Emerging drugs for head and neck cancer

PubMed Central

Wen, Yihui; Grandis, Jennifer R

2017-01-01

Introduction Despite improvements in treatment, survival rates of head and neck squamous cell carcinoma (HNSCC) are stagnant. The existing chemotherapeutic agents are non-selective and associated with toxicities. Combinations of the only the US FDA-approved epidermal growth factor receptor (EGFR)-targeted agent, cetuximab, with chemotherapy or radiation improves overall survival. However, the response rates to cetuximab are modest. Thus, there is an urgent need for new agents that can be safely integrated into current treatment regimens to improve outcome. Areas covered Current EGFR-targeted drugs under clinical development include mAbs and tyrosine kinase inhibitors. The modest efficacy of these drugs implicates intrinsic or acquired resistance. Novel molecular agents inhibiting alternative targets to overcome anti-EGFR resistance in HNSCC are under investigation. Gene therapy and immunotherapy are also promising strategies to improve efficacy and reduce toxicity. Expert opinion To date, only six drugs have been FDA-approved for the treatment of head and neck cancer. Cetuximab is the only approved molecular targeting agent for HNSCC and despite ubiquitous expression of EGFR in HNSCC tumors, clinical responses are limited. Genetic and epigenetic characterization of HNSCC tumors, coupled with improved preclinical models, should facilitate the development of more effective drugs. PMID:25826749

Molecular Basis for Necitumumab Inhibition of EGFR Variants Associated with Acquired Cetuximab Resistance.

PubMed

Bagchi, Atrish; Haidar, Jaafar N; Eastman, Scott W; Vieth, Michal; Topper, Michael; Iacolina, Michelle D; Walker, Jason M; Forest, Amelie; Shen, Yang; Novosiadly, Ruslan D; Ferguson, Kathryn M

2018-02-01

Acquired resistance to cetuximab, an antibody that targets the EGFR, impacts clinical benefit in head and neck, and colorectal cancers. One of the mechanisms of resistance to cetuximab is the acquisition of mutations that map to the cetuximab epitope on EGFR and prevent drug binding. We find that necitumumab, another FDA-approved EGFR antibody, can bind to EGFR that harbors the most common cetuximab-resistant substitution, S468R (or S492R, depending on the amino acid numbering system). We determined an X-ray crystal structure to 2.8 Å resolution of the necitumumab Fab bound to an S468R variant of EGFR domain III. The arginine is accommodated in a large, preexisting cavity in the necitumumab paratope. We predict that this paratope shape will be permissive to other epitope substitutions, and show that necitumumab binds to most cetuximab- and panitumumab-resistant EGFR variants. We find that a simple computational approach can predict with high success which EGFR epitope substitutions abrogate antibody binding. This computational method will be valuable to determine whether necitumumab will bind to EGFR as new epitope resistance variants are identified. This method could also be useful for rapid evaluation of the effect on binding of alterations in other antibody/antigen interfaces. Together, these data suggest that necitumumab may be active in patients who are resistant to cetuximab or panitumumab through EGFR epitope mutation. Furthermore, our analysis leads us to speculate that antibodies with large paratope cavities may be less susceptible to resistance due to mutations mapping to the antigen epitope. Mol Cancer Ther; 17(2); 521-31. ©2017 AACR . ©2017 American Association for Cancer Research.

Non-Covalent Assembly of Targeted Carbon Nanovectors Enables Synergistic Drug and Radiation Cancer Therapy In Vivo

PubMed Central

Sano, Daisuke; Berlin, Jacob M.; Pham, Tam T.; Marcano, Daniela C.; Valdecanas, David R.; Zhou, Ge; Milas, Luka; Myers, Jeffrey N.; Tour, James M.

2012-01-01

Current chemotherapeutics are characterized by efficient tumor cell-killing and severe side effects mostly derived from off target toxicity. Hence targeted delivery of these drugs to tumor cells is actively sought. In an in vitro system, we previously demonstrated that targeted drug delivery to cancer cells overexpressing epidermal growth factor receptor (EGFR+) can be achieved by poly(ethylene glycol)-functionalized carbon nanovectors simply mixed with a drug, paclitaxel, and an antibody that binds to the epidermal growth factor receptor, Cetuximab. This construct is unusual in that all three components are assembled through non-covalent interactions. Here we show that this same construct is effective in vivo, enhancing radiotherapy of EGFR+ tumors. This targeted nanovector system has the potential to be a new therapy for head and neck squamous cell carcinomas, deserving of further preclinical development. PMID:22316245

Optimising the use of cetuximab in the continuum of care for patients with metastatic colorectal cancer.

PubMed

Goldberg, Richard M; Montagut, Clara; Wainberg, Zev A; Ronga, Philippe; Audhuy, François; Taieb, Julien; Stintzing, Sebastian; Siena, Salvatore; Santini, Daniele

2018-01-01

The anti-epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in combination with chemotherapy is a standard of care in the first-line treatment of RAS wild-type (wt) metastatic colorectal cancer (mCRC) and has demonstrated efficacy in later lines. Progressive disease (PD) occurs when tumours develop resistance to a therapy, although controversy remains about whether PD on a combination of chemotherapy and targeted agents implies resistance to both components. Here, we propose that some patients may gain additional clinical benefit from the reuse of cetuximab after having PD on regimens including cetuximab in an earlier treatment line. We conducted a non-systematic literature search in PubMed and reviewed published and ongoing clinical trials, focusing on later-line cetuximab reuse in patients with mCRC. Evidence from multiple studies suggests that cetuximab can be an efficacious and tolerable treatment when continued or when fit patients with mCRC are retreated with it after a break from anti-EGFR therapy. Furthermore, on the basis of available preclinical and clinical evidence, we propose that longitudinal monitoring of RAS status may identify patients suitable for such a strategy. Patients who experience progression on cetuximab plus chemotherapy but have maintained RAS wt tumour status may benefit from continuation of cetuximab with a chemotherapy backbone switch because they have probably developed resistance to the chemotherapeutic agents rather than the biologic component of the regimen. Conversely, patients whose disease progresses on cetuximab-based therapy due to drug-selected clonal expansion of RAS- mutant tumour cells may regain sensitivity to cetuximab following a defined break from anti-EGFR therapy. Looking to the future, we propose that RAS status determination at disease progression by liquid, needle or excisional biopsy may identify patients eligible for cetuximab continuation and rechallenge. With this approach, treatment

Randomized phase II--study evaluating EGFR targeting therapy with cetuximab in combination with radiotherapy and chemotherapy for patients with locally advanced pancreatic cancer--PARC: study protocol [ISRCTN56652283].

PubMed

Krempien, R; Muenter, M W; Huber, P E; Nill, S; Friess, H; Timke, C; Didinger, B; Buechler, P; Heeger, S; Herfarth, K K; Abdollahi, A; Buchler, M W; Debus, J

2005-10-11

Pancreatic cancer is the fourth commonest cause of death from cancer in men and women. Advantages in surgical techniques, radiation therapy techniques, chemotherapeutic regimes, and different combined-modality approaches have yielded only a modest impact on the prognosis of patients with pancreatic cancer. Thus there is clearly a need for additional strategies. One approach involves using the identification of a number of molecular targets that may be responsible for the resistance of cancer cells to radiation or to other cytotoxic agents. As such, these molecular determinants may serve as targets for augmentation of the radiotherapy or chemotherapy response. Of these, the epidermal growth factor receptor (EGFR) has been a molecular target of considerable interest and investigation, and there has been a tremendous surge of interest in pursuing targeted therapy of cancers via inhibition of the EGFR. The PARC study is designed as an open, controlled, prospective, randomized phase II trial. Patients in study arm A will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine infusions weekly over 4 weeks. Patients in study arm B will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine weekly over 4 weeks and cetuximab infusions over 12 weeks. A total of 66 patients with locally advanced adenocarcinoma of the pancreas will be enrolled. An interim analysis for patient safety reasons will be done one year after start of recruitment. Evaluation of the primary endpoint will be performed two years after the last patient's enrollment. The primary objective of this study is to evaluate the feasibility and the toxicity profile of trimodal therapy in pancreatic adenocarcinoma with

Receptor-binding, biodistribution, and metabolism studies of 64Cu-DOTA-cetuximab, a PET-imaging agent for epidermal growth-factor receptor-positive tumors.

PubMed

Ping Li, Wen; Meyer, Laura A; Capretto, David A; Sherman, Christopher D; Anderson, Carolyn J

2008-04-01

The epidermal growth-factor receptor (EGFR) and its ligands have been recognized as critical factors in the pathophysiology of tumorigenesis. Overexpression of the EGFR plays a significant role in the tumor progression of a wide variety of solid human cancers. Therefore, the EGFR represents an attractive target for the design of novel diagnostic and therapeutic agents for cancer. Cetuximab (C225, Erbitux) was the first monoclonal antibody targeted against the ligand-binding site of EGFR approved by the Food and Drug Administration for the treatment of patients with EGFR-expressing, metastatic colorectal carcinoma, although clinical trials showed variability in the response to this treatment. The aim of this study involved using cetuximab to design a positron emission tomography (PET) agent to image the overexpression of EGFR in tumors. Cetuximab was conjugated with the chelator, DOTA, for radiolabeling with the positron-emitter, 64Cu (T(1/2) = 12.7 hours). 64Cu-DOTA-cetuximab showed high binding affinity to EGFR-positive A431 cells (K(D) of 0.28 nM). Both biodistribution and microPET imaging studies with 64Cu-DOTA-cetuximab demonstrated greater uptake at 24 hours postinjection in EGFR-positive A431 tumors (18.49% +/- 6.50% injected dose per gram [ID/g]), compared to EGFR-negative MDA-MB-435 tumors (2.60% +/- 0.35% ID/g). A431 tumor uptake at 24 hours was blocked with unlabeled cetuximab (10.69% +/- 2.72% ID/g), suggesting that the tumor uptake was receptor mediated. Metabolism experiments in vivo showed that 64Cu-DOTA-cetuximab was relatively stable in the blood of tumor-bearing mice; however, there was significant metabolism in the liver and tumors. 64Cu-DOTA-cetuximab is a potential agent for imaging EGFR-positive tumors in humans.

Inhibition of BMP signaling overcomes acquired resistance to cetuximab in oral squamous cell carcinomas.

PubMed

Yin, Jinlong; Jung, Ji-Eun; Choi, Sun Il; Kim, Sung Soo; Oh, Young Taek; Kim, Tae-Hoon; Choi, Eunji; Lee, Sun Joo; Kim, Hana; Kim, Eun Ok; Lee, Yu Sun; Chang, Hee Jin; Park, Joo Yong; Kim, Yeejeong; Yun, Tak; Heo, Kyun; Kim, Youn-Jae; Kim, Hyunggee; Kim, Yun-Hee; Park, Jong Bae; Choi, Sung Weon

2018-02-01

Despite expressing high levels of the epidermal growth factor receptor (EGFR), a majority of oral squamous cell carcinoma (OSCC) patients show limited response to cetuximab and ultimately develop drug resistance. However, mechanism underlying cetuximab resistance in OSCC is not clearly understood. Here, using a mouse orthotopic xenograft model of OSCC, we show that bone morphogenic protein-7-phosphorylated Smad-1, -5, -8 (BMP7-p-Smad1/5/8) signaling contributes to cetuximab resistance. Tumor cells isolated from the recurrent cetuximab-resistant xenograft models exhibited low EGFR expression but extremely high levels of p-Smad1/5/8. Treatment with the bone morphogenic protein receptor type 1 (BMPRI) inhibitor, DMH1 significantly reduced cetuximab-resistant OSCC tumor growth, and combined treatment of DMH1 and cetuximab remarkably reduced relapsed tumor growth in vivo. Importantly, p-Smad1/5/8 level was elevated in cetuximab-resistant patients and this correlated with poor prognosis. Collectively, our results indicate that the BMP7-p-Smad1/5/8 signaling is a key pathway to acquired cetuximab resistance, and demonstrate that combination therapy of cetuximab and a BMP signaling inhibitor as potentially a new therapeutic strategy for overcoming acquired resistance to cetuximab in OSCC. Copyright © 2017 Elsevier B.V. All rights reserved.

Inhibition of GRP78 abrogates radioresistance in oropharyngeal carcinoma cells after EGFR inhibition by cetuximab.

