treatment of uveal melanoma

    SciTech Connect

    Saunders, W.M.; Char, D.H.; Quivey, J.M.; Castro, J.R.; Chen, G.T.Y.; Collier, J.M.; Cartigny, A.; Blakely, E.A.; Lyman, J.T.; Zink, S.R.

    1985-02-01

    The authors report on 75 patients with uveal melanoma who were treated by placing the Bragg peak of a helium ion beam over the tumor volume. The technique localizes the high dose region very tightly around the tumor volume. This allows critical structures, such as the optic disc and the macula, to be excluded from the high dose region as long as they are 3 to 4 mm away from the edge of the tumor. Careful attention to tumor localization, treatment planning, patient immobilization and treatment verification is required. With a mean follow-up of 22 months (3 to 60 months) the authors have had only five patients with a local recurrence, all of whom were salvaged with another treatment. Pretreatment visual acuity has generally been preserved as long as the tumor edge is at least 4 mm away from the macula and optic disc. The only serious complication to date has been an 18% incidence of neovascular glaucoma in the patients treated at our highest dose level. Clinical results and details of the technique are presented to illustrate potential clinical precision in administering high dose radiotherapy with charged particles such as helium ions or protons.

  19. Sustained delivery of cytarabine-loaded vesicular phospholipid gels for treatment of xenografted glioma.

    PubMed

    Qi, Na; Cai, Cuifang; Zhang, Wei; Niu, Yantao; Yang, Jingyu; Wang, Lihui; Tian, Bin; Liu, Xiaona; Lin, Xia; Zhang, Yu; Zhang, Yan; He, Haibing; Chen, Kang; Tang, Xing

    2014-09-10

    This study described the development of vesicular phospholipid gels (VPGs) for sustained delivery of cytarabine (Ara-C) for the treatment of xenografted glioma. Ara-C-loaded VPGs in the state of a semisolid phospholipid dispersion looked like numerous vesicles tightly packing together under the freeze-fracture electron microscopy (FF-TEM), their release profiles displayed sustained drug release up to 384 h in vitro. The biodistribution of Ara-C in the rat brain showed that Ara-C-loaded VPGs could maintain therapeutic concentrations up to 5mm distance from the implantation site in brain tissue within 28 days. At the same time, fluorescence micrograph confirmed drug distribution in brain tissue visually. Furthermore, after single administration, Ara-C-loaded VPGs group significantly inhibited the U87-MG glioma growth in right flank in comparison with Ara-C solution (p<0.01). It was explained that the entrapped drug in VPGs could avoid degradation from cytidine deaminase and sustained release of drug from Ara-C-loaded VPGs could maintain the effective therapeutic levels for a long time around the tumor. In conclusion, Ara-C-loaded VPGs, with the properties of sustained release, high penetration capacity, nontoxicity and no shape restriction of the surgical cavity, are promising local delivery systems for post-surgical sustained chemotherapy against glioma.

  20. Use of Liposomes as Drug Delivery Vehicles for Treatment of Melanoma

    PubMed Central

    Tran, Melissa A.; Watts, Rebecca J.; Robertson, Gavin P.

    2009-01-01

    Melanoma is a progressive disease that claims many lives each year due to lack of therapeutics effective for the long-term treatment of patients. Currently, the best treatment option is early detection followed by surgical removal. Better melanoma therapies that are effectively delivered to tumors with minimal toxicity for patients are urgently needed. Nanotechnologies provide one approach to encapsulate therapeutic agents leading to improvements in circulation time, enhanced tumor uptake, avoidance of the reticulo-endothelial system, and minimization of toxicity. Liposomes in particular are a promising nanotechnology that can be used for more effective delivery of therapeutic agents to treat melanoma. Liposomes delivering chemotherapies, siRNA, asODNs, DNA, and radioactive particles are just some of the promising new nanotechnology based therapies under development for the treatment of melanoma that are discussed in this review. PMID:19493316

  1. Uveal melanoma: epidemiology, etiology, and treatment of primary disease.

    PubMed

    Krantz, Benjamin A; Dave, Nikita; Komatsubara, Kimberly M; Marr, Brian P; Carvajal, Richard D

    2017-01-01

    Uveal melanoma (UM) is the most common intraocular malignancy and arises from melanocytes in the iris, ciliary body, or choroid. Early diagnosis and local treatment is crucial, as survival correlates with primary tumor size. However, approximately 50% of patients will develop metastatic disease with 6-12 months' survival from metastatic diagnosis. Genomic analyses have led to the development of gene-expression profiles that effectively predict metastatic progression; unfortunately, no adjuvant therapy has been shown to prolong survival to date. New insights into the molecular biology of UM have found frequent activating mutations in genes encoding for the G-protein α-subunit, GNAQ and GNA11, and improved understanding of the downstream signaling pathways MAPK, PI3K/Akt, and Hippo have afforded an array of new targets for treatment of this disease. Studies are under way with rationally developed regimens targeting these pathways, and novel agents are under development. We review the diagnosis, management, and surveillance of primary UM and the adjuvant therapy trials under way.

  2. Therapeutic vaccination for the treatment of malignant melanoma.

    PubMed

    Walden, Peter

    2007-01-01

    With increasing knowledge of tumor-associated antigens and T cell epitopes, and the mechanisms of induction and regulation of T-cellular immune responses, therapeutic vaccination is increasingly being explored as a treatment option for cancer. Several clinical cancer vaccination trials, the majority of them with melanoma patients, have demonstrated efficient induction of tumor-specific cellular immune responses in patients. However, these immune responses, in most cases, do not translate into clinical responses. The clinical response rates in these trials are relatively low. The most likely causes for the lack of correlation of immunological and clinical responsiveness are loss of antigenicity and immune suppression. Nonetheless, many patients in the vaccination trials have experienced extended survival compared to clinical experience. Therapeutic vaccination thus appears suited for maintenance therapy where cure is not possible and is an interesting option for adjuvant therapy after surgical tumor resection. While the clinical efficacy of vaccination is expected to be better for early-stage cancer, advancement of the treatment of advanced-stage disease will require combination with other therapeutic principles.

  3. Uveal melanoma: epidemiology, etiology, and treatment of primary disease

    PubMed Central

    Krantz, Benjamin A; Dave, Nikita; Komatsubara, Kimberly M; Marr, Brian P; Carvajal, Richard D

    2017-01-01

    Uveal melanoma (UM) is the most common intraocular malignancy and arises from melanocytes in the iris, ciliary body, or choroid. Early diagnosis and local treatment is crucial, as survival correlates with primary tumor size. However, approximately 50% of patients will develop metastatic disease with 6–12 months’ survival from metastatic diagnosis. Genomic analyses have led to the development of gene-expression profiles that effectively predict metastatic progression; unfortunately, no adjuvant therapy has been shown to prolong survival to date. New insights into the molecular biology of UM have found frequent activating mutations in genes encoding for the G-protein α-subunit, GNAQ and GNA11, and improved understanding of the downstream signaling pathways MAPK, PI3K/Akt, and Hippo have afforded an array of new targets for treatment of this disease. Studies are under way with rationally developed regimens targeting these pathways, and novel agents are under development. We review the diagnosis, management, and surveillance of primary UM and the adjuvant therapy trials under way. PMID:28203054

  4. Patient-Derived Xenograft Models to Improve Targeted Therapy in Epithelial Ovarian Cancer Treatment

    PubMed Central

    Scott, Clare L.; Becker, Marc A.; Haluska, Paul; Samimi, Goli

    2013-01-01

    Despite increasing evidence that precision therapy targeted to the molecular drivers of a cancer has the potential to improve clinical outcomes, high-grade epithelial ovarian cancer (OC) patients are currently treated without consideration of molecular phenotype, and predictive biomarkers that could better inform treatment remain unknown. Delivery of precision therapy requires improved integration of laboratory-based models and cutting-edge clinical research, with pre-clinical models predicting patient subsets that will benefit from a particular targeted therapeutic. Patient-derived xenografts (PDXs) are renewable tumor models engrafted in mice, generated from fresh human tumors without prior in vitro exposure. PDX models allow an invaluable assessment of tumor evolution and adaptive response to therapy. PDX models have been applied to pre-clinical drug testing and biomarker identification in a number of cancers including ovarian, pancreatic, breast, and prostate cancers. These models have been shown to be biologically stable and accurately reflect the patient tumor with regards to histopathology, gene expression, genetic mutations, and therapeutic response. However, pre-clinical analyses of molecularly annotated PDX models derived from high-grade serous ovarian cancer (HG-SOC) remain limited. In vivo response to conventional and/or targeted therapeutics has only been described for very small numbers of individual HG-SOC PDX in conjunction with sparse molecular annotation and patient outcome data. Recently, two consecutive panels of epithelial OC PDX correlate in vivo platinum response with molecular aberrations and source patient clinical outcomes. These studies underpin the value of PDX models to better direct chemotherapy and predict response to targeted therapy. Tumor heterogeneity, before and following treatment, as well as the importance of multiple molecular aberrations per individual tumor underscore some of the important issues addressed in PDX models

  5. Photodynamic therapy mediated by acai oil (Euterpe oleracea Martius) in nanoemulsion: A potential treatment for melanoma.

    PubMed

    Monge-Fuentes, Victoria; Muehlmann, Luis Alexandre; Longo, João Paulo Figueiró; Silva, Jaqueline Rodrigues; Fascineli, Maria Luiza; de Souza, Paulo; Faria, Fernando; Degterev, Igor Anatolievich; Rodriguez, Anselmo; Carneiro, Fabiana Pirani; Lucci, Carolina Madeira; Escobar, Patricia; Amorim, Rivadávio Fernandes Batista; Azevedo, Ricardo Bentes

    2017-01-01

    Melanoma is the most aggressive and lethal form of skin cancer, responsible for >80% of deaths. Standard treatments for late-stage melanoma usually present poor results, leading to life-threatening side effects and low overall survival. Thus, it is necessary to rethink treatment strategies and design new tools for the treatment of this disease. On that ground, we hereby report the use of acai oil in nanoemulsion (NanoA) as a novel photosensitizer for photodynamic therapy (PDT) used to treat melanoma in in vitro and in vivo experimental models. NIH/3T3 normal cells and B16F10 melanoma cell lines were treated with PDT and presented 85% cell death for melanoma cells, while maintaining high viability in normal cells. Flow cytometry indicated that cell death occurred by late apoptosis/necrosis. Tumor bearing C57BL/6 mice treated five times with PDT using acai oil in nanoemulsion showed tumor volume reduction of 82% in comparison to control/tumor group. Necrotic tissue per tumor area reached its highest value in PDT-treated mice, supporting PDT efficacy. Overall, acai oil in nanoemulsion was an effective photosensitizer, representing a promising source of new photosensitizing molecules for PDT treatment of melanoma, a tumor with an inherent tendency to be refractory for this type of therapy. Copyright © 2016. Published by Elsevier B.V.

  6. Both sunitinib and sorafenib are effective treatments for pheochromocytoma in a xenograft model.

    PubMed

    Denorme, M; Yon, L; Roux, C; Gonzalez, B J; Baudin, E; Anouar, Y; Dubessy, C

    2014-10-01

    Pheochromocytomas and paragangliomas are rare neuroendocrine tumors which develop from chromaffin cells of the adrenal medulla and extra-adrenal sites, leading to excess catecholamine release and hypertension. Many of the tumors are characterized by a high vascularity, suggesting the possible implementation of anti-angiogenic therapies for patients. Here, the efficacy of the tyrosine kinase inhibitors sunitinib and sorafenib was investigated in vivo and in vitro. Oral treatment with either sunitinib or sorafenib (40mg/kg/day) for 14days induced a marked reduction in the volume and weight of PC12 pheochromocytoma cell tumor xenografts in mice. Assessment of tumoral neo-angiogenesis, assessed by morphometric analysis of the vascular network after CD31 immunolabeling, showed that both sunitinib and sorafenib reduced the microvessel area (-85% and -80%, respectively) and length (-80% and -78%, respectively) in treated compared to control tumors. In addition, the number of vessel nodes was significantly lower in treated tumors (-95% and -84%, respectively). Furthermore, cleaved caspase 3 immunolabeling revealed a marked increase in the number of apoptotic cells in tumors from treated animals. Sunitinib and sorafenib could exert a direct effect on PC12 cell viability in vitro. While sunitinib induced a rapid (4h) and pronounced (5-fold) increase in caspase-3/7-dependent apoptosis, sorafenib seems to exert its cytotoxic activity through a different mechanism. Altogether, our data demonstrate that sunitinib and sorafenib have the ability to impair pheochromocytoma development by inhibiting angiogenesis and reducing tumor cell viability. These results strongly suggest that both sunitinib and sorafenib could represent valuable therapeutic tools for pheochromocytoma. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  7. Effects of aurothiomalate treatment on canine osteosarcoma in a murine xenograft model.

    PubMed

    Scharf, Valery F; Farese, James P; Siemann, Dietmar W; Abbott, Jeffrey R; Kiupel, Matti; Salute, Marc E; Milner, Rowan J

    2014-03-01

    Osteosarcoma is a highly fatal cancer, with most patients ultimately succumbing to metastatic disease. The purpose of this study was to evaluate the effects of the antirheumatoid drug aurothiomalate on canine and human osteosarcoma cells and on canine osteosarcoma growth and metastasis in a mouse xenograft model. We hypothesized that aurothiomalate would decrease osteosarcoma cell survival, tumor cellular proliferation, tumor growth, and metastasis. After performing clonogenic assays, aurothiomalate or a placebo was administered to 54 mice inoculated with canine osteosarcoma. Survival, tumor growth, embolization, metastasis, histopathology, cell proliferation marker Ki67, and apoptosis marker caspase-3 were compared between groups. Statistical analysis was carried out using the Kaplan-Meier method with the log-rank test and one-way analysis of variance with the Tukey's test or Dunn's method. Aurothiomalate caused dose-dependent inhibition of osteosarcoma cell survival (P<0.001) and decreased tumor growth (P<0.001). Pulmonary macrometastasis and Ki67 labeling were reduced with low-dose aurothiomalate (P=0.033 and 0.005, respectively), and tumor emboli and pulmonary micrometastases were decreased with high-dose aurothiomalate (P=0.010 and 0.011, respectively). There was no difference in survival, tumor development, ulceration, mitotic indices, tumor necrosis, nonpulmonary metastases, and caspase-3 labeling. Aurothiomalate treatment inhibited osteosarcoma cell survival and reduced tumor cell proliferation, growth, embolization, and pulmonary metastasis. Given aurothiomalate's established utility in canine and human medicine, our results suggest that this compound may hold promise as an adjunctive therapy for osteosarcoma. Further translational research is warranted to better characterize the dose response of canine and human osteosarcoma to aurothiomalate.

  8. [Dacarbazine, a chemotherapeutic against metastatic melanoma and a reference drug for new treatment modalities].

    PubMed

    Koprowska, Kamila; Czyż, Małgorzata

    2011-11-23

    Melanoma is a tumour derived from melanocytes, cells of neuroectodermal origin. Melanoma treatment represents a challenge to oncologists due to its aggressive course and early and multiple metastases. Surgical excision of lesions is a highly effective intervention, but only in early stages. In contrast, median survival of patients with metastatic melanoma is still below one year. In 2011 the FDA and EMA have approved new drugs, ipilimumab and vemurafenib, that might be a major breakthrough in treating patients with advanced melanoma. However, time is needed to conclude whether they replace dacarbazine, a drug used for over 30 years in the therapy of metastatic melanoma, even if the response rate was only 10-15%. The mechanism of dacarbazine action is not clear but it is probably based on methylation of purine bases in DNA. The low therapeutic efficacy of dacarbazine might be the consequence of rapid removal of DNA lesions by repair systems. A high melanoma chemoresistance is also driven by the extent and nature of alterations in signal transductions in tumour cells. None of the previously conducted trials proved superiority of any treatment modality over monotherapy with dacarbazine. Higher response rates did not correlate with survival benefit, and more intense adverse effects were frequently observed. There are some expectations for targeted therapy and immunotherapy, which have already demonstrated some efficacy in clinical studies. This review aims at providing the current knowledge on dacarbazine and its analogue, temozolomide, including the latest results of clinical studies combining these drugs with other treatment protocols.

  9. [Choroidal Melanoma].

    PubMed

    Coutinho, Inês; Teixeira, Tânia; Simões, Paulo César; Lopes, João Casalta; Borrego, Margarida; Fernandes, Júlia; Cabral, João; Prieto, Isabel; Proença, Rui

    2017-08-31

    Choroidal melanoma is the most common primary intraocular malignant tumor in adults. None of the different treatments available offers advantages of survival, resorting more and more to conservative treatments such as brachytherapy, which has been available in Portugal since 2013. In this article we review the clinical characteristics, risk factors, diagnosis, complementary exams and therapeutic options in choroidal melanoma.

  10. The impact of melanoma genetics on treatment response and resistance in clinical and experimental studies.

    PubMed

    Kunz, M; Hölzel, M

    2017-02-16

    Recent attempts to characterize the melanoma mutational landscape using high-throughput sequencing technologies have identified new genes and pathways involved in the molecular pathogenesis of melanoma. Apart from mutated BRAF, NRAS, and KIT, a series of new recurrently mutated candidate genes with impact on signaling pathways have been identified such as NF1, PTEN, IDH1, RAC1, ARID2, and TP53. Under targeted treatment using BRAF and MEK1/2 inhibitors either alone or in combination, a majority of patients experience recurrences, which are due to different genetic mechanisms such as gene amplifications of BRAF or NRAS, MEK1/2 and PI3K mutations. In principle, resistance mechanisms converge on two signaling pathways, MAPK and PI3K-AKT-mTOR pathways. Resistance may be due to small subsets of resistant cells within a heterogeneous tumor mass not identified by sequencing of the bulk tumor. Future sequencing studies addressing tumor heterogeneity, e.g., by using single-cell sequencing technology, will most likely improve this situation. Gene expression patterns of metastatic lesions were also shown to predict treatment response, e.g., a MITF-low/NF-κB-high melanoma phenotype is resistant against classical targeted therapies. Finally, more recent treatment approaches using checkpoint inhibitors directed against PD-1 and CTLA-4 are very effective in melanoma and other tumor entities. Here, the mutational and neoantigen load of melanoma lesions may help to predict treatment response. Taken together, the new sequencing, molecular, and bioinformatic technologies exploiting the melanoma genome for treatment decisions have significantly improved our understanding of melanoma pathogenesis, treatment response, and resistance for either targeted treatment or immune checkpoint blockade.

  11. Antiproliferative Effects of 1α-OH-vitD3 in Malignant Melanoma: Potential Therapeutic implications

    PubMed Central

    Spath, Lucia; Ulivieri, Alessandra; Lavra, Luca; Fidanza, Laura; Carlesimo, Marta; Giubettini, Maria; Narcisi, Alessandra; Luciani, Emidio; Bucci, Barbara; Pisani, Daniela; Sciacchitano, Salvatore; Bartolazzi, Armando

    2017-01-01

    Early detection and surgery represent the mainstay of treatment for superficial melanoma, but for high risk lesions (Breslow’s thickness >0.75 mm) an effective adjuvant therapy is lacking. Vitamin D insufficiency plays a relevant role in cancer biology. The biological effects of 1α hydroxycholecalciferol on experimental melanoma models were investigated. 105 melanoma patients were checked for 25-hydroxycholecalciferol (circulating vitamin D) serum levels. Human derived melanoma cell lines and in vivo xenografts were used for studying 1α-hydroxycholecalciferol-mediated biological effects on cell proliferation and tumor growth. 99 out of 105 (94%) melanoma patients had insufficient 25-hydroxycholecalciferol serum levels. Interestingly among the six with vitamin D in the normal range, five had a diagnosis of in situ/microinvasive melanoma. Treatment with 1α-hydroxycholecalciferol induced antiproliferative effects on melanoma cells in vitro and in vivo, modulating the expression of cell cycle key regulatory molecules. Cell cycle arrest in G1 or G2 phase was invariably observed in vitamin D treated melanoma cells. The antiproliferative activity induced by 1α-hydroxycholecalciferol in experimental melanoma models, together with the discovery of insufficient 25-hydroxycholecalciferol serum levels in melanoma patients, provide the rationale for using vitamin D in melanoma adjuvant therapy, alone or in association with other therapeutic options. PMID:28074906

  12. [Psychological aspects of immunotherapies in the treatment of malignant melanoma].

    PubMed

    Kovács, Péter; Pánczél, Gitta; Melegh, Krisztina; Balatoni, Tímea; Pörneczy, Edit; Lõrincz, Lenke; Czirbesz, Kata; Gorka, Eszter; Liszkay, Gabriella

    2016-03-02

    Psychological problems may arise in connection with oncomedical treatments in three ways: 1. acute and/or 2. chronic ways, as well as 3. co-morbid psychiatric diseases that already exist must also be taken into account. Immunotherapies have the most common and also clinically relevant psychological side effects. Fatigue, anhedonia, social isolation, psychomotor slowness is reported during treatment. Anti-CTLA-4 antibody (ipilimumab) immunotherapy can present one of the most modern opportunities for adequate treatment for patients having distant metastasis or unresectable tumour. In relation to immunotherapies, acute psychological side effects (acute stress) emerging during treatments develop in a way that can mostly be linked to environmental factors, e.g. notification of diagnosis, hospitalisation, progression, deterioration in quality of life, imminent dates of control. Crisis is a temporary and threatening condition that endangers psychological balance. In such conditions, enhanced psychological vulnerability must be taken into account and doctors play a key role in the rapid recognition of the condition. Chronic psychological problems, which may arise from the depressogenic effect of the applied treatment or originated from a pre-melanoma psychiatric condition, may exceed the diagnostic and psychotherapeutic competences of a clinical psychologist. Even in case of a well-defined depressogenic biological mechanism such as the activation of the pro-inflammatory cytokine pathway, positive environmental effects can reduce symptoms and thus increase compliance. Side effects can be treated successfully using psychotherapeutic methods and/or psychiatric medicines. The application of routinely used complex psychosocial screening packages can provide the easiest method to identify worsening psychological condition during immunotherapy and give rapid feedback to the oncologist and the patient. Team work is of particular importance in a situation like this as it requires

  13. Treatment of Pancreatic Cancer Patient-Derived Xenograft Panel with Metabolic Inhibitors Reveals Efficacy of Phenformin.

    PubMed

    Rajeshkumar, N V; Yabuuchi, Shinichi; Pai, Shweta G; De Oliveira, Elizabeth; Kamphorst, Jurre J; Rabinowitz, Joshua D; Tejero, Héctor; Al-Shahrour, Fátima; Hidalgo, Manuel; Maitra, Anirban; Dang, Chi V

    2017-09-15

    Purpose: To identify effective metabolic inhibitors to suppress the aggressive growth of pancreatic ductal adenocarcinoma (PDAC), we explored the in vivo antitumor efficacy of metabolic inhibitors, as single agents, in a panel of patient-derived PDAC xenograft models (PDX) and investigated whether genomic alterations of tumors correlate with the sensitivity to metabolic inhibitors.Experimental Design: Mice with established PDAC tumors from 6 to 13 individual PDXs were randomized and treated, once daily for 4 weeks, with either sterile PBS (vehicle) or the glutaminase inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES), transaminase inhibitor aminooxyacetate (AOA), pyruvate dehydrogenase kinase inhibitor dichloroacetate (DCA), autophagy inhibitor chloroquine (CQ), and mitochondrial complex I inhibitor phenformin/metformin.Results: Among the agents tested, phenformin showed significant tumor growth inhibition (>30% compared with vehicle) in 5 of 12 individual PDXs. Metformin, at a fivefold higher dose, displayed significant tumor growth inhibition in 3 of 12 PDXs similar to BPTES (2/8 PDXs) and DCA (2/6 PDXs). AOA and CQ had the lowest response rates. Gene set enrichment analysis conducted using the baseline gene expression profile of pancreatic tumors identified a gene expression signature that inversely correlated with phenformin sensitivity, which is in agreement with the phenformin gene expression signature of NIH Library of Integrated Network-based Cellular Signatures (LINCS). The PDXs that were more sensitive to phenformin showed a baseline reduction in amino acids and elevation in oxidized glutathione. There was no correlation between phenformin response and genetic alterations in KRAS, TP53, SMAD4, or PTENConclusions: Phenformin treatment showed relatively higher antitumor efficacy against established PDAC tumors, compared with the efficacy of other metabolic inhibitors and metformin. Phenformin treatment significantly diminished

  14. Monitoring Apoptosis of Breast Cancer Xenograft After Paclitaxel Treatment With 99mTc-Labeled Duramycin SPECT/CT.

    PubMed

    Luo, Rui; Niu, Lei; Qiu, Fan; Fang, Wei; Fu, Tong; Zhao, Ming; Zhang, Ying-Jian; Hua, Zi-Chun; Li, Xiao-Feng; Wang, Feng

    2016-01-01

    Our goal was to validate the feasibility of(99m)Tc-duramycin as a potential apoptosis probe for monitoring tumor response to paclitaxel in breast cancer xenografts. The binding of(99m)Tc-duramycin to phosphatidylethanolamine was validated in vitro using paclitaxel-treated human breast carcinoma MDA-MB-231 cells. Female BALB/c mice (n = 5) bearing breast cancer xenografts were randomized into 2 groups and intraperitoneally injected with 40 mg/kg paclitaxel or phosphate-buffered saline.(99m)Tc-duramycin (37-55.5 MBq) was injected at 72 hours posttreatment, and single-photon emission computed tomography/computed tomography was performed at 2 hours postinjection. Apoptotic cells and activated caspase 3 in explanted tumor tissue were measured by flow cytometry. Cellular ultrastructural changes were assessed by light and transmission electron microscopy.(99m)Tc-duramycin with radiochemical purity of >90% exhibited rapid blood clearance and predominantly renal clearance. The tumor-to-muscle ratio in the paclitaxel-treated group (5.29 ± 0.62) was significantly higher than that in the control. Tumor volume was decreased dramatically, whereas tumor uptake of(99m)Tc-duramycin (ex vivo) significantly increased following paclitaxel treatment, which was consistent with apoptotic index, histological findings, and ultrastructural changes. Our data demonstrated the feasibility of(99m)Tc-duramycin for early detection of apoptosis after paclitaxel chemotherapy in breast carcinoma xenografts. © The Author(s) 2016.

  15. Integrating first-line treatment options into clinical practice: what's new in advanced melanoma?

    PubMed

    Dummer, Reinhard; Schadendorf, Dirk; Ascierto, Paolo A; Larkin, James; Lebbé, Celeste; Hauschild, Axel

    2015-12-01

    Melanoma remains a serious form of skin cancer in Europe and worldwide. Localized, early-stage melanomas can usually be treated with surgical excision. However, the prognosis is poorer for patients with advanced disease. Before 2011, treatment for advanced melanoma included palliative surgery and/or radiotherapy, and chemotherapy with or without immunotherapy, such as interleukin-2. As none of these treatments had shown survival benefits in patients with advanced melanoma, European guidelines had recommended that patients be entered into clinical trials. The lack of approved first-line options and varying access to clinical trials meant that European clinicians relied on experimental regimens and chemotherapy-based treatments when no other options were available. Since 2011, ipilimumab, an immuno-oncology therapy, and vemurafenib and dabrafenib, targeted agents that inhibit mutant BRAF, have been approved by the European Medicines Agency for the treatment of advanced melanoma. More recently, the MEK inhibitor, trametinib, received European marketing authorization for use in patients with BRAF mutation-positive advanced melanoma. In 2014, the anti-PD-1 antibody nivolumab was approved as a first-line therapy in Japan. Whereas nivolumab and another anti-PD-1 antibody, pembrolizumab, were approved as second-line therapies in the USA, their recent approval in Europe are for first-line use based on new clinical trial data in this setting. Together these agents are changing clinical practice and making therapeutic decisions more complex. Here, we discuss current and emerging therapeutic options for the first-line treatment of advanced melanoma, and how these therapies can be optimized to provide the best possible outcomes for patients.

  16. The safety of talimogene laherparepvec for the treatment of advanced melanoma.

    PubMed

    Gangi, Alexandra; Zager, Jonathan S

    2017-02-01

    Talimogene laherparepvec (T-VEC, IMLYGIC) is an oncolytic herpes virus type I used as intralesional therapy for the treatment of unresectable metastatic melanoma in a cutaneous, subcutaneous, or nodal location. Talimogene laherparepvec selectively replicates within and lyses tumor cells while producing granulocyte macrophage colony-stimulating factor (GM-CSF), which may promote an immune mediated antitumor response. Areas covered: The US Food and Drug Administration approved Talimogene laherparepvec in late 2015 following the completion of phase I, II and III trials that demonstrated safety and efficacy. Current NCCN practice guidelines have added Talimogene laherparepvec as a primary treatment for stage IIIB/C and stage IVM1a melanoma patients with evidence of good durable response rates, and this article sets out to review the use and safety and efficacy of T-VEC Expert opinion: Treatment options for locally advanced and metastatic melanoma are expanding with new developments in immunotherapy and immune checkpoint inhibitors. The ideal treatment of metastatic melanoma continues to be multimodal, combining systemic treatments, intralesional and regional therapies, surgery and radiotherapy to achieve optimal outcomes. Use of talimogene laherparepvec as intrelsional therapy has demonstrated promising effects in select patients with advanced melanoma. Future directions for Talimogene laherparepvec include combination therapies with other systemic immunotherapies such as anti-CTLA-4 antibody and anti-PD-1 drugs.

  17. Advances in Personalized Targeted Treatment of Metastatic Melanoma and Non-Invasive Tumor Monitoring

    PubMed Central

    Klinac, Dragana; Gray, Elin S.; Millward, Michael; Ziman, Mel

    2013-01-01

    Despite extensive scientific progress in the melanoma field, treatment of advanced stage melanoma with chemotherapeutics and biotherapeutics has rarely provided response rates higher than 20%. In the past decade, targeted inhibitors have been developed for metastatic melanoma, leading to the advent of more personalized therapies of genetically characterized tumors. Here we review current melanoma treatments and emerging targeted molecular therapies. In particular we discuss the mutant BRAF inhibitors Vemurafenib and Dabrafenib, which markedly inhibit tumor growth and advance patients’ overall survival. However this response is almost inevitably followed by complete tumor relapse due to drug resistance hampering the encouraging initial responses. Several mechanisms of resistance within and outside the MAPK pathway have now been uncovered and have paved the way for clinical trials of combination therapies to try and overcome tumor relapse. It is apparent that personalized treatment management will be required in this new era of targeted treatment. Circulating tumor cells (CTCs) provide an easily accessible means of monitoring patient relapse and several new approaches are available for the molecular characterization of CTCs. Thus CTCs provide a monitoring tool to evaluate treatment efficacy and early detection of drug resistance in real time. We detail here how advances in the molecular analysis of CTCs may provide insight into new avenues of approaching therapeutic options that would benefit personalized melanoma management. PMID:23515890

  18. Local treatment failure after globe-conserving therapy for choroidal melanoma.

    PubMed

    Chang, Melinda Y; McCannel, Tara A

    2013-07-01

    Local treatment failure after globe-conserving therapy for choroidal melanoma is a surgical complication with significant morbidity to the vision and eye. Few reports in the literature have addressed this complication exclusively. A review of the published literature with reference to local treatment failure in the management of choroidal melanoma was performed to make known the potential differences in failure rates between treatment modalities and methods. A search of the literature regarding local treatment failure was performed to identify relevant studies using combinations of the following keywords on PubMed: uveal melanoma, choroidal melanoma, local recurrence, local failure, endoresection, gamma knife, radiotherapy, helium, iodine, proton, palladium, ruthenium, trans-scleral resection, transpupillary thermotherapy. Further studies were found by searching the text and references of previously identified studies for articles reporting local treatment failure rates in choroidal melanoma. Among the 49 studies identified, the local treatment failure rate ranged from 0% to 55.6%, with follow-up ranging from 10 to 150 months. The two most widely used forms of radiation therapy, iodine-125 and ruthenium-106 brachytherapy, were both associated with a local recurrence rate of 9.6%. The weighted-average of treatment failure in all radiation therapies was 6.15% compared with 18.6% in surgical and 20.8% in laser therapies. Rates of local treatment failure for globe-conserving therapy of choroidal melanoma varied widely between modalities and between centres using similar modalities. Radiation therapy overall resulted in lower local treatment failures compared with surgical or transpupillary thermotherapy.

  19. Circulating Melanoma Cell Subpopulations: Their Heterogeneity and Differential Responses to Treatment.

    PubMed

    Gray, Elin S; Reid, Anna L; Bowyer, Samantha; Calapre, Leslie; Siew, Kelvin; Pearce, Robert; Cowell, Lester; Frank, Markus H; Millward, Michael; Ziman, Mel

    2015-08-01

    Metastatic melanoma is a highly heterogeneous tumor; thus, methods to analyze tumor-derived cells circulating in blood should address this diversity. Taking this into account, we analyzed, using multiparametric flow cytometry, the co-expression of the melanoma markers melanoma cell adhesion molecule and melanoma-associated chondroitin sulphate proteoglycan and the tumor-initiating markers ATP-binding cassette sub-family B member 5 (ABCB5), CD271, and receptor activator of NF-κβ (RANK) in individual circulating tumor cells (CTCs) from 40 late-stage (III-IV) and 16 early-stage (I-II) melanoma patients. CTCs were heterogeneous within and between patients, with limited co-expression between the five markers analyzed. Analysis of patient matched blood and metastatic tumors revealed that ABCB5 and RANK subpopulations are more common among CTCs than in the solid tumors, suggesting a preferential selection for these cells in circulation. Pairwise comparison of CTC subpopulations longitudinally before and 6-13 weeks after treatment initiation showed that the percentage of RANK(+) CTCs significantly increased in the patients undergoing targeted therapy (N=16, P<0.01). Moreover, the presence of ⩾5 RANK(+) CTCs in the blood of patients undergoing targeted therapies was prognostic of shorter progression-free survival (hazards ratio 8.73, 95% confidence interval 1.82-41.75, P<0.01). Taken together, our results provide evidence of the heterogeneity among CTC subpopulations in melanoma and the differential response of these subpopulations to targeted therapy.

  20. Testing New Drugs for Treatment of Melanoma Patients Applying Connectivity Map Database Analysis with Melanoma Gene Signatures

    DTIC Science & Technology

    2012-10-01

    U133 Plus 2.0 Array; ii) GSE8401: 31 primary melanomas and 52 metastatic melanomas; Affymetrix Human Genome U133A Array; iii) GSE15605: 46 primary...melanomas, 12 regional and distal metastases, 16 normal skins; Affymetrix Human Genome U133 Plus 2.0 Array. Data analysis was executed through the

  1. Bovine xenograft application for treatment of a metatarsal nonunion fracture in an alpaca (Vicugna pacos).

    PubMed

    Longo, F; Finotti, L; Bellini, L; Zavan, B; Busetto, R; Isola, M

    2016-05-01

    A 15-year-old female huacaya alpaca (Vicugna pacos) was referred because of a non-weight-bearing lameness (4/4) in the left pelvic limb caused by a grade three open metatarsal fracture. The referring veterinarian treated the fracture with conservative management using bandages, but it progressively evolved to a non-union. Clinical examination revealed external wounds on the medial and lateral surfaces of the metatarsus. Radiographs confirmed an open, nonarticular, displaced, diaphyseal fracture of the left metatarsus. Cancellous bone was sourced from bovine proximal and distal femur epiphyses, followed by a thermal shock procedure to achieve decellularisation, to produce a xenograft. Open reduction and internal fixation of the fracture using locking plates was performed. Alignment of the fracture fragments was corrected and the xenograft was placed at the debrided fracture site to stimulate and harness osteogenesis in situ. Clinical and radiographic follow-up was performed up to 40 weeks postoperatively. Clinical evaluations revealed that the alpaca gradually increased weight bearing following bandage removal 10 days after surgery. Serial radiographs showed correct alignment of the left metatarsus, progressive bone modelling and, complete bone union at 12 weeks. Ten months postoperatively the alpaca showed no signs of lameness and resumed normal activity. For management of a metatarsal non-union, a combination of bovine xenograft application and angular stable internal fixation progressed toward an excellent long-term recovery.

  2. Variant G6PD levels promote tumor cell proliferation or apoptosis via the STAT3/5 pathway in the human melanoma xenograft mouse model

    PubMed Central

    2013-01-01

    Background Glucose-6-phosphate dehydrogenase (G6PD), elevated in tumor cells, catalyzes the first reaction in the pentose-phosphate pathway. The regulation mechanism of G6PD and pathological change in human melanoma growth remains unknown. Methods HEM (human epidermal melanocyte) cells and human melanoma cells with the wild-type G6PD gene (A375-WT), G6PD deficiency (A375-G6PD∆), G6PD cDNA overexpression (A375-G6PD∆-G6PD-WT), and mutant G6PD cDNA (A375-G6PD∆-G6PD-G487A) were subcutaneously injected into 5 groups of nude mice. Expressions of G6PD, STAT3, STAT5, cell cycle-related proteins, and apoptotic proteins as well as mechanistic exploration of STAT3/STAT5 were determined by quantitative real-time PCR (qRT-PCR), immunohistochemistry and western blot. Results Delayed formation and slowed growth were apparent in A375-G6PD∆ cells, compared to A375-WT cells. Significantly decreased G6PD expression and activity were observed in tumor tissues induced by A375-G6PD∆, along with down-regulated cell cycle proteins cyclin D1, cyclin E, p53, and S100A4. Apoptosis-inhibited factors Bcl-2 and Bcl-xl were up-regulated; however, apoptosis factor Fas was down-regulated, compared to A375-WT cells. Moderate protein expressions were observed in A375-G6PD∆-G6PD-WT and A375-G6PD∆-G6PD-G487A cells. Conclusions G6PD may regulate apoptosis and expression of cell cycle-related proteins through phosphorylation of transcription factors STAT3 and STAT5, thus mediating formation and growth of human melanoma cells. Further study will, however, be required to determine potential clinical applications. PMID:23693134

  3. MEK inhibitors and their potential in the treatment of advanced melanoma: the advantages of combination therapy.

    PubMed

    Tran, Khiem A; Cheng, Michelle Y; Mitra, Anupam; Ogawa, Hiromi; Shi, Vivian Y; Olney, Laura P; Kloxin, April M; Maverakis, Emanual

    2016-01-01

    The treatment of melanoma has improved markedly over the last several years with the advent of more targeted therapies. Unfortunately, complex compensation mechanisms, such as those of the mitogen-activated protein kinase (MAPK) pathway, have limited the clinical benefit of these treatments. Recently, a better understanding of melanoma resistance mechanisms has given way to intelligently designed multidrug regimes. Herein, we review the extensive pathways of BRAF inhibitor (vemurafenib and dabrafenib) resistance. We also review the advantages of dual therapy, including the addition of an MEK inhibitor (cobimetinib or trametinib), which has proven to increase progression-free survival when compared to BRAF inhibitor monotherapy. Finally, this review touches on future treatment strategies that are being developed for advanced melanoma, including the possibility of triple therapy with immune checkpoint inhibitors and the work on optimizing sequential therapy.

  4. Novel Drugs and Combination Therapies for the Treatment of Metastatic Melanoma

    PubMed Central

    Vennepureddy, Adarsh; Thumallapally, Nishitha; Motilal Nehru, Vijeyaluxmy; Atallah, Jean-Paul; Terjanian, Terenig

    2016-01-01

    Metastatic melanoma (MM) still remains as one of the most worrisome cancer known to mankind. In last two decades, treatment of melanoma took a dramatic turn with the discovery of targeted therapy which targets the mutations in mitogen-activated protein kinase (MAPK) pathway and immune checkpoint inhibitors. These new findings have led to emergence of many novel drugs that have been approved by FDA. Targeted therapy drugs such as vemurafenib, trametinib and dabrafenib target the MAPK pathway whereas immunotherapies such as ipilimumab, nivolumab and pembrolizumab block immune checkpoint receptors on T lymphocytes. All these drugs have shown to improve the overall survival in MM. Despite these recent discoveries, treatment of MM remains challenging because of rapid development of resistance to targeted therapy. This review will discuss recently approved drugs and their adverse effects and also shed light on combination therapy in treatment of melanoma. PMID:26767073

  5. Pre-clinical assessment of A-674563 as an anti-melanoma agent

    SciTech Connect

    Zou, Ying; Fan, Guobiao; Wang, Xuemin

    2016-08-12

    The present study aims to investigate the anti-melanoma activity by an Akt1 specific inhibitor A-674563. We showed that A-674563 was anti-proliferative and cytotoxic when added to human melanoma cells (A375, WM-115 and SK-Mel-2 lines). A-674563 induced caspase-dependent apoptotic death of human melanoma cells, and its cytotoxicity was inhibited with pre-treatment of caspase inhibitors. Further, A-674563 treatment blocked Akt and its downstream S6 Kinase 1 (S6K1) activation in A375 melanoma cells. Significantly, restoring Akt-S6K1 activation via introduction of constitutively-active Akt1 (ca-Akt1) only partially attenuated A-674563's cytotoxicity against A375 cells. Further, A-674563 induced pro-apoptotic ceramide production in A375 cells. Significantly, sphingosine-1-phosphate (S1P) inhibited A-674563-induced ceramide production and subsequent A375 cell apoptosis. On the other hand, co-treatment with the glucosylceramide synthase (GCS) inhibitor PDMP or the cell permeable short-chain ceramide (C6) potentiated A-674563's cytotoxicity against A375 cells. In vivo, A-674563 oral gavage inhibited A375 xenograft growth in severe combined immunodeficiency (scid) mice. Akt inactivation, caspase-3 activation and ceramide production were also observed in A-674563-treated A375 xenografts. Together, these results suggest that A-674563 exerts potent anti-melanoma activity, involving Akt-dependent and Akt-independent mechanisms. - Highlights: • A-674563 inhibits human melanoma cell survival and proliferation. • A-674563 induces melanoma cell apoptotic death, inhibited by caspase inhibitors. • A-674563 inhibits melanoma cells via Akt-dependent and -independent mechanisms. • A-674563 induces ceramide production in melanoma cells, independent of Akt inhibition. • A-674563 oral administration potently inhibits A375 xenograft growth in mice.

  6. Metastatic Melanoma: Insights Into the Evolution of the Treatments and Future Challenges.

    PubMed

    Millet, Antoine; Martin, Anthony R; Ronco, Cyril; Rocchi, Stéphane; Benhida, Rachid

    2017-01-01

    Melanoma is the deadliest form of skin cancer. While associated survival prognosis is good when diagnosed early, it dramatically drops when melanoma progresses into its metastatic form. Prior to 2011, the favored therapies include interleukin-2 and chemotherapies, regardless of their low efficiency and their toxicity. Following key biological findings, two new types of therapy have been approved. First, there are the targeted therapies, which rely on small molecule B-Raf and MEK inhibitors and allow the treatment of patients with B-Raf mutated melanoma. Second, there are the immunotherapies, with anti-CTLA-4 and anti-PD-1 antibodies that are used for patients harboring a B-Raf wild-type status. Both approaches have significantly improved patient survival, compared with alkylating agents, in the treatment of unresectable melanoma. Herein, we review the evolution of the treatment of melanoma starting from early discoveries to current therapies. A focus will be provided on drug discovery, synthesis, and mode of action of relevant drugs and the future directions of the domain to overcome the emergence of the resistance events. © 2016 Wiley Periodicals, Inc.

  7. Combining immunotherapy with oncogene-targeted therapy: a new road for melanoma treatment.

    PubMed

    Aris, Mariana; Barrio, María Marcela

    2015-01-01

    Cutaneous melanoma arises from the malignant transformation of skin melanocytes; its incidence and mortality have been increasing steadily over the last 50 years, now representing 3% of total tumors. Once melanoma metastasizes, prognosis is somber and therapeutic options are limited. However, the discovery of prevalent BRAF mutations in at least 50% of melanoma tumors led to development of BRAF-inhibitors, and other drugs targeting the MAPK pathway including MEK-inhibitors, are changing this reality. These recently approved treatments for metastatic melanoma have made a significant impact on patient survival; though the results are shadowed by the appearance of drug-resistance. Combination therapies provide a rational strategy to potentiate efficacy and potentially overcome resistance. Undoubtedly, the last decade has also born a renaissance of immunotherapy, and encouraging advances in metastatic melanoma treatment are illuminating the road. Immune checkpoint blockades, such as CTLA-4 antagonist-antibodies, and multiple cancer vaccines are now invaluable arms of anti-tumor therapy. Recent work has brought to light the delicate relationship between tumor biology and the immune system. Host immunity contributes to the anti-tumor activity of oncogene-targeted inhibitors within a complex network of cytokines and chemokines. Therefore, combining immunotherapy with oncogene-targeted drugs may be the key to melanoma control. Here, we review ongoing clinical studies of combination therapies using both oncogene inhibitors and immunotherapeutic strategies in melanoma patients. We will revisit the preclinical evidence that tested sequential and concurrent schemes in suitable animal models and formed the basis for the current trials. Finally, we will discuss potential future directions of the field.

  8. Combining Immunotherapy with Oncogene-Targeted Therapy: A New Road for Melanoma Treatment

    PubMed Central

    Aris, Mariana; Barrio, María Marcela

    2015-01-01

    Cutaneous melanoma arises from the malignant transformation of skin melanocytes; its incidence and mortality have been increasing steadily over the last 50 years, now representing 3% of total tumors. Once melanoma metastasizes, prognosis is somber and therapeutic options are limited. However, the discovery of prevalent BRAF mutations in at least 50% of melanoma tumors led to development of BRAF-inhibitors, and other drugs targeting the MAPK pathway including MEK-inhibitors, are changing this reality. These recently approved treatments for metastatic melanoma have made a significant impact on patient survival; though the results are shadowed by the appearance of drug-resistance. Combination therapies provide a rational strategy to potentiate efficacy and potentially overcome resistance. Undoubtedly, the last decade has also born a renaissance of immunotherapy, and encouraging advances in metastatic melanoma treatment are illuminating the road. Immune checkpoint blockades, such as CTLA-4 antagonist-antibodies, and multiple cancer vaccines are now invaluable arms of anti-tumor therapy. Recent work has brought to light the delicate relationship between tumor biology and the immune system. Host immunity contributes to the anti-tumor activity of oncogene-targeted inhibitors within a complex network of cytokines and chemokines. Therefore, combining immunotherapy with oncogene-targeted drugs may be the key to melanoma control. Here, we review ongoing clinical studies of combination therapies using both oncogene inhibitors and immunotherapeutic strategies in melanoma patients. We will revisit the preclinical evidence that tested sequential and concurrent schemes in suitable animal models and formed the basis for the current trials. Finally, we will discuss potential future directions of the field. PMID:25709607

  9. Ipilimumab Combined with Nivolumab: A Standard of Care for the Treatment of Advanced Melanoma?

    PubMed

    Carlino, Matteo S; Long, Georgina V

    2016-08-15

    Ipilimumab, an inhibitor of CTLA-4 on T cells, was the first drug to improve overall survival in patients with advanced melanoma. Subsequently, inhibitors of PD-1, including nivolumab and pembrolizumab, were shown to be superior to ipilimumab with a more favorable safety profile. The combination of ipilimumab and nivolumab is associated with a further improvement in response rate and progression-free survival; however, the combination is associated with an increased rate of immune-related toxicities. In 2015, the FDA approved the combination for the treatment of BRAF wild-type advanced melanoma. This review examines the preclinical rationale for the combination of ipilimumab and nivolumab as well as the efficacy and toxicity data from clinical trials in patients with advanced melanoma. Finally, alternative treatment options are discussed with a focus on patient selection. Clin Cancer Res; 22(16); 3992-8. ©2016 AACR. ©2016 American Association for Cancer Research.

  10. [Descriptive study of the costs of diagnosis and treatment of cutaneous melanoma].

    PubMed

    Almazán-Fernández, F M; Serrano-Ortega, S; Moreno-Villalonga, J J

    2009-11-01

    Every year, health expenditure in Spain increases and, with it, the resources dedicated to cancer treatment. Cutaneous melanoma is the skin cancer with the highest morbidity and mortality. We performed a descriptive study of the costs, based on a theoretical model, to determine the healthcare expenditure for patients with cutaneous melanoma; the objective was to define the overall costs (direct and indirect) of the diagnostic and treatment process of cutaneous melanoma, divided into different stages or diagnostic-therapeutic steps, and the possible variations in these costs. For this purpose, we used the Andalusian analytical accountancy program of hospitals and districts (COAN-hyd) and the total costs module of the COAN for 2007, applied to the protocol we use in the melanoma unit of our hospital. The most important conclusions were that the greatest health care expenditure was observed inpatients with more advanced melanomas, with a poor prognosis. Management of the diagnostic-therapeutic process by dermatologists, the appropriate use of complementary tests, and operations performed by dermatologists reduce costs.

  11. Curcumin and treatment of melanoma: The potential role of microRNAs.

    PubMed

    Lelli, Diana; Pedone, Claudio; Sahebkar, Amirhosssein

    2017-04-01

    Melanoma is the most aggressive type of skin cancer and is characterized by poor prognosis in its advanced stages because treatments are poorly effective and burdened with severe adverse effects. MicroRNAs (miRNAs) are small non-coding RNAs that are implicated in several cellular processes; they are categorized as oncogenic and tumor suppressor miRNAs. Several miRNAs are implicated in the pathogenesis and progression of melanoma, such as the tumor suppressor miR-let7b that targets cyclin D and regulates cell cycle. Curcumin is a natural compound derived from Curcuma longa L. (turmeric) with anti-cancer properties, documented also in melanoma, and is well tolerated in humans. Pharmacological activity of curcumin is mediated by modulation of several pathways, such as JAK-2/STAT3, thus inhibiting melanoma cell migration and invasion and enhancing apoptosis of these cells. The low oral bioavailability of curcumin has led to the development of curcumin analogues, such as EF24, with greater anti-tumor efficacy and metabolic stability. Potential anti-cancer activity of curcumin and its analogues is also mediated by modulation of miRNAs such as miR21, that is implicated in cell cycle regulation and apoptosis through down-regulation of PTEN and PDCD4 proteins. Curcumin has a potential role in the treatment of melanoma, though further studies are necessary to explore its clinical efficacy. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  12. ACUTE EXUDATIVE PARANEOPLASTIC POLYMORPHOUS VITELLIFORM MACULOPATHY DURING VEMURAFENIB AND PEMBROLIZUMAB TREATMENT FOR METASTATIC MELANOMA.

    PubMed

    Sandhu, Harpal S; Kolomeyer, Anton M; Lau, Marisa K; Shields, Carol L; Schuchter, Lynn M; Nichols, Charles W; Aleman, Tomas S

    2017-06-13

    To describe a patient with BRAF mutation-positive cutaneous melanoma who developed acute exudative polymorphous vitelliform maculopathy during vemurafenib and pembrolizumab treatment for metastatic melanoma. Retrospective case report documented with wide-field fundus imaging, spectral domain optical coherence tomography, and fundus autofluorescence imaging. A 55-year-old woman with bilateral ductal breast carcinoma and BRAF mutation-positive metastatic cutaneous melanoma complained of bilateral blurred vision within 5 days of starting vemurafenib (BRAF inhibitor). She had been on pembrolizumab (program death receptor antibody) and intermittently on dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor), and had a normal ophthalmologic examination. On presentation three weeks after the introduction of vemurafenib, her visual acuity had declined to 20/40 in both eyes. Her examination showed diffuse elevation of the fovea with multifocal yellow-white, crescent-shaped subretinal deposits within the macula of both eyes and bilateral neurosensory retinal detachments by spectral domain optical coherence tomography. Discontinuation of vemurafenib and introduction of difluprednate and dorzolamide led to a gradual resolution (over four months) of the neurosensory detachments with recovery of vision. This case report suggests that acute exudative polymorphous vitelliform maculopathy may be directly associated with the use of BRAF inhibitors as treatment for metastatic cutaneous melanoma, or indirectly by triggering autoimmune-paraneoplastic processes. Future identification of similar associations is required to unequivocally link vemurafenib and/or pembrolizumab to acute exudative polymorphous vitelliform maculopathy in metastatic melanoma.

  13. Perspectives on the application of nanotechnology in photodynamic therapy for the treatment of melanoma

    PubMed Central

    Monge-Fuentes, Victoria; Muehlmann, Luis Alexandre; de Azevedo, Ricardo Bentes

    2014-01-01

    Malignant melanoma is the most aggressive form of skin cancer and has been traditionally considered difficult to treat. The worldwide incidence of melanoma has been increasing faster than any other type of cancer. Early detection, surgery, and adjuvant therapy enable improved outcomes; nonetheless, the prognosis of metastatic melanoma remains poor. Several therapies have been investigated for the treatment of melanoma; however, current treatment options for patients with metastatic disease are limited and non-curative in the majority of cases. Photodynamic therapy (PDT) has been proposed as a promising minimally invasive therapeutic procedure that employs three essential elements to induce cell death: a photosensitizer, light of a specific wavelength, and molecular oxygen. However, classical PDT has shown some drawbacks that limit its clinical application. In view of this, the use of nanotechnology has been considered since it provides many tools that can be applied to PDT to circumvent these limitations and bring new perspectives for the application of this therapy for different types of diseases. On that ground, this review focuses on the potential use of developing nanotechnologies able to bring significant benefits for anticancer PDT, aiming to reach higher efficacy and safety for patients with malignant melanoma. PMID:25317253

  14. Subacute CNS Demyelination after Treatment with Nivolumab for Melanoma.

    PubMed

    Maurice, Catherine; Schneider, Raphael; Kiehl, Tim-Rasmus; Bavi, Prashant; Roehrl, Michael H A; Mason, Warren P; Hogg, David

    2015-12-01

    Immunotherapy with monoclonal antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) or programmed cell death 1 (PD-1) has improved the survival of patients with metastatic melanoma. These agents carry a certain risk of adverse immune-related events. We present a patient with widely metastatic melanoma who was initially treated with ipilimumab and subsequently with nivolumab. After four infusions of nivolumab, he developed subacute multifocal central nervous system (CNS) demyelination. Nivolumab was discontinued and, despite immunosuppressive therapy, the largest lesion progressed significantly, whereas another lesion showed radiographic improvement. After further progression, the patient succumbed to his CNS lesions 4 months later. Autopsy revealed extensive demyelination, a mild multifocal T-cell-rich perivascular lymphoid infiltrate, abundant macrophages, and necrosis. There was no metastatic melanoma in the brain. CNS demyelination has not been described in association with nivolumab. We hypothesize that the combination therapy of ipilimumab and subsequent nivolumab accounted for the severity of the demyelinating process in this patient. This case, with comprehensive clinical, molecular, and neuropathologic characterization, illustrates the need for awareness of these potential CNS complications with the use of multiple checkpoint inhibitors.

  15. Curcumin analog DM-1 in monotherapy or combinatory treatment with dacarbazine as a strategy to inhibit in vivo melanoma progression.

    PubMed

    Faião-Flores, Fernanda; Quincoces Suarez, José Agustín; Fruet, Andréa Costa; Maria-Engler, Silvya Stuchi; Pardi, Paulo Celso; Maria, Durvanei Augusto

    2015-01-01

    Malignant melanoma is a highly aggressive form of skin cancer with a high mortality rate if not discovered in early stages. Although a limited number of treatment options for melanoma currently exist, patients with a more aggressive form of this cancer frequently decline treatment. DM-1 is a sodium phenolate and curcumin analog with proven anticancer, anti-proliferative and anti-metastatic properties. In this paper, the DM-1 compound showed in vivo antitumor activity alone or in combination with chemotherapeutic DTIC in B16F10 melanoma-bearing mice. Beneficial effects such as melanoma tumor burden reduction with pyknotic nuclei, decreased nuclei/cytoplasmic ratio and nuclear degradation occurred after DM-1 treatment. No toxicological changes were observed in the liver, kidneys, spleen and lungs after DM-1 monotherapy or DTIC combined therapy. DTIC+DM-1 treatment induced the recovery of anemia arising from melanoma and immunomodulation. Both DM-1 treatment alone and in combination with DTIC induced apoptosis with the cleavage of caspase-3, -8 and -9. Furthermore, melanoma tumors treated with DM-1 showed a preferential apoptotic intrinsic pathway by decreasing Bcl-2/Bax ratio. Considering the chemoresistance exhibited by melanoma towards conventional chemotherapy drugs, DM-1 compound in monotherapy or in combination therapy provides a promising improvement in melanoma treatment with a reduction of side effects.