PubMed

Sun, Chaonan; Han, Chuyang; Jiang, Yuanjun; Han, Ning; Zhang, Miao; Li, Guang; Qiao, Qiao

2017-01-01

The EGFR-specific mAb cetuximab is one of the most effective treatments for oropharyngeal carcinoma, while patient responses to EGFR inhibitors given alone are modest. Combination treatment with radiation can improve the efficacy of treatment through increasing radiosensitivity, while resistance to radiation after administration of cetuximab limits its efficiency. Radiation and drugs can damage the endoplasmic reticulum (ER) homeostatic state and result in ER stress (ERS), subsequently causing resistance to radiation and drugs. Whether the ERS pathway is involved in radioresistance after administration of cetuximab has not been reported. Herein, we show that cetuximab could increase the radiosensitivity of FaDu cells but not Detroit562 cells. In addition, cetuximab inhibited the radiation-induced activation of the ERS signalling pathway IRE1α/ATF6-GRP78 in FaDu cells, while this effect was absent in Detroit562 cells. Silencing GRP78 increased the radiosensitivity of oropharyngeal carcinoma cells and inhibited radiation-induced DNA double-strand-break (DSB) repair and autophagy. More interestingly, silencing GRP78 abrogated resistance to cetuximab and radiation in Detroit562 cells and had a synergistic effect with cetuximab in increasing the radiosensitivity of FaDu cells. Immunohistochemistry showed that overexpression of both GRP78 and EGFR was associated with a poor prognosis in oropharyngeal carcinoma patients (P<0.05). Overall, the results of this study show that radioresistance after EGFR inhibition by cetuximab is mediated by the ERS signalling pathway IRE1α/ATF6-GRP78. This suppression was consequently unable to inhibit radiation-induced DSB repair and autophagy in oropharyngeal carcinoma cells, which conferred resistance to radiotherapy and cetuximab. These results suggest that the cooperative effects of radiotherapy and cetuximab could be further improved by inhibiting GRP78 in non-responsive oropharyngeal carcinoma patients.

Cetuximab for treating non-small cell lung cancer.

PubMed

Mazzarella, Luca; Guida, Alessandro; Curigliano, Giuseppe

2018-04-01

Epidermal Growth Factor Receptor (EGFR)-dependent signaling plays a crucial role in epithelial cancer biology, and dictated the development of several targeting agents. The mouse-human chimeric antibody Cetuximab was among the first to be developed. After about two decades of clinical research it has gained a significant place in the management of advanced colorectal and head and neck cancers, whereas its development in non small cell lung cancer (NSCLC) has not led to a place in routine clinical practice, because of marginal clinical benefit despite statistically significant Phase III trials. Recent data from ongoing trials suggest that more careful selection based on molecular markers may identify good responders. Areas covered: In this article, the authors review the literature concerning basic science studies identifying EGFR as a therapeutic target, pharmacological development of Cetuximab, its pharmacodynamics and pharmacokinetics, and clinical trials on Cetuximab in NSCLC, focusing on recent findings on putative predictive biomarkers. Expert opinion: Cetuximab currently has no role in NSCLC treatment outside of research settings. We argue that failure to identify a predictive biomarker early on has hampered its chances to enter routine practice. Although recent research suggests benefit in highly selected patient subsets, its potential impact is severely dampened by lack of regulatory body approval and the emergence of competitors for the same niches.

Radiolabeled F(ab')2-cetuximab for theranostic purposes in colorectal and skin tumor-bearing mice models.

PubMed

Bellaye, P-S; Moreau, M; Raguin, O; Oudot, A; Bernhard, C; Vrigneaud, J-M; Dumont, L; Vandroux, D; Denat, F; Cochet, A; Brunotte, F; Collin, B

2018-05-17

This study aimed to investigate theranostic strategies in colorectal and skin cancer based on fragments of cetuximab, an anti-EGFR mAb, labeled with radionuclide with imaging and therapeutic properties, 111 In and 177 Lu, respectively. We designed F(ab') 2 -fragments of cetuximab radiolabeled with 111 In and 177 Lu. 111 In-F(ab') 2 -cetuximab tumor targeting and biodistribution were evaluated by SPECT in BalbC nude mice bearing primary colorectal tumors. The efficacy of 111 In-F(ab') 2 -cetuximab to assess therapy efficacy was performed on BalbC nude mice bearing colorectal tumors receiving 17-DMAG, an HSP90 inhibitor. Therapeutic efficacy of the radioimmunotherapy based on 177 Lu-F(ab') 2 -cetuximab was evaluated in SWISS nude mice bearing A431 tumors. Radiolabeling procedure did not change F(ab') 2 -cetuximab and cetuximab immunoreactivity nor affinity for HER1 in vitro. 111 In-DOTAGA-F(ab') 2 -cetuximab exhibited a peak tumor uptake at 24 h post-injection and showed a high tumor specificity determined by a significant decrease in tumor uptake after the addition of an excess of unlabeled-DOTAGA-F(ab') 2 -cetuximab. SPECT imaging of 111 In-DOTAGA-F(ab') 2 -cetuximab allowed an accurate evaluation of tumor growth and successfully predicted the decrease in tumor growth induced by 17-DMAG. Finally, 177 Lu-DOTAGA-F(ab') 2 -cetuximab radioimmunotherapy showed a significant reduction of tumor growth at 4 and 8 MBq doses. 111 In-DOTAGA-F(ab') 2 -cetuximab is a reliable and stable tool for specific in vivo tumor targeting and is suitable for therapy efficacy assessment. 177 Lu-DOTAGA-F(ab') 2 -cetuximab is an interesting theranostic tool allowing therapy and imaging.

Cetuximab-conjugated iron oxide nanoparticles for cancer imaging and therapy

PubMed Central

Tseng, Shih-Heng; Chou, Min-Yuan; Chu, I-Ming

2015-01-01

We have developed a theranostic nanoparticle, ie, cet-PEG-dexSPIONs, by conjugation of the anti-epidermal growth factor receptor (EGFR) monoclonal antibody, cetuximab, to dextran-coated superparamagnetic iron oxide nanoparticles (SPIONs) via periodate oxidation. Approximately 31 antibody molecules were conjugated to each nanoparticle. Cet-PEG-dexSPIONs specifically bind to EGFR-expressing tumor cells and enhance image contrast on magnetic resonance imaging. Cet-PEG-dexSPION-treated A431 cells showed significant inhibition of epidermal growth factor-induced EGFR phosphorylation and enhancement of EGFR internalization and degradation. In addition, a significant increase in apoptosis was detected in EGFR-overexpressing cell lines, A431 and 32D/EGFR, after 24 hours of incubation at 37°C with cet-PEG-dexSPIONs compared with cetuximab alone. The antibody-dependent cell-mediated cytotoxicity of cetuximab was observed in cet-PEG-dexSPIONs. The results demonstrated that cet-PEG-dexSPIONs retained the therapeutic effect of cetuximab in addition to having the ability to target and image EGFR-expressing tumors. Cet-PEG-dexSPIONs represent a promising targeted magnetic probe for early detection and treatment of EGFR-expressing tumor cells. PMID:26056447

Review of cetuximab in the treatment of squamous cell carcinoma of the head and neck

PubMed Central

Merlano, Marco; Occelli, Marcella

2007-01-01

Cetuximab is a monoclonal antibody able to inhibit and to degrade the transmembrane receptor Her-1, also known as epidermal growth factor receptor (EGFR). The inhibition of EGFR is of major importance since the receptor influences many important tumor cell activities including tumor growth, neo-angiogenesis, inhibition of the apoptotic response to chemotherapy and radiotherapy. Available experimental data suggest that cetuximab may enhance chemotherapy and radiotherapy activity, reverse resistance to some anticancer drugs and has itself anticancer activity Early clinical data support experimental results. This paper reviews the published experiences on cetuximab in the treatment of advanced head and neck cancer and points out the future objectives of the clinical research on this drug. PMID:18473010

Erlotinib is a viable treatment for tumors with acquired resistance to cetuximab

PubMed Central

Brand, Toni M; Dunn, Emily F; Iida, Mari; Myers, Rebecca A; Kostopoulos, Kellie T; Li, Chunrong; Peet, Chimera R

2011-01-01

The epidermal growth factor receptor (EGFR) is an ubiquitously expressed receptor tyrosine kinase (RTK) and is recognized as a key mediator of tumorigenesis in many human tumors. Currently there are five EGFR inhibitors used in oncology, two monoclonal antibodies (panitumumab and cetuximab) and three tyrosine kinase inhibitors (erlotinib, gefitinib and lapatinib). Both strategies of EGFR inhibition have demonstrated clinical success; however, many tumors remain non-responsive or acquire resistance during therapy. To explore potential molecular mechanisms of acquired resistance to cetuximab we previously established a series of cetuximab-resistant clones by chronically exposing the NCI-H226 NSCLC cell line to escalating doses of cetuximab. Cetuximab-resistant clones exhibited a dramatic increase in the activation of EGFR, HER2 and HER3 receptors as well as increased signaling through the MAP K and AKT pathways. RNAi studies demonstrated dependence of cetuximab-resistant clones on the EGFR signaling network. These findings prompted investigation on whether or not cells with acquired resistance to cetuximab would be sensitive to the EGFR targeted TKI erlotinib. In vitro, erlotinib was able to decrease signaling through the EGFR axis, decrease cellular proliferation and induce apoptosis. To determine if erlotinib could have therapeutic benefit in vivo, we established cetuximab-resistant NCI-H226 mouse xenografts, and subsequently treated them with erlotinib. Mice harboring cetuximab-resistant tumors treated with erlotinib exhibited either a tumor regression or growth delay as compared with vehicle controls. Analysis of the erlotinib treated tumors demonstrated a decrease in cell proliferation and increased rates of apoptosis. The work presented herein suggests that (1) cells with acquired resistance to cetuximab maintain their dependence on EGFR and (2) tumors developing resistance to cetuximab can benefit from subsequent treatment with erlotinib, providing rationale

Characterization of 7A7, an anti-mouse EGFR monoclonal antibody proposed to be the mouse equivalent of cetuximab.

PubMed

He, Xuzhi; Cruz, Jazmina L; Joseph, Shannon; Pett, Nicola; Chew, Hui Yi; Tuong, Zewen K; Okano, Satomi; Kelly, Gabrielle; Veitch, Margaret; Simpson, Fiona; Wells, James W

2018-02-23

The Epidermal Growth Factor Receptor (EGFR) is selectively expressed on the surface of numerous tumours, such as non-small cell lung, ovarian, colorectal and head and neck carcinomas. EGFR has therefore become a target for cancer therapy. Cetuximab is a chimeric human/mouse monoclonal antibody (mAb) that binds to EGFR, where it both inhibits signaling and induces cell death by antibody-dependent cell mediated cytotoxicity (ADCC). Cetuximab has been approved for clinical use in patients with head and neck squamous cell carcinoma (HNSCC) and colorectal cancer. However, only 15-20% patients benefit from this drug, thus new strategies to improve cetuximab efficiency are required. We aimed to develop a reliable and easy preclinical mouse model to evaluate the efficacy of EGFR-targeted antibodies and examine the immune mechanisms involved in tumour regression. We selected an anti-mouse EGFR mAb, 7A7, which has been reported to be "mouse cetuximab" and to exhibit similar properties to its human counterpart. Unfortunately, we were unable to reproduce previous results obtained with the 7A7 mAb. In our hands, 7A7 failed to recognize mouse EGFR, both in native and reducing conditions. Moreover, in vivo administration of 7A7 in an EGFR-expressing HPV38 tumour model did not have any impact on tumour regression or animal survival. We conclude that 7A7 does not recognize mouse EGFR and therefore cannot be used as the mouse equivalent of cetuximab use in humans. As a number of groups have spent effort and resources with similar issues we feel that publication is a responsible approach.

IND-directed safety and biodistribution study of intravenously injected cetuximab-IRDye800 in cynomolgus macaques.

PubMed

Zinn, Kurt R; Korb, Melissa; Samuel, Sharon; Warram, Jason M; Dion, David; Killingsworth, Cheryl; Fan, Jinda; Schoeb, Trenton; Strong, Theresa V; Rosenthal, Eben L

2015-02-01

The use of receptor-targeted antibodies conjugated to fluorophores is actively being explored for real-time imaging of disease states; however, the toxicity of the bioconjugate has not been assessed in non-human primates. To this end, the in vivo toxicity and pharmacokinetics of IRDye800 conjugated to cetuximab (cetuximab-IRDye800; 21 mg/kg; equivalent to 250 mg/m(2) human dose) were assessed in male cynomolgus monkeys over 15 days following intravenous injection and compared with an unlabeled cetuximab-dosed control group. Cetuximab-IRDye800 was well tolerated. There were no infusion reactions, adverse clinical signs, mortality, weight loss, or clinical histopathology findings. The plasma half-life for the cetuximab-IRDye800 and cetuximab groups was equivalent (2.5 days). The total recovered cetuximab-IRDye800 in all tissues at study termination was estimated to be 12 % of the total dose. Both cetuximab-IRDye800 and cetuximab groups showed increased QTc after dosing. The QTc for the cetuximab-dosed group returned to baseline by day 15, while the QTc of the cetuximab-IRDye800 remained elevated compared to baseline. IRDye800 in low molar ratios does not significantly impact cetuximab half-life or result in organ toxicity. These studies support careful cardiac monitoring (ECG) for human studies using fluorescent dyes.

Cetuximab in locally advanced head-and-neck cancer: defining the population

PubMed Central

Ho, C.

2010-01-01

Encouraging data for targeted therapy in head-and-neck squamous cell carcinoma are opening new options for treatment. Phase III trials of cetuximab, an antibody directed against the epidermal growth factor receptor (egfr) have demonstrated benefit in the locally advanced and metastatic settings. Recognizing the importance of emerging therapies, Cancer Care Ontario published guideline recommendations for egfr-targeted therapy in stage iii and iv head-and-neck cancer. The present paper takes a further look at the population for whom an offer of cetuximab therapy may be appropriate. PMID:20697514

Identification and validation of cetuximab resistance associated long noncoding RNA biomarkers in metastatic colorectal cancer.

PubMed

Peng, Ke; Liu, Ruiqi; Yu, Yiyi; Liang, Li; Yu, Shan; Xu, Xiaojing; Liu, Tianshu

2018-01-01

Cetuximab is one of the most widely used epidermal growth factor receptor (EGFR) inhibitors to treat patients with metastatic colorectal cancer (mCRC) harboring wild-type of RAS/RAF status. However, primary and acquired resistance to cetuximab is often found during target therapy. To gain insights into the functions of long non-coding RNA (lncRNA) in cetuximab resistance, we used a lncRNA-mining approach to distinguish lncRNA specific probes in Affymetrix HG-U133A 2.0 arrays. Then we performed lncRNA expression profiling in a cetuximab treated mCRC cohort from Gene Expression Ominus (GEO). The potential lncRNAs were further validated in acquired cetuximab resistant cell lines and clinical samples of our hospital. The functions and associated pathways of the prognostic lncRNA were predicted by GO and KEGG analyses. 249 lncRNA-specific probe sets (corresponding to 212 lncRNAs) were represented in Affymetrix HG-U133A 2.0 arrays. We found that 9 lncRNAs were differentially expressed between disease control group (DCG) and non-responders, and 5 of these 9 lncRNAs were significantly related with the progression-free survival (PFS) of the patients. Among those 5 lncRNAs, POU5F1P4 was also down-regulated in acquired cetuximab resistant cells, as well as in cetuximab resistant patients. Downregulation of POU5F1P4 decreased the sensitivity of colorectal cancer cells to cetuximab. Our findings indicate the potential roles of lncRNAs in cetuximab resistance, and may provide the useful information for discovery of new biomarkers and therapeutic targets. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Cetuximab Prevents Methotrexate-Induced Cytotoxicity in Vitro through Epidermal Growth Factor Dependent Regulation of Renal Drug Transporters

PubMed Central

2017-01-01

The combination of methotrexate with epidermal growth factor receptor (EGFR) recombinant antibody, cetuximab, is currently being investigated in treatment of head and neck carcinoma. As methotrexate is cleared by renal excretion, we studied the effect of cetuximab on renal methotrexate handling. We used human conditionally immortalized proximal tubule epithelial cells overexpressing either organic anion transporter 1 or 3 (ciPTEC-OAT1/ciPTEC-OAT3) to examine OAT1 and OAT3, and the efflux pumps breast cancer resistance protein (BCRP), multidrug resistance protein 4 (MRP4), and P-glycoprotein (P-gp) in methotrexate handling upon EGF or cetuximab treatment. Protein kinase microarrays and knowledge-based pathway analysis were used to predict EGFR-mediated transporter regulation. Cytotoxic effects of methotrexate were evaluated using the dimethylthiazol bromide (MTT) viability assay. Methotrexate inhibited OAT-mediated fluorescein uptake and decreased efflux of Hoechst33342 and glutathione-methylfluorescein (GS-MF), which suggested involvement of OAT1/3, BCRP, and MRP4 in transepithelial transport, respectively. Cetuximab reversed the EGF-increased expression of OAT1 and BCRP as well as their membrane expressions and transport activities, while MRP4 and P-gp were increased. Pathway analysis predicted cetuximab-induced modulation of PKC and PI3K pathways downstream EGFR/ERBB2/PLCg. Pharmacological inhibition of ERK decreased expression of OAT1 and BCRP, while P-gp and MRP4 were increased. AKT inhibition reduced all transporters. Exposure to methotrexate for 24 h led to a decreased viability, an effect that was reversed by cetuximab. In conclusion, cetuximab downregulates OAT1 and BCRP while upregulating P-gp and MRP4 through an EGFR-mediated regulation of PI3K-AKT and MAPKK-ERK pathways. Consequently, cetuximab attenuates methotrexate-induced cytotoxicity, which opens possibilities for further research into nephroprotective comedication therapies. PMID:28493713

Cetuximab Prevents Methotrexate-Induced Cytotoxicity in Vitro through Epidermal Growth Factor Dependent Regulation of Renal Drug Transporters.

PubMed

Caetano-Pinto, Pedro; Jamalpoor, Amer; Ham, Janneke; Goumenou, Anastasia; Mommersteeg, Monique; Pijnenburg, Dirk; Ruijtenbeek, Rob; Sanchez-Romero, Natalia; van Zelst, Bertrand; Heil, Sandra G; Jansen, Jitske; Wilmer, Martijn J; van Herpen, Carla M L; Masereeuw, Rosalinde

2017-06-05

The combination of methotrexate with epidermal growth factor receptor (EGFR) recombinant antibody, cetuximab, is currently being investigated in treatment of head and neck carcinoma. As methotrexate is cleared by renal excretion, we studied the effect of cetuximab on renal methotrexate handling. We used human conditionally immortalized proximal tubule epithelial cells overexpressing either organic anion transporter 1 or 3 (ciPTEC-OAT1/ciPTEC-OAT3) to examine OAT1 and OAT3, and the efflux pumps breast cancer resistance protein (BCRP), multidrug resistance protein 4 (MRP4), and P-glycoprotein (P-gp) in methotrexate handling upon EGF or cetuximab treatment. Protein kinase microarrays and knowledge-based pathway analysis were used to predict EGFR-mediated transporter regulation. Cytotoxic effects of methotrexate were evaluated using the dimethylthiazol bromide (MTT) viability assay. Methotrexate inhibited OAT-mediated fluorescein uptake and decreased efflux of Hoechst33342 and glutathione-methylfluorescein (GS-MF), which suggested involvement of OAT1/3, BCRP, and MRP4 in transepithelial transport, respectively. Cetuximab reversed the EGF-increased expression of OAT1 and BCRP as well as their membrane expressions and transport activities, while MRP4 and P-gp were increased. Pathway analysis predicted cetuximab-induced modulation of PKC and PI3K pathways downstream EGFR/ERBB2/PLCg. Pharmacological inhibition of ERK decreased expression of OAT1 and BCRP, while P-gp and MRP4 were increased. AKT inhibition reduced all transporters. Exposure to methotrexate for 24 h led to a decreased viability, an effect that was reversed by cetuximab. In conclusion, cetuximab downregulates OAT1 and BCRP while upregulating P-gp and MRP4 through an EGFR-mediated regulation of PI3K-AKT and MAPKK-ERK pathways. Consequently, cetuximab attenuates methotrexate-induced cytotoxicity, which opens possibilities for further research into nephroprotective comedication therapies.

A method for predicting target drug efficiency in cancer based on the analysis of signaling pathway activation.

PubMed

Artemov, Artem; Aliper, Alexander; Korzinkin, Michael; Lezhnina, Ksenia; Jellen, Leslie; Zhukov, Nikolay; Roumiantsev, Sergey; Gaifullin, Nurshat; Zhavoronkov, Alex; Borisov, Nicolas; Buzdin, Anton

2015-10-06

A new generation of anticancer therapeutics called target drugs has quickly developed in the 21st century. These drugs are tailored to inhibit cancer cell growth, proliferation, and viability by specific interactions with one or a few target proteins. However, despite formally known molecular targets for every "target" drug, patient response to treatment remains largely individual and unpredictable. Choosing the most effective personalized treatment remains a major challenge in oncology and is still largely trial and error. Here we present a novel approach for predicting target drug efficacy based on the gene expression signature of the individual tumor sample(s). The enclosed bioinformatic algorithm detects activation of intracellular regulatory pathways in the tumor in comparison to the corresponding normal tissues. According to the nature of the molecular targets of a drug, it predicts whether the drug can prevent cancer growth and survival in each individual case by blocking the abnormally activated tumor-promoting pathways or by reinforcing internal tumor suppressor cascades. To validate the method, we compared the distribution of predicted drug efficacy scores for five drugs (Sorafenib, Bevacizumab, Cetuximab, Sorafenib, Imatinib, Sunitinib) and seven cancer types (Clear Cell Renal Cell Carcinoma, Colon cancer, Lung adenocarcinoma, non-Hodgkin Lymphoma, Thyroid cancer and Sarcoma) with the available clinical trials data for the respective cancer types and drugs. The percent of responders to a drug treatment correlated significantly (Pearson's correlation 0.77 p = 0.023) with the percent of tumors showing high drug scores calculated with the current algorithm.

Anti-cetuximab IgE ELISA for identification of patients at a high risk of cetuximab-induced anaphylaxis.

PubMed

Mariotte, Delphine; Dupont, Benoît; Gervais, Radj; Galais, Marie-Pierre; Laroche, Dominique; Tranchant, Aurore; Comby, Elisabeth; Bouhier-Leporrier, Karine; Reimund, Jean-Marie; Le Mauff, Brigitte

2011-01-01

Cetuximab, a chimeric mouse-human IgG1 monoclonal antibody against the epidermal growth factor receptor, has proven effective in the treatment of metastatic colorectal cancer and squamous cell carcinoma of the head and neck. However, a high incidence of immediate hypersensitivity reactions (HSR) to cetuximab after the first infusion has been observed. We have developed a test for identification of patients likely to show treatment-related HSR to cetuximab. An enzyme-linked immunosorbent assay (ELISA) for detecting anti-cetuximab IgEs was developed and tested on serum samples collected from cancer patients before start of cetuximab treatment, and from healthy blood donors. Similar levels of anti-cetuximab IgE were detected in pre-treatment patient sera (24/92, 26.1%) and sera from healthy blood donors (33/117, 28.2%). HSR were observed in 14 out of the 92 patients (15.2%), and 8 of these (57.1%) were grade 3-4. Anti-cetuximab IgEs were detected in 7/8 of the patients (87.5%) with severe HSRs as compared with 14/78 patients (17.9%) with no HSR (p=0.0002). Predictive value of the anti-cetuximab IgE test for HSR events of grades 3-4 was calculated using Receiver Operating Characteristics analysis. With a cut-off value of 29 arbitrary units for the anti-cetuximab IgE, the ELISA test showed a sensitivity of 87.5%, specificity of 82.1%, positive predictive value of 33.3% and negative predictive value of 98.5%. Anti-cetuximab IgE ELISA detection could be a valuable tool to help the physician anticipate an anaphylaxis episode following cetuximab infusion and opt for a suitable alternative treatment.

SMAD4 and NF1 mutations as potential biomarkers for poor prognosis to cetuximab-based therapy in Chinese metastatic colorectal cancer patients.

PubMed

Mei, Zhu; Shao, Yang W; Lin, Peinan; Cai, Xiaomin; Wang, Biao; Ding, Yan; Ma, Xiangyuan; Wu, Xue; Xia, Yewei; Zhu, Dongqin; Shu, Yongqian; Fu, Zan; Gu, Yanhong

2018-04-27

Cetuximab, an anti-EGFR monoclonal antibody, is used in combination with chemotherapy in clinic to enhance the outcome in metastatic colorectal cancer (mCRC) patients with only ~ 20% response rate. To date only activating mutations in KRAS and NRAS have been identified as poor prognosis biomarkers in cetuximab-based treatment, which makes an urgent need for identification of novel prognosis biomarkers to precisely predict patients' response in order to maximize the benefit. In this study, we analysed the mutation profiles of 33 Chinese mCRC patients using comprehensive next-generation sequencing (NGS) targeting 416 cancer-relevant genes before cetuximab treatment. Upon receiving cetuximab-based therapy, patients were evaluated for drug response, and the progression-free survival (PFS) was monitored. The association of specific genetic alterations and cetuximab efficacy was analyzed. Patients carrying SMAD4 mutations (SMAD4 mut , n = 8) or NF1 mutations (NF1 mut , n = 4) had significantly shorter PFS comparing to those carrying wildtype SMAD4 (SMAD4 wt , n = 25) (P = 0.0081) or wildtype NF1 (NF1 wt , n = 29) (P = 0.0028), respectively. None of the SMAD4 mut or NF1 mut patients showed response to cetuximab when assessed at 12-week post-treatment. Interestingly, two patients carrying both SMAD4 mut and NF1 mut showed the shortest PFS among all the patients. Our results demonstrated that SMAD4 and NF1 mutations can serve as potential biomarkers for poor prognosis to cetuximab-based therapy in Chinese mCRC patients.