  16. Curcumin Analog DM-1 in Monotherapy or Combinatory Treatment with Dacarbazine as a Strategy to Inhibit In Vivo Melanoma Progression

    PubMed Central

    Faião-Flores, Fernanda; Quincoces Suarez, José Agustín; Fruet, Andréa Costa; Maria-Engler, Silvya Stuchi; Pardi, Paulo Celso; Maria, Durvanei Augusto

    2015-01-01

    Malignant melanoma is a highly aggressive form of skin cancer with a high mortality rate if not discovered in early stages. Although a limited number of treatment options for melanoma currently exist, patients with a more aggressive form of this cancer frequently decline treatment. DM-1 is a sodium phenolate and curcumin analog with proven anticancer, anti-proliferative and anti-metastatic properties. In this paper, the DM-1 compound showed in vivo antitumor activity alone or in combination with chemotherapeutic DTIC in B16F10 melanoma-bearing mice. Beneficial effects such as melanoma tumor burden reduction with pyknotic nuclei, decreased nuclei/cytoplasmic ratio and nuclear degradation occurred after DM-1 treatment. No toxicological changes were observed in the liver, kidneys, spleen and lungs after DM-1 monotherapy or DTIC combined therapy. DTIC+DM-1 treatment induced the recovery of anemia arising from melanoma and immunomodulation. Both DM-1 treatment alone and in combination with DTIC induced apoptosis with the cleavage of caspase-3, -8 and -9. Furthermore, melanoma tumors treated with DM-1 showed a preferential apoptotic intrinsic pathway by decreasing Bcl-2/Bax ratio. Considering the chemoresistance exhibited by melanoma towards conventional chemotherapy drugs, DM-1 compound in monotherapy or in combination therapy provides a promising improvement in melanoma treatment with a reduction of side effects. PMID:25742310

  17. Variability in melanoma post-treatment surveillance practices by country and physician specialty: a systematic review.

    PubMed

    Cromwell, Kate D; Ross, Merrick I; Xing, Yan; Gershenwald, Jeffrey E; Royal, Richard E; Lucci, Anthony; Lee, Jeffrey E; Cormier, Janice N

    2012-10-01

    There are no evidence-based guidelines for the surveillance of patients with melanoma following surgical treatment. We carried out a systematic review to identify by country and physician specialty the current stage-specific surveillance practices for patients with melanoma. Three major medical indices, MEDLINE, the Cochrane Library database, and Scopus, were reviewed to identify articles published from January 1970 to October 2011 that included detailed information about the surveillance of patients with melanoma after the initial surgical treatment. Data on surveillance intervals and recommended evaluation were extracted and categorized by country and, when reported, physician specialty. One hundred and four articles from 10 countries and four physician specialties (dermatology, surgical oncology, medical oncology, and general practice) fulfilled the inclusion criteria, including 43 providing specific patient-level data. The articles showed a wide variation with respect to the surveillance intervals and recommended evaluations. The variation was greatest for patients with stage I disease, for whom the follow-up frequency ranged from one to six visits per year during years 1 and 2 after treatment. All four physician specialties agreed that for years 1-3, the follow-up frequency should be four times per year for all patients. For years 4 and 5, surgical oncologists recommended two follow-up visits per year, whereas general practitioners, dermatologists, and medical oncologists recommended four visits per year. Recommended imaging and laboratory evaluations were most intense in the UK and most minimalist in the Netherlands. Although general practitioners did not recommend routine laboratory or imaging tests for surveillance, all other specialties utilized both in their surveillance practice. Self skin-examination was recommended for surveillance in all countries and by all practitioner specialties. There are significant intercountry and interspecialty variations in

  18. Successful treatment of metastatic malignant melanoma with Viscum album extract (Iscador M).

    PubMed

    Kirsch, Angelika

    2007-05-01

    Recent study results demonstrate possible clinical benefit from adjuvant treatment with a standardized mistletoe (Viscum album) extract in patients with malignant melanoma. We present a male patient, currently 68 years of age, with one malignant melanoma at the upper part of the right arm since 1992, and another nodular melanoma at the left shoulder, first diagnosed in 1999. After discovery of the second melanoma and surgical resection, the patient was exclusively treated with standardized mistletoe extract (Iscador, (R)M; Weleda AG, CH-Arlesheim, Switzerland). COURSE OF THERAPY AND RESULTS: In June 1992, histologic analysis confirmed the presence of stage IA superficially spreading malignant melanoma with low infiltration of the papillary dermis in a skin excision sample from the upper part of the right arm. In November 1999, another melanoma was surgically removed at the patient's right shoulder. In this case, the histologic examination revealed nodular melanoma, stage IIA (pT3, pN0, M0). Therapy with mistletoe extract was introduced shortly afterwards as the sole adjuvant treatment. During the course of the mistletoe therapy, axillary removal of 8 lymph nodes became necessary, 3 of which proved to be metastatic. First signs of a defined solitary liver metastasis in an area next to segments IV and V were detected during an abdominal ultrasound examination in September 2001. This finding was confirmed by further sonographic examinations. The solitary liver metastasis was not resected, nor was classical antitumor treatment (chemotherapy or radiotherapy) initiated. The patient continued subcutaneous treatment with Iscador M after dose adaptation to 2 mg twice weekly (0.2 mL of a 10-mg vial); the treatment is still ongoing to the present. By June 2002, complete remission of the liver metastasis was diagnosed by liver ultrasound examination. There has been no local relapse so far, and the patient has been in stable condition ever since. No further metastases were

  19. Gaining momentum: New options and opportunities for the treatment of advanced melanoma.

    PubMed

    Michielin, Olivier; Hoeller, Christoph

    2015-09-01

    Before 2011, patients with advanced or metastatic melanoma had a particularly poor long-term prognosis. Since traditional treatments failed to confer a survival benefit, patients were preferentially entered into clinical trials of investigational agents. A greater understanding of the epidemiology and biology of disease has underpinned the development of newer therapies, including six agents that have been approved in the EU, US and/or Japan: a cytotoxic T-lymphocyte antigen-4 inhibitor (ipilimumab), two programmed cell death-1 receptor inhibitors (nivolumab and pembrolizumab), two BRAF inhibitors (vemurafenib and dabrafenib) and a MEK inhibitor (trametinib). The availability of these treatments has greatly improved the outlook for patients with advanced melanoma; however, a major consideration for physicians is now to determine how best to integrate these agents into clinical practice. Therapeutic decisions are complicated by the need to consider patient and disease characteristics, and individual treatment goals, alongside the different efficacy and safety profiles of agents with varying mechanisms of action. Long-term survival, an outcome largely out of reach with traditional systemic therapies, is now a realistic goal, creating the additional need to re-establish how clinical benefit is evaluated. In this review we summarise the current treatment landscape in advanced melanoma and discuss the promise of agents still in development. We also speculate on the future of melanoma treatment and discuss how combination and sequencing approaches may be used to optimise patient care in the future.

  20. Current therapeutic leads for the treatment of melanoma: targeted immunotherapy in the post-genomic era.

    PubMed

    Papanastasiou, Anastasios D; Sirinian, Chaido; Kalofonos, Haralabos P; Repanti, Maria

    2014-01-01

    Metastatic melanoma has a poor prognosis and until today most therapeutic approaches are ineffective. Advances in molecular pathology and genome analysis technologies have led to the identification of genetic events and immune regulatory checkpoints that provide novel targets for pharmaceutical intervention in melanoma. Development of selective mitogen-activated kinase (MAPK) pathway inhibitors was the first major achievement coming from genetic studies that identified a constitutively active MAP kinase pathway and BRAF activating mutations in melanoma. At the same time, the manipulation of immune system checkpoints through monoclonal antibodies changed clinical practice and led to further improvement of patient outcomes. In an effort to further develop melanoma targeted therapies that depend on the genetic profile of a given patient, high-throughput genome wide approaches (next-generation sequencing [NGS], gene arrays, etc) have been employed for the characterization of genetic alterations in the patient's tumor. In the near future, the combined information from the genetic and immune background of an individual will provide the basis for a personalized, highly targeted approach in the treatment of melanoma.

  1. Brazilian guidelines for diagnosis, treatment and follow-up of primary cutaneous melanoma - Part II*

    PubMed Central

    Castro, Luiz Guilherme Martins; Bakos, Renato Marchiori; Duprat Neto, João Pedreira; Bittencourt, Flávia Vasques; Giacomo, Thais Helena Bello Di; Serpa, Sérgio Schrader; Messina, Maria Cristina de Lorenzo; Loureiro, Walter Refkalefsky; Macarenco, Ricardo Silvestre e Silva; Stolf, Hamilton Ometto; Gontijo, Gabriel

    2016-01-01

    The last Brazilian guidelines on melanoma were published in 2002. Development in diagnosis and treatment made updating necessary. The coordinators elaborated ten clinical questions, based on PICO system. A Medline search, according to specific MeSH terms for each of the 10 questions was performed and articles selected were classified from A to D according to level of scientific evidence. Based on the results, recommendations were defined and classified according to scientific strength. The present Guidelines were divided in two parts for editorial and publication reasons. In this second part, the following clinical questions were answered: 1) which patients with primary cutaneous melanoma benefit from sentinel lymph node biopsy? 2) Follow-up with body mapping is indicated for which patients? 3) Is preventive excision of acral nevi beneficious to patients? 4) Is preventive excision of giant congenital nevi beneficious to patients? 5) How should stages 0 and I primary cutaneous melanoma patients be followed? PMID:26982779

  2. Brazilian guidelines for diagnosis, treatment and follow-up of primary cutaneous melanoma - Part II.

    PubMed

    Castro, Luiz Guilherme Martins; Bakos, Renato Marchiori; Duprat Neto, João Pedreira; Bittencourt, Flávia Vasques; Di Giacomo, Thais Helena Bello; Serpa, Sérgio Schrader; Messina, Maria Cristina de Lorenzo; Loureiro, Walter Refkalefsky; Macarenco, Ricardo Silvestre e Silva; Stolf, Hamilton Ometto; Gontijo, Gabriel

    2016-01-01

    The last Brazilian guidelines on melanoma were published in 2002. Development in diagnosis and treatment made updating necessary. The coordinators elaborated ten clinical questions, based on PICO system. A Medline search, according to specific MeSH terms for each of the 10 questions was performed and articles selected were classified from A to D according to level of scientific evidence. Based on the results, recommendations were defined and classified according to scientific strength. The present Guidelines were divided in two parts for editorial and publication reasons. In this second part, the following clinical questions were answered: 1) which patients with primary cutaneous melanoma benefit from sentinel lymph node biopsy? 2) Follow-up with body mapping is indicated for which patients? 3) Is preventive excision of acral nevi beneficious to patients? 4) Is preventive excision of giant congenital nevi beneficious to patients? 5) How should stages 0 and I primary cutaneous melanoma patients be followed?

  3. Dabrafenib: a new opportunity for the treatment of BRAF V600-positive melanoma

    PubMed Central

    Banzi, Maria; De Blasio, Simona; Lallas, Aimilios; Longo, Caterina; Moscarella, Elvira; Alfano, Roberto; Argenziano, Giuseppe

    2016-01-01

    Prior to 2011, the 1-year survival rates for patients suffering from advanced or metastatic melanoma was as low as 33%, with a median overall survival of about 9 months. Several chemotherapeutic regimens have been applied, either as monochemotherapy or as polychemotherapy, overall not resulting in an improvement of progression-free or overall survival. Novel insights into the epidemiology and biology of melanoma allowed the development of newer therapies. The discovery of mutations in BRAF, a part of the mitogen-activated protein kinase, allowed the development of two BRAF inhibitors, vemurafenib and dabrafenib, which significantly improved the outcome of metastatic melanoma treatment. This article reviews the mechanism of action, efficacy, and safety profile of dabrafenib. An in-depth knowledge of this medication will encourage clinicians to select the appropriate therapeutic strategy for each patient, as well as to prevent or adequately manage side effects, optimizing, thus, the drug’s applicability. PMID:27226731

  4. A rat model for the treatment of melanoma metastatic to the brain by means of neutron capture therapy

    SciTech Connect

    Matalka, K.Z.; Bailey, M.Q.; Barth, R.F.; Staubus, A.E.; Adams, D.M.; Soloway, A.H.; James, S.M.; Goodman, J.H. ); Coderre, J.A.; Fairchild, R.G. ); Rofstad, E.K. )

    1991-01-01

    Melanoma metastatic to the brain is a serious clinical problem for which there currently is no satisfactory treatment. Boron neutron capture therapy (BNCT) has been shown by Mishima et al. to be clinically effective in the treatment of cutaneous melanoma using {sup 10}B-enriched boronophenylalaine (BPA) as the capture agent. In the present pilot study we have observed a significant prolongation in survival time of nude rats bearing intracerebral implants of the human melanoma cell line MRA 27 following administration of BPA and neutron irradiation. These findings suggest therapeutic efficacy, but unequivocal proof depends upon confirmation in a more definitive experiment using large numbers of animals with both solitary and multiple implants of melanoma. If our preliminary results are confirmed, then this will lay the groundwork for a clinical study of BNCT for the treatment of melanoma metastatic to the brain. 7 refs., 2 figs., 2 tabs.

  5. Label-free longitudinal monitoring of melanogenesis in the evolution of melanoma treatment resistance (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Osseiran, Sam; Wang, Hequn; Dutton-Regester, Ken; Garraway, Levi A.; Evans, Conor L.

    2017-02-01

    While melanoma is not the most common form of skin cancer, it represents the vast majority of skin cancer-related deaths. Indeed, while combination therapies such as Dabrafenib and Trametinib have shown great promise in clinical trials for treating metastatic disease, some melanoma subtypes nevertheless develop resistances to front-line treatments. Under in vitro conditions, some metastatic human melanoma cell lines have been observed to evolve resistance to treatment while simultaneously changing color under brightfield microscopy, hinting at perturbations in pigment synthesis. The process known as melanogenesis gives rise to the two forms of melanin found in mammals: eumelanin, a dark brown/black pigment, and pheomelanin, a much more pale red/blond pigment. Interestingly, pheomelanin has been shown to contribute to the onset and development of melanoma in an ultraviolet-radiation-independent manner through a mechanism of oxidative stress. Eumelanin, on the other hand, is a known antioxidant whose chemical properties seem to shield cells against oxidative damage. To study these pigments in closer detail, nonlinear optical microscopy including coherent anti-Stokes Raman scattering (CARS) was used for the specific visualization and quantification of the relative abundance of pheomelanin and eumelanin within these treatment resistant cell lines. These microscopy toolkits provide a means to monitor changes in pigmentation in a noninvasive and non-destructive manner without the use of exogenous dyes to better understand the molecular basis of treatment resistance.

  6. Dose De-Escalation With Gamma Knife Radiosurgery in the Treatment of Choroidal Melanoma

    SciTech Connect

    Schirmer, Clemens M.; Chan, Michael; Mignano, John; Duker, Jay; Melhus, Christopher S.; Williams, Lloyd B.; Wu, Julian K.; Yao, Kevin C.

    2009-09-01

    Purpose: Single-fraction targeted radiation therapy delivered by the Leksell Gamma Knife system is a minimally invasive treatment option for choroidal melanoma that has been used as an alternative to enucleation, proton beam therapy, or brachytherapy. Previously reported Gamma Knife series involved the treatment of choroidal melanomas with a dose of 40 to 50 Gy at the tumor margin. We report our institutional experience using a significantly lower dose. Methods and Materials: Fourteen patients with choroidal melanoma were treated with the Leksell Gamma Knife at our institution over a 7-year period. The treatment and clinical data were analyzed in a retrospective fashion after a mean follow-up of 32.2 months. Results: The mean dose to the tumor margin was 22.2 {+-} 2.4 Gy (range, 20- 25 Gy). Mean treated tumor volume was 1.1 {+-} 1.2 cc. Local control was achieved in 13 cases (93%). In 1 patient both intraocular spread and distant metastatic disease developed after treatment. Visual function of the affected eye was preserved in 5 patients (36%) at latest follow-up, in 9 patients (64%) visual loss ensued. Mild to moderate radiation toxicity developed in 8 patients. Conclusions: Choroidal melanoma can be safely and effectively treated using Leksell Gamma Knife stereotactic radiosurgery with a marginal dose of less than 25 Gy.

  7. Should high-dose interleukin-2 still be the preferred treatment for patients with metastatic melanoma?

    PubMed

    Dillman, Robert O; Barth, Neil M; VanderMolen, Louis A; Mahdavi, Khosrow; McClure, Stephanie E

    2012-08-01

    For more than 20 years interleukin-2 (IL2) was the preferred treatment for medically fit metastatic melanoma patients, but recently two new agents, ipilimumab and vemurafenib, were approved for stage IV disease. Single-institution data were used to determine the long-term survival rate for IL2-treated melanoma patients, and whether use of inpatient IL2 had declined recently. Between May 1987 and April 2010, 150 patients were hospitalized for high-dose, intravenous (i.v.) IL2. The average number of IL2 patients increased from 5.4 per year during 1987-1991 to 5.8 during 1992-1997 after regulatory approval of IL2, to 8.3 during 1998-2006 after a marketing indication in metastatic melanoma was granted, but dropped to 3.0 during 2007-2010. At the time of treatment, median age was 52 years; 27% were 60 years of age or older. At the time of analysis 122 patients were deceased. Median survival from the start date of IL2 treatment was 15.6 months, with a 20% 5-year survival. Among patients enrolled in clinical trials, there were as many nonresponders who survived 5 years as responders, which is consistent with a delayed immunotherapy benefit. In the absence of long-term survival data for these newer agents, IL2 probably should still be the preferred initial treatment for most patients with metastatic melanoma who are medically fit.

  8. Dabrafenib in the treatment of metastatic or unresectable melanoma.

    PubMed

    Khoja, Leila; Hogg, David

    2015-03-01

    Dabrafenib is a potent inhibitor of mutant BRAF. Trials to date have shown it to be well tolerated, with significant activity in unresectable stage III or IV metastatic melanoma. Overall response rates of approximately 50% were seen in addition to improved progression-free and overall survival of 6 and 18 months, respectively. Preclinical studies suggested that combining BRAF and MEK inhibition would increase response rates and decrease toxicity. Clinical trials with the combination of dabrafenib and trametinib have improved progression-free and overall survival in interim analyses. Future improvements in responses and outcomes will depend on additional combination strategies, possibly employing immunotherapy.

  9. [Choroidal melanoma].

    PubMed

    Desjardins, Laurence

    2016-03-01

    Choroidal melanoma is the most common form of eye cancer in adults. Treatments enabling the tumour to be destroyed or removed while preserving the eye socket are mainly based on surgery, proton therapy and brachytherapy.

  10. Current State of Animal (Mouse) Modeling in Melanoma Research

    PubMed Central

    Kuzu, Omer F.; Nguyen, Felix D.; Noory, Mohammad A.; Sharma, Arati

    2015-01-01

    Despite the considerable progress in understanding the biology of human cancer and technological advancement in drug discovery, treatment failure remains an inevitable outcome for most cancer patients with advanced diseases, including melanoma. Despite FDA-approved BRAF-targeted therapies for advanced stage melanoma showed a great deal of promise, development of rapid resistance limits the success. Hence, the overall success rate of melanoma therapy still remains to be one of the worst compared to other malignancies. Advancement of next-generation sequencing technology allowed better identification of alterations that trigger melanoma development. As development of successful therapies strongly depends on clinically relevant preclinical models, together with the new findings, more advanced melanoma models have been generated. In this article, besides traditional mouse models of melanoma, we will discuss recent ones, such as patient-derived tumor xenografts, topically inducible BRAF mouse model and RCAS/TVA-based model, and their advantages as well as limitations. Although mouse models of melanoma are often criticized as poor predictors of whether an experimental drug would be an effective treatment, development of new and more relevant models could circumvent this problem in the near future. PMID:26483610

  11. Tumor Sequencing and Patient-Derived Xenografts in the Neoadjuvant Treatment of Breast Cancer

    PubMed Central

    Kalari, Krishna R.; Suman, Vera J.; Moyer, Ann M.; Yu, Jia; Visscher, Daniel W.; Dockter, Travis J.; Vedell, Peter T.; Sinnwell, Jason P.; Tang, Xiaojia; Thompson, Kevin J.; McLaughlin, Sarah A.; Moreno-Aspitia, Alvaro; Copland, John A; Northfelt, Donald W.; Gray, Richard J.; Hunt, Katie; Conners, Amy; Weinshilboum, Richard; Wang, Liewei; Boughey, Judy C.

    2017-01-01

    Background: Breast cancer patients with residual disease after neoadjuvant chemotherapy (NAC) have increased recurrence risk. Molecular characterization, knowledge of NAC response, and simultaneous generation of patient-derived xenografts (PDXs) may accelerate drug development. However, the feasibility of this approach is unknown. Methods: We conducted a prospective study of 140 breast cancer patients treated with NAC and performed tumor and germline sequencing and generated patient-derived xenografts (PDXs) using core needle biopsies. Chemotherapy response was assessed at surgery. Results: Recurrent “targetable” alterations were not enriched in patients without pathologic complete response (pCR); however, upregulation of steroid receptor signaling and lower pCR rates (16.7%, 1/6) were observed in triple-negative breast cancer (TNBC) patients with luminal androgen receptor (LAR) vs basal subtypes (60.0%, 21/35). Within TNBC, TP53 mutation frequency (75.6%, 31/41) did not differ comparing basal (74.3%, 26/35) and LAR (83.3%, 5/6); however, TP53 stop-gain mutations were more common in basal (22.9%, 8/35) vs LAR (0.0%, 0/6), which was confirmed in The Cancer Genome Atlas and British Columbia data sets. In luminal B tumors, Ki-67 responses were observed in tumors that harbored mutations conferring endocrine resistance (p53, AKT, and IKBKE). PDX take rate (27.4%, 31/113) varied according to tumor subtype, and in a patient with progression on NAC, sequencing data informed drug selection (olaparib) with in vivo antitumor activity observed in the primary and resistant (postchemotherapy) PDXs. Conclusions: In this study, we demonstrate the feasibility of tumor sequencing and PDX generation in the NAC setting. “Targetable” alterations were not enriched in chemotherapy-resistant tumors; however, prioritization of drug testing based on sequence data may accelerate drug development. PMID:28376176

  12. [Breast lesions of a metastatic melanoma on a radiotherapy territory: Treatment by vemurafenib and carcinologic surgery].

    PubMed

    Fernandez, J; Montaudié, H; Courdi, A; Georgiou, C; Camuzard, O; Chignon-Sicard, B

    2016-02-01

    This article describes the unique case of a female patient who presented distant melanoma metastasis on the breast while having irradiation therapy for breast cancer. This happened eight months after the initial treatment for a melanoma of the back (under the right scapula). Furthermore, this case report demonstrates the efficiency of Vemurafenib® as a treatment for late stage melanomas. The patient was a 47-year-old female that had a superficial spreading melanoma under the right scapula (Breslow 1.02mm) that was treated with 2cm skin excision and sentinel lymph node sampling that was negative. The melanoma was positive for the BRAF600E mutation. One month after this incident, the patient developed breast cancer that was treated with conservative surgery and radiotherapy. Three months after the end of the irradiation treatment, she developed multiple melanoma metastasis on the skin of the breast. Our multidisciplinary team decided to initiate a treatment with vemurafenib. The patient showed an excellent response, so the surgical team completed the treatment with a radical mastectomy and immediate reconstruction with a pedicled latissimus dorsi flap. The histologic report of the mastectomy specimen showed no sign of melanocytic proliferation, that demonstrates the efficacy of vemurafenib. The patient showed no relapse after two years of follow-up. The speed of development and location of cutaneous metastases in this case brought us to think about the effects of radiation therapy on the skin. Radiation therapy causes acute complications (radiodermatitis) by cellular and molecular mechanisms. Moreover, depressed immunity is found after irradiation. Association of these mecanisms could explain the appearance of these metastases in irradiation field. The efficiency of vemurafenib found in our case is consistent with what is described in literature, especially with the improvement in median overall survival. This case demonstrates a unique case of distant melanoma

  13. Estimating healthcare resource use associated with the treatment of metastatic melanoma in eight countries.

    PubMed

    McKendrick, Jan; Gijsen, Merel; Quinn, Casey; Barber, Beth; Zhao, Zhongyun

    2016-06-01

    Objectives Studies reporting healthcare resourse use (HRU) for melanoma, one of the most costly cancers to treat, are limited. Using consistent, robust methodology, this study estimated HRU associated with the treatment of metastatic melanoma in eight countries. Methods Using published literature and clinician input, treatment phases were identified: active systemic treatment (pre-progression); disease progression; best supportive care (BSC)/palliative care; and terminal care. HRU elements were identified for each phase and estimates of the magnitude and frequency of use in clinical practice were obtained through country-specific Delphi panels, comprising healthcare professionals with experience in oncology (n = 8). Results Medical oncologists are the key care providers for patients with metastatic melanoma, although in Germany dermato-oncologists also lead care. During the active systemic treatment phase, each patient was estimated to require 0.83-2 consultations with a medical oncologist/month across countries; the median number of such assessments in 3 months was highest in Canada (range = 3.5-5) and lowest in France, the Netherlands and Spain (1). Resource use during the disease progression phase was intensive and similar across countries: all patients were estimated to consult with medical oncologists and 10-40% with a radiation oncologist; up to 40% were estimated to require a brain MRI scan. During the BSC/palliative care phase, all patients were estimated to consult with medical oncologists, and most to consult with a primary care physician (40-100%). Limitations Panelists were from centers of excellence, thus results may not reflect care within smaller hospitals; data obtained from experts may be less variable than data from broader clinical practice. Treatments for metastatic melanoma are continually emerging, thus some elements of our work could be superseded. Conclusions HRU estimates were substantial and varied across countries for some

  14. The influence of the combined treatment with Vadimezan (ASA404) and taxol on the growth of U251 glioblastoma xenografts

    PubMed Central

    2012-01-01

    Background One of the most important biological characteristics of Glioblastoma multiforme (GBM) is high vascular density. Vadimezan (ASA404, DMXAA) belongs to the class of small molecule vascular disrupting agents (VDA) that cause disruption of established tumor vessels and subsequent tumor hemorrhagic necrosis. Its selective antivascular effect is mediated by intratumoral induction of several cytokines including tumor necrosis factor-α (TNF-α), granulocyte-colony-stimulating factor (G-CSF), interleukin 6 (IL-6) and macrophage inflammatory protein 1α (MIP-1α). Preclinical studies have demonstrated that ASA404 acts synergistically with taxanes. In this study, we investigated if treatment of mice bearing U251 human glioblastoma xenografts with ASA404 and taxol may be synergistic. Therapy response was evaluated by measuring changes in tumor size and metabolic activity using 18F-FDG PET (Fluorodeoxyglucose - positron emision tomography) imaging. Methods U251 cells were inoculated s.c. in the right hind limb of NMRI-Foxn1nu athymic female nude mice. Animals were randomly assigned into 4 groups (7–9 animals/group) for treatment: control, taxol, ASA404, and ASA404 plus taxol. The animals received either a single dose of taxol (10 mg/kg), ASA404 (27.5 mg/kg), or taxol (10 mg/kg) plus ASA404 (27.5 mg/kg) administered i.p.; ASA404 was administred 24 h after the treatment with taxol. 4 and 24 h after treatment with ASA404 (28 and 48 h hours after treatment with taxol) 18 F-FDG PET scans were performed. Results The treatment with taxol did not affect the tumor growth in comparison to untreated controls. The treatment of animals with single dose ASA404 alone or in combination with taxol caused a significant delay in tumor growth. The combined treatment did not decrease the growth of the xenografts significantly more than ASA404 alone, but early changes in tumor 18 F-FDG uptake preceded subsequent growth inhibition. The tumor weights, which were

  15. Antitumoral, antioxidant, and antimelanogenesis potencies of Hawthorn, a potential natural agent in the treatment of melanoma.

    PubMed

    Mustapha, Nadia; Mokdad-Bzéouich, Imèn; Maatouk, Mouna; Ghedira, Kamel; Hennebelle, Thierry; Chekir-Ghedira, Leila

    2016-06-01

    The lack of an efficient agent that does not have the disadvantage of low activity (kojic acid), high cytotoxicity, and mutagenicity (hydroquinone), poor skin penetration (arbutin), or low stability in formulation (glabridin) led us to continue our research on new antipigmentation/skin-lightening agents. Therefore, research of natural products that can modulate the metabolism of pigmentation is of great interest. Otherwise, malignant melanoma is one of the most aggressive forms of skin cancer, with high metastatic potential, and currently, there is no effective chemotherapy against invasive melanoma. Therefore, it is necessary to develop new drugs with potent activity and weak side effects against melanoma. The in-vitro anticancer effect of hawthorn was analyzed against B16F10 melanoma cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The effect of isolated compounds from hawthorn on melanogenesis in B16F10 melanoma cells was investigated by measuring the amounts of melanin and tyrosinase spectrophotometrically at 475 nm. Balb/c mice models inoculated with B16F10 mouse tumor cells were used to evaluate the in-vivo antitumoral potential of hawthorn by assessing its effect on the growth of transplanted tumors. The antioxidant potential of tested samples was evaluated in B16F10 and primary human keratinocyte cells using a cellular antioxidant activity assay. Hawthorn tested samples inhibited effectively the growth of melanoma cells in vitro. Furthermore, it appears that tested samples from hawthorn reduced melanogenesis by inhibiting the tyrosinase activity of B16F10 cells in a dose-dependent manner. In-vivo studies showed that hawthorn total oligomer flavonoids extract treatment at a dose of 150 mg/kg body weight for 21 days in implanted tumor mice resulted in significant inhibition of the tumor growth volume and weight. In addition, tested samples showed significant cellular antioxidant capacity against the reactive oxygen species

  16. Circulating Melanoma Cell Subpopulations: Their Heterogeneity and Differential Responses to Treatment

    PubMed Central

    Gray, Elin S; Reid, Anna L; Bowyer, Samantha; Calapre, Leslie; Siew, Kelvin; Pearce, Robert; Cowell, Lester; Frank, Markus H; Millward, Michael; Ziman, Mel

    2015-01-01

    Metastatic melanoma is a highly heterogeneous tumor; thus, methods to analyze tumor-derived cells circulating in blood should address this diversity. Taking this into account, we analyzed, using multiparametric flow cytometry, the co-expression of the melanoma markers melanoma cell adhesion molecule and melanoma-associated chondroitin sulphate proteoglycan and the tumor-initiating markers ATP-binding cassette sub-family B member 5 (ABCB5), CD271, and receptor activator of NF-κβ (RANK) in individual circulating tumor cells (CTCs) from 40 late-stage (III–IV) and 16 early-stage (I–II) melanoma patients. CTCs were heterogeneous within and between patients, with limited co-expression between the five markers analyzed. Analysis of patient matched blood and metastatic tumors revealed that ABCB5 and RANK subpopulations are more common among CTCs than in the solid tumors, suggesting a preferential selection for these cells in circulation. Pairwise comparison of CTC subpopulations longitudinally before and 6–13 weeks after treatment initiation showed that the percentage of RANK+ CTCs significantly increased in the patients undergoing targeted therapy (N=16, P<0.01). Moreover, the presence of ⩾5 RANK+ CTCs in the blood of patients undergoing targeted therapies was prognostic of shorter progression-free survival (hazards ratio 8.73, 95% confidence interval 1.82–41.75, P<0.01). Taken together, our results provide evidence of the heterogeneity among CTC subpopulations in melanoma and the differential response of these subpopulations to targeted therapy. PMID:25830652

  17. Metabotropic glutamate receptor 1 and glutamate signaling in human melanoma.

    PubMed

    Namkoong, Jin; Shin, Seung-Shick; Lee, Hwa Jin; Marín, Yarí E; Wall, Brian A; Goydos, James S; Chen, Suzie

    2007-03-01

    Recently, several laboratories have started to investigate the involvement of glutamate signaling in cancer. In previous studies, we reported on a transgenic mouse model that develops melanoma spontaneously. Subsequent studies in these mice identified that the aberrant expression of metabotropic glutamate receptor 1 (GRM1) in melanocytes played a critical role in the onset of melanoma. Confirmation of the etiologic role of GRM1 in melanoma development was shown in a second transgenic line with GRM1 expression under the regulation of a melanocyte-specific dopachrome tautomerase promoter. Ectopic expression of GRM1 was also detected in a subset of human melanoma cell lines and biopsies, suggesting that aberrant expression of GRM1 in melanocytes may contribute to the development of human melanoma. GRM1, a seven-transmembrane domain G protein-coupled receptor, is normally expressed and functional in neuronal cells, and its ligand, glutamate, is the major excitatory neurotransmitter. Human melanoma cells are shown here to release elevated levels of glutamate, implying a possible autocrine loop. Treatment of GRM1-expressing human melanoma cells with a GRM1 antagonist (LY367385 or BAY36-7620) or a glutamate release inhibitor (riluzole) leads to a suppression of cell proliferation as well as a decrease in levels of extracellular glutamate. Treatment of human melanoma cell xenografts with riluzole for 18 days via p.o. gavage or i.v. injection leads to inhibition of tumor growth by 50% in comparison with controls. These data suggest the importance of glutamate signaling in human melanoma and imply that the suppression of glutamate signaling may be a new target for melanoma therapy.

  18. Interposition Dermal Matrix Xenografts: A Successful Alternative to Traditional Treatment of Massive Rotator Cuff Tears.

    PubMed

    Neumann, Julie A; Zgonis, Miltiadis H; Rickert, Kathleen D; Bradley, Kendall E; Kremen, Thomas J; Boggess, Blake R; Toth, Alison P

    2017-05-01

    Management of massive rotator cuff tears in shoulders without glenohumeral arthritis remains problematic for surgeons. Repairs of massive rotator cuff tears have failure rates of 20% to 94% at 1 to 2 years postoperatively as demonstrated with arthrography, ultrasound, and magnetic resonance imaging. Additionally, inconsistent outcomes have been reported with debridement alone of massive rotator cuff tears, and limitations have been seen with other current methods of operative intervention, including arthroplasty and tendon transfers. The use of interposition porcine acellular dermal matrix xenograft in patients with massive rotator cuff tears will result in improved subjective outcomes, postoperative pain, function, range of motion, and strength. Case series; Level of evidence, 4. Sixty patients (61 shoulders) were prospectively observed for a mean of 50.3 months (range, 24-63 months) after repair of massive rotator cuff tears with porcine acellular dermal matrix xenograft as an interposition graft. Subjective outcome data were obtained with visual analog scale for pain score (0-10, 0 = no pain) and Modified American Shoulder and Elbow Surgeons (MASES) score. Active range of motion in flexion, external rotation, and internal rotation were recorded. Strength in the supraspinatus and infraspinatus muscles was assessed manually on a 10-point scale and by handheld dynamometer. Ultrasound was used to assess the integrity of the repair during latest follow-up. Mean visual analog scale pain score decreased from 4.0 preoperatively to 1.0 postoperatively ( P < .001). Mean active forward flexion improved from 140.7° to 160.4° ( P < .001), external rotation at 0° of abduction from 55.6° to 70.1° ( P = .001), and internal rotation at 90° of abduction from 52.0° to 76.2° ( P < .001). Supraspinatus manual strength increased from 7.7 to 8.8 ( P < .001) and infraspinatus manual strength from 7.7 to 9.3 ( P < .001). Mean dynamometric strength in forward flexion was 77.7 N

  19. Novel Approaches to Treatment of Advanced Melanoma: A Review on Targeted Therapy and Immunotherapy

    PubMed Central

    Niezgoda, Anna; Niezgoda, Piotr; Czajkowski, Rafał

    2015-01-01

    The incidence of malignant melanoma is increasing. The majority of patients are diagnosed in early stages when the disease is highly curable. However, the more advanced or metastatic cases have always been a challenge for clinicians. The poor prognosis for patients with melanoma is now changing as numerous of promising approaches have appeared recently. The discovery of aberrations of pathways responsible for intracellular signal transduction allowed us to introduce agents specifically targeting the mutated cascades. Numerous clinical studies have been conducted to improve effectiveness of melanoma treatment. From 2011 until now, the U.S. FDA has approved seven novel agents, such as BRAF-inhibitors (vemurafenib 2011, dabrafenib 2013), MEK-inhibitors (trametinib 2013), anti-PD1 antibodies (nivolumab 2014, pembrolizumab 2014), anti-CTLA-4 antibody (ipilimumab 2011), or peginterferon-alfa-2b (2011) intended to be used in most advanced cases of melanoma. Nevertheless, clinicians continue working on new possible methods of treatment as resistance to the novel drugs is a commonly observed problem. This paper is based on latest data published until the end of January 2015. PMID:26171394

  20. [Primary malignant melanoma of the vagina and treatment options: a case report].

    PubMed

    Tsvetkov, Ch; Gorchev, G; Tomov, S; Hinkova, N; Nikolova, M; Veselinova, T

    2014-01-01

    To present and analyze the clinical characteristics, treatment, and treatment options for a patient with primary malignant melanoma of the vagina and review of literature. A 71-year-old patient with a history of vaginal bleeding caused by four tumor growths located in the vagina is presented. The size of each formation was about 2 cm. Three of them were located in the proximal two-thirds of the anterior wall of the vagina and one in the distal third. Excisional biopsy was performed of the lesion located near the entrance of the vagina. Histopathological examination revealed that it was a malignant melanoma of the vagina, which was confirmed immunohistochemically. After ruling out a tumor of an unknown primary site, the patient underwent radical hysterectomy type IV total vaginectomy and pelvic lymph node dissection. Hystological examination proved a clinically asymptomatic melanoma lesion of the uterine cervix. After surgery, the patient was given chemotherapy with Dacarbasine and monthly immunotherapy with BCG vaccine. The patient survived 21 months after surgery without developing a local relapse and died of distant metastases in the spine. Radical surgery for primary melanoma of the vagina is a secure way of achieving locoregional control of multifocal disease. The wide local excision can be used in unifocal lesions with security in achieving clean surgical margins.

  1. Evaluation of the pharmacokinetics and metabolism of pembrolizumab in the treatment of melanoma.

    PubMed

    Longoria, Teresa C; Tewari, Krishnansu S

    2016-10-01

    Advanced melanoma is a devastating disease that has propelled research in therapeutics beyond chemotherapy and radiotherapy. Being highly immunogenic, melanoma is a model tumor for immunotherapy and has highlighted the therapeutic potential of the immune checkpoint inhibitors. This review discusses the pharmacologic properties, clinical efficacy, and safety profile of pembrolizumab, an IgG4-kappa humanized monoclonal antibody against the programmed cell death protein 1 (PD-1) receptor, for the treatment of unresectable or metastatic melanoma. Pembrolizumab was the first PD-1 inhibitor to be approved by the U.S. Food and Drug Administration (FDA). Remarkably, this accelerated approval for the treatment of advanced, heavily pretreated melanoma was based on response rates alone from a phase I trial. As anticipated, pembrolizumab confirmed a survival advantage in phase II and III trials and has led the way for the study of other drugs that share its mechanism of action. Defining disease and patient characteristics associated with a response remains amongst the most pressing priorities.

  2. miR-204-5p acts as a tumor suppressor by targeting matrix metalloproteinases-9 and B-cell lymphoma-2 in malignant melanoma

    PubMed Central

    Luan, Wenkang; Qian, Yao; Ni, Xin; Bu, Xuefeng; Xia, Yun; Wang, Jinlong; Ruan, Hongru; Ma, Shaojun; Xu, Bin

    2017-01-01

    An increasing number of microRNAs have been found to be involved in tumorigenesis, including melanoma tumorigenesis. miR-204-5p is down-regulated and functions as a tumor suppressor in many human malignant tumors. miR-204-5p expression is also decreased in melanoma tissues, but its biological roles and molecular mechanisms in malignant melanoma remain unclear. In this study, the aberrant down-regulation of miR-204-5p was detected in melanoma, especially in metastatic melanoma. miR-204-5p also served as a protective factor for the prognosis of melanoma patients. We determined that miR-204-5p suppresses cell proliferation, migration and invasion, and promotes cell apoptosis in melanoma. Matrix metalloproteinases-9 and B-cell lymphoma-2 are the functional targets of miR-204-5p, through which it plays an important biological role in malignant melanoma. The effect of miR-204-5p on malignant melanoma is verified using a xenograft model. We also determined that miR-204-5p increases 5-fluorouracil and cisplatin (DDP) chemosensitivity in malignant melanoma cells. This finding elucidates new functions and mechanisms for miR-204-5p in melanoma development, and provides potential therapeutic targets for the treatment of melanoma. PMID:28280358

  3. Failed operative treatment in two cases of pseudarthrosis of the clavicle using internal fixation and bovine cancellous xenograft (Tutobone).

    PubMed

    Elliot, Robin R; Richards, Robert H

    2011-09-01

    The most commonly reported technique of reconstructive surgery for congenital pseudarthrosis of the clavicle involves resection of the pseudarthrosis, insertion of autologous iliac crest bone graft and internal fixation. In an attempt to avoid the potential complications of iliac crest bone graft harvest we used bovine cancellous xenograft (Tutobone). Two cases of pseudarthrosis of the clavicle treated with resection of the pseudarthrosis, Tutobone graft and internal fixation are presented. Both cases resulted in treatment failures, which were associated with significant osteolysis and failure of incorporation of the graft material. This required removal of the loose metal work and debridement of the failed graft material. We would caution surgeons against the use of Tutobone as a graft material in the surgical management of pseudarthrosis of the clavicle. The level of evidence was level IV case series.

  4. Shotgun proteomic analysis to study the decrease of xenograft tumor growth after rosemary extract treatment.

    PubMed

    Valdés, Alberto; García-Cañas, Virginia; Pérez-Sánchez, Almudena; Barrajón-Catalán, Enrique; Ruiz-Torres, Verónica; Artemenko, Konstantin A; Micol, Vicente; Bergquist, Jonas; Cifuentes, Alejandro

    2017-05-26

    The antiproliferative activity of Rosemary (Rosmarinus officinalis) has been widely studied in different in vitro and in vivo models, which demonstrate that rosemary extracts inhibit the cellular proliferation due to its ability to interact with a wide spectrum of molecular targets. However, a comprehensive proteomics study in vivo has not been carried out yet. In the present work, the effects of rosemary extract on xenograft tumor growth has been studied and, for the first time, a shotgun proteomic analysis based on nano-LC-MS/MS together with stable isotope dimethyl labeling (DML) has been applied to investigate the global protein changes in vivo. Our results show that the daily administration of a polyphenol-enriched rosemary extract reduces the progression of colorectal cancer in vivo with the subsequent deregulation of 74 proteins. The bioinformatic analysis of these proteins indicates that the rosemary extract mainly alters the RNA Post-Transcriptional Modification, the Protein Synthesis and the Amino Acid Metabolism functions and suggests the inactivation of the oncogene MYC. These results demonstrate the high utility of the proposed analytical methodology to determine, simultaneously, the expression levels of a large number of protein biomarkers and to generate new hypothesis about the molecular mechanisms of this extract in vivo. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Melanoma chemotherapy leads to the selection of ABCB5-expressing cells.

    PubMed

    Chartrain, Marine; Riond, Joëlle; Stennevin, Aline; Vandenberghe, Isabelle; Gomes, Bruno; Lamant, Laurence; Meyer, Nicolas; Gairin, Jean Edouard; Guilbaud, Nicolas; Annereau, Jean Philippe

    2012-01-01

    Metastatic melanoma is the most aggressive skin cancer. Recently, phenotypically distinct subpopulations of tumor cells were identified. Among them, ABCB5-expressing cells were proposed to display an enhanced tumorigenicity with stem cell-like properties. In addition, ABCB5(+) cells are thought to participate to chemoresistance through a potential efflux function of ABCB5. Nevertheless, the fate of these cells upon drugs that are used in melanoma chemotherapy remains to be clarified. Here we explored the effect of anti-melanoma treatments on the ABCB5-expressing cells. Using a melanoma xenograft model (WM266-4), we observed in vivo that ABCB5-expressing cells are enriched after a temozolomide treatment that induces a significant tumor regression. These results were further confirmed in a preliminary study conducted on clinical samples from patients that received dacarbazine. In vitro, we showed that ABCB5-expressing cells selectively survive when exposed to dacarbazine, the reference treatment of metastatic melanoma, but also to vemurafenib, a new inhibitor of the mutated kinase V600E BRAF and other various chemotherapeutic drugs. Our results show that anti-melanoma chemotherapy might participate to the chemoresistance acquisition by selecting tumor cell subpopulations expressing ABCB5. This is of particular importance in understanding the relapses observed after anti-melanoma treatments and reinforces the interest of ABCB5 and ABCB5-expressing cells as potential therapeutic targets in melanoma.

  6. Melanoma Chemotherapy Leads to the Selection of ABCB5-Expressing Cells

    PubMed Central

    Stennevin, Aline; Vandenberghe, Isabelle; Gomes, Bruno; Lamant, Laurence; Meyer, Nicolas; Gairin, Jean Edouard; Guilbaud, Nicolas; Annereau, Jean Philippe

    2012-01-01

    Metastatic melanoma is the most aggressive skin cancer. Recently, phenotypically distinct subpopulations of tumor cells were identified. Among them, ABCB5-expressing cells were proposed to display an enhanced tumorigenicity with stem cell-like properties. In addition, ABCB5+ cells are thought to participate to chemoresistance through a potential efflux function of ABCB5. Nevertheless, the fate of these cells upon drugs that are used in melanoma chemotherapy remains to be clarified. Here we explored the effect of anti-melanoma treatments on the ABCB5-expressing cells. Using a melanoma xenograft model (WM266-4), we observed in vivo that ABCB5-expressing cells are enriched after a temozolomide treatment that induces a significant tumor regression. These results were further confirmed in a preliminary study conducted on clinical samples from patients that received dacarbazine. In vitro, we showed that ABCB5-expressing cells selectively survive when exposed to dacarbazine, the reference treatment of metastatic melanoma, but also to vemurafenib, a new inhibitor of the mutated kinase V600E BRAF and other various chemotherapeutic drugs. Our results show that anti-melanoma chemotherapy might participate to the chemoresistance acquisition by selecting tumor cell subpopulations expressing ABCB5. This is of particular importance in understanding the relapses observed after anti-melanoma treatments and reinforces the interest of ABCB5 and ABCB5-expressing cells as potential therapeutic targets in melanoma. PMID:22675422

  7. NGcGM3/VSSP vaccine as treatment for melanoma patients.

    PubMed

    Pérez, Kirenia; Osorio, Marta; Hernández, Julio; Carr, Adriana; Fernández, Luis Enrique

    2013-06-01

    Gangliosides are glycosphingolipids that are present in the plasma membranes of vertebrates and are involved in multiple cellular processes. In the Center of Molecular Immunology an NGcGM3 ganglioside based vaccine has been developed and is conceptualized as a targeted therapy in cancer. NGcGM3/VSSP vaccine had been used as treatment of metastatic melanoma patients and had showed to be safe and immunogenic. The treatment improved antitumoral response or maintain the response obtained with previous onco-specific treatment as chemotherapy. The results indicate that the vaccine improved overall survival of metastatic melanoma patients after first line-chemotherapy. The clinical trial ongoing currently will allow corroborating these results.

  8. The discovery of vemurafenib for the treatment of BRAF-mutated metastatic melanoma.

    PubMed

    Kim, Alex; Cohen, Mark S

    2016-09-01

    In the era of precision medicine and sophisticated modern genetics, the discovery of the BRAF(V600) inhibitor, vemurafenib, quickly became the model for targeted therapy in melanomas. As early as 2002, the majority of metastatic melanomas were described to harbor the BRAF(V600) mutation, setting the stage for an explosion of interest for targeting this protein as a novel therapeutic strategy. The highly selective BRAF(V600) inhibitor, vemurafenib, was identified initially through a large-scale drug screen. Here we examine vemurafenib's journey from discovery to clinical use in metastatic melanoma. Topics covered include preclinical data, single agent Phase 1,2 and 3 clinical trials, resistance issues and mechanisms, adverse effects including the development of squamous cell cancers, and combination trials. Due to its tolerance, low toxicity profile, rapid tumor response, and improved outcomes in melanoma patients with BRAF(V600) mutations, vemurafenib was advanced rapidly through clinical trials to receive FDA approval in 2011. While its efficacy is well documented, durability has become an issue for most patients who experience therapeutic resistance in approximately 6-8 months. In addition, a concerning toxicity observed in patients taking the drug include development of localized cutaneous squamous cell carcinomas (SCCs). It is hypothesized that drug resistance and SCC development result from a similar paradoxical activation of protein signaling pathways, specifically MAPK. Identification of these mechanisms has led to additional treatment strategies involving new combination therapies.

  9. CT based treatment planning system of proton beam therapy for ocular melanoma

    NASA Astrophysics Data System (ADS)

    Nakano, Takashi; Kanai, Tatsuaki; Furukawa, Shigeo; Shibayama, Kouichi; Sato, Sinichiro; Hiraoka, Takeshi; Morita, Shinroku; Tsujii, Hirohiko

    2003-09-01

    A computed tomography (CT) based treatment planning system of proton beam therapy was established specially for ocular melanoma treatment. A technique of collimated proton beams with maximum energy of 70 MeV are applied for treatment for ocular melanoma. The vertical proton beam line has a range modulator for spreading beams out, a multi-leaf collimator, an aperture, light beam localizer, field light, and X-ray verification system. The treatment planning program includes; eye model, selecting the best direction of gaze, designing the shape of aperture, determining the proton range and range modulation necessary to encompass the target volume, and indicating the relative positions of the eyes, beam center and creation of beam aperture. Tumor contours are extracted from CT/MRI images of 1 mm thickness by assistant by various information of fundus photography and ultrasonography. The CT image-based treatment system for ocular melanoma is useful for Japanese patients as having thick choroid membrane in terms of dose sparing to skin and normal organs in the eye. The characteristics of the system and merits/demerits were reported.

  10. Radiation Therapy Field Extent for Adjuvant Treatment of Axillary Metastases From Malignant Melanoma

    SciTech Connect

    Beadle, Beth M.; Guadagnolo, B. Ashleigh Ballo, Matthew T.; Lee, Jeffrey E.; Gershenwald, Jeffrey E.; Cormier, Janice N.; Mansfield, Paul F.; Ross, Merrick I.; Zagars, Gunar K.

    2009-04-01

    Purpose: To compare treatment-related outcomes and toxicity for patients with axillary lymph node metastases from malignant melanoma treated with postoperative radiation therapy (RT) to either the axilla only or both the axilla and supraclavicular fossa (extended field [EF]). Methods and Materials: The medical records of 200 consecutive patients treated with postoperative RT for axillary lymph node metastases from malignant melanoma were retrospectively reviewed. All patients received postoperative hypofractionated RT for high-risk features; 95 patients (48%) received RT to the axilla only and 105 patients (52%) to the EF. Results: At a median follow-up of 59 months, 111 patients (56%) had sustained relapse, and 99 patients (50%) had died. The 5-year overall survival, disease-free survival, and distant metastasis-free survival rates were 51%, 43%, and 46%, respectively. The 5-year axillary control rate was 88%. There was no difference in axillary control rates on the basis of the treated field (89% for axilla only vs. 86% for EF; p = 0.4). Forty-seven patients (24%) developed treatment-related complications. On both univariate and multivariate analyses, only treatment with EF irradiation was significantly associated with increased treatment-related complications. Conclusions: Adjuvant hypofractionated RT to the axilla only for metastatic malignant melanoma with high-risk features is an effective method to control axillary disease. Limiting the radiation field to the axilla only produced equivalent axillary control rates to EF and resulted in lower treatment-related complication rates.

  11. TOPICAL APPLICATION OF BLEACHING PHENOLS; IN VIVO STUDIES AND MECHANISM OF ACTION RELEVANT TO MELANOMA TREATMENT

    PubMed Central

    Hariharan, Vidhya; Toole, Timothy; Klarquist, Jared; Longley, Jack B; Mosenson, Jeffrey; Le Poole1, I. Caroline

    2012-01-01

    Skin depigmentation represents a well established treatment for extensive vitiligo and may likewise be suited to prevent tumor recurrences and as a prophylactic treatment of familial melanoma, as common bleaching agents are cytotoxic to melanocytes. Effective melanoma prevention requires a bleaching agent-induced loss of exposed melanocytes supported by an immune response to distant pigment cells. Studies on human explant cultures treated with depigmenting agents, 4-tertiary butyl phenol (4-TBP) or monobenzyl ether of hydroquinone (MBEH) revealed a significant increase in the migration of Langerhans cells towards the dermis only upon MBEH treatment thus suggesting selective elicitation of an immune response. To assess the depigmenting potential of bleaching agents in vivo, 4-TBP and MBEH were topically applied to C57BL/6 wild type as well as k14-SCF transgenic, epidermally pigmented mice. MBEH induced significant skin depigmentation in both strains, not observed upon 4-TBP treatment. Cytokine expression patterns in MBEH treated skin support activation of a Th1 mediated immune response corresponding to an influx of T cells and macrophages. Importantly, despite insensitivity of tumor cells to MBEH induced cytotoxicity, significantly retarded tumor growth was observed in B16 challenged k14-SCF mice pretreated with MBEH, likely due to an abundance of cytotoxic T cells accompanied by an increased expression of Th1 and Th17 cytokines. These data support the use of MBEH as a prophylactic treatment for melanoma. PMID:21317816

  12. Current Status of Biological Therapies for the Treatment of Metastatic Melanoma.

    PubMed

    Tang, Tianyi; Eldabaje, Robert; Yang, Lixi

    2016-07-01

    Compared to early-stage melanoma when surgical excision is possible, metastatic disease continues to offer a much grimmer prognosis as traditional chemotherapy treatment regimens offer relatively little survival benefit. This has led to changes in treatment approaches over the preceding two decades as contemporary methods for the treatment of advanced or metastatic melanoma now involve a number of biological modalities, which include immunotherapeutic approaches, targeted therapies and epigenetic modification therapies. Clinically available immunotherapeutic agents include interleukin 2 (IL-2), as well as drugs targeting the important immune checkpoint molecules, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). The targeted therapeutic agents modulate specific pro-oncogenic mutations such as v-Raf murine sarcoma viral oncogene homolog B (BRAF), receptor tyrosine kinases, MEK inhibitors and potential future therapeutic targets, such as the CDK4/CDK6, PTEN and GNAQ/GNA11 genes. Additionally, an increasing understanding of the role of epigenetic alterations in the development and progression of melanoma now offers a new potential drug target. Several of these agents have shown promising results; however, in many investigations, combinations of different therapeutic approaches, each with different mechanisms of action, have yielded improved outcomes as treatment regimens continue to be further optimized by active research and patient disease sub-group analyses. This review summarizes the novel biological agents and new treatments, directly contributing to the significant improvement of biological therapies and markedly advancing knowledge of clinical application of newly approved and developed therapies in treatment of patients with metastatic melanoma. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  13. Circulating Tumor Cells as a Biomarker of Response to Treatment in Patient-Derived Xenograft Mouse Models of Pancreatic Adenocarcinoma

    PubMed Central

    Torphy, Robert J.; Tignanelli, Christopher J.; Kamande, Joyce W.; Moffitt, Richard A.; Herrera Loeza, Silvia G.; Soper, Steven A.; Yeh, Jen Jen

    2014-01-01

    Circulating tumor cells (CTCs) are cells shed from solid tumors into circulation and have been shown to be prognostic in the setting of metastatic disease. These cells are obtained through a routine blood draw and may serve as an easily accessible marker for monitoring treatment effectiveness. Because of the rapid progression of pancreatic ductal adenocarcinoma (PDAC), early insight into treatment effectiveness may allow for necessary and timely changes in treatment regimens. The objective of this study was to evaluate CTC burden as a biomarker of response to treatment with a oral phosphatidylinositol-3-kinase inhibitor, BKM120, in patient-derived xenograft (PDX) mouse models of PDAC. PDX mice were randomized to receive vehicle or BKM120 treatment for 28 days and CTCs were enumerated from whole blood before and after treatment using a microfluidic chip that selected for EpCAM (epithelial cell adhesion molecule) positive cells. This microfluidic device allowed for the release of captured CTCs and enumeration of these cells via their electrical impedance signatures. Median CTC counts significantly decreased in the BKM120 group from pre- to post-treatment (26.61 to 2.21 CTCs/250 µL, p = 0.0207) while no significant change was observed in the vehicle group (23.26 to 11.89 CTCs/250 µL, p = 0.8081). This reduction in CTC burden in the treatment group correlated with tumor growth inhibition indicating CTC burden is a promising biomarker of response to treatment in preclinical models. Mutant enriched sequencing of isolated CTCs confirmed that they harbored KRAS G12V mutations, identical to the matched tumors. In the long-term, PDX mice are a useful preclinical model for furthering our understanding of CTCs. Clinically, mutational analysis of CTCs and serial monitoring of CTC burden may be used as a minimally invasive approach to predict and monitor treatment response to guide therapeutic regimens. PMID:24586805

  14. Review and proposal of regional surgical management for melanoma: revisiting of integumentectomy and incontinuity dissection in treatment of skin melanoma.