Quantitative assessment of Zirconium-89 labeled cetuximab using PET/CT imaging in patients with advanced head and neck cancer: a theragnostic approach.

PubMed

Even, Aniek J G; Hamming-Vrieze, Olga; van Elmpt, Wouter; Winnepenninckx, Véronique J L; Heukelom, Jolien; Tesselaar, Margot E T; Vogel, Wouter V; Hoeben, Ann; Zegers, Catharina M L; Vugts, Daniëlle J; van Dongen, Guus A M S; Bartelink, Harry; Mottaghy, Felix M; Hoebers, Frank; Lambin, Philippe

2017-01-17

Biomarkers predicting treatment response to the monoclonal antibody cetuximab in locally advanced head and neck squamous cell carcinomas (LAHNSCC) are lacking. We hypothesize that tumor accessibility is an important factor in treatment success of the EGFR targeting drug. We quantified uptake of cetuximab labeled with Zirconium-89 (89Zr) using PET/CT imaging.Seventeen patients with stage III-IV LAHNSCC received a loading dose unlabeled cetuximab, followed by 10 mg 54.5±9.6 MBq 89Zr-cetuximab. PET/CT images were acquired either 3 and 6 or 4 and 7 days post-injection. 89Zr-cetuximab uptake was quantified using standardized uptake value (SUV) and tumor-to-background ratio (TBR), and correlated to EGFR immunohistochemistry. TBR was compared between scan days to determine optimal timing.Uptake of 89Zr-cetuximab varied between patients (day 6-7: SUVpeak range 2.5-6.2). TBR increased significantly (49±28%, p < 0.01) between first (1.1±0.3) and second scan (1.7±0.6). Between groups with a low and high EGFR expression a significant difference in SUVmean (2.1 versus 3.0) and SUVpeak (3.2 versus 4.7) was found, however, not in TBR. Data is available at www.cancerdata.org (DOI: 10.17195/candat.2016.11.1).In conclusion, 89Zr-cetuximab PET imaging shows large inter-patient variety in LAHNSCC and provides additional information over FDG-PET and EGFR expression. Validation of the predictive value is recommended with scans acquired 6-7 days post-injection.

Quantitative assessment of Zirconium-89 labeled cetuximab using PET/CT imaging in patients with advanced head and neck cancer: a theragnostic approach

PubMed Central

van Elmpt, Wouter; Winnepenninckx, Véronique J.L.; Heukelom, Jolien; Tesselaar, Margot E.T.; Vogel, Wouter V.; Hoeben, Ann; Zegers, Catharina M.L.; Vugts, Daniëlle J.; van Dongen, Guus A.M.S.; Bartelink, Harry; Mottaghy, Felix M.; Hoebers, Frank; Lambin, Philippe

2017-01-01

Biomarkers predicting treatment response to the monoclonal antibody cetuximab in locally advanced head and neck squamous cell carcinomas (LAHNSCC) are lacking. We hypothesize that tumor accessibility is an important factor in treatment success of the EGFR targeting drug. We quantified uptake of cetuximab labeled with Zirconium-89 (89Zr) using PET/CT imaging. Seventeen patients with stage III-IV LAHNSCC received a loading dose unlabeled cetuximab, followed by 10 mg 54.5±9.6 MBq 89Zr-cetuximab. PET/CT images were acquired either 3 and 6 or 4 and 7 days post-injection. 89Zr-cetuximab uptake was quantified using standardized uptake value (SUV) and tumor-to-background ratio (TBR), and correlated to EGFR immunohistochemistry. TBR was compared between scan days to determine optimal timing. Uptake of 89Zr-cetuximab varied between patients (day 6-7: SUVpeak range 2.5-6.2). TBR increased significantly (49±28%, p < 0.01) between first (1.1±0.3) and second scan (1.7±0.6). Between groups with a low and high EGFR expression a significant difference in SUVmean (2.1 versus 3.0) and SUVpeak (3.2 versus 4.7) was found, however, not in TBR. Data is available at www.cancerdata.org (DOI: 10.17195/candat.2016.11.1). In conclusion, 89Zr-cetuximab PET imaging shows large inter-patient variety in LAHNSCC and provides additional information over FDG-PET and EGFR expression. Validation of the predictive value is recommended with scans acquired 6-7 days post-injection. PMID:27965472

A network meta-analysis on the efficacy of sixteen targeted drugs in combination with chemotherapy for treatment of advanced/metastatic colorectal cancer

PubMed Central

Ba-Sang, Dan-Zeng; Long, Zi-Wen; Teng, Hao; Zhao, Xu-Peng; Qiu, Jian; Li, Ming-Shan

2016-01-01

Objective A network meta-analysis was conducted comparing the short-term efficacies of 16 targeted drugs in combination with chemotherapy for treatment of advanced/metastatic colorectal cancer (CRC). Results Twenty-seven RCTs were ultimately incorporated into this network meta-analysis. Compared with chemotherapy alone, bevacizumab + chemotherapy, panitumumab + chemotherapy and conatumumab + chemotherapy had higher PR rate. Bevacizumab + chemotherapy, cetuximab + chemotherapy, panitumumab + chemotherapy, trebananib + chemotherapy and conatumumab + chemotherapy had higher ORR rate in comparison to chemotherapy alone. Furthermore, bevacizumab + chemotherapy had higher DCR rate than chemotherapy alone. The results of our cluster analysis showed that chemotherapy combined with bevacizumab, cetuximab, panitumumab, conatumumab, ganitumab, or brivanib + cetuximab had better efficacies for the treatment of advanced/metastatic CRC in comparison to chemotherapy alone. Materials and Methods Electronic databases were comprehensively searched for potential and related randomized controlled trials (RCTs). Direct and indirect evidence were incorporated for evaluation of stable disease (SD), progressive disease (PD), complete response (CR), partial response (PR), disease control rate (DCR) and overall response ratio (ORR) by calculating odds ratio (OR) and 95% confidence intervals (CI), and using the surface under the cumulative ranking curve (SUCRA). Conclusions These results indicated that bevacizumab + chemotherapy, panitumumab + chemotherapy, conatumumab + chemotherapy and brivanib + cetuximab + chemotherapy may have better efficacies for the treatment of advanced/metastatic CRC. PMID:27806321

First-Line Cetuximab Monotherapy in KRAS/NRAS/BRAF Mutation-Negative Colorectal Cancer Patients.

PubMed

Moiseyenko, Vladimir M; Moiseyenko, Fedor V; Yanus, Grigoriy A; Kuligina, Ekatherina Sh; Sokolenko, Anna P; Bizin, Ilya V; Kudriavtsev, Alexey A; Aleksakhina, Svetlana N; Volkov, Nikita M; Chubenko, Vyacheslav A; Kozyreva, Kseniya S; Kramchaninov, Mikhail M; Zhuravlev, Alexandr S; Shelekhova, Kseniya V; Pashkov, Denis V; Ivantsov, Alexandr O; Venina, Aigul R; Sokolova, Tatyana N; Preobrazhenskaya, Elena V; Mitiushkina, Natalia V; Togo, Alexandr V; Iyevleva, Aglaya G; Imyanitov, Evgeny N

2018-06-01

Colorectal carcinomas (CRCs) are sensitive to treatment by anti-epidermal growth factor receptor (EGFR) antibodies only if they do not carry activating mutations in down-stream EGFR targets (KRAS/NRAS/BRAF). Most clinical trials for chemo-naive CRC patients involved combination of targeted agents and chemotherapy, while single-agent cetuximab or panitumumab studies included either heavily pretreated patients or subjects who were not selected on the basis of molecular tests. We hypothesized that anti-EGFR therapy would have significant efficacy in chemo-naive patients with KRAS/NRAS/BRAF mutation-negative CRC. Nineteen patients were prospectively included in the study. Two (11%) patients experienced partial response (PR) and 11 (58%) subjects showed stable disease (SD). Median time to progression approached 6.1 months (range 1.6-15.0 months). Cetuximab efficacy did not correlate with RNA expression of EGFR and insulin-like growth factor 2 (IGF2). Only one tumor carried PIK3CA mutation, and this CRC responded to cetuximab. Exome analysis of patients with progressive disease (PD) revealed 1 CRC with high-level microsatellite instability and 1 instance of HER2 oncogene amplification; 3 of 4 remaining patients with PD had allergic reactions to cetuximab, while none of the subjects with PR or SD had this complication. Comparison with 19 retrospective KRAS/NRAS/BRAF mutation-negative patients receiving first-line fluoropyrimidines revealed no advantages or disadvantages of cetuximab therapy. Cetuximab demonstrates only modest efficacy when given as a first-line monotherapy to KRAS/NRAS/BRAF mutation-negative CRC patients. It is of question, why meticulous patient selection, which was undertaken in the current study, did not result in the improvement of outcomes of single-agent cetuximab treatment.

A collagen-binding EGFR antibody fragment targeting tumors with a collagen-rich extracellular matrix.

PubMed

Liang, Hui; Li, Xiaoran; Wang, Bin; Chen, Bing; Zhao, Yannan; Sun, Jie; Zhuang, Yan; Shi, Jiajia; Shen, He; Zhang, Zhijun; Dai, Jianwu

2016-02-17

Many tumors over-express collagen, which constitutes the physical scaffold of tumor microenvironment. Collagen has been considered to be a target for cancer therapy. The collagen-binding domain (CBD) is a short peptide, which could bind to collagen and achieve the sustained release of CBD-fused proteins in collagen scaffold. Here, a collagen-binding EGFR antibody fragment was designed and expressed for targeting the collagen-rich extracellular matrix in tumors. The antibody fragment (Fab) of cetuximab was fused with CBD (CBD-Fab) and expressed in Pichia pastoris. CBD-Fab maintained antigen binding and anti-tumor activity of cetuximab and obtained a collagen-binding ability in vitro. The results also showed CBD-Fab was mainly enriched in tumors and had longer retention time in tumors in A431 s.c. xenografts. Furthermore, CBD-Fab showed a similar therapeutic efficacy as cetuximab in A431 xenografts. Although CBD-Fab hasn't showed better therapeutic effects than cetuximab, its smaller molecular and special target may be applicable as antibody-drug conjugates (ADC) or immunotoxins.

A collagen-binding EGFR antibody fragment targeting tumors with a collagen-rich extracellular matrix

PubMed Central

Liang, Hui; Li, Xiaoran; Wang, Bin; Chen, Bing; Zhao, Yannan; Sun, Jie; Zhuang, Yan; Shi, Jiajia; Shen, He; Zhang, Zhijun; Dai, Jianwu

2016-01-01

Many tumors over-express collagen, which constitutes the physical scaffold of tumor microenvironment. Collagen has been considered to be a target for cancer therapy. The collagen-binding domain (CBD) is a short peptide, which could bind to collagen and achieve the sustained release of CBD-fused proteins in collagen scaffold. Here, a collagen-binding EGFR antibody fragment was designed and expressed for targeting the collagen-rich extracellular matrix in tumors. The antibody fragment (Fab) of cetuximab was fused with CBD (CBD-Fab) and expressed in Pichia pastoris. CBD-Fab maintained antigen binding and anti-tumor activity of cetuximab and obtained a collagen-binding ability in vitro. The results also showed CBD-Fab was mainly enriched in tumors and had longer retention time in tumors in A431 s.c. xenografts. Furthermore, CBD-Fab showed a similar therapeutic efficacy as cetuximab in A431 xenografts. Although CBD-Fab hasn’t showed better therapeutic effects than cetuximab, its smaller molecular and special target may be applicable as antibody–drug conjugates (ADC) or immunotoxins. PMID:26883295

The distribution of the therapeutic monoclonal antibodies cetuximab and trastuzumab within solid tumors.