    PubMed

    Hayashi, Toshihiko; Furukawa, Hiroshi; Kitamura, Takashi; Shichinohe, Ryuji; Murao, Naoki; Oyama, Akihiko; Funayama, Emi; Maeda, Taku; Yamamoto, Yuhei

    2017-06-01

    Past studies showed that integumentectomy and incontinuity could be effective procedures in the surgical management of melanoma patients. The present study reports on the historical background of these procedures. In addition, we analyze the ICG assisted integumentectomy and incontinuity techniques and algorithms that we had created when performing this procedure. In accordance with our algorithm, we performed ICG assisted integumentectomy/incontinuity procedures on 17 patients with stage III melanomas between 2008 and 2016. We also investigated the locoregional recurrence rate in a control group comprising 60 patients at stage III without using the algorithm. The former group exhibited a tendency of locoregional recurrence rate suppression. Melanoma cells in the dissected intervening tissue were microscopically identified in 2 out of 17 cases. Our ICG assisted integumentectomy or incontinuity procedures could be effective in controlling locoregional recurrence rates in melanoma cases. Moreover, our method can be generally applied because the dissection is only performed within the lymphatic pathway region identified using indocyanine green.

  15. Two-year patient-reported outcomes following treatment of uveal melanoma.

    PubMed

    Hope-Stone, L; Brown, S L; Heimann, H; Damato, B; Salmon, P

    2016-12-01

    PurposeTreatment of uveal melanoma can impair patients' psychological well-being. We evaluated patient-reported outcome measures (PROMs) of anxiety, depression, and quality of life (QoL) over 2 years following treatment in a consecutive sample of uveal melanoma patients, compared observations to population normative values and examined whether outcomes differed according to patients' age, gender, and whether or not they were treated by enucleation or had a poor prognosis (presence of monosomy 3).DesignProspective longitudinal study.ParticipantsPatients (N=411) with uveal melanoma treated between 2008 and 2011.MethodsSelf-report questionnaire study. We compared mean PROMs scores obtained 6 months, 1 year, and 2 years after treatment to published population normative values using 2-sample t-tests, and tested the association of these scores with gender, age, treatment by enucleation, and monosomy 3 using mixed-model ANOVAs.ResultsOn QoL and depression, patients were similar to or better than normative values at all time points, but there was some evidence that females were more anxious than female normative values (Ps<0.001-<0.05). Younger patients (P<0.01) and female patients (P<0.01) were the most anxious overall. Enucleation was not associated with PROMs. Patients with monosomy 3 showed more depressed mood at all the three time points (P<0.05).ConclusionsPatients treated for uveal melanoma can expect, within 6 months of treatment, to have a QoL that is similar to that of the general population. Younger female patients and patients with monosomy 3 are more likely to be distressed, and clinicians will need to be alert to this.

  16. Conjunctival melanoma: a review of conceptual and treatment advances

    PubMed Central

    Lim, Li-Anne; Madigan, Michele C; Conway, R Max

    2013-01-01

    The aim of this study was to review the available literature and identify recent advances in the classification and management of conjunctival melanoma (CM) for clinicians working in this field. English-based articles were identified using the MEDLINE® database, and additional cited works not detected in the initial search were also obtained. Articles were assessed according to the Australian National Health and Medical Research Council levels of evidence criteria. Review of the literature indicated that the current classification and management of CM is predominantly based upon primarily nonrandomized, single-institution, retrospective case series. While these studies provide the basis for the recent seventh edition of the tumor node metastasis staging classification, this classification more accurately reflects the current knowledge of prognostic factors for CM. Application of this revised classification system together with prospective trials will provide the opportunity for future consistent and comparable data collection across centers, and it will improve the quality of evidence upon which current classification and management of CM is based. Furthermore, the high risk of local recurrence with current standard management suggests that adjuvant therapy, particularly mitomycin C and/or brachytherapy, may improve outcomes regardless of clinical staging. Finally, the use of sentinel lymph node biopsy may have significant benefit for a select group of CM patients. PMID:23515569

  17. Ultrasound-mediated destruction of oxygen and paclitaxel loaded dual-targeting microbubbles for intraperitoneal treatment of ovarian cancer xenografts.

    PubMed

    Luo, Tingting; Sun, Jiangchuan; Zhu, Shenyin; He, Juan; Hao, Lan; Xiao, Linlin; Zhu, Yi; Wang, Qianqian; Pan, Xin; Wang, Zhigang; Chang, Shufang

    2017-04-10

    Folate receptor (FR) is overexpressed in many epithelial cancers and tumor-associated macrophages (TAMs), which enable it to function as an appropriate target for cancer treatment. We have successfully synthesized multifunctional folate-targeted and oxygen/paclitaxel loaded microbubbles (TOPLMBs) for ultrasound (US) mediated delivery for combination therapy in an intraperitoneal ovarian cancer xenograft model. The TOPLMBs target both ovarian cancer cells and TAMs and provide a promising drug delivery strategy for the combination treatment of ovarian cancer and tumor microenvironment. Microscopic imaging and flow cytometric analysis showed that TOPLMBs significantly penetrated into ovarian cancer cells and tumor-associated macrophages (TAMs) within tumor ascites fluid and the tumor nodules. Immunohistochemical analyses of dissected tumor tissue confirmed the increased tumor apoptosis, the reduced expression of vascular endothelial growth factor (VEGF) and microvascular density (MVD), and the reduced expression of CD68 after treatment (P < 0.05). Our experiment results suggest that intraperitoneal injection of dual-targeting TOPLMBs followed by US mediation provide a promising drug delivery strategy for combination treatment of ovarian cancer and tumor microenvironment with the therapeutic outcome superior to that of conventional therapeutic options. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  18. [Size-based classification of choroidal melanoma and its role in treatment decision-making].

    PubMed

    Brovkina, A F; Stoyukhina, A S; Chesalin, I P

    2016-01-01

    To specify indications for brachytherapy (BT) in large choroidal melanoma (CM) so that tumor size and vital prognosis were considered. We retrospectively analyzed data from 161 CM patients who were treated with BT and followed-up at either the Ophthalmological Clinical Hospital or some other Moscow medical facility and also registered by the City Cancer Registry. Patient age at the time of starting the treatment lied within the range of 17 to 84 years and averaged 56.89±1.93 years. During the follow-up period (12-275 months, 95.65±8.4 months on average) hematogenous metastases were found in 23 (14.29%) patients. Liver involvement was diagnosed in 8 patients within the average of 23.13 months after treatment. Their average survival time was 11 months. A total of 142 patients were followed up for more than 36 months (104.87 months on average). Of them, 15 patients were diagnosed with metastatic CM within 37-167 months after BT (80.27 months on average). Despite metastatic disease they generally survived 2.8 time longer than the aforementioned patients (30.8 months). The cases were then divided into 3 groups according to J. Shields classification of CM. Small melanoma patients did not develop metastases within 99.96±12.47 months of follow-up. In medium melanomas, as many as 13.35% of cases were metastatic (with the average survival time of 20.66 months); in large melanomas - 19.51% (with the average survival time of 13.5 months). Treatment modality and follow-up periods being the same (7-8 years after BT), larger choroidal melanomas has been shown to be associated with higher risk of hematogenous metastases. For local treatment to be successive, the maximal diameter of the tumor should not exceed 10 mm. Every fifth patient of those with CM larger than 15 mm is likely to develop hematogenous metastases. The results obtained indicate the necessity of decreasing the size thresholds for choroidal melanomas, small and medium in the first place.

  19. PLGA-loaded nanomedicines in melanoma treatment: Future prospect for efficient drug delivery

    PubMed Central

    Das, Sreemanti; Khuda-Bukhsh, Anisur Rahman

    2016-01-01

    Current treatment methods for melanoma have some limitations such as less target-specific action, severe side effects and resistance to drugs. Significant progress has been made in exploring novel drug delivery systems based on suitable biochemical mechanisms using nanoparticles ranging from 10 to 400 nm for drug delivery and imaging, utilizing their enhanced penetration and retention properties. Poly-lactide-co-glycolide (PLGA), a copolymer of poly-lactic acid and poly-glycolic acid, provides an ideally suited performance-based design for better penetration into skin cells, thereby having a greater potential for the treatment of melanoma. Moreover, encapsulation protects the drug from deactivation by biological reactions and interactions with biomolecules, ensuring successful delivery and bioavailability for effective treatment. Controlled and sustained delivery of drugs across the skin barrier that otherwise prohibits entry of larger molecules can be successfully made with adequately stable biocompatible nanocarriers such as PLGA for taking drugs through the small cutaneous pores permitting targeted deposition and prolonged drug action. PLGA is now being extensively used in photodynamic therapy and targeted therapy through modulation of signal proteins and drug-DNA interactions. Recent advances made on these nanomedicines and their advantages in the treatment of skin melanoma are highlighted and discussed in this review. PMID:27934796

  20. Electrochemotherapy for the Treatment of Unresectable Locoregionally Advanced Cutaneous Melanoma: A Systematic Review.

    PubMed

    Aguado-Romeo, M J; Benot-López, S; Romero-Tabares, A

    2017-03-01

    Electrochemotherapy is a therapeutic option for the treatment of cutaneous and subcutaneous metastases from melanoma and other tumors. The procedure consists of the administration of anticancer drugs followed by locally applied electrical impulses to achieve an effect known as electroporation, which facilitates entry into the cytosol of drugs that cannot cross the cell membrane. The aim of this review is to evaluate the evidence that supports the use of electrochemotherapy as a therapeutic strategy in melanoma. We conducted a qualitative systematic review of the literature using advanced searches of bibliographic databases and full text reviews. Seven studies (3 systematic reviews and 4 cases series) were selected. The quality of the evidence was not good, but the coincidence of results for certain variables supports their consistency. Results of the meta-analyses favored electrochemotherapy over chemotherapy. Electrochemotherapy appears to be an effective procedure for the local treatment of malignant tumor nodules (evidence of intermediate or low quality). This inexpensive method is simple to apply, well tolerated, and achieves objective responses under certain circumstances. There is no evidence that electrochemotherapy alters the natural course of the disease and it should therefore be considered a palliative treatment. With an evidence level of 1- (minus), electrochemotherapy can be recommended for the palliative treatment of unresectable, locoregionally advanced melanoma (grade B recommendation). Copyright © 2016 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

  1. Hair and nail adverse events during treatment with targeted therapies for metastatic melanoma.

    PubMed

    Dika, Emi; Patrizi, Annalisa; Ribero, Simone; Fanti, Pier Alessandro; Starace, Michela; Melotti, Barbara; Sperandi, Francesca; Piraccini, Bianca Maria

    2016-06-01

    Targeted therapies for melanoma have shown clinical benefit in increasing the survival of metastatic patients. Cutaneous adverse events have been reported, but hair and nail data have been rarely detailed. Patients treated with BRAF and MEK inhibitors for metastatic melanoma underwent dermatological evaluation before the start of each treatment and after every four weeks. Pull test, global photography, dermoscopy/trichoscopy and scalp biopsy were performed. Appendages adverse events were graded using the National Cancer Institute's Common Terminology Criteria. Of the 24 patients included, 14 underwent treatment with a selective BRAF inhibitor; 10 received a combined treatment (dabrafenib/trametinib). Adnexal adverse events were common in the group of patients receiving vemurafenib, and included hair kinking, acute hair loss, and hair colour changes, often present in association, classified as G2 in three patients and G1 in eight. Dabrafenib alone induced hair kinking and colour changes in 60% of the patients. Combined treatment with dabrafenib/trametinib did not induce hair changes. Onycholysis was the most common nail side effect, and the unique side effect of dabrafenib (alone or in combination). Vemurafenib also induced acute paronychia and brittle nails. All nail side effects were graded as G1. Hair and nail side effects during targeted therapy for melanoma are not rare. The early recognition and cure of such side effects by dermatologists is of benefit to ensure the need for dose reduction or drug discontinuation.

  2. Treatment of Metastatic Melanoma Using Interleukin-2 Alone or in Conjunction with Vaccines

    PubMed Central

    Smith, Franz O.; Downey, Stephanie G.; Klapper, Jacob A.; Yang, James C.; Sherry, Richard M.; Royal, Richard E.; Kammula, Udai S.; Hughes, Marybeth S.; Restifo, Nicholas P.; Levy, Catherine L.; White, Donald E.; Steinberg, Seth M.; Rosenberg, Steven A.

    2008-01-01

    Purpose To identify prognostic factors associated with survival beyond 4 years and overall response in patients with metastatic melanoma treated with high-dose bolus i.v. interleukin-2 (IL-2) given either alone or in combination with a variety of melanoma vaccines. Study Design 684 consecutive patients with metastatic melanoma received high-dose bolus i.v. IL-2 either alone or in conjunction with a variety of melanoma vaccines. Treatments occurred between August 1, 1985 and January 1, 2006. Results The overall objective response rate was 13% for patients receiving IL-2 alone and 16% for patients who received IL-2 with vaccine. In patients treated with IL-2 alone (n = 305) and IL-2 with vaccine (n = 379), having an objective response was associated with survival beyond 4 years (P < 0.0001). No pretreatment factors could be identified that were strongly associated with increased rate of objective response or long-term survival in patients receiving IL-2 alone. In patients receiving IL-2 with vaccines, there were increased response rates in patients with s.c. or cutaneous disease only and lower response rates with visceral disease only. Patients who received the gp100:209-217(210M) peptide plus IL-2 showed a strong trend to increased objective responses compared with IL-2 alone (22% versus 12.8%; P = 0.01) and also compared with patients who received a variety of vaccines that did not include this immunogenic peptide (13.8%; P = 0.009). Conclusion IL-2 can produce a modest response rate in patients with metastatic melanoma including patients with durable complete responses. S.c. or cutaneous disease only and vaccination with gp100:209-217(210M) peptide was associated with significant increase in response rates. PMID:18765555

  3. Effect of biopsy type on outcomes in the treatment of primary cutaneous melanoma.

    PubMed

    Mills, Jane K; White, Ian; Diggs, Brian; Fortino, Jeanine; Vetto, John T

    2013-05-01

    Surgical excision remains the primary and only potentially curative treatment for melanoma. Although current guidelines recommend excisional biopsy as the technique of choice for evaluating lesions suspected of being primary melanomas, other biopsy types are commonly used. We sought to determine the impact of biopsy type (excisional, shave, or punch) on outcomes in melanoma. A prospectively collected, institutional review board-approved database of primary clinically node-negative melanomas (stages cT1-4N0) was reviewed to determine the impact of biopsy type on T-staging accuracy, wide local excision (WLE) area (cm(2)), sentinel lymph node biopsy (SLNB) identification rates and results, tumor recurrence, and patient survival. Seven hundred nine patients were diagnosed by punch biopsy (23%), shave biopsy (34%), and excisional biopsy (43%). Shave biopsy results showed significantly more positive deep margins (P < .001). Both shave and punch biopsy results showed more positive peripheral margins (P < .001) and a higher risk of finding residual tumor (with resulting tumor upstaging) in the WLE (P < .001), compared with excisional biopsy. Punch biopsy resulted in a larger mean WLE area compared with shave and excisional biopsies (P = .030), and this result was sustained on multivariate analysis. SLNB accuracy was 98.5% and was not affected by biopsy type. Similarly, biopsy type did not confer survival advantage or impact tumor recurrence; the finding of residual tumor in the WLE impacted survival on univariate but not multivariate analysis. Both shave and punch biopsies demonstrated a significant risk of finding residual tumor in the WLE, with pathologic upstaging of the WLE. Punch biopsy also led to a larger mean WLE area compared with other biopsy types. However, biopsy type did not impact SLNB accuracy or results, tumor recurrence, or disease-specific survival (DSS). Punch and shave biopsies, when used appropriately, should not be discouraged for the diagnosis of

  4. Combined treatment with dabrafenib and trametinib with immune-stimulating antibodies for BRAF mutant melanoma

    PubMed Central

    Homet Moreno, Blanca; Mok, Stephen; Comin-Anduix, Begonya; Hu-Lieskovan, Siwen; Ribas, Antoni

    2016-01-01

    The combination of targeted therapy with BRAF and MEK inhibitors has become the standard of care in patients with BRAFV600E mutant melanoma, but responses are not durable. In addition, the impressive clinical benefits with anti-PD-1 and anti-PD-L1 antibodies (Ab) in patients with heavily pretreated metastatic melanoma and the synergistic effect of dabrafenib, trametinib and anti-PD-1 compared with single therapy alone groups support the idea that combining dabrafenib, trametinib and immunotherapy based on PD-1 blockade could be an interesting approach in the treatment of metastatic melanoma. With our mouse model of syngeneic BRAFV600E driven melanoma (SM1), we tested whether the addition of an immunostimulatory Ab targeting CD137 (4-1BB) and/or CD134 (OX40) would enhance the antitumor effect of dabrafenib, trametinib and anti-PD-1 or anti-PD-L1 therapy. In vitro studies showed that the combination group of dabrafenib, trametinib and anti-PD-1 increases CD8+ tumor infiltrating lymphocytes (TILs), as well as CD4+ T cells and tumor-associated macrophages (TAMs). An upregulation of PD-L1 was observed in the combination of dabrafenib, trametinib and anti-PD-1 therapy. Combination of dabrafenib, trametinib and anti-PD-1, with either anti-CD137 or anti-CD134, showed a superior antitumor effect, but the five-agent combination was not superior to the four-agent combinations. In conclusion, the combination of dabrafenib, trametinib, anti-PD1 or anti-PD-L1 therapy results in robust antitumor activity, which is further improved by adding the immune-stimulating Ab anti-CD137 or anti-CD134. Our findings support the testing of these combinations in patients with BRAFV600E mutant metastatic melanoma. PMID:27622011

  5. BRAF-mutant melanoma: treatment approaches, resistance mechanisms, and diagnostic strategies

    PubMed Central

    Spagnolo, Francesco; Ghiorzo, Paola; Orgiano, Laura; Pastorino, Lorenza; Picasso, Virginia; Tornari, Elena; Ottaviano, Vincenzo; Queirolo, Paola

    2015-01-01

    BRAF inhibitors vemurafenib and dabrafenib achieved improved overall survival over chemotherapy and have been approved for the treatment of BRAF-mutated metastatic melanoma. More recently, the combination of BRAF inhibitor dabrafenib with MEK inhibitor trametinib has shown improved progression-free survival, compared to dabrafenib monotherapy, in a Phase II study and has received approval by the US Food and Drug Administration. However, even when treated with the combination, most patients develop mechanisms of acquired resistance, and some of them do not achieve tumor regression at all, because of intrinsic resistance to therapy. Along with the development of BRAF inhibitors, immunotherapy made an important step forward: ipilimumab, an anti-CTLA-4 monoclonal antibody, was approved for the treatment of metastatic melanoma; anti-PD-1 agents achieved promising results in Phase I/II trials, and data from Phase III studies will be ready soon. The availability of such drugs, which are effective regardless of BRAF status, has made the therapeutic approach more complex, as first-line treatment with BRAF inhibitors may not be the best choice for all BRAF-mutated patients. The aim of this paper is to review the systemic therapeutic options available today for patients affected by BRAF V600-mutated metastatic melanoma, as well as to summarize the mechanisms of resistance to BRAF inhibitors and discuss the possible strategies to overcome them. Moreover, since the molecular analysis of tumor specimens is now a pivotal and decisional factor in the treatment strategy of metastatic melanoma patients, the advances in the molecular detection techniques for the BRAF V600 mutation will be reported. PMID:25653539

  6. Utilize conjugated melanotropins for the earlier diagnosis and treatment of Melanoma

    PubMed Central

    Cai, Minying; Liu, Zhonglin; Qu, Hongchang; Fan, Helen; Zheng, Zhiping; Hruby, Victor J.

    2011-01-01

    Peptides serve as effective drugs and the contrast agents in the clinic today. However the inherent drawbacks of peptide structures can limit their efficacy as drugs. To overcome this we have been developing new methods to create ‘tailor-made’ peptides and peptide mimetics with improved pharmacological and physical properties. In this work we introduce novel peptide and small molecule conjugated molecules for the earlier diagnosis and treatment of melanoma. PMID:21315067

  7. Histopathology of normal skin and melanomas after nanosecond pulsed electric field treatment.

    PubMed

    Chen, Xinhua; James Swanson, R; Kolb, Juergen F; Nuccitelli, Richard; Schoenbach, Karl H

    2009-12-01

    Nanosecond pulsed electric fields (nsPEFs) can affect the intracellular structures of cells in vitro. This study shows the direct effects of nsPEFs on tumor growth, tumor volume, and histological characteristics of normal skin and B16-F10 melanoma in SKH-1 mice. A melanoma model was set up by injecting B16-F10 into female SKH-1 mice. After a 100-pulse treatment with an nsPEF (40-kV/cm field strength; 300-ns duration; 30-ns rise time; 2-Hz repetition rate), tumor growth and histology were studied using transillumination, light microscopy with hematoxylin and eosin stain and transmission electron microscopy. Melanin and iron within the melanoma tumor were also detected with specific stains. After nsPEF treatment, tumor development was inhibited with decreased volumes post-nsPEF treatment compared with control tumors (P<0.05). The nsPEF-treated tumor volume was reduced significantly compared with the control group (P<0.01). Hematoxylin and eosin stain and transmission electron microscopy showed morphological changes and nuclear shrinkage in the tumor. Fontana-Masson stain indicates that nsPEF can externalize the melanin. Iron stain suggested nsPEF caused slight hemorrhage in the treated tissue. Histology confirmed that repeated applications of nsPEF disrupted the vascular network. nsPEF treatment can significantly disrupt the vasculature, reduce subcutaneous murine melanoma development, and produce tumor cell contraction and nuclear shrinkage while concurrently, but not permanently, damaging peripheral healthy skin tissue in the treated area, which we attribute to the highly localized electric fields surrounding the needle electrodes.

  8. Guidelines of the Brazilian Dermatology Society for diagnosis, treatment and follow up of primary cutaneous melanoma - Part I*

    PubMed Central

    Castro, Luiz Guilherme Martins; Messina, Maria Cristina; Loureiro, Walter; Macarenco, Ricardo Silvestre; Duprat Neto, João Pedreira; Giacomo, Thais Helena Bello Di; Bittencourt, Flávia Vasques; Bakos, Renato Marchiori; Serpa, Sérgio Schrader; Stolf, Hamilton Ometto; Gontijo, Gabriel

    2015-01-01

    The last Brazilian guidelines on melanoma were published in 2002. Development in diagnosis and treatment made updating necessary. The coordinators elaborated ten clinical questions, based on PICO system. A Medline search, according to specific MeSH terms for each of the 10 questions was performed and articles selected were classified from A to D according to level of scientific evidence. Based on the results, recommendations were defined and classified according to scientific strength. The present Guidelines were divided in two parts for editorial and publication reasons. In the first part, the following clinical questions were answered: 1) The use of dermoscopy for diagnosis of primary cutaneous melanoma brings benefits for patients when compared with clinical examination? 2) Does dermoscopy favor diagnosis of nail apparatus melanoma? 3) Is there a prognostic difference when incisional or excisional biopsies are used? 4) Does revision by a pathologist trained in melanoma contribute to diagnosis and treatment of primary cutaneous melanoma? What margins should be used to treat lentigo maligna melanoma and melanoma in situ? PMID:26734867

  9. Guidelines of the Brazilian Dermatology Society for diagnosis, treatment and follow up of primary cutaneous melanoma--Part I.

    PubMed

    Castro, Luiz Guilherme Martins; Messina, Maria Cristina; Loureiro, Walter; Macarenco, Ricardo Silvestre; Duprat Neto, João Pedreira; Di Giacomo, Thais Helena Bello; Bittencourt, Flávia Vasques; Bakos, Renato Marchiori; Serpa, Sérgio Schrader; Stolf, Hamilton Ometto; Gontijo, Gabriel

    2015-01-01

    The last Brazilian guidelines on melanoma were published in 2002. Development in diagnosis and treatment made updating necessary. The coordinators elaborated ten clinical questions, based on PICO system. A Medline search, according to specific MeSH terms for each of the 10 questions was performed and articles selected were classified from A to D according to level of scientific evidence. Based on the results, recommendations were defined and classified according to scientific strength. The present Guidelines were divided in two parts for editorial and publication reasons. In the first part, the following clinical questions were answered: 1) The use of dermoscopy for diagnosis of primary cutaneous melanoma brings benefits for patients when compared with clinical examination? 2) Does dermoscopy favor diagnosis of nail apparatus melanoma? 3) Is there a prognostic difference when incisional or excisional biopsies are used? 4) Does revision by a pathologist trained in melanoma contribute to diagnosis and treatment of primary cutaneous melanoma? What margins should be used to treat lentigo maligna melanoma and melanoma in situ?

  10. Antineoplastic Effects of Honokiol on Melanoma

    PubMed Central

    Guillermo-Lagae, Ruth; Santha, Sreevidya; Thomas, Milton; Zoelle, Emily; Stevens, Jonathan

    2017-01-01

    Honokiol, a plant lignan has been shown to have antineoplastic effects against nonmelanoma skin cancer developments in mice. In this study, antineoplastic effects of honokiol were investigated in malignant melanoma models. In vitro effects of honokiol treatment on SKMEL-2 and UACC-62 melanoma cells were evaluated by measuring the cell viability, proliferation, apoptosis, cell cycle analysis, and expressions of various proteins associated with cell cycle progression and apoptosis. For the in vivo study, male nude mice inoculated with SKMEL-2 or UACC-62 cells received injections of sesame oil or honokiol for two to seven weeks. In vitro honokiol treatment caused significant decrease in cell viability, proliferation, cell cycle arrest, increased apoptosis, and modulation of apoptotic and cell cycle regulatory proteins. Honokiol caused an accumulation of cells in the G2/M phase of the cell cycle in SKMEL-2 and G0/G1 phase in UACC-62 cells. An elevated level of caspases and PARP were observed in both cell lines treated with honokiol. A decrease in the expression of various cell cycle regulatory proteins was also observed in honokiol treated cells. Honokiol caused a significant reduction of tumor growth in SKMEL-2 and UACC-62 melanoma xenografts. These findings suggest that honokiol is a good candidate for further studies as a possible treatment for malignant melanoma. PMID:28194418

  11. Antineoplastic Effects of Honokiol on Melanoma.

    PubMed

    Guillermo-Lagae, Ruth; Santha, Sreevidya; Thomas, Milton; Zoelle, Emily; Stevens, Jonathan; Kaushik, Radhey S; Dwivedi, Chandradhar

    2017-01-01

    Honokiol, a plant lignan has been shown to have antineoplastic effects against nonmelanoma skin cancer developments in mice. In this study, antineoplastic effects of honokiol were investigated in malignant melanoma models. In vitro effects of honokiol treatment on SKMEL-2 and UACC-62 melanoma cells were evaluated by measuring the cell viability, proliferation, apoptosis, cell cycle analysis, and expressions of various proteins associated with cell cycle progression and apoptosis. For the in vivo study, male nude mice inoculated with SKMEL-2 or UACC-62 cells received injections of sesame oil or honokiol for two to seven weeks. In vitro honokiol treatment caused significant decrease in cell viability, proliferation, cell cycle arrest, increased apoptosis, and modulation of apoptotic and cell cycle regulatory proteins. Honokiol caused an accumulation of cells in the G2/M phase of the cell cycle in SKMEL-2 and G0/G1 phase in UACC-62 cells. An elevated level of caspases and PARP were observed in both cell lines treated with honokiol. A decrease in the expression of various cell cycle regulatory proteins was also observed in honokiol treated cells. Honokiol caused a significant reduction of tumor growth in SKMEL-2 and UACC-62 melanoma xenografts. These findings suggest that honokiol is a good candidate for further studies as a possible treatment for malignant melanoma.

  12. Stereotactic Radiosurgery and Fractionated Stereotactic Radiation Therapy for the Treatment of Uveal Melanoma.

    PubMed

    Yazici, Gozde; Kiratli, Hayyam; Ozyigit, Gokhan; Sari, Sezin Yuce; Cengiz, Mustafa; Tarlan, Bercin; Mocan, Burce Ozgen; Zorlu, Faruk

    2017-05-01

    To evaluate treatment results of stereotactic radiosurgery or fractionated stereotactic radiation therapy (SRS/FSRT) for uveal melanoma. We retrospectively evaluated 181 patients with 182 uveal melanomas receiving SRS/FSRT between 2007 and 2013. Treatment was administered with CyberKnife. According to Collaborative Ocular Melanoma Study criteria, tumor size was small in 1%, medium in 49.5%, and large in 49.5% of the patients. Seventy-one tumors received <45 Gy, and 111 received ≥45 Gy. Median follow-up time was 24 months. Complete and partial response was observed in 8 and 104 eyes, respectively. The rate of 5-year overall survival was 98%, disease-free survival 57%, local recurrence-free survival 73%, distant metastasis-free survival 69%, and enucleation-free survival 73%. There was a significant correlation between tumor size and disease-free survival, SRS/FSRT dose and enucleation-free survival; and both were prognostic for local recurrence-free survival. Enucleation was performed in 41 eyes owing to progression in 26 and complications in 11. The radiation therapy dose is of great importance for local control and eye retention; the best treatment outcome was achieved using ≥45 Gy in 3 fractions. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Spotlight on talimogene laherparepvec for the treatment of melanoma lesions in the skin and lymph nodes

    PubMed Central

    Orloff, Marlana

    2016-01-01

    On October 27, 2015, talimogene laherparepvec (T-VEC), a first in class intralesional oncolytic virotherapy, was granted the US Food and Drug Administration approval for the treatment of melanoma in the skin and lymph nodes. Its approval has added yet another therapeutic option to the growing list of effective therapies for melanoma. Though the Phase III OPTiM trial has demonstrated its efficacy as a single agent, the target patient population remains narrow. With numerous effective and tolerable treatments available for unresectable and metastatic melanoma, intralesional therapies such as T-VEC are still finding their niche. T-VEC is now widely accepted as option for treatment; however, its combination with various other agents in an effort to expand its use and synergize with other interventions is still being explored. This article will review the pre-clinical and clinical work that eventually led to the Food and Drug Administration approval of this first-in-class agent, as well as address concerns about clinical application and ongoing research. PMID:27785448

  14. BET and BRAF inhibitors act synergistically against BRAF-mutant melanoma.

    PubMed

    Paoluzzi, Luca; Hanniford, Douglas; Sokolova, Elena; Osman, Iman; Darvishian, Farbod; Wang, Jinhua; Bradner, James E; Hernando, Eva

    2016-06-01

    Despite major advances in the treatment of metastatic melanoma, treatment failure is still inevitable in most cases. Manipulation of key epigenetic regulators, including inhibition of Bromodomain and extra-terminal domain (BET) family members impairs cell proliferation in vitro and tumor growth in vivo in different cancers, including melanoma. Here, we investigated the effect of combining the BET inhibitor JQ1 with the BRAF inhibitor Vemurafenib in in vitro and in vivo models of BRAF-mutant melanoma. We performed cytotoxicity and apoptosis assays, and a xenograft mouse model to determine the in vitro and in vivo efficacy of JQ1 in combination with Vemurafenib against BRAF-mutant melanoma cell lines. Further, to investigate the molecular mechanisms underlying the effects of combined treatment, we conducted antibody arrays of in vitro drug-treated cell lines and RNA sequencing of drug-treated xenograft tumors. The combination of JQ1 and Vemurafenib acted synergistically in BRAF-mutant cell lines, resulting in marked apoptosis in vitro, with upregulation of proapoptotic proteins. In vivo, combination treatment suppressed tumor growth and significantly improved survival compared to either drug alone. RNA sequencing of tumor tissues revealed almost four thousand genes that were uniquely modulated by the combination, with several anti-apoptotic genes significantly down-regulated. Collectively, our data provide a rationale for combined BET and BRAF inhibition as a novel strategy for the treatment of melanoma.

  15. Survival curves after X-ray and heat treatments for melanoma cells derived directly from surgical specimens of tumours in man.

    PubMed

    Rofstad, E K; Wahl, A; Tveit, K M; Monge, O R; Brustad, T

    1985-08-01

    X-ray and heat survival curves were established for melanoma cells derived directly from surgical specimens of tumours in man by using the Courtenay soft agar colony assay. The plating efficiency for 11 of the 14 melanomas studied was sufficiently high (PE = 0.3-58%) to measure cell survival over at least two decades. Experiments repeated with cells stored in liquid nitrogen showed that the survival assay gave highly reproducible results. The melanomas exhibited individual and characteristic survival curves whether exposed to radiation or heat (43.5 degrees C). The Do-values were in the ranges 0.63-1.66 Gy (X-rays) and 33-58 min (heat). The survival curves were similar to those reported previously for human melanoma xenografts. The radiation sensitivity of the cells was not correlated to the heat sensitivity. Since the melanomas appeared to be very heterogeneous in radiation response in vitro as melanomas are known to be clinically, it is suggested that melanomas may be suitable for prospective studies aimed at establishing whether clinical radioresponsiveness somehow is related to in vitro survival curve parameters.

  16. [Initial evaluation, diagnosis, staging, treatment, and follow-up of patients with primary cutaneous malignant melanoma. Consensus statement of the Network of Catalan and Balearic Melanoma Centers].

    PubMed

    Mangas, C; Paradelo, C; Puig, S; Gallardo, F; Marcoval, J; Azon, A; Bartralot, R; Bel, S; Bigatà, X; Curcó, N; Dalmau, J; del Pozo, L J; Ferrándiz, C; Formigón, M; González, A; Just, M; Llambrich, A; Llistosella, E; Malvehy, J; Martí, R M; Nogués, M E; Pedragosa, R; Rocamora, V; Sàbat, M; Salleras, M

    2010-03-01

    The consensus statement on the management of primary cutaneous melanoma that we present here was based on selection, discussion, review, and comparison of recent literature (including national and international guidelines). The protocols for the diagnosis, treatment, and follow-up used in the hospital centers throughout Catalonia and the Balearic Isles belonging to the Network of Catalan and Balearic Melanoma Centers were also considered. The main objective of this statement was to present the overall management of melanoma patients typically used in our region at the present time. As such, the statement was not designed to be an obligatory protocol for health professionals caring for this group of patients, and neither can it nor should it be used for this purpose. Professionals reading the statement should not therefore consider it binding on their practice, and in no case can this text be used to guarantee or seek responsibility for a given medical opinion. The group of dermatologists who have signed this statement was created 3 years ago with the aim of making our authorities aware of the importance of this complex tumor, which, in comparison with other types of cancer, we believe does not receive sufficient attention in Spain. In addition, the regular meetings of the group have produced interesting proposals for collaboration in various epidemiological, clinical, and basic applied research projects on the subject of malignant melanoma in our society.

  17. Effect of combined treatment with micelle-incorporated cisplatin (NC-6004) and S-1 on human gastric cancer xenografts.

    PubMed

    Kudo, Masahisa; Yamamoto, Yoshiyuki; Koga, Yoshikatsu; Hamaguchi, Tetsuya; Akimoto, Tetsuo; Yasunaga, Masahiro; Matsumura, Yasuhiro

    2016-12-01

    Combination therapy with S-1 and cisplatin (CDDP) is the standard chemotherapy for advanced gastric cancer in Japan; however, its administration requires hospitalization for hydration to prevent nephrotoxicity from CDDP. By contrast, NC-6004 appears to reduce the renal toxicity of CDDP and may be used on an outpatient basis. Thus, the effects of combined treatment with S-1 and NC-6004 were compared with those of S-1 and CDDP in a human gastric cancer model. In vitro cytotoxic effects were investigated in 44As3Luc, MKN45 and MKN74 human gastric cancer cell lines. The effects of NC-6004 and 5-fluorouracil (5-FU) were compared with the effects of CDDP and 5-FU using the combination index method. The in vivo antitumor effects of S-1/NC-6004 and S-1/CDDP were evaluated in mice bearing 44As3Luc xenografts. Both combinations exhibited synergistic activity in MKN45 and MKN74 cells and additive effects in 44As3Luc cells. Moreover, the in vivo antitumor effects did not differ between the S-1/NC-6004 and S-1/CDDP treatment groups. However, a significantly lower body weight loss was observed in S-1/NC-6004-treated mice compared with the S-1/CDDP-treated mice. Our data warrant a clinical evaluation of S-1/NC-6004 combination therapy.

  18. Effect of combined treatment with micelle-incorporated cisplatin (NC-6004) and S-1 on human gastric cancer xenografts

    PubMed Central

    Kudo, Masahisa; Yamamoto, Yoshiyuki; Koga, Yoshikatsu; Hamaguchi, Tetsuya; Akimoto, Tetsuo; Yasunaga, Masahiro; Matsumura, Yasuhiro

    2016-01-01

    Combination therapy with S-1 and cisplatin (CDDP) is the standard chemotherapy for advanced gastric cancer in Japan; however, its administration requires hospitalization for hydration to prevent nephrotoxicity from CDDP. By contrast, NC-6004 appears to reduce the renal toxicity of CDDP and may be used on an outpatient basis. Thus, the effects of combined treatment with S-1 and NC-6004 were compared with those of S-1 and CDDP in a human gastric cancer model. In vitro cytotoxic effects were investigated in 44As3Luc, MKN45 and MKN74 human gastric cancer cell lines. The effects of NC-6004 and 5-fluorouracil (5-FU) were compared with the effects of CDDP and 5-FU using the combination index method. The in vivo antitumor effects of S-1/NC-6004 and S-1/CDDP were evaluated in mice bearing 44As3Luc xenografts. Both combinations exhibited synergistic activity in MKN45 and MKN74 cells and additive effects in 44As3Luc cells. Moreover, the in vivo antitumor effects did not differ between the S-1/NC-6004 and S-1/CDDP treatment groups. However, a significantly lower body weight loss was observed in S-1/NC-6004-treated mice compared with the S-1/CDDP-treated mice. Our data warrant a clinical evaluation of S-1/NC-6004 combination therapy. PMID:28101359

  19. Enrichment of circulating melanoma cells (CMCs) using negative selection from patients with metastatic melanoma

    PubMed Central

    Joshi, Powrnima; Jacobs, Barbara; Derakhshan, Adeeb; Moore, Lee R.; Elson, Paul; Triozzi, Pierre L.; Borden, Ernest; Zborowski, Maciej

    2014-01-01

    Circulating tumor cells have emerged as prognostic biomarkers in the treatment of metastatic cancers of epithelial origins viz., breast, colorectal and prostate. These tumors express Epithelial Cell Adhesion Molecule (EpCAM) on their cell surface which is used as an antigen for immunoaffinity capture. However, EpCAM capture technologies are of limited utility for non-epithelial cancers such as melanoma. We report a method to enrich Circulating Melanoma Cells (CMCs) that does not presuppose malignant cell characteristics. CMCs were enriched by centrifugation of blood samples from healthy (N = 10) and patient (N = 11) donors, followed by RBC lysis and immunomagnetic depletion of CD45-positive leukocytes in a specialized magnetic separator. CMCs were identified by immunocytochemistry using Melan-A or S100B as melanoma markers and enumerated using automated microscopy image analyses. Separation was optimized for maximum sensitivity and recovery of CMCs. Our results indicate large number of CMCs in Stage IV melanoma patients. Analysis of survival suggested a trend toward decreased survival with increased number of CMCs. Moreover, melanoma-associated miRs were found to be higher in CMC-enriched fractions in two patients when compared with the unseparated samples, validating this method as applicable for molecular analyses. Negative selection is a promising approach for isolation of CMCs and other EpCAM -negative CTCs, and is amenable to molecular analysis of CMCs. Further studies are required to validate its efficacy at capturing specific circulating cells for genomic analysis, and xenograft studies. PMID:24811334

  20. Enrichment of circulating melanoma cells (CMCs) using negative selection from patients with metastatic melanoma.

    PubMed

    Joshi, Powrnima; Jacobs, Barbara; Derakhshan, Adeeb; Moore, Lee R; Elson, Paul; Triozzi, Pierre L; Borden, Ernest; Zborowski, Maciej

    2014-05-15

    Circulating tumor cells have emerged as prognostic biomarkers in the treatment of metastatic cancers of epithelial origins viz., breast, colorectal and prostate. These tumors express Epithelial Cell Adhesion Molecule (EpCAM) on their cell surface which is used as an antigen for immunoaffinity capture. However, EpCAM capture technologies are of limited utility for non-epithelial cancers such as melanoma. We report a method to enrich Circulating Melanoma Cells (CMCs) that does not presuppose malignant cell characteristics. CMCs were enriched by centrifugation of blood samples from healthy (N = 10) and patient (N = 11) donors, followed by RBC lysis and immunomagnetic depletion of CD45-positive leukocytes in a specialized magnetic separator. CMCs were identified by immunocytochemistry using Melan-A or S100B as melanoma markers and enumerated using automated microscopy image analyses. Separation was optimized for maximum sensitivity and recovery of CMCs. Our results indicate large number of CMCs in Stage IV melanoma patients. Analysis of survival suggested a trend toward decreased survival with increased number of CMCs. Moreover, melanoma-associated miRs were found to be higher in CMC-enriched fractions in two patients when compared with the unseparated samples, validating this method as applicable for molecular analyses. Negative selection is a promising approach for isolation of CMCs and other EpCAM -negative CTCs, and is amenable to molecular analysis of CMCs. Further studies are required to validate its efficacy at capturing specific circulating cells for genomic analysis, and xenograft studies.

  1. Splicing Modulation as a Potential Treatment for Vemurafenib-Resistant Melanoma | Center for Cancer Research

    Cancer.gov

    Over half of melanomas contain mutations in the serine/threonine kinase BRAF. The most common mutation, BRAF(V600E), leads to excessive activation of the MAPK proliferation pathway. Vemurafenib is a potent kinase inhibitor with remarkable clinical activity in BRAF(V600E)-positive melanoma tumors. Patients initially respond to treatment with vemurafenib, but inevitably develop resistance. One known resistance mechanism is aberrant splicing of the BRAF RNA. To understand the molecule mechanism of BRAF mis-splicing, Tom Misteli, Ph.D., and Maayan Salton, Ph.D., of CCR’s Laboratory of Receptor Biology and Gene Expression, and NCI colleagues set out on a molecular investigation to identify the mechanism behind generation of the vemurafenib-resistant BRAF isoforms. Their results led to insight into the molecular mechanism of BRAF splicing in vemurafenib resistance and point to splicing inhibitors as a novel therapeutic strategy to overcome vemurafenib resistance.

  2. First BNCT treatment of a skin melanoma in Argentina: dosimetric analysis and clinical outcome.

    PubMed

    González, S J; Bonomi, M R; Santa Cruz, G A; Blaumann, H R; Calzetta Larrieu, O A; Menéndez, P; Jiménez Rebagliati, R; Longhino, J; Feld, D B; Dagrosa, M A; Argerich, C; Castiglia, S G; Batistoni, D A; Liberman, S J; Roth, B M C

    2004-11-01

    A Phase I/II protocol for treating cutaneuos melanomas with BNCT was designed in Argentina by the Comisión Nacional de Energía Atómica and the medical center Instituto Roffo. The first of a cohort of thirty planned patients was treated on October 9, 2003. This article depicts the protocol-based procedure and describes the first clinical case, treatment regime and planning, patient irradiation, retrospective dosimetric analysis and clinical outcome. Considering the low acute skin toxicity and the complete response in 21 of the 25 subcutaneous melanoma nodules treated, a second irradiation was performed in a different location of the extremity of the same patient. The corresponding clinical outcome is still under evaluation.

  3. High-energy neodymium laser radiation for the treatment of face cutaneous melanoma.

    PubMed

    Moskalik, K G; Kozlov, A P; Demin, E V

    2010-01-01

    This study retrospectively evaluated the curative efficacy of two powerful pulsed Neodymium (Nd) lasers (lambda = 1060 nm, pulse duration 1 and 4.5 msec, maximum pulse energy 700 and 1000 J, respectively) for the treatment of 47 patients with histologically confirmed stage I cutaneous melanoma of the face who were followed-up 5 years and more. The estimated 5-year survival rate was 82.9%. Regional and distant metastases developed in 23.4% of the patients. There were no cases with local recurrences. High-energy pulsed Nd laser radiation is effective in treating flat and / or slightly raised cutaneous stage I facial melanomas, while the therapeutic result is also accompanied by positive cosmetic result.

  4. Targeted Therapies in Combination With Immune Therapies for the Treatment of Metastatic Melanoma.

    PubMed

    Christiansen, Shelly A; Khan, Shaheer; Gibney, Geoffrey T

    In recent years, the field of oncology has witnessed many breakthroughs in the treatment of advanced malignancies, particularly in patients with advanced melanoma. Targeted and immune checkpoint therapies have emerged as the primary treatment strategies for these patients. Molecular profiling of melanoma is incorporated into routine practice to identify potential therapeutic targets, and patients are offered either a targeted or immune checkpoint inhibitor therapy approach. Both strategies have limitations where not all patients experience durable responses. Preclinical data have demonstrated the ability of targeted therapy to enhance activity of effector T cells, reduce immunosuppressive cytokine production, and increase tumor cell antigen presentation, which can augment antitumor immunity. In vivo models have shown synergy with improved tumor control when targeted and immune checkpoint agents are combined. Therefore, combination strategies with targeted and immune checkpoint therapy may improve patient outcomes. Early clinical data with anti-programmed cell-death protein 1/programmed cell-death ligand 1 agents in combination with targeted inhibitors appear to have acceptable toxicity rates and the potential for enhanced antitumor activity. This review explores the current status of preclinical and clinical development for these combination approaches in patients with advanced melanoma.

  5. Outcomes of treatment with stereotactic radiosurgery or proton beam therapy for choroidal melanoma.

    PubMed

    Sikuade, M J; Salvi, S; Rundle, P A; Errington, D G; Kacperek, A; Rennie, I G

    2015-09-01

    To present our experience of the use of stereotactic radiosurgery and proton beam therapy to treat posterior uveal melanoma over a 10 year period. Case notes of patients treated with stereotactic radiosurgery (SRS), or Proton beam therapy (PBT) for posterior uveal melanoma were reviewed. Data collected included visual acuity at presentation and final review, local control rates, globe retention and complications. We analysed post-operative visual outcomes and if visual outcomes varied with proximity to the optic nerve or fovea. 191 patients were included in the study; 85 and 106 patients received Stereotactic radiosurgery and Proton beam therapy, respectively. Mean follow up period was 39 months in the SRS group and 34 months in the PBT group. Both treatments achieved excellent local control rates with eye retention in 98% of the SRS group and 95% in the PBT group. The stereotactic radiosurgery group showed a poorer visual prognosis with 65% losing more than 3 lines of Snellen acuity compared to 45% in the PBT group. 33% of the SRS group and 54% of proton beam patients had a visual acuity of 6/60 or better. Stereotactic radiosurgery and proton beam therapy are effective treatments for larger choroidal melanomas or tumours unsuitable for plaque radiotherapy. Our results suggest that patients treated with proton beam therapy retain better vision post-operatively; however, possible confounding factors include age, tumour location and systemic co-morbidities. These factors as well as the patient's preference should be considered when deciding between these two therapies.

  6. Stereotactic Fractionated Radiotherapy in the Treatment of Juxtapapillary Choroidal Melanoma: The McGill University Experience

    SciTech Connect

    Al-Wassia, Rolina; Dal Pra, Alan; Shun, Kitty; Shaban, Ahmed; Corriveau, Christine; Edelstein, Chaim; Deschenes, Jean; Ruo, Russel; Patrocinio, Horacio; Cury, Fabio L.B.; DeBlois, Francois; Shenouda, George

    2011-11-15

    Purpose: To report our experience with linear accelerator-based stereotactic fractionated radiotherapy in the treatment of juxtapapillary choroidal melanoma. Methods and Materials: We performed a retrospective review of 50 consecutive patients diagnosed with juxtapapillary choroidal melanoma and treated with linear accelerator-based stereotactic fractionated radiotherapy between April 2003 and December 2009. Patients with small to medium sized lesions (Collaborative Ocular Melanoma Study classification) located within 2 mm of the optic disc were included. The prescribed radiation dose was 60 Gy in 10 fractions. The primary endpoints included local control, enucleation-free survival, and complication rates. Results: The median follow-up was 29 months (range, 1-77 months). There were 31 males and 29 females, with a median age of 69 years (range, 30-92 years). Eighty-four percent of the patients had medium sized lesions, and 16% of patients had small sized lesions. There were four cases of local progression (8%) and three enucleations (6%). Actuarial local control rates at 2 and 5 years were 93% and 86%, respectively. Actuarial enucleation-free survival rates at 2 and 5 years were 94% and 84%, respectively. Actuarial complication rates at 2 and 5 years were 33% and 88%, respectively, for radiation-induced retinopathy; 9.3% and 46.9%, respectively, for dry eye; 12% and 53%, respectively, for cataract; 30% and 90%, respectively, for visual loss [Snellen acuity (decimal equivalent), <0.1]; 11% and 54%, respectively, for optic neuropathy; and 18% and 38%, respectively, for neovascular glaucoma. Conclusions: Linear accelerator-based stereotactic fractionated radiotherapy using 60 Gy in 10 fractions is safe and has an acceptable toxicity profile. It has been shown to be an effective noninvasive treatment for juxtapapillary choroidal melanomas.

  7. [Advances in clinical treatment of malignant melanoma: B-RAF kinase inhibition].

    PubMed

    Heneberg, P

    2011-01-01

    Malignant melanoma is an aggressive cancer of pigment-producing cells, derivates of the neural crest. Surgical resection is the most effective form of treatment during initial phases of the disease. Advanced stages are usually treated by adjuvant immunotherapy (interferon alpha) or dacarbazine + multiferon. Response and survival rates are extremely poor. The emerging approach of personalized medicine brings about significant advances in the treatment of melanoma. Apart from administration of imatinib for a small subgroup of melanomas harbouring KIT mutations, the most promising approach is the use of B-RAF kinase inhibitors. The previously tested RAF inhibitors (e.g. sorafenib) did not perform better compared to conventional chemotherapy or immunotherapy. However, the results are much more promising with the recently developed inhibitor PLX4032 (Plexxikon; RG7204, Roche Pharmaceuticals; vemurafenib). This inhibitor targets tumours harbouring B-RAF(V600E) of B-RAF(V600K) activating mutations, which are present in 40-70% of malignant melanomas. An absence of the above mentioned activating mutations or parallel presence of activating RAS mutations (e.g. RAS(G12D)) should be used as contraindications. The use of PLX4032 provides better outcome than any of the currently used therapies, including partial or complete response recorded in 81% of patients, and prolonged median survival. Currently, this drug is being tested in phase II and III trials. The incidence of PLX4032-related adverse effects is relatively high; acquired resistance repeatedly occurring within several months of treatment may also represent a significant problem. Combined therapy is probably needed to further increase the complete response rate and to prolong survival. This should either include some of the currently used chemotherapeutics, or alternatively it may employ inhibitors of some of the kinases capable of stimulating the MEK and ERK kinases independently of B-RAF (e.g. COT). Nevertheless, even

  8. Treatment of resistant metastatic melanoma using sequential epigenetic therapy (decitabine and panobinostat) combined with chemotherapy (temozolomide).

    PubMed

    Xia, Chang; Leon-Ferre, Roberto; Laux, Douglas; Deutsch, Jeremy; Smith, Brian J; Frees, Melanie; Milhem, Mohammed

    2014-10-01

    To explore the safety and tolerability of combining two epigenetic drugs: decitabine (a DNA methyltransferase inhibitor) and panobinostat (a histone deacetylase inhibitor), with chemotherapy with temozolomide (an alkylating agent). The purpose of such combination is to evaluate the use of epigenetic priming to overcome resistance of melanoma to chemotherapy. A Phase I clinical trial enrolling patients aged 18 years or older, with recurrent or unresectable stage III or IV melanoma of any site. This trial was conducted with full Institutional Review Board approval and was registered with the National Institutes of Health under the clinicaltrials.gov identifier NCT00925132. Patients were treated with subcutaneous decitabine 0.1 or 0.2 mg/kg three times weekly for 2 weeks (starting on day 1), in combination with oral panobinostat 10, 20, or 30 mg every 96 h (starting on day 8), and oral temozolomide 150 mg/m(2)/day on days 9 through 13. In cycle 2, temozolomide was increased to 200 mg/m(2)/day if neutropenia or thrombocytopenia had not occurred. Each cycle lasted 6 weeks, and patients could receive up to six cycles. Patients who did not demonstrate disease progression were eligible to enter a maintenance protocol with combination of weekly panobinostat and thrice-weekly decitabine until tumor progression, unacceptable toxicity, or withdrawal of consent. Twenty patients were initially enrolled, with 17 receiving treatment. The median age was 56 years. Eleven (65%) were male, and 6 (35%) were female. Eleven (64.7%) had cutaneous melanoma, 4 (23.5%) had ocular melanoma, and 2 (11.8%) had mucosal melanoma. All patients received at least one treatment cycle and were evaluable for toxicity. Patients received a median of two 6-week treatment cycles (range 1-6). None of the patients experienced DLT. MTD was not reached. Adverse events attributed to treatment included grade 3 lymphopenia (24%), anemia (12%), neutropenia (12%), and fatigue (12%), as well as grade 2 leukopenia

  9. CXCR4 antibody treatment suppresses metastatic spread to the lung of intratibial human osteosarcoma xenografts in mice.

    PubMed

    Brennecke, Patrick; Arlt, Matthias J E; Campanile, Carmen; Husmann, Knut; Gvozdenovic, Ana; Apuzzo, Tiziana; Thelen, Marcus; Born, Walter; Fuchs, Bruno

    2014-03-01

    Current combined surgical and neo-adjuvant chemotherapy of primary metastatic osteosarcoma (OS) is ineffective, reflected by a 5-year survival rate of affected patients of less than 20 %. Studies in experimental OS metastasis models pointed to the CXCR4/CXCL12 homing axis as a novel target for OS metastasis-suppressive treatment. The present study investigated for the first time the CXCR4-blocking principle in a spontaneously metastasizing human 143B OS cell line-derived orthotopic xenograft mouse model. The highly metastatic 143B cells, unlike the parental non-metastatic HOS cells, express functional CXCR4 receptors at the cell surface, as revealed in this study by RT/PCR of gene transcripts, by FACS analysis with the monoclonal anti CXCR4 antibody 12G5 (mAb 12G5) and by CXCL12 time- and dose-dependent stimulation of AKT and ERK phosphorylation. A significantly (p < 0.05) higher CXCL12 dose-dependent chemotactic response of 143B compared to HOS cells in a Boyden chamber trans-well migration assay suggested a crucial role of the CXCL12/CXCR4 homing axis in 143B cell lung metastasis. Repetitive treatment of mice with 143B cell-derived intratibial tumors given intravenous bolus injections of mAb12G5 indeed inhibited significantly (p < 0.01) the number of X-gal-stainable lung micrometastases of lacZ-transduced 143B cells. Antibody treatment had also a mild inhibitory effect on primary tumor growth associated with remarkably less osteolysis, but it did not affect the number of developing lung macrometastases. In conclusion, these results demonstrate considerable potential of high-affinity CXCR4-blocking agents for OS tumor cell homing suppressive treatment in metastasizing OS complementary to current (neo)-adjuvant chemotherapy.

  10. A Multi-Parametric Imaging Investigation of the Response of C6 Glioma Xenografts to MLN0518 (Tandutinib) Treatment

    PubMed Central

    Boult, Jessica K. R.; Terkelsen, Jennifer; Walker-Samuel, Simon; Bradley, Daniel P.; Robinson, Simon P.

    2013-01-01

    Angiogenesis, the development of new blood vessels, is essential for tumour growth; this process is stimulated by the secretion of numerous growth factors including platelet derived growth factor (PDGF). PDGF signalling, through its receptor platelet derived growth factor receptor (PDGFR), is involved in vessel maturation, stimulation of angiogenesis and upregulation of other angiogenic factors, including vascular endothelial growth factor (VEGF). PDGFR is a promising target for anti-cancer therapy because it is expressed on both tumour cells and stromal cells associated with the vasculature. MLN0518 (tandutinib) is a potent inhibitor of type III receptor tyrosine kinases that demonstrates activity against PDGFRα/β, FLT3 and c-KIT. In this study a multi-parametric MRI and histopathological approach was used to interrogate changes in vascular haemodynamics, structural response and hypoxia in C6 glioma xenografts in response to treatment with MLN0518. The doubling time of tumours in mice treated with MLN0518 was significantly longer than tumours in vehicle treated mice. The perfused vessel area, number of alpha smooth muscle actin positive vessels and hypoxic area in MLN0518 treated tumours were also significantly lower after 10 days treatment. These changes were not accompanied by alterations in vessel calibre or fractional blood volume as assessed using susceptibility contrast MRI. Histological assessment of vessel size and total perfused area did not demonstrate any change with treatment. Intrinsic susceptibility MRI did not reveal any difference in baseline R2* or carbogen-induced change in R2*. Dynamic contrast-enhanced MRI revealed anti-vascular effects of MLN0518 following 3 days treatment. Hypoxia confers chemo- and radio-resistance, and alongside PDGF, is implicated in evasive resistance to agents targeted against VEGF signalling. PDGFR antagonists may improve potency and efficacy of other therapeutics in combination. This study highlights the challenges

  11. In vivo hyperspectral imaging of microvessel response to trastuzumab treatment in breast cancer xenografts

    PubMed Central

    McCormack, Devin R.; Walsh, Alex J.; Sit, Wesley; Arteaga, Carlos L.; Chen, Jin; Cook, Rebecca S.; Skala, Melissa C.