PubMed

Lee, Carol M; Tannock, Ian F

2010-06-03

Poor distribution of some anticancer drugs in solid tumors may limit their anti-tumor activity. Here we used immunohistochemistry to quantify the distribution of the therapeutic monoclonal antibodies cetuximab and trastuzumab in relation to blood vessels and to regions of hypoxia in human tumor xenografts. The antibodies were injected into mice implanted with human epidermoid carcinoma A431 or human breast carcinoma MDA-MB-231 transfected with ERBB2 (231-H2N) that express high levels of ErbB1 and ErbB2 respectively, or wild-type MDA-MB-231, which expresses intermediate levels of ErbB1 and low levels of ErbB2. The distribution of cetuximab in A431 xenografts and trastuzumab in 231-H2N xenografts was time and dose dependent. At early intervals after injection of 1 mg cetuximab into A431 xenografts, the concentration of cetuximab decreased with increasing distance from blood vessels, but became more uniformly distributed at later times; there remained however limited distribution and binding in hypoxic regions of tumors. Injection of lower doses of cetuximab led to heterogeneous distributions. Similar results were observed with trastuzumab in 231-H2N xenografts. In MDA-MB-231 xenografts, which express lower levels of ErbB1, homogeneity of distribution of cetuximab was achieved more rapidly. Cetuximab and trastuzumab distribute slowly, but at higher doses achieve a relatively uniform distribution after about 24 hours, most likely due to their long half-lives in the circulation. There remains poor distribution within hypoxic regions of tumors.

CTLA-4+ Regulatory T Cells Increased in Cetuximab Treated Head and Neck Cancer Patients Suppress NK Cell Cytotoxicity and Correlate with Poor Prognosis

PubMed Central

Jie, Hyun-Bae; Schuler, Patrick J.; Lee, Steve C.; Srivastava, Raghvendra M.; Argiris, Athanassios; Ferrone, Soldano; Whiteside, Theresa L.; Ferris, Robert L.

2015-01-01

The EGFR-targeted antibody cetuximab is effective against head and neck cancer (HNC), but in only 15 – 20% of patients, and the variability and extent of cetuximab-mediated cellular immunity is not fully understood. We hypothesized that regulatory T cells (Treg) may exert a functional and clinical impact on antitumor immunity in cetuximab-treated individuals. The frequency, immunosuppressive phenotype and activation status of Treg and NK cells were analyzed in the circulation and tumor microenvironment of cetuximab-treated HNC patients enrolled in a novel neoadjuvant, single-agent cetuximab clinical trial. Notably, cetuximab treatment increased the frequency of CD4+FOXP3+ intratumoral Treg expressing CTLA-4, CD39 and TGF-β. These Treg suppressed cetuximab-mediated ADCC and their presence correlated with poor clinical outcome in two prospective clinical trial cohorts. Cetuximab expanded CTLA-4+FOXP3+ Treg in vitro, in part by inducing DC maturation, in combination with TGF-β and TCR triggering. Importantly, cetuximab-activated NK cells selectively eliminated intratumoral Treg but preserved effector T cells. In ex vivo assays, ipilimumab targeted CTLA-4+ Treg and restored cytolytic functions of NK cells mediating ADCC. Taken together, our results argue that differences in Treg-mediated suppression contribute to the clinical response to cetuximab treatment, suggesting its improvement by adding ipilimumab or other strategies of Treg ablation to promote anti-tumor immunity. PMID:25832655

CETUXIMAB AND IRINOTECAN INTERACT SYNERGISTICALLY TO INHIBIT THE GROWTH OF ORTHOTOPIC ANAPLASTIC THYROID CARCINOMA XENOGRAFTS IN NUDE MICE

PubMed Central

Kim, Seungwon; Prichard, Christopher N.; Younes, Maher N.; Yazici, Yasemin D.; Jasser, Samar A.; Bekele, B. Nebiyou; Myers, Jeffrey N.

2006-01-01

Objective Anaplastic thyroid carcinoma (ATC) remains one of the most lethal known human cancers. Targeted molecular therapy with cetuximab, a monoclonal antibody against EGFR, offers new treatment potentials for patient with ATC. Cetuximab has also been reported to have synergistic effects when combined with irinotecan, a topoisomerase inhibitor. Therefore, we hypothesized that cetuximab and irinotecan would be effective in inhibiting the growth and progression of ATC in a murine orthotopic model. Design The in vitro anti-proliferative effects of cetuximab and irinotecan on ATC cell line ARO were examined. We also studied the in vivo effects of cetuximab and irinotecan on the growth, invasion, and metastasis of orthotopic ATC tumors in nude mice. The in vivo antitumor efficacy of cetuximab/irinotecan combination was also compared with that of doxorubicin. Results Cetuximab alone did not show any anti-proliferative or pro-apoptotic effect on this cell line. However, when combined with irinotecan, cetuximab potentiated the in vitro anti-proliferative and pro-apoptotic effect of irinotecan. Cetuximab, irinotecan, and cetuximab/irinotecan combination resulted in 77%, 79%, and 93% in vivo inhibition of tumor growth, respectively. Incidences of lymph node metastasis, laryngeal invasion, and tumor microvessel density were also significantly decreased in these treatment groups. Furthermore, the cetuximab/irinotecan combination was significantly more effective than doxorubicin in inhibiting the growth of orthotopic ATC xenografts. Conclusions Combination therapy with cetuximab/irinotecan inhibits the growth and progression of orthotopic ATC xenografts in nude mice. Given the lack of curative options for patients with ATC, combination therapy with cetuximab and irinotecan treatment warrants further study. PMID:16428506

Targeting Nuclear EGFR: Strategies for Improving Cetuximab Therapy in Lung Cancer

DTIC Science & Technology

2013-09-01

has been identified in various human tumor tissues, including cancers of the breast, ovary, oropharynx, and esophagus , and has predicted poor patient...been identified in various human tumor tissues, including cancers of the breast, ovary, oropharynx, and esophagus , and has predicted...Improving Cetuximab Therapy in Lung Cancer PRINCIPAL INVESTIGATOR: Deric L Wheeler

[Cetuximab in combination with icotinib overcomes the acquired resistance caused by EGFR T790M mutation in non-small cell lung cancer].

PubMed

Wang, Meng; Zhang, Lianmin; Zhao, Xiaoliang; Liu, Jun; Chen, Yulong; Wang, Changli

2014-09-01

The aim of this study was to investigate the effects of combination of icotinib and cetuximab on the acquired drug resistance caused by T790M mutation of EGFR in NSCLC, and provide experimental evidence for rational treatment of NSCLC. The effects of these two agents on cell proliferation, apoptosis, and EGFR-dependent signaling were evaluated using 3-(4, 5-dimethylthiazol-2-yl)- 5-diphenyltetrazolium bromide (MTT) assay, annexin V staining, and Western blotting. The expression of molecular markers of tumor proliferation PCNA and Ki-67 protein was further examined by immunohistochemistry, and the expression of EGFR-signaling-related proteins in tissue sections taken from H1975 tumor xenografts was assessed by Western blot assay. Sensitivity to EGFR inhibitors was detected in human H1975 tumor xenograft in nude mice. The in vitro experiment showed that the proliferative ability of H1975 cells was inhibited in a dose-dependent manner, along with the increasing doses of cetuximab and icotinib, and the combination of cetuximab with icotinib resulted in a more pronounced growth inhibition of the H1975 cells. The apoptosis rate of H1975 cells after treatment with 0.5 µmol/L icotinib and 1 µg/ml cetuximab was (22.03 ± 2.41)% and that after treatment with 5 µmol/L icotinib and 10 µg/ml cetuximab was (42.75 ± 2.49)%, both were significantly higher than that after treatment with the same dose of icotinib or cetuximab alone (P < 0.05). The nude mouse experiment showed that the transplanted tumor was growing to (614.5 ± 10.8) mm(3) in the blank control group and to (611.2 ± 8.7) mm(3) at 28 days after icotinib treatment, but (30.8 ± 2.0) mm(3) in the cetuximab treatment group and 0 mm(3) in the cetuximab combined with icotinib group. There was a significantly decreased expression of Ki-67 and PCNA proteins and down-regulation of phosphorylation of EGFR signaling-related proteins in the cetuximab combined with icotinib group. The combination of icotinib with cetuximab

Acquired resistance of EGFR-mutant lung adenocarcinomas to afatinib plus cetuximab is associated with activation of mTORC1

PubMed Central

Pirazzoli, Valentina; Nebhan, Caroline; Song, Xiaoling; Wurtz, Anna; Walther, Zenta; Cai, Guoping; Zhao, Zhongming; Jia, Peilin; de Stanchina, Elisa; Shapiro, Erik M.; Gale, Molly; Yin, Ruonan; Horn, Leora; Carbone, David P.; Stephens, Philip J; Miller, Vincent; Gettinger, Scott; Pao, William; Politi, Katerina

2014-01-01

SUMMARY Patients with EGFR-mutant lung adenocarcinomas (LUADs) who initially respond to first-generation TKIs develop resistance to these drugs. A combination of the irreversible TKI afatinib and the EGFR antibody cetuximab can be used to overcome resistance to first-generation TKIs; however, resistance to this drug combination eventually emerges. We identified activation of the mTORC1 signaling pathway as a mechanism of resistance to dual inhibition of EGFR in mouse models. Addition of rapamycin reversed resistance in vivo. Analysis of afatinib+cetuximab-resistant biopsy specimens revealed the presence of genomic alterations in genes that modulate mTORC1 signaling including NF2 and TSC1. These findings pinpoint enhanced mTORC1 activation as a mechanism of resistance to afatinib+cetuximab and identify genomic mechanisms that lead to activation of this pathway, revealing a potential therapeutic strategy for treating patients with resistance to these drugs. PMID:24813888

Maintenance Treatment with Cetuximab and BAY86-9766 Increases Antitumor Efficacy of Irinotecan plus Cetuximab in Human Colorectal Cancer Xenograft Models.

PubMed

Troiani, Teresa; Napolitano, Stefania; Martini, Giulia; Martinelli, Erika; Cardone, Claudia; Normanno, Nicola; Vitagliano, Donata; Morgillo, Floriana; Fenizia, Francesca; Lambiase, Matilde; Formisano, Luigi; Bianco, Roberto; Ciardiello, Davide; Ciardiello, Fortunato

2015-09-15

The use of cetuximab in the treatment of metastatic colorectal cancer is limited by development of resistance. We have investigated in three models of highly epidermal growth factor receptor (EGFR)-dependent colorectal cancer xenografts, the effect of maintenance therapy with different kinase inhibitors alone or in combination with cetuximab, after cytotoxic treatment induction with irinotecan plus cetuximab. SW48, LIM 1215, and GEO colorectal cancer cell lines were engrafted into nude mice and treated for 3 weeks with irinotecan and/or cetuximab. The combined treatment induced a significant reduction of tumor size. A subsequent experiment was performed in all three xenograft models in which after an induction treatment with irinotecan plus cetuximab, mice were randomly assigned to one of the following treatments: control, cetuximab, regorafenib, a selective PIK3CA inhibitor (PIK3CAi), a selective MEK inhibitor (MEKi), and/or the combination of each inhibitor with cetuximab. The cetuximab plus MEKi treatment determined the best antitumor activity with suppression of tumor growth. This effect was prolonged for 13 to 15 weeks after cessation of therapy and was accompanied by prolonged survival. Antitumor activity was accompanied by inhibition of the MAPK and MEK pathways. Moreover, in the cetuximab plus MEKi-treated SW48 xenograft group, KRAS mutations as a mechanism of acquired resistance were detected in 25% of cases compared with 75% KRAS mutations in the MEKi-treated group. A possible strategy to prevent and/or overcome resistance to anti-EGFR inhibitors in metastatic colorectal cancer is a maintenance therapy with cetuximab plus MEKi after an initial treatment with irinotecan plus cetuximab. ©2015 American Association for Cancer Research.

Economic Analysis of First-Line Treatment with Cetuximab or Panitumumab for RAS Wild-Type Metastatic Colorectal Cancer in England.

PubMed

Tikhonova, Irina A; Huxley, Nicola; Snowsill, Tristan; Crathorne, Louise; Varley-Campbell, Jo; Napier, Mark; Hoyle, Martin

2018-03-01

Combination therapies with cetuximab (Erbitux ® ; Merck Serono UK Ltd) and panitumumab (Vectibix ® ; Amgen UK Ltd) are shown to be less effective in adults with metastatic colorectal cancer who have mutations in exons 2, 3 and 4 of KRAS and NRAS oncogenes from the rat sarcoma (RAS) family. The objective of the study was to estimate the cost effectiveness of these drugs in patients with previously untreated RAS wild-type (i.e. non-mutated) metastatic colorectal cancer, not eligible for liver resection at baseline, from the UK National Health Service and Personal Social Services perspective. We constructed a partitioned survival model to evaluate the long-term costs and benefits of cetuximab and panitumumab combined with either FOLFOX (folinic acid, fluorouracil and oxaliplatin) or FOLFIRI (folinic acid, fluorouracil and irinotecan) vs. FOLFOX or FOLFIRI alone. The economic analysis was based on three randomised controlled trials. Costs and quality-adjusted life-years were discounted at 3.5% per annum. Based on the evidence available, both drugs fulfil the National Institute for Health and Care Excellence's end-of-life criteria. In the analysis, assuming discount prices for the drugs from patient access schemes agreed by the drug manufacturers with the Department of Health, predicted mean incremental cost-effectiveness ratios for cetuximab + FOLFOX, panitumumab + FOLFOX and cetuximab + FOLFIRI compared with chemotherapy alone appeared cost-effective at the National Institute for Health and Care Excellence's threshold of £50,000 per quality-adjusted life-year gained, applicable to end-of-life treatments. Cetuximab and panitumumab were recommended by the National Institute for Health and Care Excellence for patients with previously untreated RAS wild-type metastatic colorectal cancer, not eligible for liver resection at baseline, for use within the National Health Service in England. Both treatments are available via the UK Cancer Drugs Fund.

Interstitial lung disease secondary to Cetuximab in bladder cancer: an Oncologist's perspective.

PubMed

Price, Louise; Glynn, Patricia; Zarkar, Anjali

2017-12-20

A wide variety of cytotoxic medications cause interstitial lung disease (ILD). For the first time, we describe ILD in an 82-year-old woman with muscle invasive bladder cancer 10 days after receiving cetuximab as part of a novel trial. She had no significant medical history or drug allergies, had good exercise tolerance and a 5 pack-year smoking history. She received neoadjuvant chemotherapy (gemcitabine, cisplatin) with a good response on MRI. She was eligible for a phase 2 trial of cetuximab with chemotherapy and radiotherapy for muscle invasive bladder cancer (TUXEDO), in which the trial arm used cetuximab plus standard chemoradiotherapy to the bladder (64 grey in 32 fractions plus mitomycinandfluorouracil). Ten days after her third infusion of cetuximab, she was presented with type 1 respiratory failure. Thoracic CT scan demonstrated new widespread ground glass change in the lungs. She received high-dose steroids (prednisolone 1 mg/kg), broad spectrum antibacterial cover and non-invasive ventilation. She survived to be discharged with residual respiratory failure. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Acetyl-CoA carboxylase rewires cancer metabolism to allow cancer cells to survive inhibition of the Warburg effect by cetuximab

PubMed Central

Luo, Jingtao; Hong, Yun; Lu, Yang; Qiu, Songbo; Chaganty, Bharat K. R.; Zhang, Lun; Wang, Xudong; Li, Qiang; Fan, Zhen

2016-01-01

Cetuximab inhibits HIF-1-regulated glycolysis in cancer cells, thereby reversing the Warburg effect and leading to inhibition of cancer cell metabolism. AMP-activated protein kinase (AMPK) is activated after cetuximab treatment, and a sustained AMPK activity is a mechanism contributing to cetuximab resistance. Here, we investigated how acetyl-CoA carboxylase (ACC), a downstream target of AMPK, rewires cancer metabolism in response to cetuximab treatment. We found that introduction of experimental ACC mutants lacking the AMPK phosphorylation sites (ACC1_S79A and ACC2_S212A) into head and neck squamous cell carcinoma (HNSCC) cells protected HNSCC cells from cetuximab-induced growth inhibition. HNSCC cells with acquired cetuximab resistance contained not only high levels of T172-phosphorylated AMPK and S79-phosphorylated ACC1 but also an increased level of total ACC. These findings were corroborated in tumor specimens of HNSCC patients treated with cetuximab. Cetuximab plus TOFA (an allosteric inhibitor of ACC) achieved remarkable growth inhibition of cetuximab-resistant HNSCC xenografts. Our data suggest a novel paradigm in which cetuximab-mediated activation of AMPK and subsequent phosphorylation and inhibition of ACC is followed by a compensatory increase in total ACC, which rewires cancer metabolism from glycolysis-dependent to lipogenesis-dependent. PMID:27693630

Acetyl-CoA carboxylase rewires cancer metabolism to allow cancer cells to survive inhibition of the Warburg effect by cetuximab.

PubMed

Luo, Jingtao; Hong, Yun; Lu, Yang; Qiu, Songbo; Chaganty, Bharat K R; Zhang, Lun; Wang, Xudong; Li, Qiang; Fan, Zhen

2017-01-01

Cetuximab inhibits HIF-1-regulated glycolysis in cancer cells, thereby reversing the Warburg effect and leading to inhibition of cancer cell metabolism. AMP-activated protein kinase (AMPK) is activated after cetuximab treatment, and a sustained AMPK activity is a mechanism contributing to cetuximab resistance. Here, we investigated how acetyl-CoA carboxylase (ACC), a downstream target of AMPK, rewires cancer metabolism in response to cetuximab treatment. We found that introduction of experimental ACC mutants lacking the AMPK phosphorylation sites (ACC1_S79A and ACC2_S212A) into head and neck squamous cell carcinoma (HNSCC) cells protected HNSCC cells from cetuximab-induced growth inhibition. HNSCC cells with acquired cetuximab resistance contained not only high levels of T172-phosphorylated AMPK and S79-phosphorylated ACC1 but also an increased level of total ACC. These findings were corroborated in tumor specimens of HNSCC patients treated with cetuximab. Cetuximab plus TOFA (an allosteric inhibitor of ACC) achieved remarkable growth inhibition of cetuximab-resistant HNSCC xenografts. Our data suggest a novel paradigm in which cetuximab-mediated activation of AMPK and subsequent phosphorylation and inhibition of ACC is followed by a compensatory increase in total ACC, which rewires cancer metabolism from glycolysis-dependent to lipogenesis-dependent. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Combined cetuximab and genistein treatment shows additive anti-cancer effect on oral squamous cell carcinoma.

PubMed

Park, Sung-Jin; Kim, Myung-Jin; Kim, Yu-Kyoung; Kim, Soung-Min; Park, Ju-Yong; Myoung, Hoon

2010-06-01

The purpose of this study was to evaluate the potency of EGFR pathway inhibition achieved by combining cetuximab, an anti-EGFR monoclonal antibody, and genistein, a tyrosine kinase inhibitor, which target extracellular and intracellular domains of the receptor, respectively, in oral squamous cell carcinoma (OSCC) in vitro and in vivo. Two OSCC cell lines, HSC3 and KB, were treated with cetuximab (C, 0-400mug/ml), genistein (G, 0-80muM), or a combination of both at a range of concentrations. Downstream protein expression of EGFR, p-EGFR, and p-Akt were evaluated by Western blot. Cell proliferation and apoptosis indices were calculated to assess anti-cancer effects in vitro. The in vivo effects of cetuximab and genistein on tumor cell growth were examined using an OSCC xenografted nude mouse model and immunohistochemical analyses of proliferation (PCNA) and microvessel density (CD31). Treatment of cells with dual anti-EGFR agents reduced the expressions of p-EGFR, and p-Akt in HSC3 cell line, but there was no significant difference in downregulation between cetuximab alone and in combination with genistein in KB cells. Both HSC3 and KB cells showed a dose-dependent decrease in cell proliferation significantly with single agent treatment and combination (p<0.05). In low concentration, combined cetuximab and genistein therapy resulted in additive growth inhibition and more apoptosis compared to that achieved with single-agent exposure in both cell lines. A combination of cetuximab and genistein significantly inhibited tumor growth and caused a substantial growth delay in in vivo models of both cell lines while each single-agent exposure caused no delay of tumor growth. Immunohistochemical staining with PCNA revealed that the group receiving combined cetuximab and genistein exhibited the lowest number of proliferating cells and microvessel density (p<0.05). Combined therapy with genistein and cetuximab can add the potency of EGFR signaling inhibition. Because not all

Overcoming cetuximab resistance in HNSCC: the role of AURKB and DUSP proteins.

PubMed

Boeckx, Carolien; Op de Beeck, Ken; Wouters, An; Deschoolmeester, Vanessa; Limame, Ridha; Zwaenepoel, Karen; Specenier, Pol; Pauwels, Patrick; Vermorken, Jan B; Peeters, Marc; Van Camp, Guy; Baay, Marc; Lardon, Filip

2014-11-28

Unraveling the underlying mechanisms of cetuximab resistance in head and neck squamous cell carcinoma (HNSCC) is of major importance as many tumors remain non-responsive or become resistant. Our microarray results suggest that "resistant" cells still exhibit RAS-MAPK pathway signaling contributing to drug resistance, as witnessed by low expression of DUSP5 and DUSP6, negative regulators of ERK1/2, and increased expression of AURKB, a key regulator of mitosis. Therefore, interrupting the RAS-MAPK pathway by an ERK1/2 inhibitor (apigenin) or an AURKB inhibitor (barasertib) might be a new strategy for overcoming cetuximab resistance in HNSCC. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Cetuximab-induced hypomagnesaemia aggravates peripheral sensory neurotoxicity caused by oxaliplatin

PubMed Central

Satomi, Machiko; Asama, Toshiyuki; Ebisawa, Yoshiaki; Chisato, Naoyuki; Suno, Manabu; Karasaki, Hidenori; Furukawa, Hiroyuki; Matsubara, Kazuo

2010-01-01

Calcium and magnesium replacement is effective in reducing oxaliplatin-induced neurotoxicity. However, cetuximab treatment has been associated with severe hypomagnesaemia. Therefore, we retrospectively investigated whether cetuximab-induced hypomagnesaemia exacerbated oxaliplatin-induced neurotoxicity. Six patients with metastatic colorectal cancer who were previously treated with oxaliplatin-fluorouracil combination therapy were administered cetuximab in combination with irinotecan alone or irinotecan and fluorouracil as a second-line treatment. All patients had normal magnesium levels before receiving cetuximab. The Common Terminology Criteria for Adverse Events version 3.0 was used to evaluate the grade of neurotoxicity, hypomagnesaemia, hypocalcaemia, and hypokalemia every week. All six patients had grade 1 or higher hypomagnesaemia after starting cetuximab therapy. The serum calcium and potassium levels were within the normal range at the onset of hypomagnesaemia. Oxaliplatin-induced neurotoxicity occurred in all patients at the beginning of cetuximab therapy, with grade 1 neurotoxicity in five patients and grade 2 in one patient. After cetuximab administration, the neurotoxicity worsened in all six patients, and three progressed to grade 3. Among the three patients with grade 3 neurotoxicity, two required a dose reduction and one had to discontinue cetuximab therapy. A discontinuation or dose reduction in cetuximab therapy was associated with exacerbated oxaliplatin-induced neurotoxicity due to cetuximab-induced hypomagnesaemia in half of patients who had previously received oxaliplatin. Therefore, when administering cetuximab after oxaliplatin therapy, we suggest serially evaluating serum magnesium levels and neurotoxicity. PMID:22811813

Targeting Nuclear EGFR: Strategies for Improving Cetuximab Therapy in Lung Cancer

DTIC Science & Technology

2015-12-01

xenograft models to determine if, in vivo, SFK or AKT inhibition can block EGFR translocation to the nucleus leading to increased membrane expression...resistant NSCLC tumors using mouse xenografts . Mice bearing resistant tumors will be treated with 1) vehicle, 2) cetuximab, 3) dasatinib, 4) MK2206...phosphorylation of Y1101 and EGFR dimerization with HER3 leading to nuclear translocation. Key Research Accomplishments for Aim 2: • In vivo xenograft tumors

Cetuximab intensifies the ADCC activity of adoptive NK cells in a nude mouse colorectal cancer xenograft model.

PubMed

Chen, Shanshan; Li, Xuechun; Chen, Rongming; Yin, Mingang; Zheng, Qiuhong

2016-09-01

Natural killer (NK) cells, discovered ~40 years ago, are believed to be the most effective cytotoxic lymphocytes to counteract cancer; however, adoptive NK cell therapy in vivo has encountered certain limitations, including a lack of specificity. The drug cetuximab can mediate antibody dependent cell mediated cytotoxicity (ADCC) activity through NK cells in vivo , and has been approved for the first-line treatment of epidermal growth factor receptor (EGFR)-positive metastatic colorectal cancer (CRC). However, the ADCC activity of adoptive NK cells, induced by cetuximab in a nude mouse CRC xenograft model, has not been previously reported. The aim of the present study was to explore the ADCC activity of cetuximab combined with adoptive NK cells in CRC xenograft models with various EGFR expressions. The nude mouse xenograft models were established by subcutaneously injecting LOVO or SW620 cells. The mice were then randomly divided into 6 groups: Phosphate-buffered saline, cetuximab, human immunoglobulin G (hIgG), NK cells, hIgG plus NK cells and cetuximab plus NK cells. The ADCC antitumor activity was evaluated in these CRC models. The results indicated that the cetuximab plus NK cells group showed the greatest tumor inhibition effect compared with the NK cells group in LOVO xenograft tumor models with positive EGFR expression. However, the combination of cetuximab and NK cells did not show a stronger tumor inhibitory effect against the SW620 xenograft tumor models compared with the efficiency of NK cells. In conclusion, cetuximab could intensify the ADCC antitumor activity of adoptive NK cells towards CRC with an increased EGFR expression. The combination of cetuximab and NK cells may be a potential immunotherapy for metastatic CRC patients with positive EGFR expression.