    2014-01-01

    HER2-amplified (HER2 + ) breast cancers are treated with the anti-HER2 monoclonal antibody trastuzumab. Although trastuzumab reduces production of the angiogenic factor VEGF in HER2 + tumors, the acute and sustained effects of trastuzumab on the tumor vasculature are not understood fully, particularly in trastuzumab-resistant tumors. We used mouse models of trastuzumab sensitive and trastuzumab-resistant HER2 + breast cancers to measure dynamic changes in tumor microvessel density and hemoglobin oxygenation (sO2) in vivo using quantitative hyperspectral imaging at 2, 5, 9, and 14 days after antibody treatment. Further analysis quantified the distribution of microvessels into low and high oxygenation groups, and monitored changes in these distributions with trastuzumab treatment. Gold standard immunohistochemistry was performed to validate complementary markers of tumor cell and vascular response to treatment. Trastuzumab treatment in both responsive and resistant tumors resulted in decreased sO2 5 days after initial treatment when compared to IgG-treated controls (p<0.05). Importantly, responsive tumors showed significantly higher vessel density and significantly lower sO2 than all other groups at 5 days post-treatment (p<0.05). Distribution analysis of vessel sO2 showed a significant (p<0.05) shift of highly oxygenated vessels towards lower oxygenation over the time-course in both trastuzumab-treated responsive and resistant tumors. This study suggests that longitudinal hyperspectral imaging of microvessel sO2 and density could distinguish trastuzumab-responsive from trastuzumab-resistant tumors, a finding that could be exploited in the post-neoadjuvant setting to guide post-surgical treatment decisions. PMID:25071962

  12. Successful treatment of human chronic lymphocytic leukemia xenografts with combination biological agents auristatin PE and bryostatin 1.

    PubMed

    Mohammad, R M; Varterasian, M L; Almatchy, V P; Hannoudi, G N; Pettit, G R; Al-Katib, A

    1998-05-01

    We tested the activity of dolastatin 10 (a natural product derived from the shell-less marine mollusk, Dolabella auricularia, a sea hare) and its structural modification, auristatin PE, alone and in combination with bryostatin 1 (a protein kinase C activator derived from the marine bryozoan Bugula neritina) on a human B-cell chronic lymphocytic leukemia cell line (WSU-CLL) and in a severe combined immune deficient (SCID) mouse xenograft model bearing this cell line. WSU-CLL cells were cultured in RPMI 1640 at a concentration of 2 x 10(5)/ml using a 24-well plate. Agents were added to triplicate wells, and cell count, viability, mitosis, and apoptosis were assessed after 24 h of incubation at 37 degrees C. Results showed that dolastatin 10 had no apparent inhibition of cell growth at concentrations less than 500 pg/ml. Auristatin PE, on the other hand, showed significant growth inhibition at concentrations as low as 50 pg/ml. Auristatin PE-treated cultures, at this concentration, exhibited 27 and 4.5% mitosis and apoptosis, respectively. Dolastatin 10, at the same concentration, did not exert any effect and was comparable with that of control cultures. In the WSU-CLL-SCID mouse xenograft model, the efficacy of these agents alone and in combination with bryostatin 1 was evaluated. Tumor growth inhibition (T/C), tumor growth delay (T-C), and log10 kill for dolastatin 10, auristatin PE, and bryostatin 1 were 14%, 25 days, and 1.98; 2%, 25 days, and 1.98; 19%, 13 days, and 1.03, respectively. Auristatin-PE produced cure in three of five mice, whereas dolastatin 10 showed activity but no cures. When given in combination, auristatin PE + bryostatin 1-treated animals were all free of tumors (five of five) for 150 days and were considered cured. Dolastatin 10 + bryostatin 1-treated animals produced cure in only two of five mice. We conclude that: (a) auristatin-PE is more effective in this model than dolastatin 10; (b) auristatin PE can be administered at a concentration 10

  13. Histological evaluation of intratumoral myxoma virus treatment in an immunocompetent mouse model of melanoma

    PubMed Central

    Doty, Rosalinda A; Liu, Jia; McFadden, Grant; Roy, Edward J; MacNeill, Amy L

    2013-01-01

    Two recombinant myxoma viruses (MYXV expressing a fluorescent protein [MYXV-Tred] and MYXV-Tred encoding murine interleukin-15 [MYXV-IL15]) were evaluated for therapeutic effects in an aggressive B16F10 melanoma model in immunocompetent mice. It was hypothesized that continuous expression of IL-15 within a tumor would recruit cytotoxic effector cells to induce an antitumor immune response and improve treatment efficacy. Weekly intratumoral injections were given to evaluate the effect of treatment on the median survival time of C57BL/6 mice bearing established B16F10 melanomas. Mice that received MYXV-Tred or MYXV-IL15 lived significantly longer than mice given treatment controls. Unexpectedly, the median survival time of MYXV-IL15-treated mice was similar to that of MYXV-treated mice. At 1, 2, and 4 days postinoculation, viral plaque assays detected replicating MYXV-Tred and MYXV-IL15 within treated tumors. At these time points in MYXV-IL15-treated tumors, IL-15 concentration, lymphocyte grades, and cluster of differentiation-3+ cell counts were significantly increased when compared to other treatment groups. However, viral titers, recombinant protein expression, and lymphocyte numbers within the tumors diminished rapidly at 7 days postinoculation. These data indicate that treatment with recombinant MYXV should be repeated at least every 4 days to maintain recombinant protein expression within a murine tumor. Additionally, neutrophilic inflammation was significantly increased in MYXV-Tred- and MYXV-IL15-treated tumors at early time points. It is speculated that neutrophilic inflammation induced by intratumoral replication of recombinant MXYV contributes to the antitumoral effect of MYXV treatment in this melanoma model. These findings support the inclusion of neutrophil chemotaxins in recombinant poxvirus oncolytic virotherapy. PMID:25866742

  14. Histological evaluation of intratumoral myxoma virus treatment in an immunocompetent mouse model of melanoma.

    PubMed

    Doty, Rosalinda A; Liu, Jia; McFadden, Grant; Roy, Edward J; MacNeill, Amy L

    2013-01-01

    Two recombinant myxoma viruses (MYXV expressing a fluorescent protein [MYXV-Tred] and MYXV-Tred encoding murine interleukin-15 [MYXV-IL15]) were evaluated for therapeutic effects in an aggressive B16F10 melanoma model in immunocompetent mice. It was hypothesized that continuous expression of IL-15 within a tumor would recruit cytotoxic effector cells to induce an antitumor immune response and improve treatment efficacy. Weekly intratumoral injections were given to evaluate the effect of treatment on the median survival time of C57BL/6 mice bearing established B16F10 melanomas. Mice that received MYXV-Tred or MYXV-IL15 lived significantly longer than mice given treatment controls. Unexpectedly, the median survival time of MYXV-IL15-treated mice was similar to that of MYXV-treated mice. At 1, 2, and 4 days postinoculation, viral plaque assays detected replicating MYXV-Tred and MYXV-IL15 within treated tumors. At these time points in MYXV-IL15-treated tumors, IL-15 concentration, lymphocyte grades, and cluster of differentiation-3+ cell counts were significantly increased when compared to other treatment groups. However, viral titers, recombinant protein expression, and lymphocyte numbers within the tumors diminished rapidly at 7 days postinoculation. These data indicate that treatment with recombinant MYXV should be repeated at least every 4 days to maintain recombinant protein expression within a murine tumor. Additionally, neutrophilic inflammation was significantly increased in MYXV-Tred- and MYXV-IL15-treated tumors at early time points. It is speculated that neutrophilic inflammation induced by intratumoral replication of recombinant MXYV contributes to the antitumoral effect of MYXV treatment in this melanoma model. These findings support the inclusion of neutrophil chemotaxins in recombinant poxvirus oncolytic virotherapy.

  15. Measurements of tumor cell autophagy predict invasiveness, resistance to chemotherapy, and survival in melanoma

    PubMed Central

    Ma, Xiaohong; Piao, Shengfu; Wang, Dan; Mcafee, Quentin; Nathanson, Katherine L.; Lum, Julian J.; Li, Lin Z.; Amaravadi, Ravi K.

    2011-01-01

    Purpose Autophagy consists of lysosome-dependent degradation of cytoplasmic contents sequestered by autophagic vesicles (AV). The role of autophagy in determining tumor aggressiveness and response to therapy in melanoma was investigated in this study. Experimental Design Autophagy was measured in tumor biopsies obtained from metastatic melanoma patients enrolled on a phase II trial of temozolomide and sorafenib and correlated to clinical outcome. These results were compared to autophagy measurements in aggressive and indolent melanoma cells grown in two and three dimensional culture and as xenograft tumors. The effects of autophagy inhibition with either hydroxychloroquine or inducible shRNA against the autophagy gene ATG5 were assessed in three dimensional spheroids. Results Patients whose tumors had a high autophagic index were less likely to respond to treatment and had a shorter survival compared to those with a low autophagic index. Differences in autophagy were less evident in aggressive and indolent melanoma cells grown in monolayer culture. In contrast, autophagy was increased in aggressive compared to indolent melanoma xenograft tumors. This difference was recapitulated when aggressive and indolent melanoma cells were grown as spheroids. Autophagy inhibition with either hydroxychloroquine or inducible shRNA against ATG5 resulted in cell death in aggressive melanoma spheroids, and significantly augmented temozolomide-induced cell death. Conclusions Autophagy is a potential prognostic factor and therapeutic target in melanoma. Three dimensional culture mimics the tumor microenvironment better than monolayer culture and is an appropriate model for studying therapeutic combinations involving autophagy modulators autophagy inhibition should be tested clinically in patients with melanoma. PMID:21325076

  16. Antrodia camphorata Grown on Germinated Brown Rice Suppresses Melanoma Cell Proliferation by Inducing Apoptosis and Cell Differentiation and Tumor Growth

    PubMed Central

    Song, Minjung; Park, Dong Ki; Park, Hye-Jin

    2013-01-01

    Antrodia camphorata grown on germinated brown rice (CBR) was prepared to suppress melanoma development. CBR extracts were divided into hexane, EtOAc, BuOH, and water fractions. Among all the fractions, EtOAc fraction showed the best suppressive effect on B16F10 melanoma cell proliferation by CCK-8 assay. It also showed the increased cell death and the changed cellular morphology after CBR treatment. Annexin V-FITC/PI, flow cytometry, and western blotting were performed to elucidate anticancer activity of CBR. The results showed that CBR induced p53-mediated apoptotic cell death of B16F10. CBR EtOAc treatment increased melanin content and melanogenesis-related proteins of MITF and TRP-1 expressions, which supports its anticancer activity. Its potential as an anticancer agent was further investigated in tumor-xenografted mouse model. In melanoma-xenografted mouse model, melanoma tumor growth was significantly suppressed under CBR EtOAc fraction treatment. HPLC analysis of CBR extract showed peak of adenosine. In conclusion, CBR extracts notably inhibited B16F10 melanoma cell proliferation through the p53-mediated apoptosis induction and increased melanogenesis. These findings suggest that CBR EtOAc fraction can act as an effective anticancer agent to treat melanoma. PMID:23533475

  17. Antrodia camphorata Grown on Germinated Brown Rice Suppresses Melanoma Cell Proliferation by Inducing Apoptosis and Cell Differentiation and Tumor Growth.

    PubMed

    Song, Minjung; Park, Dong Ki; Park, Hye-Jin

    2013-01-01

    Antrodia camphorata grown on germinated brown rice (CBR) was prepared to suppress melanoma development. CBR extracts were divided into hexane, EtOAc, BuOH, and water fractions. Among all the fractions, EtOAc fraction showed the best suppressive effect on B16F10 melanoma cell proliferation by CCK-8 assay. It also showed the increased cell death and the changed cellular morphology after CBR treatment. Annexin V-FITC/PI, flow cytometry, and western blotting were performed to elucidate anticancer activity of CBR. The results showed that CBR induced p53-mediated apoptotic cell death of B16F10. CBR EtOAc treatment increased melanin content and melanogenesis-related proteins of MITF and TRP-1 expressions, which supports its anticancer activity. Its potential as an anticancer agent was further investigated in tumor-xenografted mouse model. In melanoma-xenografted mouse model, melanoma tumor growth was significantly suppressed under CBR EtOAc fraction treatment. HPLC analysis of CBR extract showed peak of adenosine. In conclusion, CBR extracts notably inhibited B16F10 melanoma cell proliferation through the p53-mediated apoptosis induction and increased melanogenesis. These findings suggest that CBR EtOAc fraction can act as an effective anticancer agent to treat melanoma.

  18. Diagnosis and treatment of concurrent dermal malignant melanoma and melanocytomas in a pygmy hippopotamus (Choeropsis liberiensis).

    PubMed

    Saunders, Richard A; Killick, Rowena S; Barrows, Michelle G; Bowlt, Kelly A; Denk, Daniella

    2017-10-01

    Dermal melanocytic neoplasms are common in some even-toed ungulates (Artiodactyla), yet this entity has not been reported in the pygmy hippopotamus to date. Concurrent occurrence of multiple benign and malignant melanocytic neoplasms is unusual. Malignant transformation occurs in a small percentage of benign melanocytic tumours in people but this phenomenon has not been well documented in animals. To report the diagnosis and treatment of concurrent dermal melanocytomas and malignant melanomas in a pygmy hippopotamus. A 36-year-old intact male pygmy hippopotamus, part of a zoological collection, housed with a 10-year-old female of the same species, presented with multiple raised and pigmented skin masses. Initial impression smears of one ulcerated lesion were consistent with inflammation; subsequent histopathological findings from a skin biopsy revealed an underlying malignant melanoma. The animal was anaesthetised, ultrasonographic imaging of the local lymph nodes indicated no local involvement and all skin lesions were removed. Recovery from anaesthesia was unremarkable, skin healing was within normal limits for the species. There was no sign of recurrence 34 months post-surgery. A diagnosis of malignant melanomas and concurrent melanocytomas was made on histopathological evaluation. To the best of the authors' knowledge, this is the first reported case of melanocytic neoplasia in the pygmy hippopotamus. The occurrence of both benign and malignant melanocytic skin tumours should be considered in this species. © 2017 ESVD and ACVD.

  19. Psoralea glandulosa as a Potential Source of Anticancer Agents for Melanoma Treatment

    PubMed Central

    Madrid, Alejandro; Cardile, Venera; González, César; Montenegro, Ivan; Villena, Joan; Caggia, Silvia; Graziano, Adriana; Russo, Alessandra

    2015-01-01

    With the aim of identifying novel agents with antigrowth and pro-apoptotic activity on melanoma cancer, the present study was undertaken to investigate the biological activity of the resinous exudate of aerial parts from Psoralea glandulosa, and its active components (bakuchiol (1), 3-hydroxy-bakuchiol (2) and 12-hydroxy-iso-bakuchiol (3)) against melanoma cells (A2058). In addition, the effect in cancer cells of bakuchiol acetate (4), a semi-synthetic derivative of bakuchiol, was examined. The results obtained show that the resinous exudate inhibited the growth of cancer cells with IC50 value of 10.5 μg/mL after 48 h of treatment, while, for pure compounds, the most active was the semi-synthetic compound 4. Our data also demonstrate that resin is able to induce apoptotic cell death, which could be related to an overall action of the meroterpenes present. In addition, our data seem to indicate that the apoptosis correlated to the tested products appears, at least in part, to be associated with an increase of reactive oxygen species (ROS) production. In summary, our study provides the first evidence that P. glandulosa may be considered a source of useful molecules in the development of analogues with more potent efficacy against melanoma cells. PMID:25860949

  20. Treatment of posterior uveal melanoma with multi-dose photodynamic therapy.

    PubMed

    Rundle, Paul

    2014-04-01

    To report on the use of multi-dose photodynamic therapy (PDT) in the treatment of posterior uveal melanoma. Prospective case series. 18 patients with posterior uveal melanoma were treated with a minimum of three sessions of PDT. Mean tumour thickness was 1.92 mm (median 1.75, range 0.5-4.4 mm) while the mean basal diameter was 7.1 mm (median 6.3, range 5.2-11 mm). Patients were assessed for visual acuity, complications, tumour status and systemic metastases. In 16 cases, the tumour regressed with stable or improved vision in 15 patients (83%) over a mean follow-up period of 28 months (median 26.5, range 12-44 months). One patient developed an edge recurrence on two occasions ultimately requiring proton beam therapy while one patient showed no response to PDT before being successfully treated with proton beam therapy. Two patients developed scleritis requiring a short course of systemic steroids. No patient developed metastatic disease in the study period. Posterior uveal melanomas may be successfully treated with high dose PDT with retention of good vision in the majority of cases, at least in the short-term. Longer follow-up is required to see if these encouraging results are maintained.

  1. A Micro/Nano Composite for Combination Treatment of Melanoma Lung Metastasis.

    PubMed

    Mi, Yu; Mu, Chaofeng; Wolfram, Joy; Deng, Zaian; Hu, Tony Ye; Liu, Xuewu; Blanco, Elvin; Shen, Haifa; Ferrari, Mauro

    2016-04-20

    The successful treatment of malignant disease generally requires the use of multiple therapeutic agents that are coordinated in a spatiotemporal manner to enable synergy. Here, a porous silicon-based micro/nano composite (MNC) that is capable of simultaneously delivering chemotherapeutic agents and small interfering RNA (siRNA) to the lungs following intravenous injection is designed. The pores of the silicon microparticles are loaded with B-Raf proto-oncogene serine/threonine kinase (BRAF) siRNA-containing liposomes, while the surface is conjugated with docetaxel-encapsulated polymeric nanoparticles. The synergistic antitumor effect of the MNC is demonstrated in vitro in melanoma cells and in vivo using a mouse model for melanoma lung metastasis. The MNC displays superior therapeutic efficacy and increased accumulation in metastatic melanoma lesions in the lungs in comparison to combination therapy with liposomes and polymers. The results indicate that the MNC can be used as an effective delivery vehicle for simultaneous enrichment of multiple therapeutic agents in the lungs. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Psoralea glandulosa as a potential source of anticancer agents for melanoma treatment.

    PubMed

    Madrid, Alejandro; Cardile, Venera; González, César; Montenegro, Ivan; Villena, Joan; Caggia, Silvia; Graziano, Adriana; Russo, Alessandra

    2015-04-09

    With the aim of identifying novel agents with antigrowth and pro-apoptotic activity on melanoma cancer, the present study was undertaken to investigate the biological activity of the resinous exudate of aerial parts from Psoralea glandulosa, and its active components (bakuchiol (1), 3-hydroxy-bakuchiol (2) and 12-hydroxy-iso-bakuchiol (3)) against melanoma cells (A2058). In addition, the effect in cancer cells of bakuchiol acetate (4), a semi-synthetic derivative of bakuchiol, was examined. The results obtained show that the resinous exudate inhibited the growth of cancer cells with IC50 value of 10.5 μg/mL after 48 h of treatment, while, for pure compounds, the most active was the semi-synthetic compound 4. Our data also demonstrate that resin is able to induce apoptotic cell death, which could be related to an overall action of the meroterpenes present. In addition, our data seem to indicate that the apoptosis correlated to the tested products appears, at least in part, to be associated with an increase of reactive oxygen species (ROS) production. In summary, our study provides the first evidence that P. glandulosa may be considered a source of useful molecules in the development of analogues with more potent efficacy against melanoma cells.

  3. Current treatment patterns in non-melanoma skin cancer across Europe.

    PubMed

    Schmook, T; Stockfleth, E

    2003-01-01

    With marked increases in the annual incidence of non-melanoma skin cancer (NMSC) across the globe, its management is of increasing concern to dermatologists. This paper summarises the epidemiology and risk factors and provides an overview of treatment approaches in NMSC across Europe, including surgery, topical 5-fluorouracil and cryotherapy, in the context of the trade-offs that exist in finding optimal treatment outcomes. The paper will also briefly examine new approaches such as immunomodulators and the growing body of data on photodynamic therapy (PDT) using methyl aminolevulinate (MAL), including the authors' personal experience of the efficacy and cosmetic results obtained with these newer therapies.

  4. Cetuximab sensitivity of head and neck squamous cell carcinoma xenografts is associated with treatment-induced reduction in EGFR, pEGFR, and pSrc.

    PubMed

    Jedlinski, Adam; Garvin, Stina; Johansson, Ann-Charlotte; Edqvist, Per-Henrik; Ponten, Fredrik; Roberg, Karin

    2017-10-01

    The aims of this study were to validate in vitro drug sensitivity testing of head and neck squamous cell carcinoma (HNSCC) cell lines in an in vivo xenograft model and to identify treatment-induced changes in the epidermal growth factor receptor (EGFR) signaling pathway that could be used as markers for cetuximab treatment response. The in vitro and in vivo cetuximab sensitivity of two HNSCC cell lines, UT-SCC-14 and UT-SCC-45, was assessed using a crystal violet assay and xenografts in nude mice, respectively. The expression of EGFR, phosphorylated EGFR (pEGFR), phosphorylated Src (pSrc), and Ki-67 was investigated by immunohistochemistry. To verify these results, the in vitro expression of EGFR and pEGFR was analyzed with ELISA in a panel of 10 HNSCC cell lines. A close correlation was found between in vitro and in vivo cetuximab sensitivity data in the two investigated HNSCC cell lines. In treatment sensitive UT-SCC-14 xenografts, there was a decrease in EGFR, pEGFR, and pSrc upon cetuximab treatment. Interestingly, in insensitive UT-SCC-45 xenografts, an increased expression of these three proteins was found. The change in EGFR and pEGFR expression in vivo was confirmed in cetuximab-sensitive and cetuximab-insensitive HNSCC cell lines using ELISA. High sensitivity to cetuximab was strongly associated with a treatment-induced reduction in pEGFR both in vivo and in vitro in a panel of HNSCC cell lines, suggesting that EGFR and pEGFR dynamics could be used as a predictive biomarker for cetuximab treatment response. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Nitric Oxide Synthase Inhibition Enhances the Antitumor Effect of Radiation in the Treatment of Squamous Carcinoma Xenografts

    PubMed Central

    Cardnell, Robert J. G.; Mikkelsen, Ross B.

    2011-01-01

    This study tests whether the nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine (L-NNA), combines favorably with ionizing radiation (IR) in controlling squamous carcinoma tumor growth. Animals bearing FaDu and A431 xenografts were treated with L-NNA in the drinking water. IR exposure was 10 Gy for tumor growth and survival studies and 4 Gy for ex vivo clonogenic assays. Cryosections were examined immunohistochemically for markers of apoptosis and hypoxia. Blood flow was assayed by fluorescent microscopy of tissue cryosections after i.v. injection of fluorospheres. Orally administered L-NNA for 24 hrs reduces tumor blood flow by 80% (p<0.01). Within 24 hrs L-NNA treatment stopped tumor growth for at least 10 days before tumor growth again ensued. The growth arrest was in part due to increased cell killing since a combination of L-NNA and a single 4 Gy IR caused 82% tumor cell killing measured by an ex vivo clonogenic assay compared to 49% by L-NNA or 29% by IR alone. A Kaplan-Meyer analysis of animal survival revealed a distinct survival advantage for the combined treatment. Combining L-NNA and IR was also found to be at least as effective as a single i.p. dose of cisplatin plus IR. In contrast to the in vivo studies, exposure of cells to L-NNA in vitro was without effect on clonogenicity with or without IR. Western and immunochemical analysis of expression of a number of proteins involved in NO signaling indicated that L-NNA treatment enhanced arginase-2 expression and that this may represent vasculature remodeling and escape from NOS inhibition. For tumors such as head and neck squamous carcinomas that show only modest responses to inhibitors of specific angiogenic pathways, targeting NO-dependent pro-survival and angiogenic mechanisms in both tumor and supporting stromal cells may present a potential new strategy for tumor control. PMID:21647438

  6. Geant4 studies of the CNAO facility system for hadrontherapy treatment of uveal melanomas

    NASA Astrophysics Data System (ADS)

    Rimoldi, A.; Piersimoni, P.; Pirola, M.; Riccardi, C.

    2014-06-01

    The Italian National Centre of Hadrontherapy for Cancer Treatment (CNAO -Centro Nazionale di Adroterapia Oncologica) in Pavia, Italy, has started the treatment of selected cancers with the first patients in late 2011. In the coming months at CNAO plans are to activate a new dedicated treatment line for irradiation of uveal melanomas using the available active beam scan. The beam characteristics and the experimental setup should be tuned in order to reach the necessary precision required for such treatments. Collaboration between CNAO foundation, University of Pavia and INFN has started in 2011 to study the feasibility of these specialised treatments by implementing a MC simulation of the transport beam line and comparing the obtained simulation results with measurements at CNAO. The goal is to optimise an eye-dedicated transport beam line and to find the best conditions for ocular melanoma irradiations. This paper describes the Geant4 toolkit simulation of the CNAO setup as well as a modelised human eye with a tumour inside. The Geant4 application could be also used to test possible treatment planning systems. Simulation results illustrate the possibility to adapt the CNAO standard transport beam line by optimising the position of the isocentre and the addition of some passive elements to better shape the beam for this dedicated study.

  7. Uveal Melanoma

    PubMed Central

    Papastefanou, Vasilios P.; Cohen, Victoria M. L.

    2011-01-01

    Uveal melanoma is the most common primary intraocular malignancy and the leading primary intraocular disease which can be fatal in adults. In this paper epidemiologic, pathogenetic, and clinical aspects of uveal melanoma are discussed. Despite the advance in local ocular treatments, there has been no change in patient survival for three decades. Development of metastases affects prognosis significantly. Current survival rates, factors predictive of metastatic potential and metastatic screening algorithms are discussed. Proposed and emerging treatments for uveal melanoma metastases are also overviewed. Current advances in genetics and cytogenetics have provided a significant insight in tumours with high metastatic potential and the molecular mechanisms that underlie their development. Biopsy of those lesions may prove to be important for prognostication and to allow further research into genetic mutations and potential new therapeutic targets in the future. PMID:21773036

  8. Treatment patterns of advanced malignant melanoma (stage III-IV) - A review of current standards in Europe.

    PubMed

    Harries, Mark; Malvehy, Josep; Lebbe, Céleste; Heron, Louise; Amelio, Justyna; Szabo, Zsolt; Schadendorf, Dirk

    2016-06-01

    With the recent emergence of immunotherapies and novel targeted treatments for advanced and metastatic melanoma such as selective B-Raf inhibitors and checkpoint inhibitors, the treatment landscape in Europe has changed considerably. The aim of this review was to provide an overview of current treatment pathways in Europe for the treatment of advanced melanoma, unresectable stage III-IV. A literature search of four databases was conducted to identify publications reporting on the treatment patterns of advanced and metastatic melanoma (stage III-IV) in European populations. Seven full-text publications and two conference abstracts reported on observational studies of melanoma treatment practices in France, Italy and the United Kingdom. Treatment patterns were identified for two time periods: 2005-2009 and 2011-2012. Common treatments reported for both periods included chemotherapy with dacarbazine, fotemustine or temozolomide. The main differences between the two periods were the introduction and prescription of immunotherapy ipilimumab and targeted therapy vemurafenib between 2011 and 2012. Across the three countries studied, the types of treatments prescribed between 2005 and 2009 were relatively similar, however, with noticeable differences in the frequency and priority of administration. Treatment practices for advanced melanoma vary markedly across different European countries and continue to evolve with the introduction of new therapies. The results of this review highlight a considerable evidence gap with regards to recent treatment patterns for advanced melanoma in Europe, especially post-2011 after the introduction of novel therapeutic agents, and more recently with the introduction of programmed cell death 1 inhibitors. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. What Happens after Treatment for Melanoma Skin Cancer?

    MedlinePlus

    ... that is based on their specific situation. Keeping health insurance and copies of your medical records Even after treatment, it’s very important to keep health insurance . Tests and doctor visits cost a lot, and ...

  10. Use of a Non-cross-linked Xenograft (Xenform) in Surgical Treatment of Peyronie's Disease.

    PubMed

    Caraceni, Enrico; Leone, Luca; Utizi, Lilia; Marronaro, Angelo

    2016-09-01

    To evaluate the effectiveness in Peyronie's disease surgical treatment using Xenform, a non-cross-linked graft derived from dermal bovine tissue, to close the defect obtained after plaque incision, without penile prosthesis implant. A further objective is to evaluate the satisfaction of patients. We treated with plaque incision 28 patients with a stable penile curvature ≥60° hindering penetration and with erectile function conserved. International Index of Erectile Function-15 and a not-validated questionnaire constituted of 7 questions about their satisfaction were administered after 1 year of follow-up. Furthermore, specific questions were relative about penile straightening, penile postoperative length, glandular sensitivity, and feeling palpability. Graft is resulted compatible with albugineal features, like thickness, consistency, and elasticity; it is waterproof, allowing the visualization of complete correction of the curvature after the suture. No severe complications were observed except 1 hematoma requiring surgical revision. Sixteen patients were seen after at least 1 year of follow-up. Curvature improvement was obtained in all cases, with the complete straightening in 75%; we did not observe any retraction of the graft and any recurrence on the curvature. Significant reduced glans sensibility and erectile dysfunction were the more frequent postoperative complications, resulting in 43.8% and 25%, respectively. All patients are satisfied with the straightening. Only 2 patients are dissatisfied about the overall result. Plaque incision corporoplasty with Xenform graft is an effective and safe surgical treatment. Xenform is a secure and a reliable albugineal substitute, comparable to other heterologous graft. We have not observed any retraction. Patient's satisfaction is linked to the treatment result and to sexual life. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Microplasma effect on skin scaffold for melanoma cancer treatment

    NASA Astrophysics Data System (ADS)

    Abdullah, Zulaika; Zaaba, S. K.; Mustaffa, M. T.; Mohamad, C. W. S. R.; Zakaria, A.

    2017-03-01

    An atmospheric plasma system using Helium gas was developed. The effect of helium plasma treatment on skin scaffold surface was studied by scanning electron microscopy (SEM). The changes of skin scaffold surfaces before and after helium plasma treatment was recorded. The surface of skin scaffold changed with the prolonged of helium plasma treatment time. The depth of helium plasma penetration was studied using methylene blue dye staining method. The methylene blue will detect the presence or absence of an oxygen that was induced from plasma excitation. The presence of the oxygen indicated on the depth of helium plasma penetration. Results showed plasma are able to penetrate 4mm of skin scaffold after 1200 seconds of exposure.

  12. Red laser cyclophotocoagulation in the treatment of secondary glaucoma in eyes with uveal melanoma.

    PubMed

    Piirtola, Anni; Puska, Päivi; Kivelä, Tero

    2014-01-01

    To evaluate retrospectively the usefulness of the red diode and krypton laser for transscleral contact cyclophotocoagulation (CPC) in the treatment of secondary glaucoma in eyes with uveal melanoma. Twenty-seven eyes of 27 patients (mean age, 66 y; range, 33 to 85 y) with a uveal melanoma and secondary glaucoma were treated with a transscleral 670-nm diode (40 treatments) and 647-nm krypton (5 treatments) laser CPC; 25 eyes had been or were subsequently treated with brachytherapy. The energy used was 420 mW at the tip of the probe (exposure time, 10 s). Seventeen eyes were treated once, 6 eyes twice, and 4 eyes 3 to 6 times. The aim was to preserve vision in 21 patients and to relieve pain in 6 patients. Fourteen patients (52%) died during follow-up. With ≥1 CPCs, the intraocular pressure decreased from a median of 40 mm Hg at baseline to 28 mm Hg at 12 months (n=18) and 23 mm Hg at 24 months (n=10). Hypotony developed in 6 eyes. Before CPC, 12 eyes had a best corrected visual acuity (BCVA) of 20/400 or better. At 12 months, 5 of 18 eyes had BCVA 20/400 or better, and at 24 months 4 of 10 eyes. Four eyes were removed. At the latest visit, 15 of 23 eyes had no light perception, but were preserved. All patients whose aim of treatment was to relieve pain achieved pain relief. CPC lowered intraocular pressure and the number of medications needed for secondary glaucoma in eyes with uveal melanoma, also providing pain relief.

  13. ORAL AMELANOTIC MELANOMA

    PubMed Central

    Adisa, A.O.; Olawole, W.O.; Sigbeku, O.F.

    2012-01-01

    Malignant melanomas of the mucosal regions of the head and neck are extremely rare neoplasms accounting for less than 1% of all melanomas. Approximately half of all head and neck melanomas occur in the oral cavity. Less than 2% of all melanomas lack pigmentation, in the oral mucosa however, up to 75% of cases are amelanotic. No etiologic factors or risk factors have been recognized for oral melanomas. Some authors have suggested that oral habits and selfmedication may be of etiological significance. Oral melanoma is rare but it is relatively frequent in countries like Japan, Uganda, and India. It is rarely identified under the age of 20 years. In Australia where cutaneous melanomas are relatively common primary melanoma of the oral mucosa is rare. The surface architecture of oral melanomas ranges from macular to ulcerated and nodular. The lesion is said to be asymptomatic in the early stages but may become ulcerated and painful in advanced lesions. The diagnosis of amelanotic melanoma is more difficult than that of pigmented lesions. The neoplasm consists of spindle-shaped cells with many mitotic figures and no cytoplasmic melanin pigmentation. Immunohistochemistry using S-100, HMB-45, Melan-A and MART-1 will help in establishing the correct diagnosis. Radical surgery with ample margins and adjuvant chemotherapy are appropriate management protocol for malignant melanoma. Oral melanoma is associated with poor prognosis but its amelanotic variant has even worse prognosis because it exhibits a more aggressive biology and because of difficulty in diagnosis which leads to delayed treatment. PMID:25161399

  14. Treatment outcomes in pediatric melanoma-Are there benefits to specialized care?

    PubMed

    Freemyer, Benjamin; Hamilton, Emma; Warneke, Carla L; Ali, Ali M; Herzog, Cynthia; Hayes-Jordan, Andrea; Austin, Mary

    2016-12-01

    The purpose of this study was to evaluate the impact of hospital specialization on survival in pediatric melanoma. We reviewed all patients under 18years old with cutaneous melanoma evaluated at MD Anderson Cancer Center, a National Cancer Institute (NCI)-designated center, from 2000 to 2014. We compared overall survival (OS) and disease-free survival (DFS) between patients who underwent all treatments at MDACC (Group A, n=146) and those who underwent initial surgical treatment at a non-NCI center (Group B, n=58). Kaplan-Meier survival curves were compared using the log-rank test. Group A patients had significantly better OS and DFS (both p<0.001). Five-year OS was 97% (95% CI 92%-99%) in Group A versus 88% (95% CI 74%-94%) in Group B. Group survival differences were most notable in Stage 3 and 4 patients. Group A patients presenting with stage III or IV disease had a 5-year OS rate of 91.2% (95% CI 75.1%-97.1%) compared to 80.8% (95% CI 59.8%-91.5%) in Group B. The DFS rate was 94.4% (95% CI 88.5%-97.3%) in Group A versus 77.2% (95% CI 62.5%-86.7%) in Group B. Surgical treatment at a comprehensive cancer center may improve outcomes for pediatric melanoma especially for patients presenting with later stage disease. Case-control study: Level III. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Human metastatic melanoma cell lines express high levels of growth hormone receptor and respond to GH treatment.

    PubMed

    Sustarsic, Elahu G; Junnila, Riia K; Kopchick, John J

    2013-11-08

    Accumulating evidence implicates the growth hormone receptor (GHR) in carcinogenesis. While multiple studies show evidence for expression of growth hormone (GH) and GHR mRNA in human cancer tissue, there is a lack of quantification and only a few cancer types have been investigated. The National Cancer Institute's NCI60 panel includes 60 cancer cell lines from nine types of human cancer: breast, CNS, colon, leukemia, melanoma, non-small cell lung, ovarian, prostate and renal. We utilized this panel to quantify expression of GHR, GH, prolactin receptor (PRLR) and prolactin (PRL) mRNA with real-time RT qPCR. Both GHR and PRLR show a broad range of expression within and among most cancer types. Strikingly, GHR expression is nearly 50-fold higher in melanoma than in the panel as a whole. Analysis of human metastatic melanoma biopsies confirmed GHR gene expression in melanoma tissue. In these human biopsies, the level of GHR mRNA is elevated in advanced stage IV tumor samples compared to stage III. Due to the novel finding of high GHR in melanoma, we examined the effect of GH treatment on three NCI60 melanoma lines (MDA-MB-435, UACC-62 and SK-MEL-5). GH increased proliferation in two out of three cell lines tested. Further analysis revealed GH-induced activation of STAT5 and mTOR in a cell line dependent manner. In conclusion, we have identified cell lines and cancer types that are ideal to study the role of GH and PRL in cancer, yet have been largely overlooked. Furthermore, we found that human metastatic melanoma tumors express GHR and cell lines possess active GHRs that can modulate multiple signaling pathways and alter cell proliferation. Based on this data, GH could be a new therapeutic target in melanoma. Published by Elsevier Inc.

  16. Diagnosis and treatment of a dermal malignant melanoma in an African lion (Panthera leo).

    PubMed

    Steeil, James C; Schumacher, Juergen; Baine, Katherine; Ramsay, Edward C; Sura, Patricia; Hodshon, Rebecca; Donnell, Robert L; Lee, Nathan D

    2013-09-01

    A 13-yr-old intact male African lion (Panthera leo) presented with a 4-mo history of left maxillary lip swelling. On physical examination, a 10-cm-diameter, ulcerated, round, firm, and pigmented mass at the level of the left maxillary canine tooth was noticed. All other organ systems examined were within normal limits. Multiple biopsies of the mass were collected and fixed in 10% neutral buffered formalin. Histopathologic evaluation of the biopsies revealed a malignant dermal melanoma. Hematologic and plasma biochemical parameters were within normal reference ranges. Thoracic radiographs taken 3 days following initial presentation showed no evidence of metastasis of the tumor. Computed tomography of the skull and neck was performed to evaluate local tumor invasion and to plan for hypofractionated radiation therapy. Therapy included four weekly treatments of 8 gray external-beam hypofractionated radiation and four bimonthly immunotherapy treatments. Following this treatment regime, the tumor size was reduced by 50%, and surgical excision was performed. No major side effects associated with radiation or immunotherapy were seen. Six months after diagnosis, hematologic and plasma biochemical parameters were within normal limits, thoracic radiographs showed no evidence of metastasis, and the lion showed no clinical signs of disease. The lion will continue to receive immunotherapy every 6 mo for the rest of its life. To the authors' knowledge, this is the first report of a successful treatment of a malignant dermal melanoma with external-beam hypofractionated radiation, immunotherapy, and surgical excision in an African lion.

  17. Upregulated MicroRNA-25 Mediates the Migration of Melanoma Cells by Targeting DKK3 through the WNT/β-Catenin Pathway.

    PubMed

    Huo, Jia; Zhang, Yanfei; Li, Ruilian; Wang, Yuan; Wu, Jiawen; Zhang, Dingwei

    2016-10-27

    Previous research indicates that microRNA-25 (miR-25) regulates carcinogenesis and the progression of various cancers, but the role of miR-25 in melanoma remains unclear. We observed that miR-25 was significantly upregulated in melanoma cell lines and tissue samples. Downregulation of miR-25 markedly suppressed invasion and proliferation of melanoma cells in vitro; however, overexpression of miR-25 markedly increased melanoma cell invasion and proliferation. Moreover, we observed Dickkopf-related protein 3 (DKK3) as a direct target of miR-25 in vitro. Upregulation of DKK3 partially attenuated the oncogenic effect of miR-25 on melanoma cells. Ectopic expression of miR-25 in melanoma cells induced β-catenin accumulation in nuclear and inhibited TCF4 (T cell factor 4) activity, as well as the expression of c-Myc and Cyclin D1. In a nude xenograft model, miR-25 upregulation significantly increased A375 melanoma growth. In summary, miR-25 is upregulated in melanoma and promotes melanoma cell proliferation and invasion, partially by targeting DKK3. These results were indicated that miR-25 may serve as a potential target for the treatment of melanoma in the future.

  18. Upregulated MicroRNA-25 Mediates the Migration of Melanoma Cells by Targeting DKK3 through the WNT/β-Catenin Pathway

    PubMed Central

    Huo, Jia; Zhang, Yanfei; Li, Ruilian; Wang, Yuan; Wu, Jiawen; Zhang, Dingwei

    2016-01-01

    Previous research indicates that microRNA-25 (miR-25) regulates carcinogenesis and the progression of various cancers, but the role of miR-25 in melanoma remains unclear. We observed that miR-25 was significantly upregulated in melanoma cell lines and tissue samples. Downregulation of miR-25 markedly suppressed invasion and proliferation of melanoma cells in vitro; however, overexpression of miR-25 markedly increased melanoma cell invasion and proliferation. Moreover, we observed Dickkopf-related protein 3 (DKK3) as a direct target of miR-25 in vitro. Upregulation of DKK3 partially attenuated the oncogenic effect of miR-25 on melanoma cells. Ectopic expression of miR-25 in melanoma cells induced β-catenin accumulation in nuclear and inhibited TCF4 (T cell factor 4) activity, as well as the expression of c-Myc and Cyclin D1. In a nude xenograft model, miR-25 upregulation significantly increased A375 melanoma growth. In summary, miR-25 is upregulated in melanoma and promotes melanoma cell proliferation and invasion, partially by targeting DKK3. These results were indicated that miR-25 may serve as a potential target for the treatment of melanoma in the future. PMID:27801786

  19. Photothermal therapy combined with dinitrophenyl hapten for the treatment of late stage malignant melanoma

    NASA Astrophysics Data System (ADS)

    Li, Xiaosong; Du, Nan; Li, Haijun; Long, Shan; Chen, Dianjun; Zhou, Feifan; Xu, Yuanyuan; Wang, Fuli; Chen, Wei R.

    2017-02-01

    To evaluate the efficacy and safety of photothermal with dinitrophenyl hapten (DNP) for patients with malignant melanoma (MM), Patients with pathology confirmed stage III or IV MM were enrolled. Seventy-two patients were randomized into two groups, DNP alone group (n=36) and DNP plus photothermal therapy group (n=36). The results showed that the patients in the combination treatment group had longer median progression-free survival time (19.0m vs. 12.0m, p=0.007). No severe adverse events were observed in both groups. Thus, the combination of photothermal therapy and DNP maybe a new therapeutic strategy for patients with advanced MM.

  20. Design of compact electromagnetic impulse radiating antenna for melanoma treatment.

    PubMed

    Arockiasamy, Petrishia; Mohan, Sasikala

    2016-01-01

    Cancer therapy is one of the several new applications which use nanosecond and subnanosecond high voltage pulses. New treatment based on electromagnetic (EM) fields have been developed as non-surgical and minimally invasive treatments of tumors. In particular, subnanosecond pulses can introduce important non-thermal changes in cell biology, especially the permeabilization of the cell membrane. The motivation behind this work is to launch intense subnanosecond pulses to the target (tumors) non-invasively. This works focuses on the design of a compact intense pulsed EM radiating antenna. In tense EM waves radiated at the first focal point of the Prolate Spheroidal Reflector (PSR) are focused at the second focal point where the target (tumor) is present. Two antennas with PSR but fed with different compact wave radiator are designed to focus pulsed field at the second focal point. The PSR with modified bicone antenna feed and PSR with elliptically tapered horn antenna feed are designed. The design parameters and radiation performance are discussed.

  1. Treatment of human colon cancer xenografts with TRA-8 anti-death receptor 5 antibody alone or in combination with CPT-11.

    PubMed

    Oliver, Patsy G; LoBuglio, Albert F; Zinn, Kurt R; Kim, Hyunki; Nan, Li; Zhou, Tong; Wang, Wenquan; Buchsbaum, Donald J

    2008-04-01

    This study was designed to evaluate the in vitro cytotoxicity and in vivo efficacy of TRA-8, a mouse monoclonal antibody that binds to the DR5 death receptor for tumor necrosis factor-related apoptosis-inducing ligand (also called Apo2L), alone and in combination with CPT-11, against human colon cancer cells and xenografts. DR5 expression was assessed on human colon cancer cell lines using flow cytometry, and cellular cytotoxicity after TRA-8 treatment, alone and in combination with SN-38, was determined by measuring cellular ATP levels. Tumor growth inhibition and regression rates of well-established subcutaneous COLO 205, SW948, HCT116, and HT-29 colon cancer xenografts in athymic nude mice treated with TRA-8 or CPT-11 alone and in combination were determined. (99m)Tc-TRA-8 was used to examine tumor localization of TRA-8 in animals bearing each of the four xenografts. In addition, whole-body biodistribution and imaging was carried out in COLO 205-bearing animals using in vivo single-photon emission computed tomography imaging and tissue counting. DR5 expression was highest on HCT116, intermediate on SW948 and COLO 205 cells, and lowest on HT-29 cells. COLO 205 cells were the most sensitive to TRA-8-induced cytotoxicity in vitro, SW948 and HCT116 cell lines were moderately sensitive, and HT-29 cells were resistant. Combination treatment with TRA-8 and SN-38 produced additive to synergistic cytotoxicity against all cell lines compared with either single agent. The levels of apoptosis in all cell lines, including HT-29, were increased by combination treatment with SN-38. In vivo, combination therapy with TRA-8 and CPT-11 was superior to either single-agent regimen for three of the xenografts: COLO 205, SW948, and HCT116. COLO 205 tumors were most responsive to therapy with 73% complete regressions after combination therapy. HT-29 cells derived no antitumor efficacy from TRA-8 therapy. Tumor xenografts established from the four colon cancer cell lines had comparable

  2. Treatment of Human Colon Cancer Xenografts with TRA-8 Anti-death Receptor 5 Antibody Alone or in Combination with CPT-11

    PubMed Central

    Oliver, Patsy G.; LoBuglio, Albert F.; Zinn, Kurt R.; Kim, Hyunki; Nan, Li; Zhou, Tong; Wang, Wenquan; Buchsbaum, Donald J.

    2009-01-01

    Purpose This study was designed to evaluate the in vitro cytotoxicity and in vivo efficacy of TRA-8, a mouse monoclonal antibody that binds to the DR5 death receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L), alone and in combination with CPT-11 against human colon cancer cells and xenografts. Experimental Design DR5 expression was assessed on human colon cancer cell lines using flow cytometry, and cellular cytotoxicity following TRA-8 treatment, alone and in combination with SN-38 was determined by measuring cellular ATP levels. Tumor growth inhibition and regression rates of well-established s.c. COLO 205, SW948, HCT116 and HT-29 colon cancer xenografts in athymic nude mice treated with TRA-8 or CPT-11 alone and in combination were determined. 99mTc-TRA-8 was utilized to examine tumor localization of TRA-8 in animals bearing each of the 4 xenografts. In addition, whole body biodistribution and imaging was carried out in COLO 205 bearing animals using in vivo SPECT imaging and tissue counting. Results DR5 expression was highest on HCT116, intermediate on SW948 and COLO 205 cells, and lowest on HT-29 cells. COLO 205 cells were the most sensitive to TRA-8-induced cytotoxicity in vitro, SW948 and HCT116 cell lines were moderately sensitive, and HT-29 cells were resistant. Combination treatment with TRA-8 and SN-38 produced additive to synergistic cytotoxicity against all cell lines compared to either single agent. The levels of apoptosis in all cell lines, including HT-29, were increased by combination treatment with SN-38. In vivo, combination therapy with TRA-8 and CPT-11 was superior to either single agent regimen for three of the xenografts; COLO 205, SW948, and HCT116. COLO 205 tumors were most responsive to therapy with 73% complete regressions following combination therapy. HT-29 cells derived no anti-tumor efficacy from TRA-8 therapy. Tumor xenografts established from the 4 colon cancer cell lines had comparable specific

  3. Basic and clinical aspects of malignant melanoma

    SciTech Connect

    Nathanson, L. )

    1987-01-01

    This book contains the following 10 chapters: The role of oncogenes in the pathogenesis of malignant melanoma; Laminin and fibronectin modulate the metastatic activity of melanoma cells; Structure, function and biosynthesis of ganglioside antigens associated with human tumors derived from the neuroectoderm; Epidemiology of ocular melanoma; Malignant melanoma: Prognostic factors; Endocrine influences on the natural history of human malignant melanoma; Psychosocial factors associated with prognostic indicators, progression, psychophysiology, and tumor-host response in cutaneous malignant melanoma; Central nervous system metastases in malignant melanoma; Interferon trials in the management of malignant melanoma and other neoplasms: an overview; and The treatment of malignant melanoma by fast neutrons.

  4. Vitamin E δ-tocotrienol triggers endoplasmic reticulum stress-mediated apoptosis in human melanoma cells

    PubMed Central

    Montagnani Marelli, Marina; Marzagalli, Monica; Moretti, Roberta M.; Beretta, Giangiacomo; Casati, Lavinia; Comitato, Raffaella; Gravina, Giovanni L.; Festuccia, Claudio; Limonta, Patrizia

    2016-01-01

    Malignant melanoma is the leading cause of death from skin cancer. Drug toxicity and resistance represent a serious challange for melanoma treatments. Evidence demonstrates that natural compounds may play a crucial role in cancer prevention, growth and progression. Vitamin E tocotrienols (TT) were shown to possess antitumor activity. Here, we analyzed the effects of δ-TT on melanoma cell growth and the involvement of the endoplasmic reticulum (ER) stress in this activity. The experiments were performed on human melanoma cell lines, BLM and A375. δ-TT exerted a significant proapoptotic effect on both cell lines, involving the intrinsic apoptosis pathway; importantly, this compound did not affect the viability of normal human melanocytes. In melanoma cells, δ-TT exerted its antitumor effect through activation of the PERK/p-eIF2α/ATF4/CHOP, IRE1α and caspase-4 ER stress-related branches. Salubrinal, an inhibitor of the ER stress, counteracted the cytotoxic activity of δ-TT. In vivo experiments performed in nude mice bearing A375 xenografts evidenced that δ-TT reduces tumor volume and tumor mass; importantly, tumor progression was significantly delayed by δ-TT treatment. In conclusion, δ-TT exerts a proapoptotic activity on melanoma cells, through activation of the ER stress-related pathways. δ-TT might represent an effective option for novel chemopreventive/therapeutic strategies for melanoma. PMID:27461002

  5. Vitamin E δ-tocotrienol triggers endoplasmic reticulum stress-mediated apoptosis in human melanoma cells.

    PubMed

    Montagnani Marelli, Marina; Marzagalli, Monica; Moretti, Roberta M; Beretta, Giangiacomo; Casati, Lavinia; Comitato, Raffaella; Gravina, Giovanni L; Festuccia, Claudio; Limonta, Patrizia

    2016-07-27

    Malignant melanoma is the leading cause of death from skin cancer. Drug toxicity and resistance represent a serious challange for melanoma treatments. Evidence demonstrates that natural compounds may play a crucial role in cancer prevention, growth and progression. Vitamin E tocotrienols (TT) were shown to possess antitumor activity. Here, we analyzed the effects of δ-TT on melanoma cell growth and the involvement of the endoplasmic reticulum (ER) stress in this activity. The experiments were performed on human melanoma cell lines, BLM and A375. δ-TT exerted a significant proapoptotic effect on both cell lines, involving the intrinsic apoptosis pathway; importantly, this compound did not affect the viability of normal human melanocytes. In melanoma cells, δ-TT exerted its antitumor effect through activation of the PERK/p-eIF2α/ATF4/CHOP, IRE1α and caspase-4 ER stress-related branches. Salubrinal, an inhibitor of the ER stress, counteracted the cytotoxic activity of δ-TT. In vivo experiments performed in nude mice bearing A375 xenografts evidenced that δ-TT reduces tumor volume and tumor mass; importantly, tumor progression was significantly delayed by δ-TT treatment. In conclusion, δ-TT exerts a proapoptotic activity on melanoma cells, through activation of the ER stress-related pathways. δ-TT might represent an effective option for novel chemopreventive/therapeutic strategies for melanoma.

  6. New Perspectives in the Pharmacological Treatment of Non-Melanoma Skin Cancer.

    PubMed

    Savoia, Paola; Cremona, Ottavio; Fava, Paolo

    2016-01-01

    Non-melanoma skin cancers are the most common malignancy in humans, with a basal/squamous cell carcinoma incidence ratio of 4:1 in immunocompetent patients. Basal cell carcinoma rarely metastasizes but commonly causes significant local tissue destruction and disfigurement, whereas squamous cell carcinoma is associated with a substantial risk of recurrence and metastasis; the prognosis in metastatic patients is poor. Surgical approaches give a cure rate greater than 90% if appropriately applied, on the basis of the characteristics of the primary tumors and of the patients, but in selected cases, medical treatment (5-fluorouracil, imiquimod, diclofenac and, more recently, ingenol mebutate) is preferable to invasive procedures and provides a good chance of cure, with generally excellent cosmetic outcomes. In case of advanced and metastatic non-melanoma skin cancer, newly developed molecularly targeted therapy represents a reasonably promising alternative to classical cytostatics. In particular, the monoclonal antibody cetuximab, directed against the epidermal growth factor receptor, is effective and well-tolerated in squamous cell carcinoma patients. Moreover, the recent identification of mutations in the Hedgehog signaling pathway in basal cell carcinoma lead to the development of the smoothened Hedgehog pathway inhibitor vismodegib, that was recently approved for the treatment of locally advanced or metastatic basal cell carcinoma. In this review we provide an overview of the molecular pathways involved in NMSC pathogenesis, focusing on the mechanisms of action, indications, efficacy, side effects and contraindications of new medical treatments that specifically tackle molecular targets of these pathways.

  7. Novel Treatments for Metastatic Cutaneous Melanoma and the Management of Emergent Toxicities

    PubMed Central

    Lemech, Charlotte; Arkenau, Hendrik-Tobias

    2012-01-01

    The last 12 months have seen the beginning of a new era in the treatment options available for patients with metastatic cutaneous melanoma, a disease previously characterised by its poor prognosis and limited treatment options. Two mechanistically diverse agents have now demonstrated an overall survival benefit in different patient subgroups and further clinical trials are ongoing with emerging single agents and novel combinations. The first agent to demonstrate an overall survival benefit was the CTLA-4 antibody, ipilimumab, illustrating the importance of the immune system and immunomodulation in melanoma tumorigenesis. The second group of agents to show a survival benefit were the selective BRAF inhibitors, vemurafenib and GSK2118436, in patients who are BRAF V600 mutation positive. In addition, in the same BRAF mutant patient population, MEK inhibitors also show promising results and are currently under investigation in later stage trials. Although ipilimumab, BRAF and MEK inhibitors are just passing through the clinical trials arena, their use will rapidly become more widespread. Along with their significant clinical benefits, there are also unique adverse events related to these agents. Although the majority are mild and can be managed with supportive treatment, some toxicities require special management strategies. We outline up-to-date clinical development and management guidelines for ipilimumab, as well as the BRAF and MEK inhibitors. PMID:22253555

  8. Paradox-Breaking RAF Inhibitors that Also Target SRC Are Effective in Drug-Resistant BRAF Mutant Melanoma

    PubMed Central

    Girotti, Maria Romina; Lopes, Filipa; Preece, Natasha; Niculescu-Duvaz, Dan; Zambon, Alfonso; Davies, Lawrence; Whittaker, Steven; Saturno, Grazia; Viros, Amaya; Pedersen, Malin; Suijkerbuijk, Bart M.J.M.; Menard, Delphine; McLeary, Robert; Johnson, Louise; Fish, Laura; Ejiama, Sarah; Sanchez-Laorden, Berta; Hohloch, Juliane; Carragher, Neil; Macleod, Kenneth; Ashton, Garry; Marusiak, Anna A.; Fusi, Alberto; Brognard, John; Frame, Margaret; Lorigan, Paul; Marais, Richard; Springer, Caroline

    2015-01-01

    Summary BRAF and MEK inhibitors are effective in BRAF mutant melanoma, but most patients eventually relapse with acquired resistance, and others present intrinsic resistance to these drugs. Resistance is often mediated by pathway reactivation through receptor tyrosine kinase (RTK)/SRC-family kinase (SFK) signaling or mutant NRAS, which drive paradoxical reactivation of the pathway. We describe pan-RAF inhibitors (CCT196969, CCT241161) that also inhibit SFKs. These compounds do not drive paradoxical pathway activation and inhibit MEK/ERK in BRAF and NRAS mutant melanoma. They inhibit melanoma cells and patient-derived xenografts that are resistant to BRAF and BRAF/MEK inhibitors. Thus, paradox-breaking pan-RAF inhibitors that also inhibit SFKs could provide first-line treatment for BRAF and NRAS mutant melanomas and second-line treatment for patients who develop resistance. PMID:25500121

  9. Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanoma.

    PubMed

    Girotti, Maria Romina; Lopes, Filipa; Preece, Natasha; Niculescu-Duvaz, Dan; Zambon, Alfonso; Davies, Lawrence; Whittaker, Steven; Saturno, Grazia; Viros, Amaya; Pedersen, Malin; Suijkerbuijk, Bart M J M; Menard, Delphine; McLeary, Robert; Johnson, Louise; Fish, Laura; Ejiama, Sarah; Sanchez-Laorden, Berta; Hohloch, Juliane; Carragher, Neil; Macleod, Kenneth; Ashton, Garry; Marusiak, Anna A; Fusi, Alberto; Brognard, John; Frame, Margaret; Lorigan, Paul; Marais, Richard; Springer, Caroline

    2015-01-12

    BRAF and MEK inhibitors are effective in BRAF mutant melanoma, but most patients eventually relapse with acquired resistance, and others present intrinsic resistance to these drugs. Resistance is often mediated by pathway reactivation through receptor tyrosine kinase (RTK)/SRC-family kinase (SFK) signaling or mutant NRAS, which drive paradoxical reactivation of the pathway. We describe pan-RAF inhibitors (CCT196969, CCT241161) that also inhibit SFKs. These compounds do not drive paradoxical pathway activation and inhibit MEK/ERK in BRAF and NRAS mutant melanoma. They inhibit melanoma cells and patient-derived xenografts that are resistant to BRAF and BRAF/MEK inhibitors. Thus, paradox-breaking pan-RAF inhibitors that also inhibit SFKs could provide first-line treatment for BRAF and NRAS mutant melanomas and second-line treatment for patients who develop resistance. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  10. The Effect of High Intensity Focused Ultrasound Treatment on Metastases in a Murine Melanoma Model

    NASA Astrophysics Data System (ADS)

    Xing, Yifei; Lu, Xiaochun; Pua, Eric C.; Zhong, Pei

    2009-04-01

    This study aims to assess the risk of high intensity focused ultrasound (HIFU) therapy on the incidence of metastases and to investigate the association of metastasis incidence with HIFU-elicited anti-tumor immunity using a melanoma model. Tumor-bearing legs were amputated immediately after or 2 days following HIFU treatment to influence the elicited anti-tumor immunity. Metastasis rates for groups undergoing amputation immediately after receiving mechanical or thermal HIFU and no treatment were comparable. However, with a 2-day delay in amputation, the corresponding metastasis rates were found to be 6.7% (1/15), 11.8% (2/17) and 40% (8/20), respectively. Animal survival rate was higher and CTL activity was enhanced in the HIFU treatment groups. Thus, HIFU treatment may elicit an anti-tumor immune response that has the potential to be harnessed to improve the overall effectiveness of cancer therapy.

  11. Human metastatic melanoma cell lines express high levels of growth hormone receptor and respond to GH treatment

    SciTech Connect

    Sustarsic, Elahu G.; Junnila, Riia K.; Kopchick, John J.

    2013-11-08

    Highlights: •Most cancer types of the NCI60 have sub-sets of cell lines with high GHR expression. •GHR is highly expressed in melanoma cell lines. •GHR is elevated in advanced stage IV metastatic tumors vs. stage III. •GH treatment of metastatic melanoma cell lines alters growth and cell signaling. -- Abstract: Accumulating evidence implicates the growth hormone receptor (GHR) in carcinogenesis. While multiple studies show evidence for expression of growth hormone (GH) and GHR mRNA in human cancer tissue, there is a lack of quantification and only a few cancer types have been investigated. The National Cancer Institute’s NCI60 panel includes 60 cancer cell lines from nine types of human cancer: breast, CNS, colon, leukemia, melanoma, non-small cell lung, ovarian, prostate and renal. We utilized this panel to quantify expression of GHR, GH, prolactin receptor (PRLR) and prolactin (PRL) mRNA with real-time RT qPCR. Both GHR and PRLR show a broad range of expression within and among most cancer types. Strikingly, GHR expression is nearly 50-fold higher in melanoma than in the panel as a whole. Analysis of human metastatic melanoma biopsies confirmed GHR gene expression in melanoma tissue. In these human biopsies, the level of GHR mRNA is elevated in advanced stage IV tumor samples compared to stage III. Due to the novel finding of high GHR in melanoma, we examined the effect of GH treatment on three NCI60 melanoma lines (MDA-MB-435, UACC-62 and SK-MEL-5). GH increased proliferation in two out of three cell lines tested. Further analysis revealed GH-induced activation of STAT5 and mTOR in a cell line dependent manner. In conclusion, we have identified cell lines and cancer types that are ideal to study the role of GH and PRL in cancer, yet have been largely overlooked. Furthermore, we found that human metastatic melanoma tumors express GHR and cell lines possess active GHRs that can modulate multiple signaling pathways and alter cell proliferation. Based on

  12. Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline - Update 2016.

    PubMed

    Garbe, Claus; Peris, Ketty; Hauschild, Axel; Saiag, Philippe; Middleton, Mark; Bastholt, Lars; Grob, Jean-Jacques; Malvehy, Josep; Newton-Bishop, Julia; Stratigos, Alexander J; Pehamberger, Hubert; Eggermont, Alexander M

    2016-08-01

    Cutaneous melanoma (CM) is potentially the most dangerous form of skin tumour and causes 90% of skin cancer mortality. A unique collaboration of multi-disciplinary experts from the European Dermatology Forum, the European Association of Dermato-Oncology and the European Organisation of Research and Treatment of Cancer was formed to make recommendations on CM diagnosis and treatment, based on systematic literature reviews and the experts' experience. Diagnosis is made clinically using dermoscopy and staging is based upon the AJCC system. CMs are excised with 1-2 cm safety margins. Sentinel lymph node dissection is routinely offered as a staging procedure in patients with tumours >1 mm in thickness, although there is as yet no clear survival benefit for this approach. Interferon-α treatment may be offered to patients with stage II and III melanoma as an adjuvant therapy, as this treatment increases at least the disease-free survival and less clear the overall survival (OS) time. The treatment is however associated with significant toxicity. In distant metastasis, all options of surgical therapy have to be considered thoroughly. In the absence of surgical options, systemic treatment is indicated. For first-line treatment particularly in BRAF wild-type patients, immunotherapy with PD-1 antibodies alone or in combination with CTLA-4 antibodies should be considered. BRAF inhibitors like dabrafenib and vemurafenib in combination with the MEK inhibitors trametinib and cobimetinib for BRAF mutated patients should be offered as first or second line treatment. Therapeutic decisions in stage IV patients should be primarily made by an interdisciplinary oncology team ('Tumour Board'). Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Long-term effects of laser-imiquimod combination in the treatment of late-stage melanoma patients

    NASA Astrophysics Data System (ADS)

    Naylor, Mark F.; Le, Henry; Li, Xiaosong; Nordquist, Robert E.; Hode, Tomas; Liu, Hong; Chen, Wei R.

    2012-03-01

    Topical application of a potent immunological modulator, imiquimod, followed by laser irradiation has been used for the treatment of late-stage melanoma patients. This novel approach, laser-assisted laser immunotherapy (LIT), targets the root course of melanoma, a highly metastatic cancer. We started a phase I clinical trial in 2006 with promising initial outcomes. The laser-imiquimod combination showed significant palliative effects for these patients with multiple treatment cycles. For the returning patients, we found that the recurrent tumors were less aggressive than usually seen in untreated patients. The current protocol uses a light-absorbing dye for selective laser photothermal interaction with a non-invasive treatment mode. It has limitations for patient treatment, particularly for large, deeper tumors, and for patients with dark pigmented skins. This study provides some information on the treated patients (both stage IV and stage IV) during the past several years. We also discuss the future directions of LIT, particularly in the area of photothermal treatment mode with a new approach of interstitial irradiation. The current results in melanoma treatment using LIT indicate that the combination of photothermal therapy and immunological stimulation may hold the key for the treatment of late-stage, metastatic cancers, not only for cutaneous cancers such as melanoma and breast cancer, but also for deep and internal tumors using different operations modes such as interstitial laser irradiation.

  14. Combining the ER-stress inducing agents bortezomib and fenretinide as a novel therapeutic strategy for metastatic melanoma

    PubMed Central

    Hill, David S.; Martin, Shaun; Armstrong, Jane L.; Flockhart, Ross; Tonison, Joge J.; Simpson, Dominic G.; Birch-Machin, Mark A.; Redfern, Christopher P.F.; Lovat, Penny E.

    2010-01-01

    Purpose Single agent chemotherapy is largely the treatment of choice for systemic therapy of metastatic melanoma but survival rates are low and novel adjuvant and systemic therapies are urgently required. Endoplasmic reticulum (ER) stress is a potential therapeutic target and two relatively new drugs, fenretinide and bortezomib (Velcade®), each acting via different cellular mechanisms, induce ER stress leading to apoptosis in melanoma cells. The aim of this study was to test the hypothesis that apoptosis of melanoma cells may be increased by combining clinically-achievable concentrations of fenretinide and bortezomib. Experimental Design Three human melanoma cell lines were used to assess changes in viability and the induction of apoptosis in response to fenretinide, bortezomib, or both drugs together. A subcutaneous xenograft model was used to test responses in vivo. Results Fenretinide and bortezomib synergistically decreased viability and increased apoptosis in all three melanoma lines at clinically-achievable concentrations. This was also reflected by increased expression of GADD153, a marker of ER stress-induced apoptosis. In vivo, fenretinide in combination with bortezomib gave a marked reduction in xenograft tumor volume and increase in apoptosis compared with fenretinide or bortezomib alone. The cell cycle stage of tumor cells in vivo were similar to that predicted from the effects of each drug or the combination in vitro. Conclusions These results suggest that fenretinide and bortezomib, both of which are available in clinical formulation, warrant clinical evaluation as a combination therapy for metastatic melanoma. PMID:19228725

  15. Combining the endoplasmic reticulum stress-inducing agents bortezomib and fenretinide as a novel therapeutic strategy for metastatic melanoma.

    PubMed

    Hill, David S; Martin, Shaun; Armstrong, Jane L; Flockhart, Ross; Tonison, Joge J; Simpson, Dominic G; Birch-Machin, Mark A; Redfern, Christopher P F; Lovat, Penny E

    2009-02-15

    Single-agent chemotherapy is largely the treatment of choice for systemic therapy of metastatic melanoma, but survival rates are low, and novel adjuvant and systemic therapies are urgently required. Endoplasmic reticulum (ER) stress is a potential therapeutic target, and two relatively new drugs, fenretinide and bortezomib (Velcade), each acting via different cellular mechanisms, induce ER stress leading to apoptosis in melanoma cells. The aim of this study was to test the hypothesis that apoptosis of melanoma cells may be increased by combining clinically achievable concentrations of fenretinide and bortezomib. Three human melanoma cell lines were used to assess changes in viability and the induction of apoptosis in response to fenretinide, bortezomib, or both drugs together. A s.c. xenograft model was used to test responses in vivo. Fenretinide and bortezomib synergistically decreased viability and increased apoptosis in all three melanoma lines at clinically achievable concentrations. This was also reflected by increased expression of GADD153, a marker of ER stress-induced apoptosis. In vivo, fenretinide in combination with bortezomib gave a marked reduction in xenograft tumor volume and an increase in apoptosis compared with fenretinide or bortezomib alone. The cell cycle stage of tumor cells in vivo were similar to that predicted from the effects of each drug or the combination in vitro. These results suggest that fenretinide and bortezomib, both of which are available in clinical formulation, warrant clinical evaluation as a combination therapy for metastatic melanoma.

  16. Ginsenoside Rg3-induced EGFR/MAPK pathway deactivation inhibits melanoma cell proliferation by decreasing FUT4/LeY expression.

    PubMed

    Shan, Xiu; Aziz, Faisal; Tian, Li Li; Wang, Xiao Qi; Yan, Qiu; Liu, Ji Wei

    2015-04-01

    Malignant melanoma is a destructive and lethal form of skin cancer with poor prognosis. An effective treatment for melanoma is greatly needed. Ginsenoside Rg3 is a herbal medicine with high antitumor activity. It is reported that abnormal glycosylation is correlated with the tumor cell growth. However, the antitumor effect of Rg3 on melanoma and its mechanism on regulating glycosylation are unknown. We found that Rg3 did not only inhibit A375 melanoma cell proliferation in a dose-dependent manner, but also decreased the expression of fucosyltransferase IV (FUT4) and its synthetic product Lewis Y (LeY), a tumor-associated carbohydrate antigen (TACA). Knocking down FUT4 expression by siRNA dramatically reduced FUT4/LeY level and inhibited cell proliferation through preventing the activation of EGFR/MAPK pathway. Consistently, the inhibitory effect of the Rg3 and FUT4 knockdown on melanoma growth was also seen in a xenograft melanoma mouse model. In conclusion, Rg3 effectively inhibited melanoma cell growth by downregulating FUT4 both in vitro and in vivo. Targeting FUT4/LeY mediated fucosylation by Rg3 inhibited the activation of EGFR/MAPK pathway and prevented melanoma growth. Results from this study suggest Rg3 is a potential novel therapy agent for melanoma treatment.

  17. Development of Bell's Palsy After Treatment With Ipilimumab and Nivolumab for Metastatic Melanoma: A Case Report.

    PubMed

    Zecchini, Julia M; Kim, Sara; Yum, Kendra; Friedlander, Philip

    2017-09-18

    Ipilimumab is a human monoclonal antibody that targets cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and it is FDA approved for the treatment of unresectable or metastatic melanoma. Immune-related adverse events (irAEs) of gastrointestinal, dermatologic, and endocrine origin are commonly seen, ranging between 18% and 44%, with immune checkpoint inhibitors (anti-CTLA-4 and anti-PD-1/PD-L1). Rare irAEs include neurological, renal, and hematologic toxicities. Bell's palsy is a form of neurological toxicity that presents as an idiopathic paralysis of the muscles on one side of the face. We report a case of Bell's palsy in a 45-year-old male patient who received 1 dose of both ipilimumab and nivolumab for the treatment of metastatic melanoma. After the resolution of symptoms, ipilimumab was permanently discontinued and single-agent nivolumab administered. The patient has remained free of neurological symptoms. This case suggests that Bell's palsy is an irAE induced by ipilimumab.

  18. [What to think of "adjuvant" or "neoadjuvant" thermotherapy in the treatment of uveal melanomas?].

    PubMed

    Grange, J D

    2001-02-01

    Before 810Nm laser thermotherapy has been usd for uveal melanoma, several authors especially in Essen (Germany) were asking themselves about the possibilities of xenon arc or argon laser effects on uveal melanomas. High rates of recurrences due to the non penetration of therapeutic light till the sclera had led to the conception of using adjuvant thermotherapy associated with radiotherapy, through microwaves, ultrasounds or ferromagnetic seeds. In Leyden (Netherlands) was proposed the use of 810Nm laser diode initially as an adjuvant to radiotherapy and later on as primary isolated treatment ("neo adjuvant" TTT), especially for small tumours located in the posterior pole (juxta-papillary tumours). TTT used alone should not be proposed for tumours of inital height of more than 3,5 to 4mm. "Neo adjuvant" thermotherapy finds some other indications like decompensated naevi responsible for macular detachment. Bigger peripheral tumours stabilized by protonbeam therapy but associated with persistent detachment after the 12(th) month could be treated with "adjuvant" TTT. Finally the importance of the quality of the tumour edges treatment should be emphasized.

  19. Conservation treatment of the eye: Conformal proton reirradiation for recurrent uveal melanoma

    SciTech Connect

    Marucci, Laura; Lane, Anne M.; Li Wenjun; Egan, Kathleen M.; Gragoudas, Evangelos S.; Adams, Judy; Collier, John M.; Munzenrider, John E. . E-mail: jmunzenrider@partners.org

    2006-03-15

    Purpose: To evaluate the outcomes of a second course of proton beam radiation therapy (PBRT) in patients with recurrent uveal melanoma. Methods and Materials: Thirty-one patients received a second course of PBRT. The mean interval between the first and the second PBRT course was 50.2 months (range, 8-165 months). Most patients (87%) received 70 cobalt Gray equivalent (CGE) for both courses. Visual acuity was 20/200 or better in 30 patients initially and in 22 patients at the second treatment. The mean follow-up time after the second treatment was 50 months (range, 6-164 months). Results: At the time of the last follow-up, 20 patients were classified as having no evidence of disease, defined as tumor regression or an absence of tumor progression. Nine eyes (29%) were enucleated because of local recurrence (n = 5) or intractable pain (n = 4). The 5-year eye retention rate was 55% (95% confidence interval: 25.2-77.4). Six of the 22 patients who retained the eye (27%) had useful vision (20/200 or better). Conclusions A second course of PBRT for recurrent uveal melanoma to total doses between 118 and 140 CGE was associated with a relatively good probability of local control and a low enucleation rate. Although most patients lost vision, the majority were able to retain the reirradiated eye. Further evaluation is needed to assess metastasis-free survival of additional proton irradiation vs. enucleation after local recurrence.

  20. FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma.

    PubMed

    Barone, Amy; Hazarika, Maitreyee; Theoret, Marc R; Mishra-Kalyani, Pallavi; Chen, Huanyu; He, Kun; Sridhara, Rajeshwari; Subramaniam, Sriram; Pfuma, Elimika; Wang, Yaning; Li, Hongshan; Zhao, Hong; Zirkelbach, Jeanne Fourie; Keegan, Patricia; Pazdur, Richard

    2017-10-01

    On December 18, 2015, the FDA granted regular approval to pembrolizumab (KEYTRUDA; Merck Sharp & Dohme Corp.) for treatment of patients with unresectable or metastatic melanoma based on results of two randomized, open-label, active-controlled clinical trials. In trial PN006, 834 patients with ipilimumab-naïve metastatic melanoma were randomized (1:1:1) to pembrolizumab 10 mg/kg i.v. every 2 or 3 weeks until disease progression or ipilimumab 3 mg/kg every 3 weeks for up to four doses. In trial PN002, 540 patients with ipilimumab-refractory metastatic melanoma were randomized (1:1:1) to pembrolizumab 2 or 10 mg/kg i.v. every 3 weeks or to investigator's choice of chemotherapy. In trial PN006, patients randomized to pembrolizumab demonstrated a statistically significant improvement in overall survival compared with ipilimumab [every-2-week arm: hazard ratio (HR) = 0.63; 95% confidence interval (CI), 0.47-0.83; P < 0.001; every-3-week arm: HR = 0.69; 95% CI, 0.52-0.90; P = 0.004]. In both trials, patients receiving pembrolizumab demonstrated statistically significant improvements in progression-free survival. The most common (≥2%) immune-mediated adverse reactions in a pooled safety analysis were hypothyroidism, pneumonitis, and hyperthyroidism. Key considerations for approval were determination of pembrolizumab dose and interpretation of tumor response-based endpoints using RECIST or immune-related RECIST. Clin Cancer Res; 23(19); 5661-5. ©2017 AACR. ©2017 American Association for Cancer Research.

  1. Melanoma complicating treatment with natalizumab for multiple sclerosis: A report from the Southern Network on Adverse Reactions (SONAR).

    PubMed

    Sabol, Rachel A; Noxon, Virginia; Sartor, Oliver; Berger, Joseph R; Qureshi, Zaina; Raisch, Dennis W; Norris, LeAnn B; Yarnold, Paul R; Georgantopoulos, Peter; Hrushesky, William J; Bobolts, Laura; Ray, Paul; Lebby, Akida; Kane, Robert C; Bennett, Charles L

    2017-07-01

    A 43-year-old female with multiple sclerosis developed urethral melanoma. The only potential risk factor was treatment with natalizumab, a humanized monoclonal antibody against α4 integrins. To investigate the risk-exposure relationship, we reviewed this case, all other published cases, and cases of natalizumab-associated melanoma reported to regulatory agencies. Data sources included the Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS) (2004-2014), a FDA Advisory Committee Meeting Report, and peer-reviewed publications. In the United States, the manufacturer maintains an FDA-mandated Tysabri Safety Surveillance Program (part of the Tysabri Outcomes Unified Commitment to Health (TOUCH)) of natalizumab-treated patients. We statistically compared reporting completeness for natalizumab-associated melanoma cases in FAERs for which information was obtained entirely from the TOUCH program versus cases where FAERS information was supplemented by TOUCH program information. FAERS included 137 natalizumab-associated melanoma reports in patients with multiple sclerosis. Median age at melanoma diagnosis was 45 years (range: 21-74 years). Changes in preexisting nevi occurred in 16%, history of cutaneous nevi occurred in 22%, diagnosis within 2 years of beginning natalizumab occurred in 34%, and 74% had primary surgical treatment. Among seven natalizumab-treated MS patients who developed biopsy-confirmed melanoma on treatment and reported in the literature, median age at diagnosis was 41 years (range: 38-48 years); and the melanoma diagnosis occurred following a median of 12 natalizumab doses (range: 1-77 doses). A history of mole or nevi was noted in four patients and a history of prior melanoma was noted in one patient. Completeness scores for reports were significantly lower for FAERS cases reported from the TOUCH program versus FAERS cases supplemented by TOUCH information (median score of 2 vs. 4 items out of 8-possible items, P < 0

  2. In Vitro Treatment of Melanoma Brain Metastasis by Simultaneously Targeting the MAPK and PI3K Signaling Pathways

    PubMed Central

    Daphu, Inderjit; Horn, Sindre; Stieber, Daniel; Varughese, Jobin K.; Spriet, Endy; Dale, Hege Avsnes; Skaftnesmo, Kai Ove; Bjerkvig, Rolf; Thorsen, Frits

    2014-01-01

    Malignant melanoma is the most lethal form of skin cancer, with a high propensity to metastasize to the brain. More than 60% of melanomas have the BRAFV600E mutation, which activates the mitogen-activated protein kinase (MAPK) pathway [1]. In addition, increased PI3K (phosphoinositide 3-kinase) pathway activity has been demonstrated, through the loss of activity of the tumor suppressor gene, PTEN [2]. Here, we treated two melanoma brain metastasis cell lines, H1_DL2, harboring a BRAFV600E mutation and PTEN loss, and H3, harboring WT (wild-type) BRAF and PTEN loss, with the MAPK (BRAF) inhibitor vemurafenib and the PI3K pathway associated mTOR inhibitor temsirolimus. Combined use of the drugs inhibited tumor cell growth and proliferation in vitro in H1_DL2 cells, compared to single drug treatment. Treatment was less effective in the H3 cells. Furthermore, a strong inhibitory effect on the viability of H1_DL2 cells, when grown as 3D multicellular spheroids, was seen. The treatment inhibited the expression of pERK1/2 and reduced the expression of pAKT and p-mTOR in H1_DL2 cells, confirming that the MAPK and PI3K pathways were inhibited after drug treatment. Microarray experiments followed by principal component analysis (PCA) mapping showed distinct gene clustering after treatment, and cell cycle checkpoint regulators were affected. Global gene analysis indicated that functions related to cell survival and invasion were influenced by combined treatment. In conclusion, we demonstrate for the first time that combined therapy with vemurafenib and temsirolimus is effective on melanoma brain metastasis cells in vitro. The presented results highlight the potential of combined treatment to overcome treatment resistance that may develop after vemurafenib treatment of melanomas. PMID:24840574

  3. Surgical treatment of primary melanoma of the umbilicus with sentinel lymph node biopsy and plastic reconstruction: case report and review of the literature.

    PubMed

    Zaccagna, A; Siatis, D; Pisacane, A; Giacone, E; Picciotto, F

    2011-03-01

    AIMS, PATIENTS AND METHODS: The umbilical melanoma is rare, and the surgical treatment can create difficulties for both radical excision and plastic reconstruction. Our aims are to present a case of primary melanoma of the umbilicus and to discuss the best surgical treatment, as well as review the relevant literature. Surgical excision of primary melanoma of the umbilicus must be carried out to reach the peritoneum. Sentinel lymph node biopsy must be carried as well as plastic reconstruction. Despite the progress in new medical therapy for melanoma, suitable surgical excision is, at present, the only treatment able to improve patient prognosis. In this report we describe the surgical treatment and plastic reconstruction of a case of umbilical melanoma. Copyright © 2010 Elsevier Ltd. All rights reserved.

  4. Selumetinib for the treatment of metastatic uveal melanoma: past and future perspectives.

    PubMed

    Komatsubara, Kimberly M; Manson, Daniel K; Carvajal, Richard D

    2016-06-01

    Uveal melanoma is a rare but aggressive subtype of melanoma. Nearly 50% of patients will develop metastatic disease despite primary enucleation or radiation therapy. There is currently no standard of care therapy for metastatic uveal melanoma, and no therapy that has been shown to prolong overall survival. Uveal melanoma is characterized by activation of signaling pathways including the MAPK pathway and the PI3K/AKT pathway, among others, via mutations in the G-α-proteins GNAQ and GNA11. MEK inhibition with selumetinib has been evaluated as a therapeutic strategy in metastatic uveal melanoma. This review will discuss preclinical and clinical studies evaluating selumetinib in metastatic uveal melanoma, as well as potential future perspectives on MEK inhibition in the management of metastatic uveal melanoma.

  5. A potent combination of the novel PI3K inhibitor, GDC-0941, with imatinib in gastrointestinal stromal tumor xenografts: long-lasting responses after treatment withdrawal

    PubMed Central

    Floris, Giuseppe; Wozniak, Agnieszka; Sciot, Raf; Li, Haifu; Friedman, Lori; Van Looy, Thomas; Wellens, Jasmien; Vermaelen, Peter; Deroose, Christophe M.; Fletcher, Jonathan A.; Debiec-Rychter, Maria; Schöffski, Patrick

    2015-01-01

    Introduction Oncogenic signaling in gastrointestinal stromal tumors (GIST) is sustained via PI3K/AKT pathway. We used a panel of six GIST xenograft models to assess efficacy of GDC-0941 as single agent or in combination with imatinib (IMA). Experimental design Nude mice (n=136) were grafted bilaterally with human GIST carrying divers KIT mutations. Mice were orally dosed over four weeks, grouped as follows: A) control; B) GDC-0941; C) IMA and D) GDC+IMA treatments. Xenografts re-growth after treatment discontinuation was assessed in group C and D for additional four weeks. Tumor response was assessed by volume measurements, micro-PET imaging, histopathology and immunoblotting. Moreover genomic alterations in PTEN/PI3K/AKT pathway were evaluated. Results In all models, GDC-0941 caused tumor growth stabilization, inhibiting tumor cells proliferation but did not induce apoptosis. Under GDC+IMA, profound tumor regression, superior to either treatment alone, was observed. This effect was associated with the best histologic response, a nearly complete proliferation arrest and increased apoptosis. Tumor re-growth assays confirmed superior activity of GDC+IMA over IMA; in three out of six models tumor volume remained reduced and stable even after treatment discontinuation. A positive correlation between response to GDC+IMA and PTEN loss, both on gene and protein levels, was found. Conclusion GDC+IMA has significant antitumor efficacy in GIST xenografts, inducing more substantial tumor regression, apoptosis and durable effects than IMA. Notably, after treatment withdrawal, tumor regression was sustained in tumors exposed to GDC+IMA, which was not observed under IMA. Assessment of PTEN status may represent a useful predictive biomarker for patient selection. PMID:23231951

  6. Temozolomide chemoresistance heterogeneity in melanoma with different treatment regimens: DNA damage accumulation contribution.

    PubMed

    Boeckmann, Lars; Nickel, Ann-Christin; Kuschal, Christiane; Schaefer, Annika; Thoms, Kai-Martin; Schön, Michael P; Thomale, Jürgen; Emmert, Steffen

    2011-06-01

    The efficacy of temozolomide in melanoma treatment is low (response rate <20%) and may depend on the activity of O-methylguanine DNA methyltransferase (MGMT) and mismatch repair. We identified melanoma cell lines with different sensitivities to single versus prolonged clinical dosing regimens of temozolomide treatment and assessed a variety of potential resistance mechanisms using this model. We measured mRNA expression and promoter methylation of MGMT and essential mismatch repair genes (MLH1, MSH2). Cell cycle distribution, apoptosis/necrosis induction, O-methylguanine-adduct formation, and ABCB1 gene expression were assessed. We found that three cell lines, MelA, MelB, and MelC, were more sensitive to a single dose regimen than to a prolonged regimen, which would be expected to exhibit higher cytotoxicity. KAII and LIBR cell sensitivity was higher with regard to the prolonged treatment regimen, as expected. Only MelC expressed MGMT. Gene expression correlated well with promoter methylation. Temozolomide exposure did not alter mRNA expression. Different sensitivities to temozolomide were caused neither by delayed apoptosis induction due to early cell cycle arrest nor by O-methylguanine-adduct formation or efflux transporter expression. MelC was the most resistant cell line with rapid elimination of O-methylguanine adducts. This was in good agreement with its MGMT expression. The sensitive cell lines KAII and LIBR accumulated O-methylguanine adducts after a second treatment cycle with temozolomide in contrast with the other three cell lines. We conclude that MGMT expression and DNA adduct accumulation are relevant factors in temozolomide chemosensitivity. Considering individualized temozolomide treatment regimens either by quantification of DNA adducts or by chemosensitivity testing seems worthwhile clinically.

  7. Real-world efficacy, toxicity and clinical management of ipilimumab treatment in metastatic melanoma.

    PubMed

    Khoja, Leila; Atenafu, Eshetu G; Ye, Qian; Gedye, Craig; Chappell, Maryanne; Hogg, David; Butler, Marcus O; Joshua, Anthony M

    2016-02-01

    Approved by the Food and Drug Administration in 2011, the anti-cytotoxic T-lymphocyte-associated protein 4 checkpoint inhibitor ipilimumab has delivered a survival benefit of ≥3 years in a subset of metastatic melanoma patients. After participating in the registration trial, patients were treated with this agent in routine practice. Toxicity and efficacy of agents in "real world" settings may differ from trials. The present study aimed to evaluate, with respect to toxicity and outcome, all patients treated with ipilimumab to date at the Princess Margaret Hospital (Toronto, Canada). Patients treated with ipilimumab between 2008 and 2013 were identified, and patient characteristics (age, gender, tumour burden, oncogenic mutation status, number of treatments received and toxicities from treatment) were collected. Progression-free survival (PFS) and overall survival (OS) were calculated from the commencement of ipilimumab treatment. Associations between clinical characteristics and outcome or toxicity were assessed. Between 2008 and 2013, 129 patients with metastatic cutaneous melanoma were treated. Since, during this period, ipilimumab was approved in the second line setting, ipilimumab was delivered in the second or subsequent line in all patients, and 70% did not receive any further anticancer therapy. Immune-related toxicities were observed, the onset of which varied from 1 to 162 days. The majority resolved within 6 weeks of the final treatment, with the exception of endocrinopathies and bowel related toxicity. The median PFS and OS were 2.83 and 8.44 months, respectively. No pre-treatment factor independently predicted toxicity. The number of infusions (4 vs. ≤3) and presence of toxicity were significantly associated with superior survival. The onset of toxicity secondary to ipilimumab could occur later than previously reported. Toxicities were manageable, but required long-term vigilance.

  8. Real-world efficacy, toxicity and clinical management of ipilimumab treatment in metastatic melanoma

    PubMed Central

    KHOJA, LEILA; ATENAFU, ESHETU G.; YE, QIAN; GEDYE, CRAIG; CHAPPELL, MARYANNE; HOGG, DAVID; BUTLER, MARCUS O.; JOSHUA, ANTHONY M.

    2016-01-01

    Approved by the Food and Drug Administration in 2011, the anti-cytotoxic T-lymphocyte-associated protein 4 checkpoint inhibitor ipilimumab has delivered a survival benefit of ≥3 years in a subset of metastatic melanoma patients. After participating in the registration trial, patients were treated with this agent in routine practice. Toxicity and efficacy of agents in “real world” settings may differ from trials. The present study aimed to evaluate, with respect to toxicity and outcome, all patients treated with ipilimumab to date at the Princess Margaret Hospital (Toronto, Canada). Patients treated with ipilimumab between 2008 and 2013 were identified, and patient characteristics (age, gender, tumour burden, oncogenic mutation status, number of treatments received and toxicities from treatment) were collected. Progression-free survival (PFS) and overall survival (OS) were calculated from the commencement of ipilimumab treatment. Associations between clinical characteristics and outcome or toxicity were assessed. Between 2008 and 2013, 129 patients with metastatic cutaneous melanoma were treated. Since, during this period, ipilimumab was approved in the second line setting, ipilimumab was delivered in the second or subsequent line in all patients, and 70% did not receive any further anticancer therapy. Immune-related toxicities were observed, the onset of which varied from 1 to 162 days. The majority resolved within 6 weeks of the final treatment, with the exception of endocrinopathies and bowel related toxicity. The median PFS and OS were 2.83 and 8.44 months, respectively. No pre-treatment factor independently predicted toxicity. The number of infusions (4 vs. ≤3) and presence of toxicity were significantly associated with superior survival. The onset of toxicity secondary to ipilimumab could occur later than previously reported. Toxicities were manageable, but required long-term vigilance. PMID:26893783

  9. Advanced Melanoma Facebook Live Event

    Cancer.gov

    In case you missed it, watch this recent Facebook Live event about the current state of research and treatment for advanced stage melanoma. To learn more, see our evidence-based information about skin cancer, including melanoma.

  10. A novel compound which sensitizes BRAF wild-type melanoma cells to vemurafenib in a TRIM16-dependent manner

    PubMed Central

    Sutton, Selina K.; Carter, Daniel R.; Kim, Patrick; Tan, Owen; Arndt, Greg M.; Zhang, Xu Dong; Baell, Jonathan; Noll, Benjamin D.; Wang, Shudong; Kumar, Naresh; McArthur, Grant A.; Cheung, Belamy B.; Marshall, Glenn M.

    2016-01-01

    There is an urgent need for better therapeutic options for advanced melanoma patients, particularly those without the BRAFV600E/K mutation. In melanoma cells, loss of TRIM16 expression is a marker of cell migration and metastasis, while the BRAF inhibitor, vemurafenib, induces melanoma cell growth arrest in a TRIM16-dependent manner. Here we identify a novel small molecule compound which sensitized BRAF wild-type melanoma cells to vemurafenib. High throughput, cell-based, chemical library screening identified a compound (C012) which significantly reduced melanoma cell viability, with limited toxicity for normal human fibroblasts. When combined with the BRAFV600E/K inhibitor, vemurafenib, C012 synergistically increased vemurafenib potency in 5 BRAFWT and 4 out of 5 BRAFV600E human melanoma cell lines (Combination Index: CI < 1), and, dramatically reduced colony forming ability. In addition, this drug combination was significantly anti-tumorigenic in vivo in a melanoma xenograft mouse model. The combination of vemurafenib and C012 markedly increased expression of TRIM16 protein, and knockdown of TRIM16 significantly reduced the growth inhibitory effects of the vemurafenib and C012 combination. These findings suggest that the combination of C012 and vemurafenib may have therapeutic potential for the treatment of melanoma, and, that reactivation of TRIM16 may be an effective strategy for patients with this disease. PMID:27447557

  11. Treatment of Head and Neck Melanoma In Situ With Staged Contoured Marginal Excisions.

    PubMed

    Glazer, Evan S; Porubsky, Caitlin F; Francis, Jeffrey D; Ibanez, Jamie; Castner, Nicholas; Messina, Jane L; Sarnaik, Amod A; Harrington, Michael A; Cruse, C Wayne; Sondak, Vernon K; Zager, Jonathan S

    2017-06-01

    Staged marginal evaluation of melanoma in situ (MIS) is performed to avoid reconstruction on positive margins. Contoured marginal excision (CME) is an excision of a 2-mm wide strip of normal-appearing skin taken approximately 5 mm from the visible tumor periphery. If positive, a new CME is excised; the tumor is resected once negative margins are confirmed. The purpose of this study is to report our experience using this technique for the treatment of head/neck MIS. Clinicopathological data were abstracted for all patients who underwent staged CME followed by central tumor resection for head/neck MIS; patients with invasive melanoma were excluded. Statistical analyses included χ test and t test. Overall, 127 patients with MIS were identified. Fifty-six percent were men; the average age was 68 years. The median number of CME procedures per patient was 1 (range, 1-4). Twenty-three percent of patients required more than 1 CME procedure to achieve negative margins. Local recurrence occurred in 3 of 127 patients after a median follow-up of 5 months. Patients requiring multiple CME procedures were more likely to experience local recurrence (P < 0.001). In conclusion, this technique is an effective method to avoid reconstruction on positive MIS margins with high local disease control rates.

  12. The safety of anti PD-1 therapeutics for the treatment of melanoma.

    PubMed

    Ramelyte, Egle; Schindler, Sabrina A; Dummer, Reinhard

    2017-01-01

    The introduction of immunotherapies into clinical practice has substantially improved the prognosis of metastatic melanoma patients as well as patients suffering from other cancers. The two FDA-approved checkpoint inhibitors against PD-1 (nivolumab and pembrolizumab) have been shown to significantly improve patient survival while being less toxic than previous treatment options. Areas covered: The current scientific literature on safety and adverse events (AEs) related to anti-PD-1 therapies has been investigated with special attention to case reports and to the latest results announced at the major clinical cancer and melanoma meetings, including ASCO (American Society of Clinical Oncology), ESMO (European Society of medical Oncology) and EADO (European Association of Dermato-Oncology) annual meetings. Expert opinion: Even though anti-PD-1 therapies are better tolerated than conventional chemo- or other immune-therapies, they still induce a plethora of AEs. Given the mechanism of action, it is supposed that most if not all of them are immune related. Fortunately, the majority are mild and manageable. However, due to the increase in patients' life expectancy, there is a substantial need to understand and prevent severe cutaneous, pulmonary, neurological and other AEs which have major impact on the quality of life. The safety profile after long term use of these medications is still unclear. In addition, non-steroid based immune interventions to control autoimmunity are still to be developed.

  13. Atmospheric-pressure plasma jet characterization and applications on melanoma cancer treatment (B/16-F10)

    NASA Astrophysics Data System (ADS)

    Mashayekh, Shahriar; Rajaee, Hajar; Akhlaghi, Morteza; Shokri, Babak; Hassan, Zuhir M.

    2015-09-01

    A new approach in medicine is the use of cold plasma for various applications such as sterilization blood coagulation and cancer cell treatment. In this paper, a pin-to-hole plasma jet for biological applications has been designed and manufactured and characterized. The characterization includes power consumption via Lissajous method, thermal behavior of atmospheric-pressure plasma jet by using Infra-red camera as a novel method and using Speicair software to determine vibrational and transitional temperatures, and optical emission spectroscopy to determine the generated species. Treatment of Melanoma cancer cells (B16/F10) was also implemented, and tetrazolium salt dye (MTT assay) and flow cytometry were used to evaluate viability. Effect of ultraviolet photons on cancerous cells was also observed using an MgF2 crystal with MTT assay. Finally, in-vivo studies on C57 type mice were also done in order to have a better understanding of the effects in real conditions.

  14. Atmospheric-pressure plasma jet characterization and applications on melanoma cancer treatment (B/16-F10)

    SciTech Connect

    Mashayekh, Shahriar; Rajaee, Hajar; Hassan, Zuhir M.; Akhlaghi, Morteza; Shokri, Babak

    2015-09-15

    A new approach in medicine is the use of cold plasma for various applications such as sterilization blood coagulation and cancer cell treatment. In this paper, a pin-to-hole plasma jet for biological applications has been designed and manufactured and characterized. The characterization includes power consumption via Lissajous method, thermal behavior of atmospheric-pressure plasma jet by using Infra-red camera as a novel method and using Speicair software to determine vibrational and transitional temperatures, and optical emission spectroscopy to determine the generated species. Treatment of Melanoma cancer cells (B16/F10) was also implemented, and tetrazolium salt dye (MTT assay) and flow cytometry were used to evaluate viability. Effect of ultraviolet photons on cancerous cells was also observed using an MgF{sub 2} crystal with MTT assay. Finally, in-vivo studies on C57 type mice were also done in order to have a better understanding of the effects in real conditions.

  15. Nivolumab for the treatment of malignant melanoma in a patient with pre-existing myasthenia gravis.

    PubMed

    Maeda, Osamu; Yokota, Kenji; Atsuta, Naoki; Katsuno, Masahisa; Akiyama, Masashi; Ando, Yuichi

    2016-02-01

    A 79-year-old man with lymph node recurrence of malignant melanoma received nivolumab, an anti-programmed death 1 (PD-1) monoclonal antibody. He had pre-existing ocular myasthenia gravis (MG) and a continued small amount of corticosteroid. Grade 3 creatine phosphokinase elevation appeared after two doses of nivolumab, and the treatment was postponed until it improved to grade 1. After three doses of nivolumab, he experienced diplopia and facial muscle weakness which were consistent with an acute exacerbation of MG, and the symptoms relieved without additional treatment for MG. He achieved shrinkage of metastasis after ten doses of nivolumab. Although a case who died due to MG after administration of nivolumab was reported recently, pre-existing MG is considered not to be always a contraindication of nivolumab.

  16. Monitoring changes in circulating tumour cells as a prognostic indicator of overall survival and treatment response in patients with metastatic melanoma

    PubMed Central

    2014-01-01

    Background New effective treatments for metastatic melanoma greatly improve survival in a proportion of patients. However biomarkers to identify patients that are more likely to benefit from a particular treatment are needed. We previously reported on a multimarker approach for the detection of heterogenous melanoma circulating tumour cells (CTCs). Here we evaluated the prognostic value of this multimarker quantification of CTCs and investigated whether changes in CTC levels during therapy can be used as a biomarker of treatment response and survival outcomes. Methods CTCs were captured by targeting the melanoma associated markers MCSP and MCAM as well as the melanoma stem cell markers ABCB5 and CD271. CTCs were quantified in 27 metastatic melanoma patients treated by surgery or with vemurafenib, ipilimumab or dacarbazine. Patients were enrolled prospectively and CTC counts performed at baseline (prior to treatment), during and after treatment. Results Baseline CTC numbers were not found to be prognostic of overall survival nor of progression free survival. However, a low baseline CTC number was associated with a rapid response to vemurafenib therapy. A decrease in CTCs after treatment initiation was associated with response to treatment and prolonged overall survival in vemurafenib treated patients. Conclusions Measuring changes in CTC numbers during treatment is useful for monitoring therapy response in melanoma patients and for providing prognostic information relating to overall survival. Further studies with larger sample sizes are required to confirm the utility of CTC quantification as a companion diagnostic for metastatic melanoma treatment. PMID:24915896

  17. Monitoring changes in circulating tumour cells as a prognostic indicator of overall survival and treatment response in patients with metastatic melanoma.

    PubMed

    Klinac, Dragana; Gray, Elin S; Freeman, James B; Reid, Anna; Bowyer, Samantha; Millward, Michael; Ziman, Melanie

    2014-06-11

    New effective treatments for metastatic melanoma greatly improve survival in a proportion of patients. However biomarkers to identify patients that are more likely to benefit from a particular treatment are needed. We previously reported on a multimarker approach for the detection of heterogenous melanoma circulating tumour cells (CTCs). Here we evaluated the prognostic value of this multimarker quantification of CTCs and investigated whether changes in CTC levels during therapy can be used as a biomarker of treatment response and survival outcomes. CTCs were captured by targeting the melanoma associated markers MCSP and MCAM as well as the melanoma stem cell markers ABCB5 and CD271. CTCs were quantified in 27 metastatic melanoma patients treated by surgery or with vemurafenib, ipilimumab or dacarbazine. Patients were enrolled prospectively and CTC counts performed at baseline (prior to treatment), during and after treatment. Baseline CTC numbers were not found to be prognostic of overall survival nor of progression free survival. However, a low baseline CTC number was associated with a rapid response to vemurafenib therapy. A decrease in CTCs after treatment initiation was associated with response to treatment and prolonged overall survival in vemurafenib treated patients. Measuring changes in CTC numbers during treatment is useful for monitoring therapy response in melanoma patients and for providing prognostic information relating to overall survival. Further studies with larger sample sizes are required to confirm the utility of CTC quantification as a companion diagnostic for metastatic melanoma treatment.

  18. Reduced Dose and Intermittent Treatment with Lapatinib and Trastuzumab for Potent Blockade of the HER Pathway in HER-2/neu Overexpressing Breast Tumor Xenografts

    PubMed Central

    Rimawi, Mothaffar F.; Wiechmann, Lisa S.; Wang, Yen-Chao; Huang, Catherine; Migliaccio, Ilenia; Wu, Meng-Fen; Gutierrez, Carolina; Hilsenbeck, Susan G.; Arpino, Grazia; Massarweh, Suleiman; Ward, Robin; Soliz, Robert; Osborne, C. Kent; Schiff, Rachel

    2010-01-01

    Purpose We have shown that incomplete blockade of the Human Epidermal Growth Factor (HER) pathway is a mechanism of resistance to treatment with trastuzumab (T) in HER2-overexpressing tumor xenografts. We now investigate whether the addition of lapatinib (L), a dual HER1/2 kinase inhibitor, to T results in more potent inhibition of the pathway and therefore inhibition of tumor growth, and whether reduced dose and intermittent treatment with the combination is equally effective. Experimental Design Nude mice bearing HER2-overexpressing MCF7/HER2-18 or BT474 xenograft tumors were treated with L, T, alone or in various combinations with other HER inhibitors. L+T for short duration (14, 42 days), intermittent administration (14 days on/off), and reduced dosing (1/2 dose) was also investigated. Inhibition of tumor growth, downstream signaling, proliferation, and induction of apoptosis were assessed. All statistical tests were two-sided. Results L+T was the most effective regimen in both MCF7/HER2-18 and BT474 xenografts with complete tumor regression (CR) observed in all mice. Intermittent and reduced dose treatment (½ dose) resulted in high rates of CR and low rates of tumor recurrence that were comparable to full dose continuous treatment. L+T resulted in significantly reduced downstream signaling and proliferation, and increased apoptosis. Conclusions L+T is a potent and effective combination even when given in reduced dose or intermittent schedule potentially resulting in lower toxicity and reduced cost if translated to patients. These findings warrant timely clinical testing. PMID:21138857

  19. Comparison of a treatment strategy combining CCI-779 plus DTIC versus DTIC monotreatment in human melanoma in SCID mice.

    PubMed

    Thallinger, Christiane; Werzowa, Johannes; Poeppl, Wolfgang; Kovar, Florian M; Pratscher, Barbara; Valent, Peter; Quehenberger, Peter; Joukhadar, Christian

    2007-10-01

    This study compares the antineoplastic potential of a novel treatment strategy combining cell cycle inhibitor-779 (CCI-779) plus dacarbazine (DTIC) versus DTIC monotreatment, the current chemotherapeutic mainstay in combating metastatic melanoma. A controlled four-group parallel study design comprising 24-40 mice per tumor cell line was used in a severe combined immunodeficiency (SCID)-mouse xenotransplantation model. SCID mice were injected with 518A2, Mel-JUSO, or 607B human melanoma cells. After they developed tumors, mice received daily CCI-779 or solvent over 14 days. From treatment day 4-8 mice were additionally injected with DTIC or saline. Treatment with CCI-779 plus DTIC was superior to single agent DTIC in two out of three cell lines (P<0.05). The tumor weight reduction was 44+/-17 and 61+/-6% compared with DTIC monotreatment in Mel-JUSO and 607B melanomas, respectively (P<0.05). In contrast, in 518A2 xenotransplants, CCI-779 plus DTIC treatment was as effective as DTIC monotreatment. CCI-779 monotherapy exerted no statistically significant antitumor effect. Collectively, these data indicate that CCI-779 has the potential to increase the chemotherapeutic efficacy, as the combination of CCI-779 plus DTIC proved to be more efficacious compared to DTIC monotherapy in two out of three melanoma cell lines in vivo.

  20. Combination with γ-secretase inhibitor prolongs treatment efficacy of BRAF inhibitor in BRAF-mutated melanoma cells.

    PubMed

    Zhu, Guannan; Yi, Xiuli; Haferkamp, Sebastian; Hesbacher, Sonja; Li, Chunying; Goebeler, Matthias; Gao, Tianwen; Houben, Roland; Schrama, David

    2016-06-28

    Oncogenic triggering of the MAPK pathway in melanocytes results in senescence, and senescence escape is considered as one critical step for melanocytic transformation. In melanoma, induction of a senescent-like state by BRAF-inhibitors (BRAFi) in a fraction of treated cells - instead of killing - contributes to the repression of tumor growth, but may also provide a source for relapse. Here, we demonstrate that NOTCH activation in melanocytes is not only growth-promoting but it also protects these cells against oncogene-induced senescence. In turn, treatment of melanoma cells with an inhibitor of the NOTCH-activating enzyme γ-secretase led to induction of a senescent-like status in a fraction of the cells but overall achieved only a moderate inhibition of melanoma cell growth. However, combination of γ-secretase inhibitor (GSI) with BRAFi markedly increased the treatment efficacy particularly in long-term culture. Moreover, even melanoma cells starting to regrow after continuous BRAFi treatment - the major problem of BRAFi therapy in patients - can still be affected by the combination treatment. Thus, combining GSI with BRAFi increases the therapeutic efficacy by, at least partially, prolonging the senescent-like state of treated cells. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  1. Peripheral blood Th9 cells are a possible pharmacodynamic biomarker of nivolumab treatment efficacy in metastatic melanoma patients.

    PubMed

    Nonomura, Yumi; Otsuka, Atsushi; Nakashima, Chisa; Seidel, Judith A; Kitoh, Akihiko; Dainichi, Teruki; Nakajima, Saeko; Sawada, Yu; Matsushita, Shigeto; Aoki, Megumi; Takenouchi, Tatsuya; Fujimura, Taku; Hatta, Naohito; Koreeda, Satoshi; Fukushima, Satoshi; Honda, Tetsuya; Kabashima, Kenji

    2016-01-01

    Although nivolumab is associated with a significant improvement in overall survival and progression-free survival, only 20 to 40% of patients experience long-term benefit. It is therefore of great interest to identify a predictive marker of clinical benefit for nivolumab. To address this issue, the frequencies of CD4(+) T cell subsets (Treg, Th1, Th2, Th9, Th17 and Th22), CD8(+) T cells, and serum cytokine levels (IFNγ, IL-4, IL-9, IL-10, TGF-β) were assessed in 46 patients with melanoma. Eighteen patients responded to nivolumab, and the other 28 patients did not. An early increase in Th9 cell counts during the treatment with nivolumab was associated with an improved clinical response. Before the first nivolumab infusion, the responders displayed elevated serum concentrations of TGF-β compared to non-responders. Th9 induction by IL-4 and TGF-β was enhanced by PD-1/PD-L1 blockade in vitro. The role of IL-9 in disease progression was further assessed using a murine melanoma model. In vivo IL-9 blockade promoted melanoma progression in mice using an autochthonous mouse melanoma model, and the cytotoxic ability of murine melanoma-specific CD8(+) T cells was enhanced in the presence of IL-9 in vitro. These findings suggest that Th9 cells, which produce IL-9, play an important role in the successful treatment of melanoma patients with nivolumab. Th9 cells therefore represent a valid biomarker to be further developed in the setting of anti-PD-1 therapy.

  2. Eosinophilic Fasciitis and Acute Encephalopathy Toxicity from Pembrolizumab Treatment of a Patient with Metastatic Melanoma.

    PubMed

    Khoja, Leila; Maurice, Catherine; Chappell, MaryAnne; MacMillan, Leslie; Al-Habeeb, Ayman S; Al-Faraidy, Nada; Butler, Marcus O; Rogalla, Patrik; Mason, Warren; Joshua, Anthony M; Hogg, David

    2016-03-01

    Anti-PD-1 inhibitors have significant activity in metastatic melanoma. Responses often occur early and may be sustained. The optimal duration of treatment with these agents is unknown. Here, we report the case of a 51-year-old woman treated with pembrolizumab, as part of the Keynote-001 trial, as first-line treatment for metastatic disease. She experienced a complete response after 13.8 months of treatment with no adverse events. One month after the last drug infusion and 18 months from starting treatment, the patient presented with eosinophilic fasciitis. She then developed acute confusion and weakness, thought to be due to intracranial vasculitis. High-dose steroids were initiated with resolution of the fasciitis. Aspirin was commenced for presumed vasculitis with resolution of the neurologic symptoms. To our knowledge, there are no previous reports of eosinophilic fasciitis or cerebral vasculitis due to anti-PD-1 agents. This case demonstrates that toxicity may occur in association with pembrolizumab treatment after a prolonged period of treatment without toxicity. Future trials should explore the optimal duration of treatment with pembrolizumab.

  3. A word of caution: do not wake sleeping dogs; micrometastases of melanoma suddenly grew after progesterone treatment

    PubMed Central

    2013-01-01

    Background Hormonal treatment might affect the immune response to tumor antigens induced in cancer patients who are being vaccinated. Case presentation A 33 years-old woman was diagnosed with cutaneous melanoma in May 2009. Her melanoma was located in the intermammary sulcus, had a Breslow thickness of 4 mm, a Clark’s level IV, it was ulcerated and highly melanotic. The bilateral sentinel node biopsy was negative. She entered into a randomized Phase II/III clinical study comparing a vaccine composed of irradiated melanoma cells plus BCG plus GM-CSF versus IFN-alpha 2b and she was assigned to the vaccine arm. During the two years treatment she remained disease-free; the final CAT scan being performed in August 2011. Between November and December 2011, her gynecologist treated her with three cycles of 200 mg progesterone/day for ten days, every two weeks, for ovary dysfunction. In November 2011 the patient returned to the Hospital for clinical and imaging evaluation and no evidence of disease was found. At the next visit in March 2012 an ultrasound revealed multiple, large metastases in the liver. A CAT scan confirmed the presence of liver, adrenal glands and spleen metastases. A needle biopsy of a liver lesion revealed metastatic melanoma of similar characteristics to the original tumor. We suggest that progesterone treatment triggered proliferation of so far dormant micrometastases that were controlled during CSF470 vaccine treatment. Conclusion The use of progesterone in patients with melanoma that are under immunological treatments should be carefully considered, since progesterone could modify the balance of pro-inflammatory and Th1 functions to a regulatory and anti-inflammatory profile of the immune system that could have an impact in tumor progression. PMID:23510193

  4. Topical treatment of melanoma metastases with imiquimod, plus administration of a cancer vaccine, promotes immune signatures in the metastases.

    PubMed

    Mauldin, Ileana S; Wages, Nolan A; Stowman, Anne M; Wang, Ena; Olson, Walter C; Deacon, Donna H; Smith, Kelly T; Galeassi, Nadedja; Teague, Jessica E; Smolkin, Mark E; Chianese-Bullock, Kimberly A; Clark, Rachael A; Petroni, Gina R; Marincola, Francesco M; Mullins, David W; Slingluff, Craig L

    2016-10-01

    Infiltration of cancers by T cells is associated with improved patient survival and response to immune therapies; however, optimal approaches to induce T cell infiltration of tumors are not known. This study was designed to assess whether topical treatment of melanoma metastases with the TLR7 agonist imiquimod plus administration of a multipeptide cancer vaccine will improve immune cell infiltration of melanoma metastases. Eligible patients were immunized with a vaccine comprised of 12 melanoma peptides and a tetanus toxoid-derived helper peptide, and imiquimod was applied topically to metastatic tumors daily. Adverse events were recorded, and effects on the tumor microenvironment were evaluated from sequential tumor biopsies. T cell responses were assessed by IFNγ ELIspot assay and T cell tetramer staining. Patient tumors were evaluated for immune cell infiltration, cytokine and chemokine production, and gene expression. Four eligible patients were enrolled, and administration of imiquimod and vaccination were well tolerated. Circulating T cell responses to the vaccine was detected by ex vivo ELIspot assay in 3 of 4 patients. Treatment of metastases with imiquimod induced immune cell infiltration and favorable gene signatures in the patients with circulating T cell responses. This study supports further study of topical imiquimod combined with vaccines or other immune therapies for the treatment of melanoma.