Cost analysis of cetuximab (Erbitux) plus radiotherapy (ERT) versus concomitant cisplatin plus radiotherapy (CRT) within an NHS oncology unit (single institution): a pilot study.

PubMed

Caroline, Brammer; Sundus, Yahya; Dawn, Dawson; Carol, Glaister; Susan, Merrick

2016-12-01

The aim of this feasibility study is to define the resource effectiveness of cetuximab vs cisplatin given concomitantly with radiotherapy for squamous cell carcinoma within a National Health Service clinical oncology unit. 20 patients with Stage 3 or 4 head and neck squamous cell cancers were randomized to receive either cetuximab with radiotherapy (ERT) or cisplatin with radiotherapy concurrent with external beam radiotherapy 70 Gy in 35 fractions on a 1 : 1 basis over a 12-month duration. The study compared the resource utilization of ERT vs cisplatin with radiotherapy taking into account drug costs, clinical management and the costs of managing treatment-related toxicity from first fraction of radiotherapy to 6 months after the completion of therapy. Outcome measures were quality of life (recorded at the entry, end of radiotherapy, 6 weeks post treatment and 6 months post treatment), admissions to hospital, delays to radiotherapy, locoregional control and survival. Total drug costs including cost of nutritional supplements for patients treated with cetuximab were £7407.45 compared with £3959.07 for patients treated with cisplatin. Unscheduled admissions for toxicity management were significantly more common in the ERT arm. Healthcare personnel spent significantly more time delivering unscheduled outpatient care for patients receiving cisplatin than for those receiving cetuximab (p = 0.01). No significant difference in the quality of life was suggested at baseline, 6 weeks and 6 months. The mean time to removal of percutaneous gastrostomy (PEG) after completion of radiotherapy was 49.7 weeks in the cisplatin arm and 18.5 weeks in the cetuximab arm (p = 0.04). There was a statistically significant difference in patient-reported use of PEG between the cisplatin and cetuximab arms at 6 months following completion of treatment (p = 0.04). At 21 months, overall survival was 80% in the cisplatin arm vs 50% in the cetuximab (p = 0.332), with

Cost analysis of cetuximab (Erbitux) plus radiotherapy (ERT) versus concomitant cisplatin plus radiotherapy (CRT) within an NHS oncology unit (single institution): a pilot study

PubMed Central

Sundus, Yahya; Dawn, Dawson; Carol, Glaister; Susan, Merrick

2016-01-01

Objective: The aim of this feasibility study is to define the resource effectiveness of cetuximab vs cisplatin given concomitantly with radiotherapy for squamous cell carcinoma within a National Health Service clinical oncology unit. Methods: 20 patients with Stage 3 or 4 head and neck squamous cell cancers were randomized to receive either cetuximab with radiotherapy (ERT) or cisplatin with radiotherapy concurrent with external beam radiotherapy 70 Gy in 35 fractions on a 1 : 1 basis over a 12-month duration. The study compared the resource utilization of ERT vs cisplatin with radiotherapy taking into account drug costs, clinical management and the costs of managing treatment-related toxicity from first fraction of radiotherapy to 6 months after the completion of therapy. Outcome measures were quality of life (recorded at the entry, end of radiotherapy, 6 weeks post treatment and 6 months post treatment), admissions to hospital, delays to radiotherapy, locoregional control and survival. Results: Total drug costs including cost of nutritional supplements for patients treated with cetuximab were £7407.45 compared with £3959.07 for patients treated with cisplatin. Unscheduled admissions for toxicity management were significantly more common in the ERT arm. Healthcare personnel spent significantly more time delivering unscheduled outpatient care for patients receiving cisplatin than for those receiving cetuximab (p = 0.01). No significant difference in the quality of life was suggested at baseline, 6 weeks and 6 months. The mean time to removal of percutaneous gastrostomy (PEG) after completion of radiotherapy was 49.7 weeks in the cisplatin arm and 18.5 weeks in the cetuximab arm (p = 0.04). There was a statistically significant difference in patient-reported use of PEG between the cisplatin and cetuximab arms at 6 months following completion of treatment (p = 0.04). At 21 months, overall survival was 80% in the cisplatin arm vs 50% in the

Cetuximab Plus Oxaliplatin May Not Be Effective Primary Treatment for Metastatic Colorectal Cancer

Cancer.gov

In a randomized phase III trial, the addition of the targeted therapy cetuximab to oxaliplatin and fluoropyrimidine chemotherapy did not prolong survival or time to disease progression of patients with advanced colorectal cancer.

Cetuximab in the treatment of head and neck cancer: preliminary results outside clinical trials

PubMed Central

Dequanter, Didier; Shahla, Mohammad; Paulus, Pascal; Lothaire, Phillippe

2010-01-01

Introduction: The purpose of this study was to evaluate the clinical efficacy in our daily practice, outside clinical trials, of cetuximab plus radiotherapy in a majority of treatment-naive patients with locoregionally advanced head and neck squamous cell carcinomas. Methods: A retrospective study was performed to evaluate outcomes in patients who were treated definitively with cetuximab and radiotherapy (ExRT). Patients with stage III or IV, nonmetastatic, measurable squamous cell carcinoma of the head and neck (SCCHN) were eligible. Results: There were 18 males and two females. The median age was 61 years (range from 49 to 87 years old). Concurrent radiotherapy and cetuximab was used, in first line, in 17 patients with locally advanced disease; two patients with recurrent SCCHN, who were intolerant of Cisplatin-based regimens, were treated with radiotherapy combined with weekly cetuximab; and 1 patient received cetuximab and radiotherapy postoperatively. The median time of response was 10 months (range from 2 to 24 months). A partial response was observed in 11 cases; a complete response in nine cases. The occurrence of grade 2–3 skin toxicity was observed in 11 cases. Skin toxicity was clearly correlated with a better response and the duration of the response to the treatment. The use of cetuximab in combination with radiotherapy does not increase the side effects of radiotherapy. At the end of the follow-up, 17 patients died. Conclusion: Cetuximab, with its highly targeted mechanism of action and synergistic activity with current treatment modalities, is a valuable treatment option in head and neck patients. The effect of the epidermal growth factor receptor antagonist occurs without any change in the pattern and the severity of toxicity usually associated with head and neck radiation. Cetuximab seems not to provide the most benefit for patients with oropharyngeal cancers but will in patients with T4 tumors. However, the median duration of local control was

Correlation of cetuximab-induced skin rash and outcomes of solid tumor patients treated with cetuximab: a systematic review and meta-analysis.

PubMed

Abdel-Rahman, Omar; Fouad, Mona

2015-02-01

We performed a systematic review and meta-analysis of the correlation between cetuximab-induced skin rash and outcomes of solid tumor patients treated with cetuximab. Eligible studies included phase I, II and III trials of patients with solid tumors on cetuximab; describing events of skin rash and correlating skin rash with overall survival (OS), progression free survival (PFS) and/or overall response rate (ORR). Our search strategy yielded 409 potentially relevant citations on CETUXIMAB from Pubmed/Medline, CENTRAL Cochrane registry and ASCO meeting library. After exclusion of ineligible studies, a total of 13 clinical trials were considered eligible for the meta-analysis, including 4 phase III trials, 8 phase II trials and one phase I trial. The occurrence of cetuximab-induced rash in patients was highly associated with improvements in PFS (HR=0.74; 95% CI: 0.63-0.86, P<0.0002), OS (HR=0.60; 95% CI: 0.47-0.76, P<0.0001), and ORR (RR=1.51, 95% CI: 1.26-1.81, P<0.00001), as compared to patients without rash. Exploratory subgroup analysis showed no effect of tumor types on the RR of ORR. Our meta-analysis has demonstrated that cetuximab-induced rash is associated with a significantly improved OS, PFS and ORR. Cetuximab-induced skin rash may represent a prognostic factor in patients with advanced solid tumors. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Cetuximab Injection

MedlinePlus

... other medications to treat a certain type of cancer of the head and neck. Cetuximab is also used alone or in combination with other medications to treat a certain type of cancer of the colon (large intestine) or rectum that ...

Overcoming Resistance to Cetuximab with Honokiol, A Small-Molecule Polyphenol.

PubMed

Pearson, Hannah E; Iida, Mari; Orbuch, Rachel A; McDaniel, Nellie K; Nickel, Kwangok P; Kimple, Randall J; Arbiser, Jack L; Wheeler, Deric L

2018-01-01

Overexpression and activation of the EGFR have been linked to poor prognosis in several human cancers. Cetuximab is a mAb against EGFR that is used for the treatment in head and neck squamous cell carcinoma (HNSCC) and metastatic colorectal cancer. Unfortunately, most tumors have intrinsic or will acquire resistance to cetuximab during the course of therapy. Honokiol is a natural compound found in the bark and leaves of the Chinese Magnolia tree and is established to have several anticancer properties without appreciable toxicity. In this study, we hypothesized that combining cetuximab and honokiol treatments could overcome acquired resistance to cetuximab. We previously developed a model of acquired resistance to cetuximab in non-small cell lung cancer H226 cell line. Treatment of cetuximab-resistant clones with honokiol and cetuximab resulted in a robust antiproliferative response. Immunoblot analysis revealed the HER family and their signaling pathways were downregulated after combination treatment, most notably the proliferation (MAPK) and survival (AKT) pathways. In addition, we found a decrease in phosphorylation of DRP1 and reactive oxygen species after combination treatment in cetuximab-resistant clones, which may signify a change in mitochondrial function. Furthermore, we utilized cetuximab-resistant HNSCC patient-derived xenografts (PDX) to test the benefit of combinatorial treatment in vivo There was significant growth delay in PDX tumors after combination treatment with a subsequent downregulation of active MAPK, AKT, and DRP1 signaling as seen in vitro Collectively, these data suggest that honokiol is a promising natural compound in overcoming acquired resistance to cetuximab. Mol Cancer Ther; 17(1); 204-14. ©2017 AACR . ©2017 American Association for Cancer Research.

Lack of Cetuximab induced skin toxicity in a previously irradiated field: case report and review of the literature

PubMed Central

2010-01-01

Introduction Mutation, amplification or dysregulation of the EGFR family leads to uncontrolled division and predisposes to cancer. Inhibiting the EGFR represents a form of targeted cancer therapy. Case report We report the case of 79 year old gentlemen with a history of skin cancer involving the left ear who had radiation and surgical excision. He had presented with recurrent lymph node in the left upper neck. We treated him with radiation therapy concurrently with Cetuximab. He developed a skin rash over the face and neck area two weeks after starting Cetuximab, which however spared the previously irradiated area. Conclusion The etiology underlying the sparing of the previously irradiated skin maybe due to either decrease in the population of EGFR expressing cells or decrease in the EGFR expression. We raised the question that "Is it justifiable to use EGFR inhibitors for patients having recurrence in the previously irradiated field?" We may need further research to answer this question which may guide the physicians in choosing appropriate drug in this scenario. PMID:20478052

Cetuximab plus gemcitabine/oxaliplatin (GEMOXCET) in first-line metastatic pancreatic cancer: a multicentre phase II study

PubMed Central

Kullmann, F; Hollerbach, S; Dollinger, M M; Harder, J; Fuchs, M; Messmann, H; Trojan, J; Gäbele, E; Hinke, A; Hollerbach, C; Endlicher, E

2009-01-01

Targeting the epidermal growth factor receptor pathway in pancreatic cancer seems to be an attractive therapeutic approach. This study assessed the efficacy of cetuximab plus the combination of gemcitabine/oxaliplatin in metastatic pancreatic cancer. Eligible subjects had histological or cytological diagnosis of metastatic pancreatic adenocarcinoma. The primary end point was response according to RECIST. Patients received cetuximab 400 mg m−2 at first infusion followed by weekly 250 mg m−2 combined with gemcitabine 1000 mg m−2 as a 100 min infusion on day 1 and oxaliplatin 100 mg m−2 as a 2-h infusion on day 2 every 2 weeks. Between January 2005 and August 2006, a total of 64 patients (22 women (34%), 42 men (66%); median age 64 years (range 31–78)) were enrolled at seven study centres. On October 2007, a total of 17 patients were alive. Sixty-two patients were evaluable for baseline and 61 for assessment of response to treatment in an intention-to-treat analysis. Six patients had an incomplete drug combination within the first cycle of the treatment plan (n=4 hypersensitivity reactions to the first cetuximab infusion, n=2 refused to continue therapy). Reported grade 3/4 toxicities (% of patients) were leukopaenia 15%, anaemia 8%, thrombocytopaenia 10%, diarrhoea 7%, nausea 18%, infection 18% and allergy 7%. Cetuximab-attributable skin reactions occurred as follows: grade 0: 20%, grade 1: 41%, grade 2: 30% and grade 3: 10%. The intention-to-treat analysis of 61 evaluable patients showed an overall response rate of 33%, including 1 (2%) complete and 19 (31%) partial remissions. There were 31% patients with stable and 36% with progressive disease or discontinuation of the therapy before re-staging. The presence of a grade 2 or higher skin rash was associated with a higher likelihood of achieving objective response. Median time to progression was 118 days, with a median overall survival of 213 days. A clinical benefit response was noted in

Cetuximab And The Head And Neck Squamous Cell Cancer.