  5. Combined inhibition of MEK and Plk1 has synergistic anti-tumor activity in NRAS mutant melanoma

    PubMed Central

    Vujic, I; Sanlorenzo, M; Ma, J; Kim, ST; Kleffel, S; Schatton, T; Rappersberger, K; Gutteridge, R; Ahmad, N; Ortiz/Urda, S

    2015-01-01

    About one third of cancers harbor activating mutations in rat sarcoma viral oncogene homolog (RAS) oncogenes. In melanoma, aberrant neuroblastoma-RAS (NRAS) signaling fuels tumor progression in about 20% of patients. Current therapeutics for NRAS driven malignancies barely impact overall survival. To date, pathway interference downstream of mutant NRAS seems to be the most promising approach. In this study, data revealed that mutant NRAS induced Plk1 expression, and pharmacologic inhibition of Plk1 stabilized the size of NRAS mutant melanoma xenografts. The combination of MEK and Plk1 inhibitors resulted in a significant growth reduction of NRAS mutant melanoma cells in vitro, and regression of xenografted NRAS mutant melanoma in vivo. Independent cell cycle arrest and increased induction of apoptosis underlies the synergistic effect of this combination. Data further suggest that the p53 signaling pathway is of key importance to the observed therapeutic efficacy. This study provides in vitro, in vivo and first mechanistic data, that a MEK/Plk1 inhibitor combination might be a promising treatment approach for patients with NRAS driven melanoma. Since mutant NRAS signaling is similar across different malignancies, this inhibitor combination could also offer a previously unreported treatment modality for NRAS mutant tumors of other cell origins. PMID:26016894

  6. INFα-2b inhibitory effects on CD4(+)CD25(+)FOXP3(+) regulatory T cells in the tumor microenvironment of C57BL/6 J mice with melanoma xenografts.

    PubMed

    Yu, Yang; Huang, Run; Zong, Xiangyun; He, Xiangming; Mo, Wenju

    2016-07-07

    Regulatory T cells (Tregs), particularly the CD4(+)CD25(+)Foxp3(+) Tregs, down regulate immunity and promote tumor cell growth by directly suppressing CD8(+) and CD4(+) T cells. Alternatively they can promote tumor growth by generating interleukin-10 (IL-10) and transforming growth factor β (TGFβ) in situ, which help tumor cells to evade the immune system. In vivo tumor models were prepared via subcutaneous injection with a suspension of B16 melanoma cells into the left upper flank of C57BL/6 J mice. The mice were randomized into five groups: radiotherapy (RT), chemotherapy (CT), radiochemotherapy (RCT), Inteferon α (INFα) groups, and a control group. Flow cytometry was used to determine the Tregs levels in the spleen and peripheral blood, and immunohistochemistry was performed to determine the expression levels of TGFβ and IL-10 in the tumor microenvironment. Tumor weight was significantly reduced in the CT or RCT groups (40.91 % and 41.83 %, respectively), while the reduction in tumor weight was relatively lower for the RT and IFNα groups (15.10 % and 13.15 %, respectively). The flow cytometry results showed that the ratios of CD4(+)CD25(+)Foxp3(+) Tregs to lymphocytes and CD4(+) cells in the spleen and in peripheral blood were significantly decreased after treatment with IFNα (P < 0.05). Expression of TGFβ and IL-10 in the tumor microenvironment in the CT and RT groups was higher compared with the control group (P < 0.01), while the expression of TGFβ and IL-10 in the INFα group was not significantly different (P > 0.05). The results show that INFα-2b inhibits cancer cell immune evasion by decreasing the levels of CD4(+)CD25(+)Foxp3(+) Tregs and suppressing the expression of TGFβ and IL-10 in the tumor microenvironment.

  7. Allosteric MEK1/2 inhibitors including cobimetanib and trametinib in the treatment of cutaneous melanomas.

    PubMed

    Roskoski, Robert

    2017-03-01

    The Ras-Raf-MEK-ERK (Map kinase) cellular pathway is a highly conserved eukaryotic signaling module that transduces extracellular signals from growth factors and cytokines into intracellular regulatory events that are involved in cell growth and proliferation or the contrary pathway of cell differentiation. Dysregulation of this pathway occurs in more than one-third of all malignancies, a process that has fostered the development of targeted Map kinase pathway inhibitors. Cutaneous melanomas, which arise from skin melanocytes, are the most aggressive form of skin cancer. Mutations that activate the Map kinase pathway occur in more than 90% of these melanomas. This has led to the development of the combination of dabrafenib and trametinib or vemurafenib and cobimetanib for the treatment of BRAF V600E mutant melanomas. Dabrafenib and vemurafenib target V600E/K BRAF mutants while trametinib and cobimetanib target MEK1/2. The latter two agents bind to MEK1/2 at a site that is adjacent to, but separate from, the ATP-binding site and are therefore classified as type III allosteric protein kinase inhibitors. These agents form a hydrogen bond with a conserved β3-lysine and they make numerous hydrophobic contacts with residues within the αC-helix, the β5 strand, and within the activation segment, regions of the protein kinase domain that exhibit greater diversity than those found within the ATP-binding site. One advantage of such allosteric inhibitors is that they do not have to compete with millimolar concentrations of cellular ATP, which most FDA-approved small molecule competitive inhibitors such as imatinib must do. Owing to the wide spread activation of this pathway in numerous neoplasms, trametinib and cobimetinib are being studied in combination with other targeted and cytotoxic drugs in a variety of clinical situations. Except for BRAF and NRAS mutations, there are no other biomarkers correlated with treatment responses following MEK1/2 inhibition and the

  8. Characteristics of malignant melanoma cells in the treatment with fast neutrons

    SciTech Connect

    Tsunemoto, H.; Morita, S.; Mori, S. )

    1989-07-01

    The radioresistance of malignant melanoma cells has been explained by the wide shoulder of the dose-cell-survival curve of the cells exposed to photon beams. Fast neutrons, 30 MeV d-Be, were used to treat patients who had malignant melanoma in order to confirm the biological effects of high linear energy transfer (LET) radiation for tumor control. Seventy-two patients suffering from malignant melanoma participated in the clinical trials with fast neutrons between November 1975 and December 1986. Of 72 patients, 45 had melanoma of the skin, 20 had melanoma of the head and neck, and seven had choroidal melanoma. Five-year survival rate of the patients who had previously untreated melanoma of the skin was 61% and for patients who received postoperative irradiation, it was 35.7% whereas no patients who had recurrent tumor survived over 4 years. Of 22 patients who had melanoma of the skin, stage I, local control in four cases was achieved by irradiation alone, whereas local control was achieved in 17 of 18 patients who required salvage surgery after fast-neutron therapy. The results of pathological studies performed with specimens obtained from salvage surgery have shown that melanoma cells growing in intradermal tissue are radioresistant, compared with cells growing in intraepidermal tissue. This might suggest that melanoma cells acquire radioresistance when the connective tissue is involved. Five-year survival rate of the patients who had locally advanced melanoma of the head and neck, previously untreated, was 15.4%. Radiation therapy with accelerated protons was suitable for patients suffering from choroidal melanoma.

  9. Characteristics of Mel Ibr Melanoma Line Subclone after Treatment with Chicken Embryo Extract.

    PubMed

    Suraeva, N M; Morozova, L F; Ryabaya, O O; Khochenkova, Yu A; Samoilov, A V; Burova, O S; Golubtsova, N V; Barmashov, A E; Baryshnikova, M A

    2017-06-01

    We continue analysis of the phenotype of human melanoma cell Mel Ibr subclone obtained previously by treatment of the parental cell line by chicken embryo extract. The present study is focused on detection of markers of epithelial-mesenchymal transition that determine enhanced metastatic and invasive potential of malignant tumors of various locations. Analysis of the expression of E-cadherin and vimentin genes in the subclone and parental cells detected activation of epithelial-mesenchymal transition in the subclone. Immunological markers CD90, CD271, and CD95 were present in the parental population, but were not detected on the subclone cells. In contrast to the parental line, cells of the analyzed subclone retain viability in serum-free medium and formed vessel-like structures characteristic of vasculogenic mimicry.

  10. INPP4B is upregulated and functions as an oncogenic driver through SGK3 in a subset of melanomas

    PubMed Central

    Wilmott, James S.; Guo, Xiang Yun; Yan, Xu Guang; Wang, Chun Yan; Liu, Xiao Ying; Jin, Lei; Tseng, Hsin-Yi; Liu, Tao; Croft, Amanda; Hondermarck, Hubert; Scolyer, Richard A.; Jiang, Chen Chen; Zhang, Xu Dong

    2015-01-01

    Inositol polyphosphate 4-phosphatase type II (INPP4B) negatively regulates PI3K/Akt signalling and has a tumour suppressive role in some types of cancers. However, we have found that it is upregulated in a subset of melanomas. Here we report that INPP4B can function as an oncogenic driver through activation of serum- and glucocorticoid-regulated kinase 3 (SGK3) in melanoma. While INPP4B knockdown inhibited melanoma cell proliferation and retarded melanoma xenograft growth, overexpression of INPP4B enhanced melanoma cell and melanocyte proliferation and triggered anchorage-independent growth of melanocytes. Noticeably, INPP4B-mediated melanoma cell proliferation was not related to activation of Akt, but was mediated by SGK3. Upregulation of INPP4B in melanoma cells was associated with loss of miRNA (miR)-494 and/or miR-599 due to gene copy number reduction. Indeed, overexpression of miR-494 or miR-599 downregulated INPP4B, reduced SGK3 activation, and inhibited melanoma cell proliferation, whereas introduction of anti-miR-494 or anti-miR-599 upregulated INPP4B, enhanced SGK3 activation, and promoted melanoma cell proliferation. Collectively, these results identify upregulation of INPP4B as an oncogenic mechanism through activation of SGK3 in a subset of melanomas, with implications for targeting INPP4B and restoring miR-494 and miR-599 as novel approaches in the treatment of melanomas with high INPP4B expression. PMID:26573229

  11. Electrochemotherapy by pulsed electromagnetic field treatment (PEMF) in mouse melanoma B16F10 in vivo.

    PubMed

    Kranjc, Simona; Kranjc, Matej; Scancar, Janez; Jelenc, Jure; Sersa, Gregor; Miklavcic, Damijan

    2016-03-01

    Pulsed electromagnetic field (PEMF) induces pulsed electric field, which presumably increases membrane permeabilization of the exposed cells, similar to the conventional electroporation. Thus, contactless PEMF could represent a promising approach for drug delivery. Noninvasive electroporation was performed by magnetic field pulse generator connected to an applicator consisting of round coil. Subcutaneous mouse B16F10 melanoma tumors were treated with intravenously injection of cisplatin (CDDP) (4 mg/kg), PEMF (480 bipolar pulses, at frequency of 80 Hz, pulse duration of 340 μs) or with the combination of both therapies (electrochemotherapy - PEMF + CDDP). Antitumor effectiveness of treatments was evaluated by tumor growth delay assay. In addition, the platinum (Pt) uptake in tumors and serum, as well as Pt bound to the DNA in the cells and Pt in the extracellular fraction were measured by inductively coupled plasma mass spectrometry. The antitumor effectiveness of electrochemotherapy with CDDP mediated by PEMF was comparable to the conventional electrochemotherapy with CDDP, with the induction of 2.3 days and 3.0 days tumor growth delay, respectively. The exposure of tumors to PEMF only, had no effect on tumor growth, as well as the injection of CDDP only. The antitumor effect in combined treatment was related to increased drug uptake into the electroporated tumor cells, demonstrated by increased amount of Pt bound to the DNA. Approximately 2-fold increase in cellular uptake of Pt was measured. The obtained results in mouse melanoma model in vivo demonstrate the possible use of PEMF induced electroporation for biomedical applications, such as electrochemotherapy. The main advantages of electroporation mediated by PEMF are contactless and painless application, as well as effective electroporation compared to conventional electroporation.

  12. Electrochemotherapy by pulsed electromagnetic field treatment (PEMF) in mouse melanoma B16F10 in vivo

    PubMed Central

    Kranjc, Simona; Kranjc, Matej; Scancar, Janez; Jelenc, Jure; Sersa, Gregor

    2016-01-01

    Introduction Pulsed electromagnetic field (PEMF) induces pulsed electric field, which presumably increases membrane permeabilization of the exposed cells, similar to the conventional electroporation. Thus, contactless PEMF could represent a promising approach for drug delivery. Materials and methods Noninvasive electroporation was performed by magnetic field pulse generator connected to an applicator consisting of round coil. Subcutaneous mouse B16F10 melanoma tumors were treated with intravenously injection of cisplatin (CDDP) (4 mg/kg), PEMF (480 bipolar pulses, at frequency of 80 Hz, pulse duration of 340 μs) or with the combination of both therapies (electrochemotherapy − PEMF + CDDP). Antitumor effectiveness of treatments was evaluated by tumor growth delay assay. In addition, the platinum (Pt) uptake in tumors and serum, as well as Pt bound to the DNA in the cells and Pt in the extracellular fraction were measured by inductively coupled plasma mass spectrometry. Results The antitumor effectiveness of electrochemotherapy with CDDP mediated by PEMF was comparable to the conventional electrochemotherapy with CDDP, with the induction of 2.3 days and 3.0 days tumor growth delay, respectively. The exposure of tumors to PEMF only, had no effect on tumor growth, as well as the injection of CDDP only. The antitumor effect in combined treatment was related to increased drug uptake into the electroporated tumor cells, demonstrated by increased amount of Pt bound to the DNA. Approximately 2-fold increase in cellular uptake of Pt was measured. Conclusions The obtained results in mouse melanoma model in vivo demonstrate the possible use of PEMF induced electroporation for biomedical applications, such as electrochemotherapy. The main advantages of electroporation mediated by PEMF are contactless and painless application, as well as effective electroporation compared to conventional electroporation. PMID:27069448

  13. Sequential treatment with cytarabine and decitabine has an increased anti-leukemia effect compared to cytarabine alone in xenograft models of childhood acute myeloid leukemia.

    PubMed

    Leonard, Sarah M; Perry, Tracey; Woodman, Ciarán B; Kearns, Pamela

    2014-01-01

    The current interest in epigenetic priming is underpinned by the belief that remodelling of the epigenetic landscape will sensitise tumours to subsequent therapy. In this pre-clinical study, paediatric AML cells expanded in culture and primary AML xenografts were treated with decitabine, a DNA demethylating agent, and cytarabine, a frontline cytotoxic agent used in the treatment of AML, either alone or in combination. Sequential treatment with decitabine and cytarabine was found to be more effective in reducing tumour burden than treatment with cytarabine alone suggesting that the sequential delivery of these agents may a have real clinical advantage in the treatment of paediatric AML. However we found no evidence to suggest that this outcome was dependent on priming with a hypomethylating agent, as the benefits observed were independent of the order in which these drugs were administered.

  14. Human Xenografts Are Not Rejected in a Naturally Occurring Immunodeficient Porcine Line: A Human Tumor Model in Pigs

    PubMed Central

    Basel, Matthew T.; Balivada, Sivasai; Beck, Amanda P.; Kerrigan, Maureen A.; Pyle, Marla M.; Dekkers, Jack C.M.; Wyatt, Carol R.; Rowland, Robert R.R.; Anderson, David E.; Bossmann, Stefan H.

    2012-01-01

    Abstract Animal models for cancer therapy are invaluable for preclinical testing of potential cancer treatments; however, therapies tested in such models often fail to translate into clinical settings. Therefore, a better preclinical model for cancer treatment testing is needed. Here we demonstrate that an immunodeficient line of pigs can host and support the growth of xenografted human tumors and has the potential to be an effective animal model for cancer therapy. Wild-type and immunodeficient pigs were injected subcutaneously in the left ear with human melanoma cells (A375SM cells) and in the right ear with human pancreatic carcinoma cells (PANC-1). All immunodeficient pigs developed tumors that were verified by histology and immunohistochemistry. Nonaffected littermates did not develop tumors. Immunodeficient pigs, which do not reject xenografted human tumors, have the potential to become an extremely useful animal model for cancer therapy because of their similarity in size, anatomy, and physiology to humans. PMID:23514746

  15. Fisetin, a dietary flavonoid, augments the anti-invasive and anti-metastatic potential of sorafenib in melanoma

    PubMed Central

    Pal, Harish C.; Diamond, Ariana C.; Strickland, Leah R.; Kappes, John C.; Katiyar, Santosh K.; Elmets, Craig A.; Athar, Mohammad; Afaq, Farrukh

    2016-01-01

    Melanoma is the most aggressive and deadly form of cutaneous neoplasm due to its propensity to metastasize. Oncogenic BRAF drives sustained activation of the BRAF/MEK/ERK (MAPK) pathway and cooperates with PI3K/AKT/mTOR (PI3K) signaling to induce epithelial to mesenchymal transition (EMT), leading to cell invasion and metastasis. Therefore, targeting these pathways is a promising preventive/therapeutic strategy. We have shown that fisetin, a flavonoid, reduces human melanoma cell invasion by inhibiting EMT. In addition, fisetin inhibited melanoma cell proliferation and tumor growth by downregulating the PI3K pathway. In this investigation, we aimed to determine whether fisetin can potentiate the anti-invasive and anti-metastatic effects of sorafenib in BRAF-mutated melanoma. We found that combination treatment (fisetin + sorafenib) more effectively reduced the migration and invasion of BRAF-mutated melanoma cells both in vitro and in raft cultures compared to individual agents. Combination treatment also effectively inhibited EMT as observed by a decrease in N-cadherin, vimentin and fibronectin and an increase in E-cadherin both in vitro and in xenograft tumors. Furthermore, combination therapy effectively inhibited Snail1, Twist1, Slug and ZEB1 protein expression compared to monotherapy. The expression of MMP-2 and MMP-9 in xenograft tumors was further reduced in combination treatment compared to individual agents. Bioluminescent imaging of athymic mice, intravenously injected with stably transfected CMV-luciferase-ires-puromycin. T2A.EGFP-tagged A375 melanoma cells, demonstrated fewer lung metastases following combination treatment versus monotherapy. Our findings demonstrate that fisetin potentiates the anti-invasive and anti-metastatic effects of sorafenib. Our data suggest that fisetin may be a worthy adjuvant chemotherapy for the management of melanoma. PMID:26517521

  16. Fisetin, a dietary flavonoid, augments the anti-invasive and anti-metastatic potential of sorafenib in melanoma.

    PubMed

    Pal, Harish C; Diamond, Ariana C; Strickland, Leah R; Kappes, John C; Katiyar, Santosh K; Elmets, Craig A; Athar, Mohammad; Afaq, Farrukh

    2016-01-12

    Melanoma is the most aggressive and deadly form of cutaneous neoplasm due to its propensity to metastasize. Oncogenic BRAF drives sustained activation of the BRAF/MEK/ERK (MAPK) pathway and cooperates with PI3K/AKT/mTOR (PI3K) signaling to induce epithelial to mesenchymal transition (EMT), leading to cell invasion and metastasis. Therefore, targeting these pathways is a promising preventive/therapeutic strategy. We have shown that fisetin, a flavonoid, reduces human melanoma cell invasion by inhibiting EMT. In addition, fisetin inhibited melanoma cell proliferation and tumor growth by downregulating the PI3K pathway. In this investigation, we aimed to determine whether fisetin can potentiate the anti-invasive and anti-metastatic effects of sorafenib in BRAF-mutated melanoma. We found that combination treatment (fisetin + sorafenib) more effectively reduced the migration and invasion of BRAF-mutated melanoma cells both in vitro and in raft cultures compared to individual agents. Combination treatment also effectively inhibited EMT as observed by a decrease in N-cadherin, vimentin and fibronectin and an increase in E-cadherin both in vitro and in xenograft tumors. Furthermore, combination therapy effectively inhibited Snail1, Twist1, Slug and ZEB1 protein expression compared to monotherapy. The expression of MMP-2 and MMP-9 in xenograft tumors was further reduced in combination treatment compared to individual agents. Bioluminescent imaging of athymic mice, intravenously injected with stably transfected CMV-luciferase-ires-puromycin.T2A.EGFP-tagged A375 melanoma cells, demonstrated fewer lung metastases following combination treatment versus monotherapy. Our findings demonstrate that fisetin potentiates the anti-invasive and anti-metastatic effects of sorafenib. Our data suggest that fisetin may be a worthy adjuvant chemotherapy for the management of melanoma.

  17. Research progress in advanced melanoma.

    PubMed

    Luo, Cong; Shen, Jiayu

    2017-07-01

    Melanoma is a malignant tumor with high rate of metastasis and poor prognosis. How melanoma develops and how to treat it will continue to be a hot topic. This review briefly summarizes the mechanism of melanoma development and the latest progress in its treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. The Effect of High Intensity Focused Ultrasound Treatment on Metastases in a Murine Melanoma Model

    PubMed Central

    Xing, Yifei; Lu, Xiaochun; Pua, Eric C.; Zhong, Pei

    2009-01-01

    This study aims to assess the risk of high intensity focused ultrasound (HIFU) therapy on the incidence of distant metastases and to investigate its association with HIFU-elicited anti-tumor immunity in a murine melanoma (B16-F10) model. Tumor-bearing legs were amputated immediately after or 2 days following HIFU treatment to differentiate the contribution of the elicited anti-tumor immunity. In mice undergoing amputation immediately after mechanical, thermal, or no HIFU treatment, metastasis rates were comparable (18.8%, 13.3% and 12.5 %). In contrast, with a 2-day delay in amputation, the corresponding metastasis rates were 6.7%, 11.8% and 40%, respectively. Animal survival rate was higher and CTL activity was enhanced in the HIFU treatment groups. Altogether, our results suggest that HIFU treatment does not increase the risk of distant metastasis. Instead, HIFU treatment can elicit an anti-tumor immune response that may be harnessed to improve the overall effectiveness and quality of cancer therapy. PMID:18727919

  19. Sargramostim plus Ipilimumab vs Ipilimumab Alone for Treatment of Metastatic Melanoma: A Randomized Clinical Trial

    PubMed Central

    Hodi, F. Stephen; Lee, Sandra; McDermott, David F.; Rao, Uma N.; Butterfield, Lisa H.; Tarhini, Ahmad A.; Leming, Philip; Puzanov, Igor; Shin, Donghoon; Kirkwood, John M.

    2015-01-01

    Importance Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) blockade with ipilimumab prolongs survival in metastatic melanoma patients. CTLA-4 blockade and granulocyte-macrophage colony stimulating factor (GM-CSF) secreting tumor vaccine combinations demonstrate therapeutic synergy in pre-clinical models. A key issue is whether systemic GM-CSF synergizes with CTLA-4 blockade. Objective To compare the effect of sargramostim plus ipilimumab vs ipilimumab alone on overall survival in patients with metastatic melanoma. Design, Setting, and Participants A phase II randomized clinical trial was conducted in the United States by Eastern Cooperative Oncology Group between December 28, 2010 and July 28, 2011. Patients with unresectable stage III or IV melanoma, ≥one prior therapy, no CNS metastases, and ECOG performance status 0/1 were eligible. Interventions Patients were randomized to ipilimumab 10 mg/kilogram intravenously day 1 plus sargramostim 250 μg subcutaneously days 1-14 of 21 day cycles versus ipilimumab alone. Ipilimumab treatment included induction for four cycles followed by maintenance every fourth cycle. Main Outcomes and Measures Primary was comparison of the length of overall survival. Secondary was progression-free survival, response rate, safety, and tolerability. Results A total of 245 patients were treated. Median follow-up was 13.3 months (range; .03-19.9). Median overall survival for sargramostim plus ipilimumab was 17.5 months (95% CI; 14.9, not reached) compared to 12.7 months (95% CI; 10.0, not reached) for ipilimumab. One-year survival rate for sargramostim was 68.9% (95% CI; 60.6%, 85.5%) compared to 52.9% (95% CI; 43.6%, 62.2%) with ipilimumab (stratified logrank one-sided P=.01; mortality hazard ratio .64, one-sided 90% repeated CI (not applicable, .90)). A planned interim analysis was conducted at 69.8% (104 observed/ 149 planned deaths) information time. O'Brien-Fleming boundary was crossed for improvement in overall survival. There

  20. Effectiveness of hydrogen peroxide and electron-beam irradiation treatment for removal and inactivation of viruses in equine-derived xenografts.

    PubMed

    Cusinato, Riccardo; Pacenti, Monia; Martello, Thomas; Fattori, Paolo; Morroni, Marco; Palù, Giorgio

    2016-06-01

    Bone grafting is a common procedure for bone reconstruction in dentistry, orthopedics, and neurosurgery. A wide range of grafts are currently used, and xenografts are regarded as an interesting alternative to autogenous bone because all mammals share the same bone mineral component composition and morphology. Antigens must be eliminated from bone grafts derived from animal tissues in order to make them biocompatible. Moreover, the processing method must also safely inactivate and/or remove viruses or other potential infectious agents. This study assessed the efficacy of two steps applied in manufacturing some equine-derived xenografts: hydrogen-peroxide and e-beam sterilization treatments for inactivation and removal of viruses in equine bone granules (cortical and cancellous) and collagen and pericardium membranes. Viruses belonging to three different human viral species (Herpes simplex virus type 1, Coxsackievirus B1, and Influenzavirus type A H1N1) were selected and used to spike semi-processed biomaterials. For each viral species, the tissue culture infective dose (TCID50) on cell lines and the number of genome copies through qPCR were assessed. Both treatments were found to be effective at virus inactivation. Considering the model viruses studied, the application of hydrogen peroxide and e-beam irradiation could also be considered effective for processing bone tissue of human origin. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. 18F-fluorothymidine PET/CT as an early predictor of tumor response to treatment with cetuximab in human lung cancer xenografts.

    PubMed

    Takeuchi, Satoshi; Zhao, Songji; Kuge, Yuji; Zhao, Yan; Nishijima, Ken-Ichi; Hatano, Toshiyuki; Shimizu, Yasushi; Kinoshita, Ichiro; Tamaki, Nagara; Dosaka-Akita, Hirotoshi

    2011-09-01

    We investigated whether 18F-fluorothymidine-positron-emission tomography/computed tomography (18F-FLT-PET/CT) is useful for the evaluation of the very early response to anti-epidermal growth factor receptor (EGFR) antibody cetuximab therapy in human lung cancer xenografts. A human tumor xenograft model was established with a human non-small cell lung cancer cell line. The mice were randomly assigned to four groups: tumor growth follow-up, ex vivo study, PET/CT imaging and non-treated control. Mice were administered saline as control or cetuximab on day 1. An immunohistochemical study with Ki-67 was performed. Tumor volume treated with cetuximab was kept significantly smaller than control after day 8, although there was no difference on day 3. On day 3, 18F-FLT distribution was higher in the tumor than in other tissues, and was significantly decreased by treatment with cetuximab. On PET/CT imaging, 18F-FLT distribution in the tumor was clearly visualized, and the maximum standardized uptake value (SUV) was significantly decreased after treatment with cetuximab (p<0.01). Ki-67 expression was also significantly decreased on day 3 (p=0.01). These results suggest that 18F-FLT-PET/CT can be a useful predictor to determine the response to molecular targeted drugs such as cetuximab at an earlier time point than the change of tumor size.

  2. Treatment with the PI3K inhibitor buparlisib (NVP-BKM120) suppresses the growth of established patient-derived GBM xenografts and prolongs survival in nude rats.

    PubMed

    Netland, I A; Førde, H E; Sleire, L; Leiss, L; Rahman, M A; Skeie, B S; Miletic, H; Enger, P Ø; Goplen, D

    2016-08-01

    Glioblastomas (GBMs) are aggressive brain tumours with a dismal prognosis, despite combined surgery, radio- and chemotherapy. Close to 90 % of all GBMs harbour a deregulated PI3K pathway, which is essential in regulating central cellular functions such as proliferation, cell growth, motility and survival. Thus, PI3K represents a potential target for molecular therapy in GBM. We investigated the anti-tumour efficacy of the PI3K inhibitor buparlisib (NVP-BKM120) in GBM cell lines in vitro and in vivo, when treatment was initiated after MRI-confirmed tumour engraftment. We found that buparlisib inhibited glioma cell proliferation in a dose dependent manner, demonstrated by MTS assay, manual cell count and BrdU incorporation. A dose dependent increase in apoptosis was observed through flow cytometric analysis. Furthermore, by immunocytochemistry and western blot, we found a dose dependent inhibition of Akt phosphorylation. Moreover, buparlisib prolonged survival of nude rats harboring human GBM xenografts in three independent studies and reduced the tumours' volumetric increase, as determined by MRI. In addition, histological analyses of xenograft rat brains showed necrotic areas and change in tumour cell nuclei in buparlisib-treated animals. The rats receiving buparlisib maintained their weight, activity level and food- and water intake. In conclusion, buparlisib effectively inhibits glioma cell proliferation in vitro and growth of human GBM xenografts in nude rats. Moreover, the compound is well tolerated when administered at doses providing anti-tumour efficacy. Thus, buparlisib may have a future role in glioma therapy, and further studies are warranted to validate this compound for human use.

  3. The initial experience of electronic brachytherapy for the treatment of non-melanoma skin cancer

    PubMed Central

    2010-01-01

    Background Millions of people are diagnosed with non-melanoma skin cancers (NMSC) worldwide each year. While surgical approaches are the standard treatment, some patients are appropriate candidates for radiation therapy for NMSC. High dose rate (HDR) brachytherapy using surface applicators has shown efficacy in the treatment of NMSC and shortens the radiation treatment schedule by using a condensed hypofractionated approach. An electronic brachytherapy (EBT) system permits treatment of NMSC without the use of a radioactive isotope. Methods Data were collected retrospectively from patients treated from July 2009 through March 2010. Pre-treatment biopsy was performed to confirm a malignant cutaneous diagnosis. A CT scan was performed to assess lesion depth for treatment planning, and an appropriate size of surface applicator was selected to provide an acceptable margin. An HDR EBT system delivered a dose of 40.0 Gy in eight fractions twice weekly with 48 hours between fractions, prescribed to a depth of 3-7 mm. Treatment feasibility, acute safety, efficacy outcomes, and cosmetic results were assessed. Results Thirty-seven patients (mean age 72.5 years) with 44 cutaneous malignancies were treated. Of 44 lesions treated, 39 (89%) were T1, 1 (2%) Tis, 1 (2%) T2, and 3 (7%) lesions were recurrent. Lesion locations included the nose for 16 lesions (36.4%), ear 5 (11%), scalp 5 (11%), face 14 (32%), and an extremity for 4 (9%). Median follow-up was 4.1 months. No severe toxicities occurred. Cosmesis ratings were good to excellent for 100% of the lesions at follow-up. Conclusions The early outcomes of EBT for the treatment of NMSC appear to show acceptable acute safety and favorable cosmetic outcomes. Using a hypofractionated approach, EBT provides a convenient treatment schedule. PMID:20875139

  4. Treatment of an amelanotic melanoma using radiation therapy in a lesser Madagascar hedgehog tenrec (Echinops telfairi).

    PubMed

    Harrison, Tara M; Dominguez, Pedro; Hanzlik, Kim; Sikarskie, James G; Agnew, Dalen; Bergin, Ingrid; Fitzgerald, Scott D; Kitchell, Barbara E; McNiel, Elizabeth

    2010-03-01

    A 15-yr-old, male lesser Madagascar hedgehog tenrec (Echinops telfairi) presented with a mass caudal to the right ear. Cytology suggested a sarcoma. Surgical removal was attempted. Histology was consistent with a soft tissue sarcoma. The mass recurred within 331 days post operation. Radiation therapy was initiated. Computed tomography was used for staging in conjunction with three-dimensional computerized treatment planning software to permit accurate lesion localization and to optimize normal tissue sparing. A total dose of 6,480 cGy was administered in 24 fractions over 46 days. Transient hind limb paresis developed during the course of the radiation therapy, but resolved after 7 days with prednisone treatment. Minimal acute radiation toxicity was observed. The mass responded with at least a 90% reduction in volume following radiation treatment. The animal survived 266 days from the initiation of treatment. On necropsy, a small mass and granulation tissue were found at the site of the initial neoplasm, indicating good regional control of the tumor; however, extensive metastases to the spleen and liver were present. Immunohistochemically, the original, recurrent, and metastatic populations were strongly positive for HMB 45 and weakly positive for S-100, and the final diagnosis was metastatic amelanotic melanoma.

  5. Topical treatment of all-trans retinoic acid inhibits murine melanoma partly by promoting CD8(+) T-cell immunity.

    PubMed

    Yin, Wei; Song, Yan; Liu, Qing; Wu, Yunyun; He, Rui

    2017-10-01

    All-trans retinoic acid (atRA), the main biologically active metabolite of vitamin A, has been implicated in immunoregulation and anti-cancer. A recent finding that vitamin A could decrease the risk of melanoma in humans indicates the beneficial role of atRA in melanoma. However, it remains unknown whether topical application of atRA could inhibit melanoma growth by influencing tumour immunity. We demonstrate topical application of tretinoin ointment (atRA as the active ingredient) effectively inhibited B16F10 melanoma growth. This is accompanied by markedly enhanced CD8(+) T-cell responses, as evidenced by significantly increased proportions of effector CD8(+) T cells expressing granzyme B, tumour necrosis factor-α, or interferon-γ, and Ki67(+) proliferating CD8(+) T cells in atRA-treated tumours compared with vaseline controls. Furthermore, topical atRA treatment promoted the differentiation of effector CD8(+) T cells in draining lymph nodes (DLN) of tumour-bearing mice. Interestingly, atRA did not affect tumoral CD4(+) T-cell response, and even inhibited the differentiation of interferon-γ-expressing T helper type 1 cells in DLN. Importantly, we demonstrated that the tumour-inhibitory effect of atRA was partly dependent on CD8(+) T cells, as CD8(+) T-cell depletion restored tumour volumes in atRA-treated mice, which, however, was still significantly smaller than those in vaseline-treated mice. Finally, we demonstrated that atRA up-regulated MHCI expression in B16F10 cells, and DLN cells from tumour-bearing mice had a significantly higher killing rate when culturing with atRA-treated B16F10 cells. Hence, our study demonstrates that topical atRA treatment effectively inhibits melanoma growth partly by promoting the differentiation and the cytotoxic function of effector CD8(+) T cells. © 2017 John Wiley & Sons Ltd.

  6. Toward the development of a novel non-RGD cyclic peptide drug conjugate for treatment of human metastatic melanoma

    PubMed Central

    Redko, Boris; Tuchinsky, Helena; Segal, Tamar; Tobi, Dror; Luboshits, Galia; Ashur-Fabian, Osnat; Pinhasov, Albert; Gerlitz, Gabi; Gellerman, Gary

    2017-01-01

    The newly discovered short (9 amino acid) non-RGD S-S bridged cyclic peptide ALOS-4 (H-cycl(Cys-Ser-Ser-Ala-Gly-Ser-Leu-Phe-Cys)-OH), which binds to integrin αvβ3 is investigated as peptide carrier for targeted drug delivery against human metastatic melanoma. ALOS4 binds specifically the αvβ3 overexpressing human metastatic melanoma WM-266-4 cell line both in vitro and in ex vivo assays. Coupling ALOS4 to the topoisomerase I inhibitor Camptothecin (ALOS4-CPT) increases the cytotoxicity of CPT against human metastatic melanoma cells while reduces dramatically the cytotoxicity against non-cancerous cells as measured by the levels of γH2A.X, active caspase 3 and cell viability. Moreover, conjugating ALOS4 to CPT even increases the chemo-stability of CPT under physiological pH. Bioinformatic analysis using Rosetta platform revealed potential docking sites of ALOS4 on the αvβ3 integrin which are distinct from the RGD binding sites. We propose to use this specific non-RGD cyclic peptide as the therapeutic carrier for conjugation of drugs in order to improve efficacy and reduce toxicity of currently available treatments of human malignant melanoma. PMID:27768593

  7. Targeted therapies for cutaneous melanoma.

    PubMed

    Kee, Damien; McArthur, Grant

    2014-06-01

    Melanoma is resistant to cytotoxic therapy, and treatment options for advanced disease have been limited historically. However, improved understanding of melanoma driver mutations, particularly those involving the mitogen-activated protein kinase pathway, has led to the development of targeted therapies that are effective in this previously treatment-refractory disease. In cutaneous melanomas with BRAF V600 mutations the selective RAF inhibitors, vemurafenib and dabrafenib, and the MEK inhibitor, trametinib, have demonstrated survival benefits. Early signals of efficacy have also been demonstrated with MEK inhibitors in melanomas with NRAS mutations, and KIT inhibitors offer promise in melanomas driven through activation of their target receptor.

  8. Individualized strategies to target specific mechanisms of disease in malignant melanoma patients displaying unique mutational signatures

    PubMed Central

    Vidal, Rebeca; Pisonero, Helena; Varela, Ignacio; León-Castillo, Alicia; Trillo, Eugenio; González-Vela, Carmen; García-Diaz, Nuria; Almaraz, Carmen; Moreno, Thaidy; Cereceda, Laura; Madureira, Rebeca; Martinez, Nerea; Ortiz-Romero, Pablo; Valdizán, Elsa; Piris, Miguel; Vaqué, José

    2015-01-01

    Targeted treatment of advanced melanoma could benefit from the precise molecular characterization of melanoma samples. Using a melanoma-specific selection of 217 genes, we performed targeted deep sequencing of a series of biopsies, from advanced melanoma cases, with a Breslow index of ≥4 mm, and/or with a loco-regional infiltration in lymph nodes or presenting distant metastasis, as well of a collection of human cell lines. This approach detected 3–4 mutations per case, constituting unique mutational signatures associated with specific inhibitor sensitivity. Functionally, case-specific combinations of inhibitors that simultaneously targeted MAPK-dependent and MAPK-independent mechanisms were most effective at inhibiting melanoma growth, against each specific mutational background. These observations were challenged by characterizing a freshly resected biopsy from a metastatic lesion located in the skin and soft tissue and by testing its associated therapy ex vivo and in vivo using melanocytes and patient-derived xenografted mice, respectively. The results show that upon mutational characterization of advanced melanoma patients, specific mutational profiles can be used for selecting drugs that simultaneously target several deregulated genes/pathways involved in tumor generation or progression. PMID:26327537

  9. Targeted knockdown of polo-like kinase 1 alters metabolic regulation in melanoma.

    PubMed

    Gutteridge, Rosie Elizabeth Ann; Singh, Chandra K; Ndiaye, Mary Ann; Ahmad, Nihal

    2017-05-28

    A limited number of studies have indicated an association of the mitotic kinase polo-like kinase 1 (PLK1) and cellular metabolism. Here, employing an inducible RNA interference approach in A375 melanoma cells coupled with a PCR array and multiple validation approaches, we demonstrated that PLK1 alters a number of genes associated with cellular metabolism. PLK1 knockdown resulted in a significant downregulation of IDH1, PDP2 and PCK1 and upregulation of FBP1. Ingenuity Pathway Analysis (IPA) identified that 1) glycolysis and the pentose phosphate pathway are major canonical pathways associated with PLK1, and 2) PLK1 inhibition-modulated genes were largely associated with cellular proliferation, with FBP1 being the key modulator. Further, BI 6727-mediated inhibition of PLK1 caused a decrease in PCK1 and increase in FBP1 in A375 melanoma cell implanted xenografts in vivo. Furthermore, an inverse correlation between PLK1 and FBP1 was found in melanoma cells, with FBP1 expression significantly downregulated in a panel of melanoma cells. In addition, BI 6727 treatment resulted in an upregulation in FBP1 in A375, Hs294T and G361 melanoma cells. Overall, our study suggests that PLK1 may be an important regulator of metabolism maintenance in melanoma cells. Published by Elsevier B.V.

  10. Enhancement of HLA class II-restricted CD4+ T cell recognition of human melanoma cells following treatment with bryostatin-1

    PubMed Central

    Zhao, Dan; Amria, Shereen; Hossain, Azim; Sundaram, Kumaran; Komlosi, Peter; Nagarkatti, Mitzi; Haque, Azizul

    2011-01-01

    The majority of melanoma cells express detectable levels of HLA class II proteins, and an increased threshold of cell surface class II is crucial for the stimulation of CD4+ T cells. Bryostatin-1, a protein kinase C (PKC) activator, has been considered as a potent chemotherapeutic agent in a variety of in vitro tumor models. Little is known about the role of bryostatin-1 in HLA class II Ag presentation and immune activation in malignant tumors, especially in melanoma. In this study, we show that bryostatin-1 treatment enhances CD4+ T cell recognition of melanoma cells in the context of HLA class II molecules. We also show that bryostatin-1 treatment of melanoma cells increases class II protein levels by upregulating the class II transactivator (CIITA) gene. Flow cytometry and confocal microscopic analyses revealed that bryostatin-1 treatment upregulated the expression of costimulatory molecules (CD80 and CD86) in melanoma cells, which could prolong the interaction of immune cells and tumors. Bryostatin-1 also induced cellular differentiation in melanoma cells, and reduced tumorigenic factors such as pro-cathepsins and matrix-metalloproteinase-9. These data suggest that bryostatin-1 could be used as a chemo-immunotherapeutic agent for reducing tumorigenic potential of melanoma cells while enhancing CD4+ T cell recognition to prevent tumor recurrence. PMID:21903207

  11. Enhancement of HLA class II-restricted CD4+ T cell recognition of human melanoma cells following treatment with bryostatin-1.

    PubMed

    Zhao, Dan; Amria, Shereen; Hossain, Azim; Sundaram, Kumaran; Komlosi, Peter; Nagarkatti, Mitzi; Haque, Azizul

    2011-01-01

    The majority of melanoma cells express detectable levels of HLA class II proteins, and an increased threshold of cell surface class II is crucial for the stimulation of CD4+ T cells. Bryostatin-1, a protein kinase C (PKC) activator, has been considered as a potent chemotherapeutic agent in a variety of in vitro tumor models. Little is known about the role of bryostatin-1 in HLA class II Ag presentation and immune activation in malignant tumors, especially in melanoma. In this study, we show that bryostatin-1 treatment enhances CD4+ T cell recognition of melanoma cells in the context of HLA class II molecules. We also show that bryostatin-1 treatment of melanoma cells increases class II protein levels by upregulating the class II transactivator (CIITA) gene. Flow cytometry and confocal microscopic analyses revealed that bryostatin-1 treatment upregulated the expression of costimulatory molecules (CD80 and CD86) in melanoma cells, which could prolong the interaction of immune cells and tumors. Bryostatin-1 also induced cellular differentiation in melanoma cells, and reduced tumorigenic factors such as pro-cathepsins and matrix-metalloproteinase-9. These data suggest that bryostatin-1 could be used as a chemo-immunotherapeutic agent for reducing tumorigenic potential of melanoma cells while enhancing CD4+ T cell recognition to prevent tumor recurrence. Copyright © 2011 Elsevier Inc. All rights reserved.

  12. Patient-derived xenografts for childhood solid tumors: a valuable tool to test new drugs and personalize treatments.

    PubMed

    Zarzosa, P; Navarro, N; Giralt, I; Molist, C; Almazán-Moga, A; Vidal, I; Soriano, A; Segura, M F; Hladun, R; Villanueva, A; Gallego, S; Roma, J

    2017-01-01

    The use of preclinical models is essential in translational cancer research and especially important in pediatric cancer given the low incidence of each particular type of cancer. Cell line cultures have led to significant advances in cancer biology. However, cell lines have adapted to growth in artificial culture conditions, thereby undergoing genetic and phenotypic changes which may hinder the translational application. Tumor grafts developed in mice from patient tumor tissues, generally known as patient-derived xenografts (PDXs), are interesting alternative approaches to reproducing the biology of the original tumor. This review is focused on highlighting the interest of PDX models in pediatric cancer research and supporting strategies of personalized medicine. This review provides: (1) a description of the background of PDX in cancer, (2) the particular case of PDX in pediatric cancer, (3) how PDX can improve personalized medicine strategies, (4) new methods to increase engraftment, and, finally, (5) concluding remarks.

  13. Local control after stereotactic radiosurgery for brain metastases in patients with melanoma with and without BRAF mutation and treatment.

    PubMed

    Ly, David; Bagshaw, Hilary P; Anker, Christopher J; Tward, Jonathan D; Grossmann, Kenneth F; Jensen, Randy L; Shrieve, Dennis C

    2015-08-01

    BRAF inhibitors improve progression-free and overall survival in patients with metastatic melanoma. Brain metastases are common, and stereotactic radiosurgery (SRS) has been used, resulting in excellent local control. Because BRAF inhibitors are associated with intracranial responses, the authors hypothesized that BRAF inhibitors would improve local control in patients with melanoma who are receiving SRS for brain metastases. The authors retrospectively identified patients with metastatic melanoma who had been tested for BRAF mutation and treated with SRS for brain metastases. Patients with previous resection, multiple brain metastases, or multiple courses of SRS were eligible. SRS was delivered in a single fraction to a median dose of 2000 cGy. Patients with a BRAF mutation were treated with a BRAF inhibitor on the basis of physician preference. The authors identified 52 patients who were treated in 82 treatment sessions for 185 brain metastases and 13 tumor beds. At a median follow-up of 10.5 months, the 1-year local control rate was 69.2%. At 1 year, the local control rate for brain metastases in patients with BRAF mutation with BRAF treatment was 85.0%, and the local control rate for brain metastases in those without BRAF treatment was 51.5% (p = 0.0077). The rates of distant brain failure, freedom from whole-brain radiation, and overall survival were not different on the basis of BRAF mutation status or inhibitor therapy. The number of new intratumoral hemorrhages after SRS was increased significantly in patients with BRAF treatment. Treatment with BRAF inhibitors was associated with improved local control after SRS in patients with melanoma and brain metastases. An increased number of intratumoral hemorrhages was associated with BRAF inhibitor therapy.

  14. Disruption of IGF-1R signaling increases TRAIL-induced apoptosis: A new potential therapy for the treatment of melanoma

    SciTech Connect

    Karasic, Thomas B.; Hei, Tom K.; Ivanov, Vladimir N.

    2010-07-15

    Resistance of cancer cells to apoptosis is dependent on a balance of multiple genetic and epigenetic mechanisms, which up-regulate efficacy of the surviving growth factor-receptor signaling pathways and suppress death-receptor signaling pathways. The Insulin-like Growth Factor-1 Receptor (IGF-1R) signaling pathway is highly active in metastatic melanoma cells by mediating downstream activation of PI3K-AKT and MAPK pathways and controlling general cell survival and proliferation. In the present study, we used human melanoma lines with established genotypes that represented different phases of cancer development: radial-growth-phase WM35, vertical-growth-phase WM793, metastatic LU1205 and WM9 [1]. All these lines have normal NRAS. WM35, WM793, LU1205 and WM9 cells have mutated BRAF (V600E). WM35 and WM9 cells express normal PTEN, while in WM793 cells PTEN expression is down-regulated; finally, in LU1205 cells PTEN is inactivated by mutation. Cyclolignan picropodophyllin (PPP), a specific inhibitor of IGF-1R kinase activity, strongly down-regulated the basal levels of AKT activity in WM9 and in WM793 cells, modestly does so in LU1205, but has no effect on AKT activity in the early stage WM35 cells that are deficient in IGF-1R. In addition, PPP partially down-regulated the basal levels of active ERK1/2 in all lines used, highlighting the role of an alternative, non-BRAF pathway in MAPK activation. The final result of PPP treatment was an induction of apoptosis in WM793, WM9 and LU1205 melanoma cells. On the other hand, dose-dependent inhibition of IGF-1R kinase activity by PPP at a relatively narrow dose range (near 500 nM) has different effects on melanoma cells versus normal cells, inducing apoptosis in cancer cells and G2/M arrest of fibroblasts. To further enhance the pro-apoptotic effects of PPP on melanoma cells, we used a combined treatment of TNF-Related Apoptosis-Inducing Ligand (TRAIL) and PPP. This combination substantially increased death by apoptosis for

  15. Immunotherapy or molecularly targeted therapy: what is the best initial treatment for stage IV BRAF-mutant melanoma?

    PubMed

    Gibney, Geoffrey T; Atkins, Michael B

    2015-07-01

    The recent developments in BRAF-targeted therapy and checkpoint inhibitor immunotherapies for metastatic melanoma patients have led to better tolerability and markedly improved clinical outcomes, including higher objective response rates and longer survival. Treatment planning has become complex in patients with metastatic BRAF-mutant melanoma, with several options for BRAF- and/or MEK-targeted therapy (vemurafenib, dabrafenib, and trametinib) and immunotherapy (interleukin 2, ipilimumab, pembrolizumab, and nivolumab). Clinicians must weigh various patient factors, including the extent of disease (eg, symptomatic visceral metastases vs limited disease) and central nervous system involvement, as well as factors related to the therapeutic agent, such as rate of clinical response, durability of response, and impact on median and long-term survival. The combination regimen of dabrafenib plus trametinib has become a standard treatment strategy, and ipilimumab plus nivolumab is emerging as a promising treatment strategy. In this review, we discuss the benchmark trials leading to the approval of these new agents and provide emerging data on their use in sequence and impact on overall survival, with the goal of helping oncologists navigate treatment decisions for patients with metastatic BRAF-mutant melanoma.

  16. Synergistic and attenuated effect of HSS in combination treatment with docetaxel plus cisplatin in human non-small-cell lung SPC-A-1 tumor xenograft.

    PubMed

    Jia, Yuping; Zhou, Dongshun; Jia, Qingwen; Ying, Yong; Chen, Shuntai

    2016-04-01

    Platinum based combination regimens are first-line treatment option in treatment of non-small cell lung cancer (NSCLC) but the clinical utility has been limited because of their toxicities. Many reports indicated that patients with tumors can benefit from adjuvant chemotherapy drugs. The aim of this study was to confirm adjuvant chemotherapy of HSS with docetaxel plus cisplatin (DP) against NSCLC by evaluating antitumor activity and attenuated effect. In vivo SPC-A-1 xenograft model was established to evaluate antitumor activity and toxicity of HSS along or combination with DP. Evaluation indexes include the relative tumor proliferation rate, tumor growth inhibition rate, body weight, food consumption, hematological and biochemical analysis. HSS treatment showed inhibited tumor growth and increased tumor inhibition of DP treatment at doses of 250 mg/kg and 500 mg/kg. No significant toxicity was found in HSS-treated mice, but significant toxicity was found in DP-treated mice. HSS combination with DP could reduce toxicity of DP treatment by improving body weight and food consumption, and increasing the number of WBC and PLT, decreasing the level of ALT, AST and BUN. HSS combined with DP treatment has additive effect which contributes to enhance tumor growth inhibition of DP treatment and attenuated effect which contributes to reduce toxicity of DP treatment. These findings indicate potential benefit for use of HSS adjuvant chemotherapy for NSCLC treatment. Copyright © 2016. Published by Elsevier Masson SAS.

  17. Basal subtype is predictive for response to cetuximab treatment in patient-derived xenografts of squamous cell head and neck cancer.

    PubMed

    Klinghammer, Konrad; Otto, Raik; Raguse, Jan-Dirk; Albers, Andreas E; Tinhofer, Ingeborg; Fichtner, Iduna; Leser, Ulf; Keilholz, Ulrich; Hoffmann, Jens

    2017-09-15

    Cetuximab is the single targeted therapy approved for the treatment of head and neck cancer (HNSCC). Predictive biomarkers have not been established and patient stratification based on molecular tumor profiles has not been possible. Since EGFR pathway activation is pronounced in basal subtype, we hypothesized this activation could be a predictive signature for an EGFR directed treatment. From our patient-derived xenograft platform of HNSCC, 28 models were subjected to Affymetrix gene expression studies on HG U133+ 2.0. Based on the expression of 821 genes, the subtype of each of the 28 models was determined by integrating gene expression profiles through centroid-clustering with previously published gene expression data by Keck et al. The models were treated in groups of 5-6 animals with docetaxel, cetuximab, everolimus, cis- or carboplatin and 5-fluorouracil. Response was evaluated by comparing tumor volume at treatment initiation and after 3 weeks of treatment (RTV). Tumors distributed over the 3 signature-defined subtypes: 5 mesenchymal/inflamed phenotype (MS), 15 basal type (BA), 8 classical type (CL). Cluster analysis revealed a strong correlation between response to cetuximab and the basal subtype. RTV MS 3.32 vs. BA 0.78 (MS vs. BA, unpaired t-test, p 0.0002). Cetuximab responders were distributed as following: 1/5 in MS, 5/8 in CL and 13/15 in the BA group. Activity of classical chemotherapies did not differ between the subtypes. In conclusion basal subtype was associated with response to EGFR directed therapy in head and neck squamous cell cancer patient-derived xenografts. © 2017 UICC.

  18. [Hypofractionated radiation therapy for the treatment of malignant melanoma and squamous cell carcinoma in dogs and cats].

    PubMed

    Kinzel, Sylvia; Hein, Sven; Stopinski, Thaddeus; Koch, Johannes; Buecker, Arno; Treusacher, Hans-Peter; Schmachtenberg, Axel; Jansen, Thomas; Eble, Michael; Küpper, Wernen

    2003-01-01

    This study describes the experience with hypofractionated radiation therapy of squamous cell carcinoma and melanoma in dogs and cats. A total dose of 32-48 Gray (Gy) was delivered once a week in 8 Gy fractions. 34 animals in which a complete surgical excision was impossible were treated. There was no tumor detectable macroscopically in 14 patients at the beginning of radiation therapy. In 20 animals the median volume of the tumor was 9.9 cm3. The median survival times and the local tumor control of squamous cell carcinoma of the oral and nasal cavities and of the body are comparable to results which were reached with a Monday-Wednesday-Friday scheme. For the treatment of Melanoma the hypofractionated radiation therapy is first choice. There are no significant side effects. Late side effects did not occur. 88% of the owners are satisfied with this kind of treatment and would choose it again.

  19. Leukocyte Count Restoration Under Dabrafenib Treatment in a Melanoma Patient With Vemurafenib-Induced Leukopenia

    PubMed Central

    Orouji, Elias; Ziegler, Birgit; Umansky, Viktor; Gebhardt, Christoffer; Utikal, Jochen

    2014-01-01

    Abstract Recent advances in melanoma therapy have influenced the management of metastatic patients. Inhibitors of the BRAF/MEK/ERK signaling cascade have been proven highly effective in the metastatic disease although displaying different side effects. Here, we report a patient with BRAF V600E-mutated stage IV melanoma who developed a severe leukopenia upon targeted therapy with the BRAF inhibitor vemurafenib. Interestingly, the immediate therapeutic switch to a different BRAF inhibitor ‘dabrafenib́ had no negative influence on the leukocyte count. This case supports recent studies, which showed a differential influence of different BRAF inhibitors on patients’ leukocytes despite similar clinical efficacy in melanoma. PMID:25526431

  20. Laser immunotherapy for treatment of patients with advanced breast cancer and melanoma

    NASA Astrophysics Data System (ADS)

    Li, Xiaosong; Hode, Tomas; Guerra, Maria C.; Ferrel, Gabriela L.; Nordquist, Robert E.; Chen, Wei R.

    2011-02-01

    Laser immunotherapy (LIT) was developed for the treatment of metastatic tumors. It combines local selective photothermal interaction and active immunological stimulation to induce a long-term, systemic anti-tumor immunity. During the past sixteen years, LIT has been advanced from bench-top to bedside, with promising outcomes. In our pre-clinical and preliminary clinical studies, LIT has demonstrated the capability in inducing immunological responses, which not only can eradicate the treated primary tumors, but also can eliminate untreated metastases at distant sites. Specifically, LIT has been used to treat advanced melanoma and breast cancer patients during the past five years. LIT was shown to be effective in controlling both primary tumors and distant metastases in late-stage patients, who have failed conventional therapies such as surgery, chemotherapy, radiation, and other more advanced approaches. The methodology and the development of LIT are presented in this paper. The patients' responses to LIT are also reported in this paper. The preliminary results obtained in these studies indicated that LIT could be an effective modality for the treatment of patients with late-stage, metastatic cancers, who are facing severely limited options.

  1. Combined Treatments with Photodynamic Therapy for Non-Melanoma Skin Cancer.

    PubMed

    Lucena, Silvia Rocío; Salazar, Nerea; Gracia-Cazaña, Tamara; Zamarrón, Alicia; González, Salvador; Juarranz, Ángeles; Gilaberte, Yolanda

    2015-10-28

    Non-melanoma skin cancer (NMSC) is the most common form of cancer in the Caucasian population. Among NMSC types, basal cell carcinoma (BCC) has the highest incidence and squamous cell carcinoma (SCC) is less common although it can metastasize, accounting for the majority of NMSC-related deaths. Treatment options for NMSC include both surgical and non-surgical modalities. Even though surgical approaches are most commonly used to treat these lesions, Photodynamic Therapy (PDT) has the advantage of being a non-invasive option, and capable of field treatment, providing optimum cosmetic outcomes. Numerous clinical research studies have shown the efficacy of PDT for treating pre-malignant and malignant NMSC. However, resistant or recurrent tumors appear and sometimes become more aggressive. In this sense, the enhancement of PDT effectiveness by combining it with other therapeutic modalities has become an interesting field in NMSC research. Depending on the characteristics and the type of tumor, PDT can be applied in combination with immunomodulatory (Imiquimod) and chemotherapeutic (5-fluorouracil, methotrexate, diclofenac, or ingenol mebutate) agents, inhibitors of some molecules implicated in the carcinogenic process (COX2 or MAPK), surgical techniques, or even radiotherapy. These new strategies open the way to a wider improvement of the prevention and eradication of skin cancer.

  2. Combined Treatments with Photodynamic Therapy for Non-Melanoma Skin Cancer

    PubMed Central

    Lucena, Silvia Rocío; Salazar, Nerea; Gracia-Cazaña, Tamara; Zamarrón, Alicia; González, Salvador; Juarranz, Ángeles; Gilaberte, Yolanda

    2015-01-01

    Non-melanoma skin cancer (NMSC) is the most common form of cancer in the Caucasian population. Among NMSC types, basal cell carcinoma (BCC) has the highest incidence and squamous cell carcinoma (SCC) is less common although it can metastasize, accounting for the majority of NMSC-related deaths. Treatment options for NMSC include both surgical and non-surgical modalities. Even though surgical approaches are most commonly used to treat these lesions, Photodynamic Therapy (PDT) has the advantage of being a non-invasive option, and capable of field treatment, providing optimum cosmetic outcomes. Numerous clinical research studies have shown the efficacy of PDT for treating pre-malignant and malignant NMSC. However, resistant or recurrent tumors appear and sometimes become more aggressive. In this sense, the enhancement of PDT effectiveness by combining it with other therapeutic modalities has become an interesting field in NMSC research. Depending on the characteristics and the type of tumor, PDT can be applied in combination with immunomodulatory (Imiquimod) and chemotherapeutic (5-fluorouracil, methotrexate, diclofenac, or ingenol mebutate) agents, inhibitors of some molecules implicated in the carcinogenic process (COX2 or MAPK), surgical techniques, or even radiotherapy. These new strategies open the way to a wider improvement of the prevention and eradication of skin cancer. PMID:26516853

  3. Cytokine-enhanced vaccine and suicide gene therapy as surgery adjuvant treatments for spontaneous canine melanoma.

    PubMed

    Finocchiaro, L M E; Glikin, G C

    2008-02-01

    We evaluated the safety, efficacy and anti-tumor effects of a surgery adjuvant treatment on canine patients with malignant melanoma. This approach combined suicide gene therapy with a subcutaneous vaccine composed by formolized tumor cells and irradiated xenogeneic cells producing human interleukin-2 and granulocyte-macrophage colony-stimulating factor. The post-surgical margin of the cavity was infiltrated with lipid-complexed thymidine kinase suicide gene coadministrated with ganciclovir. Toxicity was minimal or absent in all patients. With respect to surgery-treated controls (SC), this combined treatment (CT) significantly increased the fraction of patients local disease-free from 6 to 58% and distant metastases-free from 43 to 78% (Fisher's Exact test). In addition, CT significantly improved both SC overall 78 (23-540) and metastasis-free survival 112 (0-467) days to more than 1312 days (respective ranges: 43-1312 and 0-1312) (Kaplan-Meier analysis). In those patients subjected to partial surgery or presenting local recurrence, the efficacy of CT was verified by a 49% of objective responses that averaged 85% of tumor mass loss, while 22% displayed tumor progression as 94% of SC did. Therefore, surgery adjuvant CT controlled tumor growth, delaying or preventing post-surgical recurrence and distant metastasis, significantly extending survival and recovering the quality of life.

  4. The role of light in the treatment of non-melanoma skin cancer using methyl aminolevulinate.

    PubMed

    Brown, S B

    2003-01-01

    Photodynamic therapy (PDT) is a developing approach to the treatment of cancer and other diseases that involves the use of light to activate photosensitizer molecules. The light energy absorbed by the photosensitizer is transferred to molecular oxygen, which is converted into the highly reactive and cytotoxic species, singlet oxygen. Topical agents such as aminolevulinic acid (ALA) or methyl aminolaevulinate (MAL) may be used for PDT of non-melanoma skin cancers (NMSC) because, in vivo, these agents stimulate the production of porphyrins which act as powerful photosensitisers. This brief review focuses on the use of light to activate MAL, which is now an approved drug (Metvix for certain NMSCs in the European Union. Porphyrins produced by the action of MAL can be activated using red light, which is also capable of deeply penetrating the skin. A number of light sources are available for treatment of NMSC using MAL, including very convenient non-laser sources such as non-coherent filtered lamps and, more recently, sources containing arrays of light-emitting diodes (LEDs). The Aktilite lamp, specifically designed for use with Metvix cream, has an emission spectrum that closely matches the red light absorption profile of PpIX.

  5. Emerging options for the treatment of melanoma – focus on ipilimumab

    PubMed Central

    Roddie, Claire; Peggs, Karl S

    2014-01-01

    Ipilimumab is a fully human immunoglobulin subclass G1 anticytotoxic-T-lymphocyte-antigen-4 monoclonal antibody. It has been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency for use in advanced melanoma following clear evidence of survival benefit in randomized Phase III studies. It is also under investigation as a treatment for other solid tumors such as renal cell, lung, and prostate cancers. The purported mechanism of antitumor activity of ipilimumab is through T-cell activation, and the side effect profile reflects this. Immune-related adverse events (irAEs) affect 60% of treated patients and 15% are defined as severe. Fortunately, most irAEs are reversible with early diagnosis and correct management. FDA approval of ipilimumab is dependent on the careful execution of a risk evaluation and mitigation strategy, with the aim of increasing awareness amongst patients and clinicians of the immunological risks of treatment, and providing algorithms for management of irAEs as they develop. Ipilimumab is one of the first immunotherapies to become widely available in the setting of solid tumors, and ongoing research aims to elucidate optimal dosing, optimal scheduling, and expanded access to ipilimumab as an adjuvant or maintenance therapy where appropriate. The identification of clinical correlates or biomarkers to identify those likely to benefit from this high-cost therapy is a top priority. PMID:27482517

  6. Combined BCG and irradiation treatment of skin metastases originating from malignant melanoma

    SciTech Connect

    Plesnicar, S.; Rudolf, Z.

    1982-09-15

    Treatment with BCG (Bacillus Calmette-Guerin) followed by irradiation was attempted to improve response to therapy by cutaneous metastases from malignant skin melanomas. Both agents were applied in low doses, known to cause minimal side effects. Nineteen patients, divided into three groups, entered the clinical trial. The first group consisted of five patients with numerous, small skin metastases. The nine patients of the second group presented a small number of relatively large metastases that usually appeared as a residual disease in the surgically treated area. Five patients with numerous, large metastases were included in the third group. The treatment sequence consisted of applying BCG intralesionally in doses from 4 x 10/sup 5/ to 1.17 x 10/sup 7/ viable units. After a free interval, the affected area was irradiated with doses from 1500-2500 ret. Patients with numerous small metastases and those with a small number of larger metastases, i.e., patients of the first and second group, showed a complete response and in these cases regression affected all the noninjected nodules and was also effective when regression could not have been achieved by BCG alone.

  7. Cutaneous head and neck melanoma in OPTiM, a randomized phase 3 trial of talimogene laherparepvec versus granulocyte‐macrophage colony‐stimulating factor for the treatment of unresected stage IIIB/IIIC/IV melanoma

    PubMed Central

    Agarwala, Sanjiv S.; Ollila, David W.; Hallmeyer, Sigrun; Milhem, Mohammed; Amatruda, Thomas; Nemunaitis, John J.; Harrington, Kevin J.; Chen, Lisa; Shilkrut, Mark; Ross, Merrick; Kaufman, Howard L.

    2016-01-01

    Abstract Background Cutaneous head and neck melanoma has poor outcomes and limited treatment options. In OPTiM, a phase 3 study in patients with unresectable stage IIIB/IIIC/IV melanoma, intralesional administration of the oncolytic virus talimogene laherparepvec improved durable response rate (DRR; continuous response ≥6 months) compared with subcutaneous granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). Methods Retrospective review of OPTiM identified patients with cutaneous head and neck melanoma given talimogene laherparepvec (n = 61) or GM‐CSF (n = 26). Outcomes were compared between talimogene laherparepvec and GM‐CSF treated patients with cutaneous head and neck melanoma. Results DRR was higher for talimogene laherparepvec–treated patients than for GM‐CSF treated patients (36.1% vs 3.8%; p = .001). A total of 29.5% of patients had a complete response with talimogene laherparepvec versus 0% with GM‐CSF. Among talimogene laherparepvec–treated patients with a response, the probability of still being in response after 12 months was 73%. Median overall survival (OS) was 25.2 months for GM‐CSF and had not been reached with talimogene laherparepvec. Conclusion Treatment with talimogene laherparepvec was associated with improved response and survival compared with GM‐CSF in patients with cutaneous head and neck melanoma. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1752–1758, 2016 PMID:27407058

  8. Targeted therapy for cutaneous oncology: a review of novel treatment options for non-melanoma skin cancer: part I.

    PubMed

    Walls, Brooke; Jordan, Laura; Diaz, Lisa; Miller, Richard

    2014-08-01

    The field of cutaneous oncology is exploding with innovative treatment options, specifically in the field of targeted therapy. These advances offer new hope to select patients with high risk skin cancers. Here we provide a two part series reviewing targeted therapy for non-melanoma skin cancer. We begin our discussion with basal cell carcinoma, moving beyond the first-in-class hedgehog inhibitors and highlighting promising clinical trials.

  9. Targeted therapies and immune checkpoint inhibitors in the treatment of metastatic melanoma patients: a guide and update for pathologists.

    PubMed

    Kakavand, Hojabr; Wilmott, James S; Long, Georgina V; Scolyer, Richard A

    2016-02-01

    The previously dismal prospects for patients with advanced stage metastatic melanoma have greatly improved in recent years. Enhanced understanding of both the pathogenesis of melanoma and its molecular drivers, as well as the importance and regulation of anti-tumour immune responses, have provided new therapeutic opportunities for melanoma patients. There are two major distinct categories of systemic treatments with activity for patients with metastatic melanoma: (1) targeted therapies, which act to inhibit the oncogenes that drive the aberrant growth and dissemination of the tumour; and (2) immune checkpoint inhibitor therapies, which act to enhance anti-tumour immune responses by blocking negative regulators of immunity. Pathologists play a critical and expanding role in the selection of the most appropriate treatment for individual metastatic melanoma patients in the modern era of personalised/precision medicine. The molecular pathology testing of melanoma tumour tissue for the presence of targetable oncogenic mutations is already part of routine practice in many institutions. In addition, other potential oncogenic therapeutic targets continue to be identified and pathology testing techniques must readily adapt to this rapidly changing field. Recent research findings suggest that pathological assessment of tumour associated immune cells and immunosuppressive ligand expression of the tumour are likely to be important in identifying patients most likely to benefit from immune checkpoint inhibitors. Similarly, pathological and molecular observations of on-treatment tumour tissue biopsies taken from patients on targeted therapies have provided new insights into the mechanisms of action of targeted molecular therapies, have contributed to the identification of resistance mechanisms to these novel therapies and may be of higher value for selecting patients most likely to benefit from therapies. These data have already provided a rational biological basis for the

  10. Safety and outcome of treatment of metastatic melanoma using 3-bromopyruvate: a concise literature review and case study.

    PubMed

    El Sayed, Salah Mohamed; Mohamed, Walaa Gamal; Seddik, Minnat-Allah Hassan; Ahmed, Al-Shimaa Ahmed; Mahmoud, Asmaa Gamal; Amer, Wael Hassan; Helmy Nabo, Manal Mohamed; Hamed, Ahmed Roshdi; Ahmed, Nagwa Sayed; Abd-Allah, Ali Abdel-Rahman

    2014-07-01

    3-Bromopyruvate (3BP) is a new, promising anticancer alkylating agent with several notable functions. In addition to inhibiting key glycolysis enzymes including hexokinase II and lactate dehydrogenase (LDH), 3BP also selectively inhibits mitochondrial oxidative phosphorylation, angiogenesis, and energy production in cancer cells. Moreover, 3BP induces hydrogen peroxide generation in cancer cells (oxidative stress effect) and competes with the LDH substrates pyruvate and lactate. There is only one published human clinical study showing that 3BP was effective in treating fibrolamellar hepatocellular carcinoma. LDH is a good measure for tumor evaluation and predicts the outcome of treatment better than the presence of a residual tumor mass. According to the Warburg effect, LDH is responsible for lactate synthesis, which facilitates cancer cell survival, progression, aggressiveness, metastasis, and angiogenesis. Lactate produced through LDH activity fuels aerobic cell populations inside tumors via metabolic symbiosis. In melanoma, the most deadly skin cancer, 3BP induced necrotic cell death in sensitive cells, whereas high glutathione (GSH) content made other melanoma cells resistant to 3BP. Concurrent use of a GSH depletor with 3BP killed resistant melanoma cells. Survival of melanoma patients was inversely associated with high serum LDH levels, which was reported to be highly predictive of melanoma treatment in randomized clinical trials. Here, we report a 28-year-old man presented with stage IV metastatic melanoma affecting the back, left pleura, and lung. The disease caused total destruction of the left lung and a high serum LDH level (4,283 U/L). After ethics committee approval and written patient consent, the patient received 3BP intravenous infusions (1-2.2 mg/kg), but the anticancer effect was minimal as indicated by a high serum LDH level. This may have been due to high tumor GSH content. On combining oral paracetamol, which depletes tumor GSH, with 3BP

  11. Small molecule inhibition of polo-like kinase 1 by volasertib (BI 6727) causes significant melanoma growth delay and regression in vivo.

    PubMed

    Cholewa, Brian D; Ndiaye, Mary A; Huang, Wei; Liu, Xiaoqi; Ahmad, Nihal

    2017-01-28

    The objective of this study was to determine the therapeutic potential of polo-like kinase 1 (Plk1) inhibition in melanoma, in vivo. Employing Vectra technology, we assessed the Plk1 expression profile in benign nevi, malignant (stages I-IV) and metastatic melanomas. We found a significant elevation of Plk1 immunostaining in melanoma tissues. Further, a second generation small molecule Plk1 inhibitor, BI 6727, resulted in reductions in growth, viability and clonogenic survival, as well as an increase in apoptosis of A375 and Hs 294T melanoma cells. BI 6727 treatment also resulted in a G2/M-as well as S-phase cell cycle arrest in melanoma cells. Importantly, BI 6727 (intravenous injection; 10 and 25 mg/kg body weight) treatment resulted in significant tumor growth delay and regression in vivo in A375-and Hs 294T-implanted xenografts in athymic nude mice. These anti-melanoma effects were accompanied with a decreased cellular proliferation (Ki-67 staining) and induction of apoptosis (caspase 3 activation). In addition, BI 6727 treatment caused a marked induction of p53 and p21 in vitro as well as in vivo. Overall, we suggest that Plk1 inhibition may be a useful approach as a monotherapy as well as in combination with other existing therapeutics, for melanoma management. Published by Elsevier Ireland Ltd.

  12. Adoptive Cell Transfer Therapy Following Non-Myeloablative but Lymphodepleting Chemotherapy for the Treatment of Patients With Refractory Metastatic Melanoma

    PubMed Central

    Dudley, Mark E.; Wunderlich, John R.; Yang, James C.; Sherry, Richard M.; Topalian, Suzanne L.; Restifo, Nicholas P.; Royal, Richard E.; Kammula, Udai; White, Don E.; Mavroukakis, Sharon A.; Rogers, Linda J.; Gracia, Gerald J.; Jones, Stephanie A.; Mangiameli, David P.; Pelletier, Michelle M.; Gea-Banacloche, Juan; Robinson, Michael R.; Berman, David M.; Filie, Armando C.; Abati, Andrea; Rosenberg, Steven A.

    2006-01-01

    Purpose We investigated the combination of lymphodepleting chemotherapy followed by the adoptive transfer of autologous tumor reactive lymphocytes for the treatment of patients with refractory metastatic melanoma. Patients and Methods Thirty-five patients with metastatic melanoma, all but one with disease refractory to treatment with high-dose interleukin (IL)-2 and many with progressive disease after chemotherapy, underwent lymphodepleting conditioning with two days of cyclophosphamide (60 mg/kg) followed by five days of fludarabine (25 mg/m2). On the day following the final dose of fludarabine, all patients received cell infusion with autologous tumor-reactive, rapidly expanded tumor infiltrating lymphocyte cultures and high-dose IL-2 therapy. Results Eighteen (51%) of 35 treated patients experienced objective clinical responses including three ongoing complete responses and 15 partial responses with a mean duration of 11.5 ± 2.2 months. Sites of regression included metastases to lung, liver, lymph nodes, brain, and cutaneous and subcutaneous tissues. Toxicities of treatment included the expected hematologic toxicities of chemotherapy including neutropenia, thrombocytopenia, and lymphopenia, the transient toxicities of high-dose IL-2 therapy, two patients who developed Pneumocystis pneumonia and one patient who developed an Epstein-Barr virus-related lymphoproliferation. Conclusion Lymphodepleting chemotherapy followed by the transfer of highly avid antitumor lymphocytes can mediate significant tumor regression in heavily pretreated patients with IL-2 refractory metastatic melanoma. PMID:15800326

  13. Selenite Treatment Inhibits LAPC-4 Tumor Growth and Prostate-Specific Antigen Secretion in a Xenograft Model of Human Prostate Cancer

    SciTech Connect

    Bhattacharyya, Rumi S.; Husbeck, Bryan; Feldman, David; Knox, Susan J.

    2008-11-01

    Purpose: Selenium compounds have known chemopreventive effects on prostate cancer. However selenite, an inorganic form of selenium, has not been extensively studied as a treatment option for prostate cancer. Our previous studies have demonstrated the inhibition of androgen receptor expression and androgen stimulated prostate-specific antigen (PSA) expression by selenite in human prostate cancer cell lines. In this study, we investigated the in vivo effects of selenite as a therapy to treat mice with established LAPC-4 tumors. Methods and Materials: Male mice harboring androgen-dependent LAPC-4 xenograft tumors were treated with selenite (2 mg/kg intraperitoneally three times per week) or vehicle for 42 days. In addition, androgen-independent LAPC-4 xenograft tumors were generated in female mice over 4 to 6 months. Once established, androgen-independent LAPC-4 tumor fragments were passaged into female mice and were treated with selenite or vehicle for 42 days. Changes in tumor volume and serum PSA levels were assessed. Results: Selenite significantly decreased androgen-dependent LAPC-4 tumor growth in male mice over 42 days (p < 0.001). Relative tumor volume was decreased by 41% in selenite-treated animals compared with vehicle-treated animals. The inhibition of LAPC-4 tumor growth corresponded to a marked decrease in serum PSA levels (p < 0.01). In the androgen-independent LAPC-4 tumors in female mice, selenite treatment decreased tumor volume by 58% after 42 days of treatment (p < 0.001). Conclusions: These results suggest that selenite may have potential as a novel therapeutic agent to treat both androgen-dependent and androgen-independent prostate cancer.

  14. A comparative evaluation of bovine-derived xenograft (Bio-Oss Collagen) and type I collagen membrane (Bio-Gide) with bovine-derived xenograft (Bio-Oss Collagen) and fibrin fibronectin sealing system (TISSEEL) in the treatment of intrabony defects: A clinico-radiographic study

    PubMed Central

    Palachur, Deepthi; Prabhakara Rao, K. V.; Murthy, K. Raja V.; Kishore, D. Trinath; Reddy, M. Narendra; Bhupathi, Anitha

    2014-01-01

    Background and Objectives: The purpose of this study was to compare the efficacy of bovine-derived xenograft (Bio-Oss Collagen) and Type I collagen membrane (Bio-Gide) with bovine-derived xenograft (Bio-Oss Collagen) and fibrin fibronectin sealing system (TISSEEL) in the treatment of periodontal infrabony defects. Materials and Methods: Fourteen healthy patients in the age range of 20 to 60 years, showing bilateral or contralateral infrabony defects were selected. The defects were assigned randomly to Site A (bovine-derived xenograft [Bio-Oss Collagen] with bioresorbable Type I collagen membrane [Bio-Gide]) and Site B (fibrin fibronectin sealing system [TISSEEL] with bovine-derived xenograft [Bio-Oss Collagen]). The radiographic parameters were recorded at baseline, 6 months, and 9 months postoperatively. Results: All fourteen patients returned for recall at regular intervals till the completion of the study. Both the experimental groups showed clinically and radiographically statistically significant reduction in probing pocket depth and gain in clinical attachment level. Conclusion: Both groups showed potential for enhancing the periodontal regeneration with no statistically significant between the two groups; however, on comparison the Bio-Oss Collagen and TISSEEL group were slightly better. PMID:25024548

  15. A comparative evaluation of bovine-derived xenograft (Bio-Oss Collagen) and type I collagen membrane (Bio-Gide) with bovine-derived xenograft (Bio-Oss Collagen) and fibrin fibronectin sealing system (TISSEEL) in the treatment of intrabony defects: A clinico-radiographic study.

    PubMed

    Palachur, Deepthi; Prabhakara Rao, K V; Murthy, K Raja V; Kishore, D Trinath; Reddy, M Narendra; Bhupathi, Anitha

    2014-05-01

    The purpose of this study was to compare the efficacy of bovine-derived xenograft (Bio-Oss Collagen) and Type I collagen membrane (Bio-Gide) with bovine-derived xenograft (Bio-Oss Collagen) and fibrin fibronectin sealing system (TISSEEL) in the treatment of periodontal infrabony defects. Fourteen healthy patients in the age range of 20 to 60 years, showing bilateral or contralateral infrabony defects were selected. The defects were assigned randomly to Site A (bovine-derived xenograft [Bio-Oss Collagen] with bioresorbable Type I collagen membrane [Bio-Gide]) and Site B (fibrin fibronectin sealing system [TISSEEL] with bovine-derived xenograft [Bio-Oss Collagen]). The radiographic parameters were recorded at baseline, 6 months, and 9 months postoperatively. All fourteen patients returned for recall at regular intervals till the completion of the study. Both the experimental groups showed clinically and radiographically statistically significant reduction in probing pocket depth and gain in clinical attachment level. Both groups showed potential for enhancing the periodontal regeneration with no statistically significant between the two groups; however, on comparison the Bio-Oss Collagen and TISSEEL group were slightly better.

  16. Head and neck melanoma.

    PubMed

    Shashanka, R; Smitha, B R

    2012-01-01

    The incidence of malignant melanoma appears to be increasing at an alarming rate throughout the world over the past 30-40 years and continues to increase in the United States, Canada, Australia, Asia, and Europe. The behavior of head and neck melanoma is aggressive, and it has an overall poorer prognosis than that of other skin sites. The authors review the published literature and text books, intending to give an overall picture of malignant melanomas of the head and neck and a special emphasis on treatment considerations with controversies in treatment including biopsy, radiation therapy, sentinel node biopsy, and nodal dissection.

  17. Liver xenografts for the treatment of acute liver failure: clinical and experimental experience and remaining immunologic barriers.

    PubMed

    Hara, Hidetaka; Gridelli, Bruno; Lin, Yih Jyh; Marcos, Amadeo; Cooper, David K C

    2008-04-01

    A critical element restricting the application of liver transplantation is the shortage of human deceased donor organs. Xenotransplantation using pig organs might be a solution to this shortage. Although the problems that still require resolution include the immunologic barrier, the potential risk of transferring infectious agents with the transplanted organ, and uncertainty about whether the transplanted organ will function satisfactorily in the human environment, recent progress in the genetic manipulation of pigs has led to the prospect that clinical xenografting, at least as a bridge to allotransplantation, may be possible in the foreseeable future. Experience with clinical auxiliary and orthotopic liver xenotransplantation and experimental liver xenotransplantation in nonhuman primate and other large animal models is reviewed, and the remaining immunologic problems are discussed. Evidence suggests that, in patients with hepatic failure, the pig liver may be less susceptible to antibody-mediated injury than other pig organs, such as the heart or kidney. Pig Kupffer cells and other macrophages will recognize and phagocytose primate red blood cells, but this problem should be overcome by pretransplant depletion of macrophages from the organ-source pig. From the evidence currently available, it does not seem unduly optimistic to anticipate that a liver from an alpha1,3-galactosyltransferase gene-knockout pig would survive at least long enough to function as a successful bridge to allotransplantation. (c) 2008 AASLD.

  18. Proteomics analysis of A375 human malignant melanoma cells in response to arbutin treatment.

    PubMed

    Nawarak, Jiraporn; Huang-Liu, Rosa; Kao, Shao-Hsuan; Liao, Hsien-Hua; Sinchaikul, Supachok; Chen, Shui-Tein; Cheng, Sun-Long

    2009-02-01

    Although the toxicogenomics of A375 human malignant melanoma cells treated with arbutin have been elucidated using DNA microarray, the proteomics of the cellular response to this compound are still poorly understood. In this study, we performed proteomic analyses to investigate the anticancer effect of arbutin on the protein expression profile in A375 cells. After treatment with arbutin (8 microg/ml) for 24, 48 and 72 h, the proteomic profiles of control and arbutin-treated A375 cells were compared, and 26 differentially expressed proteins (7 upregulated and 19 downregulated proteins) were identified by MALDI-Q-TOF MS and MS/MS. Among these proteins, 13 isoforms of six identical proteins were observed. Bioinformatic tools were used to search for protein function and to predict protein interactions. The interaction network of 14 differentially expressed proteins was found to be correlated with the downstream regulation of p53 tumor suppressor and cell apoptosis. In addition, three upregulated proteins (14-3-3G, VDAC-1 and p53) and five downregulated proteins (ENPL, ENOA, IMDH2, PRDX1 and VIME) in arbutin-treated A375 cells were validated by RT-PCR analysis. These proteins were found to play important roles in the suppression of cancer development.

  19. Melanoma of the eye

    MedlinePlus

    Small melanomas may be treated with: Surgery Laser Radiation therapy (such as Gamma Knife , CyberKnife , brachytherapy) Surgery to remove the eye (enucleation) may be needed. Other treatments that may be used ...

  20. Dynamic (18)F-FDG-PET for monitoring treatment effect following anti-angiogenic therapy in triple-negative breast cancer xenografts.

    PubMed

    Kristian, Alexandr; Revheim, Mona Elisabeth; Qu, Hong; Mælandsmo, Gunhild M; Engebråten, Olav; Seierstad, Therese; Malinen, Eirik

    2013-10-01

    Dynamic (18)F-FDG PET allows the study of glucose distribution in tissues as a function of time and space. Using pharmacokinetics, the temporal uptake pattern of (18)F-FDG may be separated into components reflecting perfusion and metabolism. Bevacizumab is an angiogenesis inhibitor which prevents the growth of new blood vessels, and may potentially lead to normalization of the blood circulation in the tumor. The purpose of the study was to explore the use of dynamic PET as a tool for monitoring treatment effect, reflected by changes in perfusion and metabolism. Twelve athymic nude mice, bearing the bilateral triple-negative human breast cancer xenograft MAS98.12 were treated with bevacizumab (5 mg/kg i.p.). Dynamic PET data was acquired prior to and 24 and 72 hours after treatment for 1 hour after injection of 10 MBq (18)F-FDG and fitted with a FDG two-tissue compartment model. The changes in the rate constants k1, k3, MRFDG and the vascular fraction νB were assessed. To evaluate the effect of treatment regimes, 30 mice, randomized in 5 groups, received either vehicle (0.9% NaCl), bevacizumab (5 mg/kg i.p.), doxorubicin (8 mg/kg i.v.) or bevacizumab and doxorubicin either together, or doxorubicin 24 hours after bevacizumab treatment. Tumor volume was measured twice a week. The perfusion-related rate parameter k1 and the metabolic rate constant k3 decreased significantly 24 hours after treatment. This decrease was followed by an increase, albeit non-significant, at 72 hours post treatment. Doxorubicin given 24 hours after bevacizumab showed less antitumor effect compared to concomitant treatment. Dynamic PET can detect changes in tumor perfusion and metabolism following anti-angiogenic therapy in mouse xenograft models. Longitudinal dynamic PET, used to assess the efficacy of anti-angiogenic treatment, can identify the time frame of potential tumor vasculature re-normalization and allow optimal timing of supplementary therapy (radiation or chemotherapy).

  1. Chronic Resveratrol Treatment Inhibits MRC5 Fibroblast SASP-Related Protumoral Effects on Melanoma Cells.

    PubMed

    Menicacci, Beatrice; Laurenzana, Anna; Chillà, Anastasia; Margheri, Francesca; Peppicelli, Silvia; Tanganelli, Elisabetta; Fibbi, Gabriella; Giovannelli, Lisa; Del Rosso, Mario; Mocali, Alessandra

    2017-09-01

    Cellular senescence is related to organismal aging and is observed after DNA damaging cancer therapies, that induce tumor-suppressive modifications, but it is characterized by a strong increase in secreted factors, termed the "senescence-associated secretory phenotype" (SASP). Particularly, SASP from stroma senescent fibroblasts creates a cancer-favoring microenvironment, providing targets for anti-cancer interventions. In the present article, chronic treatment (5 weeks) with 5 µM resveratrol has been used to modulate senescence-related protumoral features of MRC5 fibroblasts, reducing SASP-related interleukins IL1α, IL1β, IL6, and IL8; transforming-growth-factor-β (TGFβ); matrix metallo-proteinases MMP3 and MMP2; urokinase plasminogen activator (uPA); receptor proteins uPAR, IL6R, insulin growth factor receptor-1 (IGF-1R), TGFβ-R2, and CXCR4. The cellular nuclear-factor-kB (NF-kB) protein level was also reduced, confirming its role in the induction of SASP. Resveratrol pretreated MRC5 fibroblasts were resistant to activation by TGFβ. Resveratrol treatment of senescent MRC5 induced the production of conditioned media (CM) which counteracted the protumoral effect of senescent CM on A375 and A375-M6 melanoma cell proliferation and invasiveness, and reduced the expression of epithelial-to-mesenchymal transition markers related to malignant features. This experimental approach proposes a treatment that targets the senescent stromal cell phenotype to induce an anti-tumor hosting microenvironment, which is suitable for both preventive and therapeutic purposes. © The Author 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  2. [Heart Transplantation;Allograft and Xenograft].

    PubMed

    Fukushima, Norihide

    2017-01-01

    Prior to starting clinical cardiac allotransplantation, cardiac xenotransplantation was performed in human in 1960s. In 1964, Hardy performed cardiac transplantation using a chimpanzee heart and Bailey performed cardiac transplantation using a baboon heart to an infant with hypoplastic left heart. The use of cyclosporine has greatly improved the outcome of clinical cardiac transplantation and cardiac allotransplantation became an established treatment strategy for the patients with end-stage heart failure. Although concordant cardiac xenotransplantation from a primate to a human may be successfully performed using current immunosuppressive regimen, a primate heart is not a good candidate for cardiac xenograft due to animal light issues and its size. Therefore, many investigators have tried to extend the survival period in discordant xenograft from pig to primate, but no prolonged surviving orthotropic cardiac xenograft has been established yet. In this review, experiments of concordant and discordant cardiac xenografts which were performed by the authors were introduced.

  3. Adenovirus-Mediated FKHRL1/TM Sensitizes Melanoma Cells to Apoptosis Induced by Temozolomide

    PubMed Central

    Egger, Michael E.; McNally, Lacey R.; Nitz, Jonathan; McMasters, Kelly M.

    2014-01-01

    Abstract Melanoma exhibits variable resistance to the alkylating agent temozolomide (TMZ). We evaluated the potential of adenovirus expressing forkhead human transcription factor like 1 triple mutant (Ad-FKHRL1/TM) to sensitize melanoma cells to TMZ. Four melanoma cell lines were treated with Ad-FKHRL1/TM and TMZ, alone or in combination. Apoptosis was assessed by activation and inhibition of caspase pathway, nuclei fragmentation, and annexin V staining. The potential therapeutic efficacy of Ad-FKHRL1/TM with TMZ was also assessed in a mouse melanoma xenograft model. Combination therapy of Ad-FKHRL1/TM and TMZ resulted in greater cell killing (<20% cell viability) compared with single therapy and controls (p<0.05). Combination indices of Ad-FKHRL1/TM and TMZ therapy indicated significant (p<0.05) synergistic killing effect. Greater apoptosis induction was found in cells treated with Ad-FKHRL1/TM and TMZ than with Ad-FKHRL1/TM or TMZ-treated cells alone. Treatment with TMZ enhanced adenovirus transgene expression in a cell type-dependent manner. In an in vivo model, combination therapy of Ad-FKHRL1/TM with TMZ results in greater tumor growth reduction in comparison with single treatments. We suggest that Ad-FKHRL1/TM is a promising vector to sensitize melanoma cells to TMZ, and that a combination of both approaches would be effective in the clinical setting. PMID:25238278

  4. PARP1 inhibitor olaparib (Lynparza) exerts synthetic lethal effect against ligase 4-deficient melanomas.

    PubMed

    Czyż, Małgorzata; Toma, Monika; Gajos-Michniewicz, Anna; Majchrzak, Kinga; Hoser, Grazyna; Szemraj, Janusz; Nieborowska-Skorska, Margaret; Cheng, Phil; Gritsyuk, Daniel; Levesque, Mitchell; Dummer, Reinhard; Sliwinski, Tomasz; Skorski, Tomasz

    2016-11-15

    Cancer including melanoma may be ''addicted" to double strand break (DSB) repair and targeting this process could sensitize them to the lethal effect of DNA damage. PARP1 exerts an important impact on DSB repair as it binds to both single- and double- strand breaks. PARP1 inhibitors might be highly effective drugs triggering synthetic lethality in patients whose tumors have germline or somatic defects in DNA repair genes. We hypothesized that PARP1-dependent synthetic lethality could be induced in melanoma cells displaying downregulation of DSB repair genes. We observed that PARP1 inhibitor olaparib sensitized melanomas with reduced expression of DNA ligase 4 (LIG4) to an alkylatimg agent dacarbazine (DTIC) treatment in vitro, while normal melanocytes remained intact. PARP1 inhibition caused accumulation of DSBs, which was associated with apoptosis in LIG4 deficient melanoma cells. Our hypothesis that olaparib is synthetic lethal with LIG4 deficiency in melanoma cells was supported by selective anti-tumor effects of olaparib used either alone or in combination with dacarbazine (DTIC) in LIG4 deficient, but not LIG4 proficient cells. In addition, olaparib combined with DTIC inhibited the growth of LIG4 deficient human melanoma xenografts. This work for the first time demonstrates the effectiveness of a combination of PARP1 inhibitor olaparib and alkylating agent DTIC for treating LIG4 deficient melanomas. In addition, analysis of the TCGA and transcriptome microarray databases revealed numerous individual melanoma samples potentially displaying specific defects in DSB repair pathways, which may predispose them to synthetic lethality triggered by PARP1 inhibitor combined with a cytotoxic drug.

  5. PARP1 inhibitor olaparib (Lynparza) exerts synthetic lethal effect against ligase 4-deficient melanomas

    PubMed Central

    Czyż, Małgorzata; Toma, Monika; Gajos-Michniewicz, Anna; Majchrzak, Kinga; Hoser, Grazyna; Szemraj, Janusz; Nieborowska-Skorska, Margaret; Cheng, Phil; Gritsyuk, Daniel; Levesque, Mitchell; Dummer, Reinhard; Sliwinski, Tomasz; Skorski, Tomasz

    2016-01-01

    Cancer including melanoma may be “addicted” to double strand break (DSB) repair and targeting this process could sensitize them to the lethal effect of DNA damage. PARP1 exerts an important impact on DSB repair as it binds to both single- and double- strand breaks. PARP1 inhibitors might be highly effective drugs triggering synthetic lethality in patients whose tumors have germline or somatic defects in DNA repair genes. We hypothesized that PARP1-dependent synthetic lethality could be induced in melanoma cells displaying downregulation of DSB repair genes. We observed that PARP1 inhibitor olaparib sensitized melanomas with reduced expression of DNA ligase 4 (LIG4) to an alkylatimg agent dacarbazine (DTIC) treatment in vitro, while normal melanocytes remained intact. PARP1 inhibition caused accumulation of DSBs, which was associated with apoptosis in LIG4 deficient melanoma cells. Our hypothesis that olaparib is synthetic lethal with LIG4 deficiency in melanoma cells was supported by selective anti-tumor effects of olaparib used either alone or in combination with dacarbazine (DTIC) in LIG4 deficient, but not LIG4 proficient cells. In addition, olaparib combined with DTIC inhibited the growth of LIG4 deficient human melanoma xenografts. This work for the first time demonstrates the effectiveness of a combination of PARP1 inhibitor olaparib and alkylating agent DTIC for treating LIG4 deficient melanomas. In addition, analysis of the TCGA and transcriptome microarray databases revealed numerous individual melanoma samples potentially displaying specific defects in DSB repair pathways, which may predispose them to synthetic lethality triggered by PARP1 inhibitor combined with a cytotoxic drug. PMID:27705909

  6. Current clinical overview of cutaneous melanoma.

    PubMed

    Lens, Marko

    This article reviews current evidence on epidemiology, diagnosis and management of cutaneous melanoma. Incidence of cutaneous melanoma is rising in all Caucasian populations across the world; thus, melanoma represents a significant public health burden. Although, incidence of melanoma is in continuous increase, a decrease of mortality and improved survival has been observed in most western European populations. Clinical characteristics of four major types of melanoma (superficial spreading, nodular, lentigo maligna melanoma and acral lentiginous melanoma) have been described. Surgical removal of melanoma remains the standard care in all primary melanomas. Current evidence suggests use of 1 to 2 cm excision margins. Wider margins may be necessary in patients with thicker melanomas with higher risk for local recurrence. In the treatment of regional lymph nodes elective lymphadenectomy has been surpassed by the sentinel lymph node biopsy (SLNB). However, although prognostic value of SLNB has been confirmed, its therapeutical benefit still needs to be evaluated. Currently there is no standard adjuvant therapy for melanoma although interferon-alpha has been the most widely used treatment in the adjuvant setting. The role of metastasectomy (removal of distant metastases) is still controversial. Chemotherapeutic agents have a limited activity in patients with metastatic melanoma with response rates up to 25%. Although different vaccines have been tested in melanoma patients their role still remain to be established in phase III trials. Progresses in molecular biology and genetics of melanoma may lead to the development of novel melanoma therapies.

  7. Effects of PHA-665752 and cetuximab combination treatment on in vitro and murine xenograft growth of human colorectal cancer cells with KRAS or BRAF mutations.

    PubMed

    Jia, Yi-Tao; Yang, Dong-Hai; Zhao, Zhaolong; Bi, Xiao-Hui; Han, Wei-Hua; Feng, Bo; Zhi, Jie; Gu, Bin; Duan, Zhihui; Wu, Jian-Hua; Ju, Ying-Chao; Wang, Ming-Xia; Li, Zhong-Xin

    2017-03-30

    It remains unknown whether blockade of c-Met signaling and epidermal growth factor receptor signaling is effective in suppressing the growth of human colorectal cancer (CRC) cells. In this study, we investigated the effects of the c-Met inhibitor PHA-665752 alone and in combination with cetuximab on the growth of human CRC cells in vitro and in mouse xenografts. Human CRC cell lines (Caco2, HCT-116, and HT-29) and mice bearing HCT-116 xenografts were treated with cetuximab in the absence or presence of PHA-665752. Cell viability and apoptosis were examined using the MTT and TUNEL assays, respectively. Vimentin was measured by immunohistochemistry as a marker for epithelial-to-mesenchymal transition. Western blotting was used to determine signaling protein expression levels. The MTT assay showed that the growth of Caco2, HCT-116, and HT-29 cells was inhibited by PHA-665752 in a dose-dependent manner, but only Caco2 cell growth was suppressed by cetuximab. Combination treatment with PHA-665752 and cetuximab inhibited the proliferation of Caco2 cells and RAS mutant CRC cell lines. However, relative to the PHA-665752-alone treatment group, HT-29 cells with a BRAF mutation showed no noticeable effect. The mean tumor volume in mice treated with cetuximab in combination with PHA-665752 was significantly smaller than that in the mice treated with only cetuximab (P = 0.033) or PHA-665752 (P < 0.01). Similarly, the expression of vimentin in the mice treated with PHA-665752 in combination with cetuximab was significantly lower than that in the mice treated with cetuximab or PHA-665752 alone (P < 0.05 in each case). TUNEL assays revealed that treatment with PHA-665752 in combination with cetuximab markedly increased CRC cell apoptosis. Western blotting analysis of signaling protein expression showed that PHA-665752 inhibited Met phosphorylation (P < 0.05). In addition, treatment with cetuximab alone or in combination with PHA-665752 effectively inhibited EGFR

  8. Experimental approaches for the treatment of murine B16 melanomas of various sizes. I: Local injection of ethanol with a combination of interleukin-2 or microwaval hyperthermia for B16 melanomas with a size of less than 7 mm in diameter.

    PubMed

    Nakayama, J; Kokuba, H; Kobayashi, J; Yoshida, Y; Hori, Y

    1997-08-01

    The effects of local absolute ethanol injection combined with administration of interleukin-2 (IL-2) or microwaval hyperthermia in murine B16 melanomas with a size of approximately 7 mm in diameter were investigated. The groups of melanoma-burdened mice treated with both local ethanol injection and local or intra-abdominal administration of IL-2 showed clear suppression of any recurrence of melanoma once the melanomas had been destroyed by ethanol injection and a concomitant prolongation of the survival times. Also, local injection of ethanol in combination with local microwaval hyperthermia at 43 degrees C for 15 min twice a week caused complete cures in B16 melanomas with a size of less than 7 mm in diameter. The infiltrations of T lymphocytes and NK cells were augmented in the melanomas treated with ethanol injection and local injection of IL-2. However, the melanomas treated with ethanol injection and intra-abdominal injection of IL-2 hardly showed any infiltration of such immune cells, although the growth of melanomas was effectively suppressed. In the case of treatment with ethanol and hyperthermia, slight infiltration of NK cells was observed in the melanoma nests as well as in the interstitials. Thus, the direct injection of absolute ethanol in combination with IL-2 or microwaval hyperthermia is effective or even curative in the treatment of murine B16 melanomas with a size of less than 7 mm in diameter.

  9. MRI-based treatment planning and dose delivery verification for intraocular melanoma brachytherapy.

    PubMed

    Zoberi, Jacqueline Esthappan; Garcia-Ramirez, Jose; Hedrick, Samantha; Rodriguez, Vivian; Bertelsman, Carol G; Mackey, Stacie; Hu, Yanle; Gach, H Michael; Rao, P Kumar; Grigsby, Perry W

    2017-08-14

    Episcleral plaque brachytherapy (EPB) planning is conventionally based on approximations of the implant geometry with no volumetric imaging following plaque implantation. We have developed an MRI-based technique for EPB treatment planning and dose delivery verification based on the actual patient-specific geometry. MR images of 6 patients, prescribed 85 Gy over 96 hours from Collaborative Ocular Melanoma Study-based EPB, were acquired before and after implantation. Preimplant and postimplant scans were used to generate "preplans" and "postplans", respectively. In the preplans, a digital plaque model was positioned relative to the tumor, sclera, and nerve. In the postplans, the same plaque model was positioned based on the imaged plaque. Plaque position, point doses, percentage of tumor volume receiving 85 Gy (V100), and dose to 100% of tumor volume (Dmin) were compared between preplans and postplans. All isodose plans were computed using TG-43 formalism with no heterogeneity corrections. Shifts and tilts of the plaque ranged from 1.4 to 8.6 mm and 1.0 to 3.8 mm, respectively. V100 was ≥97% for 4 patients. Dmin for preplans and postplans ranged from 83 to 118 Gy and 45 to 110 Gy, respectively. Point doses for tumor apex and base were all found to decrease from the preimplant to the postimplant plan, with mean differences of 16.7 ± 8.6% and 30.5 ± 11.3%, respectively. By implementing MRI for EPB, we eliminate reliance on approximations of the eye and tumor shape and the assumption of idealized plaque placement. With MRI, one can perform preimplant as well as postimplant imaging, facilitating EPB treatment planning based on the actual patient-specific geometry and dose-delivery verification based on the imaged plaque position. Copyright © 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

  10. Anticancer and Anti-Inflammatory Properties of Ganoderma lucidum Extract Effects on Melanoma and Triple-Negative Breast Cancer Treatment.

    PubMed

    Barbieri, Antonio; Quagliariello, Vincenzo; Del Vecchio, Vitale; Falco, Michela; Luciano, Antonio; Amruthraj, Nagoth Joseph; Nasti, Guglielmo; Ottaiano, Alessandro; Berretta, Massimiliano; Iaffaioli, Rosario Vincenzo; Arra, Claudio

    2017-02-28

    Among the most important traditional medicinal fungi, Ganoderma lucidum has been used as a therapeutic agent for the treatment of numerous diseases, including cancer, in Oriental countries. The aim of this study is to investigate the anti-inflammatory, anticancer and anti-metastatic activities of Ganoderma lucidum extracts in melanoma and triple-negative breast cancer cells. Ganoderma lucidum extracts were prepared by using common organic solvents; MDA-MB 231 and B16-F10 cell lines were adopted as cellular models for triple-negative breast cancer and melanoma and characterized for cell viability, wound-healing assay and measurement of cytokines secreted by cancer cells under pro-inflammatory conditions (incubation with lipopolysaccharide, LPS) and pretreatment with Ganoderma lucidum extract at different concentrations. Our study demonstrates, for the first time, how Ganoderma lucidum extracts can significantly inhibit the release of IL-8, IL-6, MMP-2 and MMP-9 in cancer cells under pro-inflammatory condition. Interestingly, Ganoderma lucidum extracts significantly also decrease the viability of both cancer cells in a time- and concentration-dependent manner, with abilities to reduce cell migration over time, which is correlated with a lower release of matrix metalloproteases. Taken together, these results indicate the possible use of Ganoderma lucidum extract for the therapeutic management of melanoma and human triple-negative breast cancer.

  11. Anticancer and Anti-Inflammatory Properties of Ganoderma lucidum Extract Effects on Melanoma and Triple-Negative Breast Cancer Treatment

    PubMed Central

    Barbieri, Antonio; Quagliariello, Vincenzo; Del Vecchio, Vitale; Falco, Michela; Luciano, Antonio; Amruthraj, Nagoth Joseph; Nasti, Guglielmo; Ottaiano, Alessandro; Berretta, Massimiliano; Iaffaioli, Rosario Vincenzo; Arra, Claudio

    2017-01-01

    Among the most important traditional medicinal fungi, Ganoderma lucidum has been used as a therapeutic agent for the treatment of numerous diseases, including cancer, in Oriental countries. The aim of this study is to investigate the anti-inflammatory, anticancer and anti-metastatic activities of Ganoderma lucidum extracts in melanoma and triple-negative breast cancer cells. Ganoderma lucidum extracts were prepared by using common organic solvents; MDA-MB 231 and B16-F10 cell lines were adopted as cellular models for triple-negative breast cancer and melanoma and characterized for cell viability, wound-healing assay and measurement of cytokines secreted by cancer cells under pro-inflammatory conditions (incubation with lipopolysaccharide, LPS) and pretreatment with Ganoderma lucidum extract at different concentrations. Our study demonstrates, for the first time, how Ganoderma lucidum extracts can significantly inhibit the release of IL-8, IL-6, MMP-2 and MMP-9 in cancer cells under pro-inflammatory condition. Interestingly, Ganoderma lucidum extracts significantly also decrease the viability of both cancer cells in a time- and concentration-dependent manner, with abilities to reduce cell migration over time, which is correlated with a lower release of matrix metalloproteases. Taken together, these results indicate the possible use of Ganoderma lucidum extract for the therapeutic management of melanoma and human triple-negative breast cancer. PMID:28264501

  12. Functional reconstruction after subtotal glossectomy in the surgical treatment of an uncommon and aggressive neoplasm in this location: Primary malignant melanoma in the base of the tongue

    PubMed Central

    Manzano-Solo-de-Zaldívar, Damián; Moreno-Sánchez, Manuel; Hernández-Vila, Cristina; Ramírez-Pérez, Francisco-Alejandro; González-Ballester, David; Ruíz-Laza, Luis; González-García, Raúl; Monje-Gil, Florencio

    2014-01-01

    Primary malignant melanoma of the oral cavity is a rare neoplasm, especially on the tongue. We report a case of mucosal melanoma at the base of the tongue, an extremely rare location (only about 30 cases have been reported in literature). The extension study doesn´t revealed distant metastatic lesions. The patient was treated by subtotal glossectomy and bilateral functional neck dissection. Tongue is one of the most difficult structures to reconstruct, because of their central role in phonation, swallowing and airway protection. The defect was reconstructed with anterolateral thigh free flap. Surgical treatment was supplemented with adjuvant immunotherapy. The post-operative period was uneventful. At present, 24 months after surgery, patient is asymptomatic, there isn´t evidence of recurrence of melanoma and he hasn´t any difficulty in swallowing or phonation. Key words:Malignant mucosal melanoma, anterolateral thigh free flap, phonation, swallowing. PMID:25593674

  13. Rapid and clinically significant response to masitinib in the treatment of mucosal primary esophageal melanoma with somatic KIT exon 11 mutation involving brain metastases: A case report.

    PubMed

    Prosvicova, Jarmila; Lukesova, Sarka; Kopecky, Jindrich; Grim, Jiri; Papik, Zdenek; Kolarova, Renata; Navratilova, Blanka; Dubreuil, Patrice; Agopian, Julie; Mansfield, Colin; Moussy, Alan; Hermine, Olivier

    2015-12-01

    Malignant melanoma in the gastrointestinal tract may be primary or metastatic. Mucosal melanoma is a quite rare and aggressive disease, growing hidden and diagnosed with a certain delay which makes treatment difficult. The authors present the first patient with c-kit exon 11 mutated primary esophageal melanoma treated with oral tyrosine kinase inhibitor masitinib. A 55-year-old-man presented with esophageal melanoma metastising into visceral organs and to the brain. The patient showed objective and clinical significant therapeutic response to masitinib. After initiation of masitinib, dysphagia and odynophagia disappeared within 1 week. Following 1 month of treatment, computed tomography showed a regression in the number and size of brain metastatic lesions and regression in visceral lesions. This therapeutic response, despite the aggressive disease on treatment initiation, effectively enabled the patient to have 6 months of quality life. This report corroborates the plausibility of treating advanced melanoma carrying a mutation of KIT with masitinib. It also raises the question of masitinib treatment beyond progression. Additionally, the observed masitinib treatment effect on the brain suggests accumulation of therapeutically relevant concentration of masitinib in the central nervous system. This observation has possible ramifications for treatment of intracranial neoplasms.

  14. Dacarbazine DTIC and carboplatin as an outpatient treatment for disseminated malignant melanoma.

    PubMed

    Nieboer, P; Mulder, N H; Van Der Graaf, W T; Willemse, P H; Hospers, G A

    2001-01-01

    Occasionally long-term survival in disseminated melanoma can be obtained through chemotherapy. We treated 22 patients with disseminated melanoma with an outpatient regimen consisting of dacarbazine (DTIC) and carboplatin. Three patients had a complete response lasting 4+, 9 and 9 months (survival 4+, 10 and 16 months), respectively; 3 patients had a partial response lasting 4, 6 and 8 months (survival 6+, 11+ and 14 months), respectively. Overall response was 27% (95% confidence interval 11-50%). Toxicity was relatively mild and mainly due to nausea. In 3 patients the dose of carboplatin was reduced because of grade 4 haematological toxicity. This described easy outpatient regimen shows comparable results as other polychemotherapeutic regimens in disseminated melanoma, but with a relatively mild toxicity profile.

  15. Immune response to bovine pericardium implanted into α1,3-galactosyltransferase knockout mice: feasibility as an animal model for testing efficacy of anticalcification treatments of xenografts.

    PubMed

    Lee, Cheul; Ahn, Hyuk; Kim, Soo Hwan; Choi, Sun Young; Kim, Yong Jin

    2012-07-01

    Glutaraldehyde (GA)-fixed xenografts are prone to calcification after implantation in humans and there is evidence that immune reaction to the Galα1,3-Galβ1,4GlcNAc-R (α-Gal) antigen may play a part in this process. The objectives of this study were to evaluate the immune response of α1,3-galactosyltransferase knockout (α-Gal KO) mice to bovine pericardium and to evaluate the effect of various anticalcification treatments on bovine pericardium using mouse subcutaneous implantation model. Bovine pericardial tissues were divided into eight groups according to the method of anticalcification treatments. Prepared tissues were subcutaneously implanted into the α-Gal KO and wild-type mice for 2 months, and anti-α-Gal antibodies were measured at 2 weeks and 2 months after implantation. Explanted tissues were examined by immunohistochemistry and calcium contents of the explanted tissues were measured. Titres of IgM and IgG antibodies in the α-Gal KO mice increased significantly according to the duration of implantation, whereas titres of IgM and IgG antibodies in the wild-type mice increased until 2 weeks after implantation without further increase thereafter. Titres of IgG antibodies measured at 2 months after implantation were significantly higher in the α-Gal KO mice than in the wild-type mice. Immunohistochemistry revealed macrophages surrounding the pericardial tissues irrespective of the mouse type into which the tissues implanted, whereas T-cells could only be observed in the tissues implanted into the α-Gal KO mice. Except the high-concentration GA-treated group, calcium contents of anticalcification-treated groups were all significantly lower or tended to be lower than that of the control group, irrespective of the mouse type. Calcium contents of the control group were significantly higher in the α-Gal KO mice than in the wild-type mice. Bovine pericardium implanted into the α-Gal KO mice caused significant increase in anti-α-Gal antibodies, showed

  16. Novel GHRH antagonists suppress the growth of human malignant melanoma by restoring nuclear p27 function

    PubMed Central

    Szalontay, Luca; Schally, Andrew V; Popovics, Petra; Vidaurre, Irving; Krishan, Awtar; Zarandi, Marta; Cai, Ren-Zhi; Klukovits, Anna; Block, Norman L; Rick, Ferenc G

    2014-01-01

    Malignant melanoma is the deadliest form of skin cancer; the treatment of advanced and recurrent forms remains a challenge. It has recently been reported that growth hormone-releasing hormone (GHRH) receptor is involved in the pathogenesis of melanoma. Therefore, we investigated the effects of our new GHRH antagonists on a human melanoma cancer cell line. Antiproliferative effects of GHRH antagonists, MIA-602, MIA-606 and MIA-690, on the human melanoma cell line, A-375, were studied in vitro using the MTS assay. The effect of MIA-690 (5 μg/day 28 d) was further evaluated in vivo in nude mice bearing xenografts of A-375. Subcellular localization of p27 was detected with Western blot and immunofluorescent staining. MIA-690 inhibited the proliferation of A-375 cells in a dose-dependent manner (33% at 10 μM, and 19.2% at 5 μM, P < 0 .05 vs. control), and suppressed the growth of xenografted tumors by 70.45% (P < 0.05). Flow cytometric analysis of cell cycle effects following the administration of MIA-690 revealed a decrease in the number of cells in G2/M phase (from 19.7% to 12.9%, P < 0.001). Additionally, Western blot and immunofluorescent studies showed that exposure of A-375 cells to MIA-690 triggered the nuclear accumulation of p27. MIA-690 inhibited tumor growth in vitro and in vivo, and increased the translocation of p27 into the nucleus thus inhibiting progression of the cell cycle. Our findings indicate that patients with malignant melanoma could benefit from treatment regimens, which combine existing chemotherapy agents and novel GHRH-antagonists. PMID:25486366

  17. Potent anti-tumour activity of a novel conditionally replicating adenovirus for melanoma via inhibition of migration and invasion

    PubMed Central

    Jiang, G; Yang, C-S; Xu, D; Sun, C; Zheng, J-N; Lei, T-C; Liu, Y-Q

    2014-01-01

    Background: Conditionally replicating adenoviruses (CRAds) represent a novel class of oncological therapeutic agents. One strategy to ensure tumour targeting is to place the essential viral genes under the control of tumour-specific promoters. Ki67 has been selected as a cancer gene therapy target, as it is expressed in most malignant cells but is barely detectable in most normal cells. This study aimed to investigate the effects of a Ki67 promoter-controlled CRAd (Ki67-ZD55-IL-24) on the proliferation and apoptosis of melanoma cells. Methods: Melanoma cells were independently treated with Ki67-ZD55-IL-24, ZD55-IL-24, Ki67-ZD55, and ZD55-EGFP. The cytotoxic potential of each treatment was assessed using cell viability measurements. Cell migration and invasion were assayed using cell migration and invasion assays. Apoptosis was assayed using the annexin V-FITC assay, western blotting, reverse transcriptase PCR (RT–PCR), haematoxylin and eosin (H&E) staining, and the TUNEL assay. Results: Our results showed that Ki67-ZD55-IL-24 had significantly enhanced anti-tumour activity as it more effectively induced apoptosis in melanoma cells than the other agents. Ki67-ZD55-IL-24 also caused the most significant inhibition of cell migration and invasion of melanoma cells. Furthermore, apoptosis was induced more effectively in melanoma xenografts in nude mice. Conclusions: This strategy holds promising potential for the further development of an effective approach to treat malignant melanoma. PMID:24714752

  18. hvTRA, a novel TRAIL receptor agonist, induces apoptosis and sustained growth retardation in melanoma

    PubMed Central

    Fleten, Karianne G; Flørenes, Vivi Ann; Prasmickaite, Lina; Hill, Oliver; Sykora, Jaromir; Mælandsmo, Gunhild M; Engesæter, Birgit

    2016-01-01

    In recent years, new treatment options for malignant melanoma patients have enhanced the overall survival for selected patients. Despite new hope, most melanoma patients still relapse with drug-resistant tumors or experience intrinsic resistance to the therapy. Therefore, novel treatment modalities beneficial for subgroups of patients are needed. TRAIL receptor agonists have been suggested as promising candidates for use in cancer treatment as they preferentially induce apoptosis in cancer cells. Unfortunately, the first generation of TRAIL receptor agonists showed poor clinical efficacy. hvTRA is a second-generation TRAIL receptor agonist with improved composition giving increased potency, and in the present study, we showed hvTRA-induced activation of apoptosis leading to an efficient and sustained reduction in melanoma cell growth in cell lines and xenograft models. Furthermore, the potential of hvTRA in a clinical setting was demonstrated by showing efficacy on tumor cells harvested from melanoma patients with lymph node metastasis in an ex vivo drug sensitivity assay. Inhibition of mutated BRAF has been shown to regulate proteins in the intrinsic apoptotic pathway, making the cells more susceptible for apoptosis induction. In an attempt to increase the efficacy of hvTRA, combination treatment with the mutated BRAF inhibitor vemurafenib was investigated. A synergistic effect by the combination was observed for several cell lines in vitro, and an initial cytotoxic effect was observed in vivo. Unfortunately, the initial increased reduction in tumor growth compared with hvTRA mono treatment was not sustained, and this was related to downregulation of the DR5 level by vemurafenib. Altogether, the presented data imply that hvTRA efficiently induce apoptosis and growth delay in melanoma models and patient material, and the potential of this TRAIL receptor agonist should be further evaluated for treatment of subgroups of melanoma patients. PMID:28028438

  19. hvTRA, a novel TRAIL receptor agonist, induces apoptosis and sustained growth retardation in melanoma.

    PubMed

    Fleten, Karianne G; Flørenes, Vivi Ann; Prasmickaite, Lina; Hill, Oliver; Sykora, Jaromir; Mælandsmo, Gunhild M; Engesæter, Birgit

    2016-01-01

    In recent years, new treatment options for malignant melanoma patients have enhanced the overall survival for selected patients. Despite new hope, most melanoma patients still relapse with drug-resistant tumors or experience intrinsic resistance to the therapy. Therefore, novel treatment modalities beneficial for subgroups of patients are needed. TRAIL receptor agonists have been suggested as promising candidates for use in cancer treatment as they preferentially induce apoptosis in cancer cells. Unfortunately, the first generation of TRAIL receptor agonists showed poor clinical efficacy. hvTRA is a second-generation TRAIL receptor agonist with improved composition giving increased potency, and in the present study, we showed hvTRA-induced activation of apoptosis leading to an efficient and sustained reduction in melanoma cell growth in cell lines and xenograft models. Furthermore, the potential of hvTRA in a clinical setting was demonstrated by showing efficacy on tumor cells harvested from melanoma patients with lymph node metastasis in an ex vivo drug sensitivity assay. Inhibition of mutated BRAF has been shown to regulate proteins in the intrinsic apoptotic pathway, making the cells more susceptible for apoptosis induction. In an attempt to increase the efficacy of hvTRA, combination treatment with the mutated BRAF inhibitor vemurafenib was investigated. A synergistic effect by the combination was observed for several cell lines in vitro, and an initial cytotoxic effect was observed in vivo. Unfortunately, the initial increased reduction in tumor growth compared with hvTRA mono treatment was not sustained, and this was related to downregulation of the DR5 level by vemurafenib. Altogether, the presented data imply that hvTRA efficiently induce apoptosis and growth delay in melanoma models and patient material, and the potential of this TRAIL receptor agonist should be further evaluated for treatment of subgroups of melanoma patients.

  20. Mucosal melanoma: an update.

    PubMed

    Ballester Sánchez, R; de Unamuno Bustos, B; Navarro Mira, M; Botella Estrada, R

    2015-03-01

    Mucosal melanoma is a rare melanoma subtype that differs from the cutaneous form of the tumor in its biology, clinical manifestations, and management. Diagnosis is usually late due to a lack of early or specific signs and the location of lesions in areas that are difficult to access on physical examination. Surgical excision is the treatment of choice for localized disease. The value of sentinel lymph node biopsy and lymphadenectomy is still unclear. Radiotherapy can be used as adjuvant therapy for the control of local disease. c-KIT mutations are more common than in other types of melanoma and this has led to significant advances in the use of imatinib for the treatment of metastatic mucosal melanoma. Copyright © 2014 Elsevier España, S.L.U. and AEDV. All rights reserved.

  1. Acral Lentiginous Melanoma.

    PubMed

    Goydos, James S; Shoen, Steven L

    2016-01-01

    Acral lentiginous melanoma (ALM) is a rare subtype of melanoma mainly arising on the palms, soles, and nail beds. ALM is the most common subtype of melanoma found in patients of Asian or African descent and tends to more advanced at presentation due to delays in diagnosis. Surgical treatment is difficult owing to the complexity and functional importance of the hands and feet and reconstruction after resection is usually needed. The prognosis for patients with ALM depends on stage of disease and tends to be worse than with other subtypes of melanoma. Newer treatment modalities such as immunotherapies and targeted agents are being tested in patients with advanced ALM with some promising preliminary results.

  2. Targeted Therapies Compared to Dacarbazine for Treatment of BRAFV600E Metastatic Melanoma: A Cost-Effectiveness Analysis

    PubMed Central

    Shih, Vanessa; ten Ham, Renske M.; Bui, Christine T.; Tran, Dan N.; Ting, Jie; Wilson, Leslie

    2015-01-01

    Purpose. Two BRAFV600E targeted therapies, dabrafenib and vemurafenib, have received US approval for treatment of metastatic melanoma in BRAFV600E patients, a mutation that affects ~50% of patients. We evaluated the cost-effectiveness of BRAF inhibitors and traditional chemotherapy for treatment of metastatic melanoma. Methods. A Markov model was developed using a societal perspective. Transition probabilities were derived from two Phase III registration trials comparing each BRAF inhibitor against dacarbazine. Costs were obtained from literature, national databases, and Medicare fee schedules. Utilities were obtained from published literature. Deterministic and probabilistic sensitivity analyses were run to test the impact of uncertainties. Results. The incremental cost-effectiveness ratio of dabrafenib was $149,035/QALY compared to dacarbazine. Vemurafenib was dominated by dabrafenib. Probabilistic sensitivity analysis showed that, at a willingness-to-pay (WTP) threshold of ≤$100,000/QALY, dacarbazine was the optimal treatment in ~85% of simulations. At a WTP threshold of ≥$150,000/QALY, dabrafenib was the optimal treatment. Conclusion. Compared with dacarbazine, dabrafenib and vemurafenib were not cost-effective at a willingness-to-pay threshold of $100,000/QALY. Dabrafenib is more efficient compared to vemurafenib. With few treatment options, dabrafenib is an option for qualifying patients if the overall cost of dabrafenib is reduced to $30,000–$31,000 or a WTP threshold of ≥$150,000/QALY is considered. More comparative data is needed. PMID:26171248

  3. Propranolol induces a favourable shift of anti-tumor immunity in a murine spontaneous model of melanoma

    PubMed Central

    Wrobel, Ludovic Jean; Bod, Lloyd; Lengagne, Renée; Kato, Masashi

    2016-01-01

    In a previous study on a xenograft model of melanoma, we showed that the beta-adrenergic receptor antagonist propranolol inhibits melanoma development by modulating angiogenesis, proliferation and cell survival. Stress hormones can influence tumor development in different ways and norepinephrine was shown to downregulate antitumor immune responses by favoring the accumulation of immunosuppressive cells, impairing the function of lymphocytes. We assessed the effect of propranolol on antitumor immune response in the MT/Ret mouse model of melanoma. Propranolol treatment delayed primary tumor growth and metastases development in MT/Ret mice. Consistent with our previous observations in human melanoma xenografts, propranolol induces a decrease in cell proliferation and vessel density in the primary tumors and in metastases. In this immunocompetent model, propranolol significantly reduced the infiltration of myeloid cells, particularly neutrophils, in the primary tumor. Inversely, cytotoxic tumor infiltrating lymphocytes were more frequent in the tumor stroma of treated mice. In a consistent manner, we observed the same shift in the proportions of infiltrating leukocytes in the metastases of treated mice. Our results suggest that propranolol, by decreasing the infiltration of immunosuppressive myeloid cells in the tumor microenvironment, restores a better control of the tumor by cytotoxic cells. PMID:27788481

  4. Induction of Vasculogenic Mimicry Overrides VEGF-A Silencing and Enriches Stem-like Cancer Cells in Melanoma.

    PubMed

    Schnegg, Caroline I; Yang, Moon Hee; Ghosh, Subrata K; Hsu, Mei-Yu

    2015-04-15

    The basis for resistance to VEGF inhibition is not fully understood despite its clinical importance. In this study, we examined the adaptive response to VEGF-A inhibition by a loss-of-function analysis using plasmid-based shRNA. Tumor xenografts that initially responded to VEGF-A inhibition underwent an adaptation in vivo, leading to acquired resistance. VEGF-A blockade in tumors was associated with HIF1α expression and an increase in CD144(+) vasculogenic mimicry (VM), leading to formation of channels displaying Tie-1 and MMP-2 upregulation. CD133(+) and CD271(+) melanoma stem-like cells (MSLC) accumulated in the perivascular niche. Tumor xenografts of melanoma cell populations that were intrinsically resistant to VEGF-A blockade did not exhibit any of these features, compared with nontarget control counterparts. Thus, melanomas that are initially sensitive to VEGF-A blockade acquire adaptive resistance by adopting VM as an alternate angiogenic strategy, thereby enriching for deposition of MSLC in the perivascular niche through an HIF1α-dependent process. Conversely, melanomas that are intrinsically resistant to VEGF-A blockade do not show any evidence of compensatory survival mechanisms that promote MSLC accumulation. Our work highlights the potential risk of anti-VEGF treatments owing to a selective pressure for an adaptive resistance mechanism that empowers the development of stem-like cancer cells, with implications for how to design combination therapies that can improve outcomes in patients. ©2015 American Association for Cancer Research.

  5. Induction of vasculogenic mimicry overrides VEGF-A silencing and enriches stem-like cancer cells in melanoma

    PubMed Central

    Schnegg, Caroline I.; Yang, Moon Hee; Ghosh, Subrata K.; Hsu, Mei-Yu

    2015-01-01

    The basis for resistance to VEGF inhibition is not fully understood despite its clinical importance. In this study, we examined the adaptive response to VEGF-A inhibition by a loss-of-function analysis using plasmid-based shRNA. Tumor xenografts that initially responded to VEGF-A inhibition underwent an adaptation in vivo leading to acquired resistance. VEGF-A blockade in tumors was associated with HIF-1α expression and an increase in CD144+ vasculogenic mimicry (VM), leading to formation of channels displaying Tie-1 and MMP-2 upregulation. CD133+ and CD271+ melanoma stem-like cells (MSLC) accumulated in the perivascular niche. Tumor xenografts of melanoma cell populations that were intrinsically resistant to VEGF-A blockade did not exhibit any of these features, compared to non-target control counterparts. Thus, melanomas which are initially sensitive to VEGF-A blockade acquire adaptive resistance by adopting VM as an alternate angiogenic strategy, thereby enriching for deposition of MSLC in the perivascular niche through a HIF-1α-dependent process. Conversely, melanomas which are intrinsically resistant to VEGF-A blockade do not show any evidence of compensatory survival mechanisms that promote MSLC accumulation. Our work highlights the potential risk of anti-VEGF treatments owing to a selective pressure for an adaptive resistance mechanism that empowers the development of stem-like cancer cells, with implications for how to design combination therapies that can improve outcomes in patients. PMID:25769726

  6. Malignant melanoma of the foot and ankle.

    PubMed

    John, K J; Hayes, D W; Green, D R; Dickerson, J

    2000-04-01

    Malignant melanoma is a serious and devastating skin disease that podiatrists may be called upon to treat. It is pertinent that delays in diagnosis and treatment of malignant melanoma be avoided. Some of the topics discussed in this article are causes, clinical features, classification, and treatment of malignant melanoma, focusing on the foot and ankle.

  7. Targeting Glutamatergic Signaling and the PI3 Kinase Pathway to Halt Melanoma Progression.

    PubMed

    Rosenberg, Stephen A; Niglio, Scot A; Salehomoum, Negar; Chan, Joseph L-K; Jeong, Byeong-Seon; Wen, Yu; Li, Jiadong; Fukui, Jami; Chen, Suzie; Shin, Seung-Shick; Goydos, James S

    2015-02-01

    Our group has previously reported that the majority of human melanomas (>60%) express the metabotropic glutamate receptor 1 (GRM1) and that the glutamate release inhibitor riluzole, a drug currently used to treat amyotrophic lateral sclerosis, can induce apoptosis in GRM1-expressing melanoma cells. Our group previously reported that in vitro riluzole treatment reduces cell growth in three-dimensional (3D) soft agar colony assays by 80% in cells with wildtype phosphoinositide 3-kinase (PI3K) pathway activation. However, melanoma cell lines harboring constitutive activating mutations of the PI3K pathway (PTEN and NRAS mutations) showed only a 35% to 40% decrease in colony formation in soft agar in the presence of riluzole. In this study, we have continued our preclinical studies of riluzole and its effect on melanoma cells alone and in combination with inhibitors of the PI3 kinase pathway: the AKT inhibitor, API-2, and the mammalian target of rapamycin (mTOR) inhibitor, rapamycin. We modeled these combinatorial therapies on various melanoma cell lines in 3D and 2D systems and in vivo. Riluzole combined with mTOR inhibition is more effective at halting melanoma anchorage-independent growth and xenograft tumor progression than either agent alone. PI3K signaling changes associated with this combinatorial treatment shows that 3D (nanoculture) modeling of cell signaling more closely resembles in vivo signaling than monolayer models. Riluzole combined with mTOR inhibition is effective at halting tumor cell progression independent of BRAF mutational status. This makes this combinatorial therapy a potentially viable alternative for metastatic melanoma patients who are BRAF WT and are therefore ineligible for vemurafenib therapy. Copyright © 2014. Published by Elsevier Inc.

  8. Targeting Glutamatergic Signaling and the PI3 Kinase Pathway to Halt Melanoma Progression12

    PubMed Central

    Rosenberg, Stephen A.; Niglio, Scot A.; Salehomoum, Negar; Chan, Joseph L.-K.; Jeong, Byeong-Seon; Wen, Yu; Li, Jiadong; Fukui, Jami; Chen, Suzie; Shin, Seung-Shick; Goydos, James S.

    2015-01-01

    Our group has previously reported that the majority of human melanomas (> 60%) express the metabotropic glutamate receptor 1 (GRM1) and that the glutamate release inhibitor riluzole, a drug currently used to treat amyotrophic lateral sclerosis, can induce apoptosis in GRM1-expressing melanoma cells. Our group previously reported that in vitro riluzole treatment reduces cell growth in three-dimensional (3D) soft agar colony assays by 80% in cells with wildtype phosphoinositide 3-kinase (PI3K) pathway activation. However, melanoma cell lines harboring constitutive activating mutations of the PI3K pathway (PTEN and NRAS mutations) showed only a 35% to 40% decrease in colony formation in soft agar in the presence of riluzole. In this study, we have continued our preclinical studies of riluzole and its effect on melanoma cells alone and in combination with inhibitors of the PI3 kinase pathway: the AKT inhibitor, API-2, and the mammalian target of rapamycin (mTOR) inhibitor, rapamycin. We modeled these combinatorial therapies on various melanoma cell lines in 3D and 2D systems and in vivo. Riluzole combined with mTOR inhibition is more effective at halting melanoma anchorage-independent growth and xenograft tumor progression than either agent alone. PI3K signaling changes associated with this combinatorial treatment shows that 3D (nanoculture) modeling of cell signaling more closely resembles in vivo signaling than monolayer models. Riluzole combined with mTOR inhibition is effective at halting tumor cell progression independent of BRAF mutational status. This makes this combinatorial therapy a potentially viable alternative for metastatic melanoma patients who are BRAF WT and are therefore ineligible for vemurafenib therapy. PMID:25749171

  9. Optical Imaging with HER2-targeted Affibody Molecules can monitor Hsp90 treatment response in a breast cancer xenograft mouse model

    PubMed Central

    van de Ven, Stephanie M.W.Y.; Elias, Sjoerd G.; Chan, Carmel T.; Miao, Zheng; Cheng, Zhen; De, Abhijit; Gambhir, Sanjiv S.

    2012-01-01

    Purpose To determine if optical imaging can be used for in vivo therapy response monitoring as an alternative to radionuclide techniques. For this we evaluated the known Her2 response to 17-DMAG treatment, a Hsp90 inhibitor. Experimental design After in vitro 17-DMAG treatment response evaluation of MCF7 parental cells and two HER2 transfected clones (Clone A medium, B high Her2 expression), we established human breast cancer xenografts in nude mice (only parental and clone B) for in vivo evaluation. Mice received 120 mg/kg of 17-DMAG in 4 doses at 12 hour intervals i.p. (n=14), or PBS as carrier control (n=9). Optical images were obtained both pre-treatment (day 0) and post-treatment (day 3, 6, and 9), always 5 hours post-injection of 500 pmol of anti-Her2 Affibody-AlexaFluor680 via tail vein (with pre-injection background subtraction). Day 3 and 9 in vivo optical imaging signal was further correlated with ex vivo Her2 levels by western blot after sacrifice. Results Her2 expression decreased with 17-DMAG dose in vitro. In vivo optical imaging signal was reduced by 22.5% in Clone B (p=0.003) and by 9% in MCF7 parental tumors (p=0.23) at 3 days after 17-DMAG treatment; optical imaging signal recovered in both tumor types at day 6–9. In the carrier group no signal reduction was observed. Pearson correlation of in vivo optical imaging signal with ex vivo Her2 levels ranged from 0.73 to 0.89. Conclusion Optical imaging with an affibody can be used to non-invasively monitor changes in Her2 expression in vivo as a response to treatment with an Hsp90 inhibitor, with results similar to response measurements in PET imaging studies. PMID:22235098

  10. Silymarin inhibits melanoma cell growth both in vitro and in vivo by targeting cell cycle regulators, angiogenic biomarkers and induction of apoptosis.

    PubMed

    Vaid, Mudit; Singh, Tripti; Prasad, Ram; Katiyar, Santosh K

    2015-11-01

    Cutaneous malignant melanoma is the leading cause of death from skin diseases and is often associated with activating mutations of the proto-oncogene BRAF. To develop more effective strategies for the prevention or treatment of melanoma, we have examined the inhibitory effects of silymarin, a flavanoid from Silybum marianum, on melanoma cells. Using A375 (BRAF-mutated) and Hs294t (non BRAF-mutated but highly metastatic) human melanoma cell lines, we found that in vitro treatment with silymarin resulted in a dose-dependent: (i) reduction in cell viability; (ii) enhancement of either Go/G1 (A375) or G2-M (Hs294t) phase cell cycle arrest with corresponding alterations in cyclins and cyclin-dependent kinases; and (iii) induction of apoptosis. The silymarin-induced apoptosis of human melanoma cells was associated with a reduction in the levels of anti-apoptotic proteins (Bcl-2 and Bcl-xl), an increase in the levels of pro-apoptotic protein (Bax), and activation of caspases. Further, oral administration of silymarin (500 mg/kg body weight/2× a week) significantly inhibited (60%, P < 0.01) the growth of BRAF-mutated A375 melanoma tumor xenografts, and this was associated with: (i) inhibition of cell proliferation; (ii) induction of apoptosis of tumor cells; (iii) alterations in cell cycle regulatory proteins; and (iv) reduced expression of tumor angiogenic biomarkers in tumor xenograft tissues. These results indicate that silymarin may have a chemotherapeutic effect on human melanoma cell growth and warrant its further evaluation. © 2014 Wiley Periodicals, Inc.

  11. Vemurafenib and concomitant stereotactic radiation for the treatment of melanoma with spinal metastases: A case report

    PubMed Central

    Stefan, Dinu; Popotte, Hosni; Stefan, Andreea Raluca; Tesniere, Audrey; Tomaszewski, Aurélie; Lesueur, Paul; Habrand, Jean-Louis; Verneuil, Laurence

    2016-01-01

    A 56-year-old man with BRAFV600E melanoma and spinal metastases treated with vemurafenib and stereotactic radiation showed a partial response without neurological, skin or mucosal toxicity, 8 months after completion of this combination. This case suggests that stereotactic radiation spares normal tissues and might be safer than conventional fractionated radiation with vemurafenib. PMID:26900362

  12. Vemurafenib and concomitant stereotactic radiation for the treatment of melanoma with spinal metastases: A case report.

    PubMed

    Stefan, Dinu; Popotte, Hosni; Stefan, Andreea Raluca; Tesniere, Audrey; Tomaszewski, Aurélie; Lesueur, Paul; Habrand, Jean-Louis; Verneuil, Laurence

    2016-01-01

    A 56-year-old man with BRAFV600E melanoma and spinal metastases treated with vemurafenib and stereotactic radiation showed a partial response without neurological, skin or mucosal toxicity, 8 months after completion of this combination. This case suggests that stereotactic radiation spares normal tissues and might be safer than conventional fractionated radiation with vemurafenib.

  13. Temozolomide for Treating Malignant Melanoma.

    PubMed

    Li, Rong-Hua; Hou, Xiao-Yang; Yang, Chun-Sheng; Liu, Wen-Lou; Tang, Jian-Qin; Liu, Yan-Qun; Jiang, Guan

    2015-09-01

    Melanoma is one of the most malignant forms of skin cancer; with a rapidly increasing prevalence. Early-stage melanoma is curable, but advanced metastatic melanoma is almost always fatal, and patients with such advanced disease have short median survival. Surgery and radiotherapy play a limited role in the treatment of metastatic melanoma. Rather, chemotherapy remains the mainstay of treatment, although other approaches, including biotherapy and gene therapy, have been attempted. The authors hereby, evaluated the use of temozolomide (TMZ) for treating metastatic melanoma compared to dacarbazine (DTIC), the effectiveness of TMZ for treating brain metastases, as well as TMZ resistance and how the efficacy of TMZ in malignant melanoma can be increased. Two chemotherapeutic regimens are commonly used for palliative treatment of malignant melanoma: intravenous administration of DTIC and oral administration of the alkylating agent temozolomide (TMZ). Compared to DTIC, TMZ is very well tolerated and has an advantage in terms of improving the quality of life of patients with metastatic melanoma. While the prognosis is currently unpromising, chemotherapy plays a palliative role for patients with metastatic melanoma. The toxicity of treatment regimens based on DTIC and TMZ do not differ significantly, although TMZ is costlier. These findings provide a reference for future researchers via a comprehensive analysis of the relevant literature.

  14. A phase 0 trial of riluzole in patients with resectable stage III and IV melanoma.

    PubMed

    Yip, Dana; Le, Maithao N; Chan, Joseph L-K; Lee, Jonathan H; Mehnert, Janice A; Yudd, Anthony; Kempf, Jeffery; Shih, Weichung J; Chen, Suzie; Goydos, James S

    2009-06-01

    Ectopic expression of GRM1 in murine melanocytes results in transformation into a form of melanoma, and more than 60% of human melanoma samples tested ectopically express GRM1. Stimulation of this receptor in vitro results in up-regulation of activated extracellular signal-regulated kinase (ERK). Furthermore, a xenograft model of melanoma treated with riluzole, an oral GRM1 blocking agent, showed decreased tumor growth compared with the untreated controls. We have now completed a phase 0 trial of riluzole in patients with melanoma. Patients enrolled on this trial underwent a pretreatment biopsy, took 200 mg of oral riluzole per day for 14 days, and then underwent resection of their remaining tumor. We compared the levels of pERK and pAKT in the pretreatment and post-treatment samples and assessed the metabolic activity of pretreatment and post-treatment tumors using fluorodeoxyglucose positron emission tomography (FDG-PET) scanning. We accrued 12 patients and all expressed GRM1. We found a significant decrease in pAKT and/or pERK in post-treatment tumor samples as compared with pretreatment samples in 4 (34%) patients. These four patients had a significant decrease in FDG-PET intensity post-treatment as well. Two other patients had a clinical response with no corresponding metabolic response; five patients had similar pretreatment and post-treatment FDG-PET scan findings; and one patient had progressive disease. Our data show that glutamate blockade with riluzole can inhibit signaling through the mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT pathways and suppress the metabolic activity of melanoma. The ectopic expression of metabotropic glutamate receptors may be important in the pathogenesis of human melanoma, and targeting this pathway may be an effective therapy.

  15. A Phase 0 Trial of Riluzole in Patients with Resectable Stage III and IV Melanoma

    PubMed Central

    Yip, Dana; Le, Maithao N.; Chan, Joseph L.-K.; Lee, Jonathan H.; Mehnert, Janice A.; Yudd, Anthony; Kempf, Jeffery; Shih, Weichung J.; Chen, Suzie; Goydos, James S.

    2010-01-01

    Purpose Ectopic expression of GRM1 in murine melanocytes results in transformation into a form of melanoma, and more than 60% of human melanoma samples tested ectopically express GRM1. Stimulation of this receptor in vitro results in up-regulation of activated extracellular signal–regulated kinase (ERK). Furthermore, a xenograft model of melanoma treated with riluzole, an oral GRM1 blocking agent, showed decreased tumor growth compared with the untreated controls. We have now completed a phase 0 trial of riluzole in patients with melanoma. Experimental Design Patients enrolled on this trial underwent a pretreatment biopsy, took 200 mg of oral riluzole per day for 14 days, and then underwent resection of their remaining tumor. We compared the levels of pERK and pAKT in the pretreatment and post-treatment samples and assessed the metabolic activity of pretreatment and post-treatment tumors using fluorodeoxyglucose positron emission tomography (FDG-PET) scanning. Results We accrued 12 patients and all expressed GRM1. We found a significant decrease in pAKT and/or pERK in post-treatment tumor samples as compared with pretreatment samples in 4 (34%) patients. These four patients had a significant decrease in FDG-PET intensity post-treatment as well. Two other patients had a clinical response with no corresponding metabolic response; five patients had similar pretreatment and post-treatment FDG-PET scan findings; and one patient had progressive disease. Conclusions Our data show that glutamate blockade with riluzole can inhibit signaling through the mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT pathways and suppress the metabolic activity of melanoma. The ectopic expression of metabotropic glutamate receptors may be important in the pathogenesis of human melanoma, and targeting this pathway may be an effective therapy. PMID:19458050

  16. High incidence of naevi-associated BRAF wild-type melanoma and dysplastic naevi under treatment with the class I BRAF inhibitor vemurafenib.

    PubMed

    Göppner, Daniela; Müller, Jan; Krüger, Sabine; Franke, Ingolf; Gollnick, Harald; Quist, Sven R

    2014-09-01

    There is growing evidence that not only malign keratinocytic but also melanocytic tumours can arise during treatment with vemurafenib. During an on-going early access trial, 13 patients harbouring a BRAF-V600E mutation received vemurafenib (Zelboraf®) 960 mg twice daily to test the safety, tolerability, efficacy and response rate for advanced melanoma. Clinically or dermatoscopically suspicious cutaneous tumours under treatment with vemurafenib were excised. The BRAF-V600E status of confirmed new primary melanoma and dysplastic naevi was tested using a genetic mutation assay and immunohistochemistry. Four of the 13 patients (31%) developed 4 new naevi-associated malignant melanomas and 5 dysplastic naevi between 6 weeks and 6 months after the start of treatment. With the exception of one in situ melanoma, all tumours were BRAF wild-type. Immunohistochemistry revealed increased expression of ERK, pERK and active Rac1-GTP in the naevi-associated melanoma and dysplastic naevi. Careful and continuous skin examination, including dermoscopy, appears to be required during treatment with vemurafenib.

  17. Gene and microRNA modulation upon trabectedin treatment in a human intrahepatic cholangiocarcinoma paired patient derived xenograft and cell line

    PubMed Central

    Peraldo Neia, Caterina; Cavalloni, Giuliana; Chiorino, Giovanna; Ostano, Paola; Aglietta, Massimo; Leone, Francesco

    2016-01-01

    Intrahepatic cholangiocarcinoma (ICC) is an aggressive and lethal malignancy with limited therapeutic options. Trabectedin has a high antitumor activity in preclinical models of biliary tract carcinoma (BTC), being a promising alternative treatment. Here, we studied the effect of trabectedin at transcriptomic level on an ICC patient derived xenograft (PDX) and on the derived cell line, MT-CHC01. Further, putative targets of trabectedin were explored in the in vitro model. In vitro, trabectedin inhibited genes involved in protein modification, neurogenesis, migration, and motility; it induced the expression of genes involved in keratinization, tissues development, and apoptotic processes. In the PDX model, trabectedin affected ECM-receptor interaction, focal adhesion, complement and coagulation cascades, Hedgehog, MAPK, EGFR signaling via PIP3 pathway, and apoptosis. Among down-regulated genes, we selected SYK and LGALS1; their silencing caused a significantly reduction of migration, but did not affect proliferation in in vitro models. In MT-CHC01 cells, 24 microRNAs were deregulated upon drug treatment, while only 5 microRNAs were perturbed by trabectedin in PDX. The target prediction analysis showed that SYK and LGALS1 are putative targets of up-regulated microRNAs. In conclusion, we described that trabectedin affected genes and microRNAs involved in tumor progression and metastatic processes, reflecting data previously obtained at macroscopically level; in particular, we identified SYK and LGALS1 as new putative targets of trabectedin. PMID:27902465

  18. Novel Treatment of Melanoma: Combined Parasite-Derived Peptide GK-1 and Anti-Programmed Death Ligand 1 Therapy.

    PubMed

    Vera-Aguilera, Jesus; Perez-Torres, Armando; Beltran, Diego; Villanueva-Ramos, Cynthia; Wachtel, Mitchell; Moreno-Aguilera, Eduardo; Vera-Aguilera, Carlos; Ventolini, Gary; Martínez-Zaguilán, Raul; Sennoune, Souad R

    2017-03-01

    Recent successes in the development of new therapies for metastatic melanoma, such as mitogen-activated protein kinase pathway inhibitors, anticytotoxic T lymphocyte-associated antigen-4, and programmed cell death protein 1/programmed cell death ligand 1 (PD-L1) pathway-blocking antibodies, as well as combination strategies, all yielded promising results, changing the continually evolving landscape of therapeutic options for patients with melanoma. One promising new treatment modality is based on the use of immunomodulatory monoclonal antibodies that enhance the function of components of the antitumor immune response such as T cells or block immunologic checkpoints that restrain effective antitumor immunity. Program death-1 receptor and its ligand, PD-L1, is a major mechanism by which a tumor suppresses T cell-mediated antitumor immune responses. Studies in mice have shown that GK-1, an 18 amino acid peptide from Taenia crassiceps cisticerci, has the potential to be used as a primary or adjuvant component for the treatment of cancers by stimulating proinflammatory cytokines. The authors hypothesized that treatment with GK-1 in combination with anti-PD-L1 will increase survival in mice bearing melanoma tumors. C57BL/6 mice were injected with B16-F10-luc2 cells and separated into four groups: control, GK-1, anti-PD-L1, and GK-1/anti-PD-L1. The tumor sizes were measured and monitored using calipers and bioluminescence. The GK-1 peptide in combination with anti-PD-L1 showed significantly longer survival (34 days) compared with the other groups (23-27 days). This means an increase; survival increased 47.82% in the mice treated with GK-1+anti-PD-L1, 21.7% in mice treated with GK-1 alone, and 6.08% in those mice treated with anti-PD-L1 only. Blood samples were collected at days 0, 14, and at euthanization or end of the experiment and monitored for cytokines using mouse-specific V-PLEX Proinflammatory Panel. A decrease in TNF-α, IL-4, IL-5, IL-6, and IL-10 serum levels

  19. Multiparametric MR diffusion-weighted imaging for monitoring the ultra-early treatment effect of sorafenib in human hepatocellular carcinoma xenografts.

    PubMed

    Chen, Xin; Ma, Zelan; Huang, Yanqi; He, Lan; Liang, Cuishan; Shi, Changzheng; Zhang, Zhongping; Liang, Changhong; Liu, Zaiyi

    2017-07-01

    To investigate the value of multiparametric magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI) for monitoring the ultra-early (within 24 hours) treatment effect of sorafenib in human hepatocellular carcinoma (HCC) xenografts. With institutional Animal Care and Use Committee approval, 16 BALB/c nude mice bearing subcutaneous HCC xenografts underwent serial Gaussian and non-Gaussian DWI at baseline and 1, 3, 6, 12, and 24 hours posttreatment using a 1.5T whole-body MRI system. Gaussian-DWI-derived apparent diffusion coefficient (ADC), D, D*, and f, and non-Gaussian-DWI-derived MD, MK, DDC, and α were calculated and compared between the control (n = 6) and sorafenib-treated groups (n = 10) with respect to each timepoint using Mann-Whitney or Wilcoxon signed-rank test. Results were validated by pathology. Compared to baseline, ADC and D at 1 hour posttreatment (P = 0.005 and P = 0.013, respectively) and MD and DDC at 3 hours posttreatment (P = 0.009 and P = 0.005, respectively) significantly decreased and remained lower through 12 hours of follow-up (P = 0.005-0.022), followed by recovery to baseline levels at 24 hours posttreatment (P = 0.139-0.646). MK significantly increased at 1 hour posttreatment (P = 0.013) and remained higher through 24 hours of follow-up (P = 0.009-0.028). No significant differences were found in D*, f, and α at different timepoints (P = 0.188-0.714). Light microscopy did not reveal abnormal findings until 3 hours posttreatment, when central patchy necrosis was observed; more prominent diffuse necrosis was observed at 24 hours. Electron microscopy revealed swollen mitochondria at 1 hour posttreatment and accumulation of intracellular autophagosomes from 3 to 24 hours posttreatment. Multiparametric DWI might evaluate therapeutic effects of sorafenib in HCC, where metrics of ADC, D, and MK could potentially serve as imaging biomarkers for monitoring therapeutic effects as early as 1

  20. Targeting Multiple Key Signaling Pathways in Melanoma using Leelamine

    PubMed Central

    Gowda, Raghavendra; Madhunapantula, SubbaRao V.; Kuzu, Omer F.; Sharma, Arati; Robertson, Gavin P.

    2015-01-01

    Melanoma is a highly drug resistant cancer with resistance developing to agents targeting single proteins. To circumvent this problem, a new class of agent inhibiting multiple key pathways important in this disease is being developed to reduce the likelihood of developing resistant disease. The PI3 kinase (PI3K), MAP kinase (MAPK) and STAT3 pathways are constitutively activated in 50–70% of melanomas promoting disease development. To identify a drug simultaneously targeting the PI3K, MAPK and STAT3 cascades, a natural product library was screened to identifying leelamine as a potential inhibitor. Leelamine was 4.5-fold more effective at inhibiting cultured melanoma cell survival than normal cells, with average IC50 values of 2 and 9.3 µmol/L, respectively. It inhibited cellular proliferation at a concentration of 2.5 µmol/L by 40–80% and longer exposure increased apoptosis 600% through a mechanism detailed in the article in the current issue of this journal by Kuzu OF et al. Leelamine inhibited the growth of preexisting xenografted melanoma tumors by an average of 60% by targeting the PI3K, MAPK and STAT3 pathways without affecting animal body weight or blood markers of major organ function. The mechanism of action of leelamine is mediated by disruption of cholesterol transport, causing decreased cellular proliferation and, consequently leading to increased tumor cell apoptosis as well as decreased tumor vascularization. Thus, a unique agent and novel mechanism of action has been identified for the treatment of melanoma that acts by inhibiting the activity of three major signaling pathways regulating the development of this disease. PMID:24688050

  1. DTIC vs. IFN-alpha plus DTIC in the treatment of patients with metastatic malignant melanoma.

    PubMed

    Rudolf, Z; Strojan, P

    1996-01-01

    In our study we evaluated and compared the therapeutic success in 70 patients with cutaneous metastatic malignant melanoma (MM) treated at the Institute of Oncology in Ljubljana during the period 1985-1994. Twenty-nine patients received DTIC in a single 800 mg/m2 i.v. dose (Group 1) and 41 patients were receiving i.m. applications of IFN-alpha in 2 MU daily doses from days 1 to 4, completing the treatment with a DTIC application on day 5, given at the same dosage as in Group 1 (Group 2). The applications were repeated in three-week intervals until progression, or-in the case of a complete response-for up to 6 months. The rate and median duration of treatment response were higher in the group of patients treated by IFN-alpha plus DTIC (17% vs. 27%; 2.7 vs. 6.1 months), though the difference was not statistically significant. The survival of responders was either significantly higher (Group 2: p = 0.0007) or borderline-significantly higher (Group 1; p = 0.078) than that of non-responders. These patients also had significantly longer median survival (Group 1: 13.7 vs. 5.1 months, p = 0.019; Group 2: 19.3 vs. 4.9 months, p = 0.0003). The patients treated with IFN-alpha plus DTIC survived significantly better than those treated with DTIC alone (p = 0.043). There were no differences in the median duration of survival between both groups (6.6 vs. 6.7 months), and neither in the median duration of survival of responders (13.7 vs. 19.3 months) or non-responders (5.1 vs. 4.9 months) from both groups. The toxicity of combined therapy was higher than that of chemotherapy alone, though it was still moderate and acceptable. In view of our results, the addition of IFN-alpha to DTIC has shown an advantage over DTIC along.

  2. Sensitization of melanoma cells to alkylating agent-induced DNA damage and cell death via orchestrating oxidative stress and IKKβ inhibition.

    PubMed

    Tse, Anfernee Kai-Wing; Chen, Ying-Jie; Fu, Xiu-Qiong; Su, Tao; Li, Ting; Guo, Hui; Zhu, Pei-Li; Kwan, Hiu-Yee; Cheng, Brian Chi-Yan; Cao, Hui-Hui; Lee, Sally Kin-Wah; Fong, Wang-Fun; Yu, Zhi-Ling

    2017-04-01

    Nitrosourea represents one of the most active classes of chemotherapeutic alkylating agents for metastatic melanoma. Treatment with nitrosoureas caused severe systemic side effects which hamper its clinical use. Here, we provide pharmacological evidence that reactive oxygen species (ROS) induction and IKKβ inhibition cooperatively enhance nitrosourea-induced cytotoxicity in melanoma cells. We identified SC-514 as a ROS-inducing IKKβ inhibitor which enhanced the function of nitrosoureas. Elevated ROS level results in increased DNA crosslink efficiency triggered by nitrosoureas and IKKβ inhibition enhances DNA damage signals and sensitizes nitrosourea-induced cell death. Using xenograft mouse model, we confirm that ROS-inducing IKKβ inhibitor cooperates with nitrosourea to reduce tumor size and malignancy in vivo. Taken together, our results illustrate a new direction in nitrosourea treatment, and reveal that the combination of ROS-inducing IKKβ inhibitors with nitrosoureas can be potentially exploited for melanoma therapy.

  3. Fibronectin induction abrogates the BRAF inhibitor response of BRAF V600E/PTEN-null melanoma cells.

    PubMed

    Fedorenko, I V; Abel, E V; Koomen, J M; Fang, B; Wood, E R; Chen, Y A; Fisher, K J; Iyengar, S; Dahlman, K B; Wargo, J A; Flaherty, K T; Sosman, J A; Sondak, V K; Messina, J L; Gibney, G T; Smalley, K S M

    2016-03-10

    The mechanisms by which some melanoma cells adapt to Serine/threonine-protein kinase B-Raf (BRAF) inhibitor therapy are incompletely understood. In the present study, we used mass spectrometry-based phosphoproteomics to determine how BRAF inhibition remodeled the signaling network of melanoma cell lines that were BRAF mutant and PTEN null. Short-term BRAF inhibition was associated with marked changes in fibronectin-based adhesion signaling that were PTEN dependent. These effects were recapitulated through BRAF siRNA knockdown and following treatment with chemotherapeutic drugs. Increased fibronectin expression was also observed in mouse xenograft models as well as specimens from melanoma patients undergoing BRAF inhibitor treatment. Analysis of a melanoma tissue microarray showed loss of PTEN expression to predict for a lower overall survival, with a trend for even lower survival being seen when loss of fibronectin was included in the analysis. Mechanistically, the induction of fibronectin limited the responses of these PTEN-null melanoma cell lines to vemurafenib, with enhanced cytotoxicity observed following the knockdown of either fibronectin or its receptor α5β1 integrin. This in turn abrogated the cytotoxic response to BRAF inhibition via increased AKT signaling, which prevented the induction of cell death by maintaining the expression of the pro-survival protein Mcl-1. The protection conveyed by the induction of FN expression could be overcome through combined treatment with a BRAF and PI3K inhibitor.

  4. Fibronectin induction abrogates the BRAF inhibitor response of BRAF V600E/PTEN-null melanoma cells

    PubMed Central

    Fedorenko, Inna V.; Abel, Ethan V.; Koomen, John M.; Fang, Bin; Wood, Elizabeth R.; Chen, Y. Ann; Fisher, Kate J.; Iyengar, Sanjana; Dahlman, Kimberly B.; Wargo, Jennifer A.; Flaherty, Keith T.; Sosman, Jeffrey A.; Sondak, Vernon K.; Messina, Jane L.; Gibney, Geoffrey T.; Smalley, Keiran S.M.

    2015-01-01

    The mechanisms by which some melanoma cells adapt to BRAF inhibitor therapy are incompletely understood. In the present study, we used mass spectrometry-based phosphoproteomics to determine how BRAF inhibition remodeled the signaling network of melanoma cell lines that were BRAF-mutant and PTEN-null. Short-term BRAF inhibition was associated with marked changes in fibronectin-based adhesion signaling that were PTEN-dependent. These effects were recapitulated through BRAF siRNA knockdown and following treatment with chemotherapeutic drugs. Increased fibronectin expression was also observed in mouse xenograft models as well as specimens from melanoma patients undergoing BRAF inhibitor treatment. Analysis of a melanoma TMA showed loss of PTEN expression to predict for a lower overall survival, with a trend for even lower survival being seen when loss of fibronectin was included in the analysis. Mechanistically, the induction of fibronectin limited the responses of these PTEN-null melanoma cell lines to vemurafenib, with enhanced cytotoxicity observed following the knockdown of either fibronectin or its receptor α5β1 integrin. This in turn abrogated the cytotoxic response to BRAF inhibition via increased AKT signaling, which prevented the induction of cell death by maintaining the expression of the pro-survival protein Mcl-1. The protection conveyed by the induction of fibronectin expression could be overcome through combined treatment with a BRAF and PI3K inhibitor. PMID:26073081

  5. Anorectal melanoma. An update.

    PubMed

    Reina, Angel; Errasti, José; Espín, Eloy

    2014-10-01

    Anorectal melanoma is an uncommon and aggressive disease. Because the patients often present with non specific complaints, a high clinical suspicion is important to avoid a delayed diagnosis. Patients undergoing radical surgery have no significant survival difference compared to those undergoing wide local excision. Abdominoperineal resection should be reserved for selected patients in whom local excision is not technically possible or cannot obtain a clear margin. The indiscriminate use of groin dissection is not advisable in anorectal melanoma and should be use in selected cases. Systemic chemotherapy is generally a non effective treatment and continues be studied. Radiation therapy can be used as hypofractionated radiation therapy combined with local excision or in a palliative setting. The oncological outcomes in anorectal melanoma are very poor. The aim of the present study is to review clinicopathology features and management of anorectal melanoma. Copyright © 2013 AEC. Published by Elsevier Espana. All rights reserved.

  6. Cytokine-Enhanced Vaccine and Interferon-β plus Suicide Gene Therapy as Surgery Adjuvant Treatments for Spontaneous Canine Melanoma.

    PubMed

    Finocchiaro, Liliana M E; Fondello, Chiara; Gil-Cardeza, María L; Rossi, Úrsula A; Villaverde, Marcela S; Riveros, María D; Glikin, Gerardo C

    2015-06-01

    We present here a nonviral immunogene therapy trial for canine malignant melanoma, an aggressive disease displaying significant clinical and histopathological overlapping with human melanoma. As a surgery adjuvant approach, it comprised the co-injection of lipoplexes bearing herpes simplex virus thymidine kinase and canine interferon-β genes at the time of surgery, combined with the periodic administration of a subcutaneous genetic vaccine composed of tumor extracts and lipoplexes carrying the genes of human interleukin-2 and human granulocyte-macrophage colony-stimulating factor. Following complete surgery (CS), the combined treatment (CT) significantly raised the portion of local disease-free canine patients from 11% to 83% and distant metastases-free (M0) from 44% to 89%, as compared with surgery-only-treated controls (ST). Even after partial surgery (PS), CT better controlled the systemic disease (M0: 82%) than ST (M0: 48%). Moreover, compared with ST, CT caused a significant 7-fold (CS) and 4-fold (PS) rise of overall survival, and >17-fold (CS) and >13-fold (PS) rise of metastasis-free survival. The dramatic increase of PS metastasis-free survival (>1321 days) and CS recurrence- and metastasis-free survival (both >2251 days) demonstrated that CT was shifting a rapidly lethal disease into a chronic one. In conclusion, this surgery adjuvant CT was able of significantly delaying or preventing postsurgical recurrence and distant metastasis, increasing disease-free and overall survival, and maintaining the quality of life. The high number of canine patients involved in CT (301) and the extensive follow-up (>6 years) with minimal or absent toxicity warrant the long-term safety and efficacy of this treatment. This successful clinical outcome justifies attempting a similar scheme for human melanoma.

  7. Cytokine-Enhanced Vaccine and Interferon-β plus Suicide Gene Therapy as Surgery Adjuvant Treatments for Spontaneous Canine Melanoma

    PubMed Central

    Fondello, Chiara; Gil-Cardeza, María L.; Rossi, Úrsula A.; Villaverde, Marcela S.; Riveros, María D.; Glikin, Gerardo C.

    2015-01-01

    Abstract We present here a nonviral immunogene therapy trial for canine malignant melanoma, an aggressive disease displaying significant clinical and histopathological overlapping with human melanoma. As a surgery adjuvant approach, it comprised the co-injection of lipoplexes bearing herpes simplex virus thymidine kinase and canine interferon-β genes at the time of surgery, combined with the periodic administration of a subcutaneous genetic vaccine composed of tumor extracts and lipoplexes carrying the genes of human interleukin-2 and human granulocyte-macrophage colony-stimulating factor. Following complete surgery (CS), the combined treatment (CT) significantly raised the portion of local disease-free canine patients from 11% to 83% and distant metastases-free (M0) from 44% to 89%, as compared with surgery-only-treated controls (ST). Even after partial surgery (PS), CT better controlled the systemic disease (M0: 82%) than ST (M0: 48%). Moreover, compared with ST, CT caused a significant 7-fold (CS) and 4-fold (PS) rise of overall survival, and >17-fold (CS) and >13-fold (PS) rise of metastasis-free survival. The dramatic increase of PS metastasis-free survival (>1321 days) and CS recurrence- and metastasis-free survival (both >2251 days) demonstrated that CT was shifting a rapidly lethal disease into a chronic one. In conclusion, this surgery adjuvant CT was able of significantly delaying or preventing postsurgical recurrence and distant metastasis, increasing disease-free and overall survival, and maintaining the quality of life. The high number of canine patients involved in CT (301) and the extensive follow-up (>6 years) with minimal or absent toxicity warrant the long-term safety and efficacy of this treatment. This successful clinical outcome justifies attempting a similar scheme for human melanoma. PMID:25762364

  8. Local cryosurgery and imiquimod: A successful combination for the treatment of locoregional cutaneous metastasis of melanoma: A case series.

    PubMed

    Rivas-Tolosa, Nancy; Ortiz-Brugués, Ariadna; Toledo-Pastrana, Tomás; Baradad, Manel; Traves, Víctor; Soriano, Virtudes; Sanmartín, Verónica; Requena, Celia; Martí, Rosa; Nagore, Eduardo

    2016-05-01

    Locoregional cutaneous metastases of melanoma (LCMM) represent a therapeutic challenge. Many treatment options are available with varying results. The combination of cryotherapy and imiquimod, two treatments with a possible synergistic effect, has not yet been described for treating this disease. In this paper, we aimed to show the response of LCMM to cryotherapy combined with topical imiquimod 5%. A retrospective review of 20 patients diagnosed with LCMM and treated with cryotherapy combined with topical imiquimod 5% between November 2000 and May 2014 at three institutions was performed. The locoregional cutaneous response was evaluated. After a mean of five sessions, 13 patients (65%) responded to treatment, eight (40%) of these completely and five (25%) partially. Systemic disease progressed in 16 (80%) patients. Cryotherapy followed by topical imiquimod 5% is simple to apply, has minimal adverse effects and provides response rates similar to other, more complex treatment options. © 2015 Japanese Dermatological Association.

  9. The Danish Melanoma Database

    PubMed Central

    Hölmich, Lisbet Rosenkrantz; Klausen, Siri; Spaun, Eva; Schmidt, Grethe; Gad, Dorte; Svane, Inge Marie; Schmidt, Henrik; Lorentzen, Henrik Frank; Ibfelt, Else Helene

    2016-01-01

    Aim of database The aim of the database is to monitor and improve the treatment and survival of melanoma patients. Study population All Danish patients with cutaneous melanoma and in situ melanomas must be registered in the Danish Melanoma Database (DMD). In 2014, 2,525 patients with invasive melanoma and 780 with in situ tumors were registered. The coverage is currently 93% compared with the Danish Pathology Register. Main variables The main variables include demographic, clinical, and pathological characteristics, including Breslow’s tumor thickness, ± ulceration, mitoses, and tumor–node–metastasis stage. Information about the date of diagnosis, treatment, type of surgery, including safety margins, results of lymphoscintigraphy in patients for whom this was indicated (tumors > T1a), results of sentinel node biopsy, pathological evaluation hereof, and follow-up information, including recurrence, nature, and treatment hereof is registered. In case of death, the cause and date are included. Currently, all data are entered manually; however, data catchment from the existing registries is planned to be included shortly. Descriptive data The DMD is an old research database, but new as a clinical quality register. The coverage is high, and the performance in the five Danish regions is quite similar due to strong adherence to guidelines provided by the Danish Melanoma Group. The list of monitored indicators is constantly expanding, and annual quality reports are issued. Several important scientific studies are based on DMD data. Conclusion DMD holds unique detailed information about tumor characteristics, the surgical treatment, and follow-up of Danish melanoma patients. Registration and monitoring is currently expanding to encompass even more clinical parameters to benefit both patient treatment and research. PMID:27822097

  10. Patient-derived xenograft platform of OSCC: a renewable human bio-bank for preclinical cancer research and a new co-clinical model for treatment optimization.

    PubMed

    Sun, Shuyang; Zhang, Zhiyuan

    2016-03-01

    Advances in next-generation sequencing and bioinformatics have begun to reveal the complex genetic landscape in human cancer genomes, including oral squamous cell carcinoma (OSCC). Sophisticated preclinical models that fully represent intra- and inter-tumoral heterogeneity are required to understand the molecular diversity of cancer and achieve the goal of personalized therapies. Over the last decade, patient-derived xenograft (PDX) models generated from human tumor samples that can retain the histological and genetic features of their donor tumors have been shown to be the preferred preclinical tool in translational cancer research compared with other conventional preclinical models. Specifically, genetically well-defined PDX models can be applied to accelerate targeted antitumor drug development and biomarker discovery. Recently, we have successfully established and characterized an OSCC PDX panel as part of our tumor bio-bank for translational cancer research. In this paper, we discuss the establishment, characterization, and preclinical applications of the PDX models. In particular, we focus on the classification and applications of the PDX models based on validated annotations, including clinicopathological features, genomic profiles, and pharmacological testing information. We also explore the translational value of this well-annotated PDX panel in the development of co-clinical trials for patient stratification and treatment optimization in the near future. Although various limitations still exist, this preclinical approach should be further tested and improved.

  11. Effects of Combined Treatment with Ionizing Radiation and the PARP Inhibitor Olaparib in BRCA Mutant and Wild Type Patient-Derived Pancreatic Cancer Xenografts.

    PubMed

    Lohse, Ines; Kumareswaran, Ramya; Cao, Pinjiang; Pitcher, Bethany; Gallinger, Steven; Bristow, Robert G; Hedley, David W

    2016-01-01

    The BRCA2 gene product plays an important role in DNA double strand break repair. Therefore, we asked whether radiation sensitivity of pancreatic cancers developing in individuals with germline BRCA2 mutations can be enhanced by agents that inhibit poly (ADP-ribose) polymerase (PARP). We compared the sensitivity of two patient-derived pancreatic cancer xenografts, expressing a truncated or wild type BRCA 2, to ionizing radiation alone or in combination with olaparib (AZD-2281). Animals were treated with either a single dose of 12Gy, 7 days of olaparib or 7 days of olaparib followed by a single dose of 12Gy. Response was assessed by tumour growth delay and the activation of damage response pathways. The BRCA2 mutated and wild type tumours showed similar radiation sensitivity, and treatment with olaparib did not further sensitize either model when compared to IR alone. While PARP inhibition has been shown to be effective in BRCA-mutated breast and ovarian cancers, it is less well established in pancreatic cancer patients. Our results show no radiosensitization in a germline BRCA 2 mutant and suggest that combining PARP inhibition and IR may not be beneficial in BRCA 2 related pancreatic tumors.

  12. Effects of Combined Treatment with Ionizing Radiation and the PARP Inhibitor Olaparib in BRCA Mutant and Wild Type Patient-Derived Pancreatic Cancer Xenografts

    PubMed Central

    Cao, Pinjiang; Pitcher, Bethany; Gallinger, Steven; Bristow, Robert G.; Hedley, David W.

    2016-01-01

    Background The BRCA2 gene product plays an important role in DNA double strand break repair. Therefore, we asked whether radiation sensitivity of pancreatic cancers developing in individuals with germline BRCA2 mutations can be enhanced by agents that inhibit poly (ADP-ribose) polymerase (PARP). Methods We compared the sensitivity of two patient-derived pancreatic cancer xenografts, expressing a truncated or wild type BRCA 2, to ionizing radiation alone or in combination with olaparib (AZD-2281). Animals were treated with either a single dose of 12Gy, 7 days of olaparib or 7 days of olaparib followed by a single dose of 12Gy. Response was assessed by tumour growth delay and the activation of damage response pathways. Results The BRCA2 mutated and wild type tumours showed similar radiation sensitivity, and treatment with olaparib did not further sensitize either model when compared to IR alone. Conclusions While PARP inhibition has been shown to be effective in BRCA-mutated breast and ovarian cancers, it is less well established in pancreatic cancer patients. Our results show no radiosensitization in a germline BRCA 2 mutant and suggest that combining PARP inhibition and IR may not be beneficial in BRCA 2 related pancreatic tumors. PMID:28033382

  13. Anti-chondroitin sulfate proteoglycan 4-specific antibodies modify the effects of vemurafenib on melanoma cells differentially in normoxia and hypoxia.

    PubMed

    Pucciarelli, Daniela; Lengger, Nina; Takacova, Martina; Csaderova, Lucia; Bartosova, Maria; Breiteneder, Heimo; Pastorekova, Silvia; Hafner, Christine

    2015-07-01

    Chondroitin sulfate proteoglycan 4 (CSPG4), a highly imm