PubMed

Concu, Riccardo; Cordeiro, Maria Natalia Dias Soeiro

2018-01-12

The head and neck squamous cell cancer (HNSCC) is the most common type of head and neck cancer (more than 90%), and all over the world more than a half million people have been developing this cancer in the last years. This type of cancer is usually marked by a poor prognosis with a really significant morbidity and mortality. Cetuximab received early favor as an exciting and promising new therapy with relatively mild side effect, and due to this received authorization in the 2004 from the European Medicines Agency (EMA) and in the 2006 from the Food and Drug Association (FDA) for the treatment of patients with squamous cell cancer of the head and neck in combination with radiation therapy for locally advanced disease. In this work we will review the application and the efficacy of the Cetuximab in the treatment of the HNSCC. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Enhanced Antitumor Effects of Epidermal Growth Factor Receptor Targetable Cetuximab-Conjugated Polymeric Micelles for Photodynamic Therapy.

PubMed

Chang, Ming-Hsiang; Pai, Chin-Ling; Chen, Ying-Chen; Yu, Hsiu-Ping; Hsu, Chia-Yen; Lai, Ping-Shan

2018-02-22

Nanocarrier-based delivery systems are promising strategies for enhanced therapeutic efficacy and safety of toxic drugs. Photodynamic therapy (PDT)-a light-triggered chemical reaction that generates localized tissue damage for disease treatments-usually has side effects, and thus patients receiving photosensitizers should be kept away from direct light to avoid skin phototoxicity. In this study, a clinically therapeutic antibody cetuximab (C225) was conjugated to the surface of methoxy poly(ethylene glycol)- b -poly(lactide) (mPEG- b -PLA) micelles via thiol-maleimide coupling to allow tumor-targetable chlorin e6 (Ce6) delivery. Our results demonstrate that more C225-conjugated Ce6-loaded polymeric micelles (C225-Ce6/PM) were selectively taken up than Ce6/PM or IgG conjugated Ce6/PM by epidermal growth factor receptor (EGFR)-overexpressing A431 cells observed by confocal laser scanning microscopy (CLSM), thereby decreasing the IC 50 value of Ce6-mediated PDT from 0.42 to 0.173 μM. No significant differences were observed in cellular uptake study or IC 50 value between C225-Ce6/PM and Ce6/PM groups in lower EGFR expression HT-29 cells. For antitumor study, the tumor volumes in the C225-Ce6/PM-PDT group (percentage of tumor growth inhibition, TGI% = 84.8) were significantly smaller than those in the Ce6-PDT (TGI% = 38.4) and Ce6/PM-PDT groups (TGI% = 53.3) ( p < 0.05) at day 21 through reduced cell proliferation in A431 xenografted mice. These results indicated that active EGFR targeting of photosensitizer-loaded micelles provides a possible way to resolve the dose-limiting toxicity of conventional photosensitizers and represents a potential delivery system for PDT in a clinical setting.

Relevance of MET activation and genetic alterations of KRAS and E-cadherin for cetuximab sensitivity of gastric cancer cell lines.

PubMed

Heindl, Stefan; Eggenstein, Evelyn; Keller, Simone; Kneissl, Julia; Keller, Gisela; Mutze, Kathrin; Rauser, Sandra; Gasteiger, Georg; Drexler, Ingo; Hapfelmeier, Alexander; Höfler, Heinz; Luber, Birgit

2012-05-01

The therapeutic activity of the epidermal growth factor receptor (EGFR)-directed monoclonal antibody cetuximab in gastric cancer is currently being investigated. Reliable biomarkers for the identification of patients who are likely to benefit from the treatment are not available. The aim of the study was to examine the drug sensitivity of five gastric cancer cell lines towards cetuximab as a single agent and to establish predictive markers for chemosensitivity in this cell culture model. The effect of a combination of cetuximab with chemotherapy was compared between a sensitive and a nonsensitive cell line. EGFR expression, activation and localisation, the presence and subcellular localisation of the cell adhesion molecule E-cadherin as well as MET activation were examined by Western blot analysis, flow cytometry and immunofluorescence staining. Cells were treated with varying concentrations of cetuximab and cisplatin and 5-fluorouracil in tumour-relevant concentrations. The biological endpoint was cell viability, which was measured by XTT cell proliferation assay. Response to treatment was evaluated using statistical methods. We assessed the activity of cetuximab in five gastric cancer cell lines (AGS, KATOIII, MKN1, MKN28 and MKN45). The viability of two cell lines, MKN1 and MKN28, was significantly reduced by cetuximab treatment. High EGFR expression and low levels of receptor activation were associated with cetuximab responsiveness. MET activation as well as mutations of KRAS and CDH1 (gene encoding E-cadherin) was associated with cetuximab resistance. These data indicate that our examinations may be clinically relevant, and the candidate markers should therefore be tested in clinical studies.

Cetuximab plus FOLFOX for Patients with Metastatic Colorectal Cancer with Poor Performance Status and/or Severe Tumor-Related Complications

PubMed Central

Shitara, Kohei; Yokota, Tomoya; Takahari, Daisuke; Shibata, Takashi; Sato, Yozo; Tajika, Masahiro; Ura, Takashi; Muro, Kei

2010-01-01

Introduction Cetuximab-based chemotherapy showed a statistically significantly higher response rate compared with chemotherapy such as FOLFOX. Therefore, FOLFOX plus cetuximab is suspected to be the best regimen to alleviate tumor-related symptoms with a high response rate. Case Report Here we present the results of 8 consecutive patients with metastatic colorectal cancer with poor performance status and/or severe complications who were treated with first-line FOLFOX with cetuximab. Six of 8 patients achieved an apparent clinical benefit, including radiological response and symptoms improvement. Two patients with BRAF mutation could achieve neither clinical benefit nor radiological response. Conclusion Although an optimal line of therapy with cetuximab is unclear yet with bevacizumab in mind, we propose that patients who need a tumor response to alleviate their symptoms due to advanced disease might be candidates for first-line cetuximab-based therapy as shown in our cases. Additionally, patients with BRAF mutant tumors might be important candidates for novel targeted therapy in the future to improve their poor prognosis. PMID:21347194

Drug-Target Kinetics in Drug Discovery.

PubMed

Tonge, Peter J

2018-01-17

The development of therapies for the treatment of neurological cancer faces a number of major challenges including the synthesis of small molecule agents that can penetrate the blood-brain barrier (BBB). Given the likelihood that in many cases drug exposure will be lower in the CNS than in systemic circulation, it follows that strategies should be employed that can sustain target engagement at low drug concentration. Time dependent target occupancy is a function of both the drug and target concentration as well as the thermodynamic and kinetic parameters that describe the binding reaction coordinate, and sustained target occupancy can be achieved through structural modifications that increase target (re)binding and/or that decrease the rate of drug dissociation. The discovery and deployment of compounds with optimized kinetic effects requires information on the structure-kinetic relationships that modulate the kinetics of binding, and the molecular factors that control the translation of drug-target kinetics to time-dependent drug activity in the disease state. This Review first introduces the potential benefits of drug-target kinetics, such as the ability to delineate both thermodynamic and kinetic selectivity, and then describes factors, such as target vulnerability, that impact the utility of kinetic selectivity. The Review concludes with a description of a mechanistic PK/PD model that integrates drug-target kinetics into predictions of drug activity.

MicroRNA-9 enhances sensitivity to cetuximab in epithelial phenotype hepatocellular carcinoma cells through regulation of the eukaryotic translation initiation factor 5A-2.

PubMed

Xue, Fei; Liang, Yuntian; Li, Zhenrong; Liu, Yanhui; Zhang, Hongwei; Wen, Yu; Yan, Lei; Tang, Qiang; Xiao, Erhui; Zhang, Dongyi

2018-01-01

Hepatocellular carcinoma (HCC) is one of the most widespread malignant human tumors worldwide. Treatment options include radiotherapy, surgical intervention and chemotherapy; however, drug resistance is an ongoing treatment concern. In the present study, the effects of a microRNA (miR/miRNA), miR-9, on the sensitivity of HCC cell lines to the epidermal growth factor receptor inhibitor, cetuximab, were examined. miR-9 has been proposed to serve a role in tumorigenesis and tumor progression. In the present study, bioinformatics analyses identified the eukaryotic translation initiation factor 5A2 (eIF-5A-2) as a target of miR-9. The expression levels of miR-9 and eIF-5A-2 were examined by reverse transcription-quantitative polymerase chain reaction and HCC cell lines were transfected with miR-9 mimics and inhibitors to determine the effects of the miRNA on cell proliferation and viability. The miR-9 mimic was revealed to significantly increase the sensitivity of epithelial phenotype HCC cells (Hep3B and Huh7) to cetuximab, while the miR-9 inhibitor triggered the opposite effect. There were no significant differences in sensitivity to cetuximab observed in mesenchymal phenotype HCC cells (SNU387 and SNU449). Cells lines displaying high expression levels of eIF-5A-2 were more resistant to cetuximab. Transfection of cells with a miR-9 mimic resulted in downregulation of the expression of eIF-5A-2 mRNA, while an miR-9 inhibitor increased expression. When expression of eIF-5A-2 was knocked down with siRNA, the effects of miR-9 on cetuximab sensitivity were no longer observed. Taken together, these data support a role for miR-9 in enhancing the sensitivity of epithelial phenotype HCC cells to cetuximab through regulation of eIF-5A-2.

INSULIN-LIKE GROWTH FACTOR-1 RECEPTOR INHIBITOR, AMG-479, IN CETUXIMAB-REFRACTORY HEAD AND NECK SQUAMOUS CELL CARCINOMA

PubMed Central

Pohlmann, Paula R.; Rothenberg, Mace L.; Burkey, Brian B.; Parker, Joel; Palka, Kevin; Aulino, Joseph; Puzanov, Igor; Murphy, Barbara

2011-01-01

Background Recurrent head and neck squamous cell carcinoma (HNSCC) remains a difficult cancer to treat. Here, we describe a patient with HNSCC who had complete response to methotrexate (MTX) after progressing on multiple cytotoxic agents, cetuximab, and AMG-479 (monoclonal antibody against insulin-like growth factor-1 receptor [IGF-1R]). Methods The clinical information was collected by a retrospective medical record review under an Institutional Review Board–approved protocol. From 4 tumors and 2 normal mucosal epithelia, global gene expression, and IGF-1R and dihydrofolate reductase (DHFR) protein levels were determined. Results Effective target inhibition in the tumor was confirmed by the decreased protein levels of total and phospho-IGF-1R after treatment with AMG-479. Decreased level of DHFR and conversion of a gene expression profile associated with cetuximab-resistance to cetuximab-sensitivity were also observed. Conclusion This suggests that the combination of AMG- 479 and MTX or cetuximab may be a promising therapeutic approach in refractory HNSCC. PMID:20652976

A retrospective analysis of cross-reacting cetuximab IgE antibody and its association with severe infusion reactions.

PubMed

Maier, Sabine; Chung, Christine H; Morse, Michael; Platts-Mills, Thomas; Townes, Leigh; Mukhopadhyay, Pralay; Bhagavatheeswaran, Prabhu; Racenberg, Jan; Trifan, Ovidiu C

2015-01-01

Severe infusion reactions (SIRs) at rates of 5% or less are known side effects of biological agents, including mAbs such as cetuximab. There are currently no prospectively validated risk factors to aid physicians in identifying patients who may be at risk of experiencing an SIR following administration of any of these drugs. A retrospective analysis of 545 banked serum or plasma samples from cancer patients participating in clinical trials of cetuximab was designed to evaluate whether the presence of pretreatment IgE antibodies against cetuximab, as determined by a commercially available assay system, is associated with SIRs during the initial cetuximab infusion. Patients with a positive test indicating the presence of pretreatment antibodies had a higher risk of experiencing an SIR; however, at the prespecified cutoff utilized in this analysis, the test has a relatively low-positive predictive value (0.577 [0.369-0.766]) and a negative predictive value of 0.961 (0.912-0.987) in an unselected patient population. Data collected in this large retrospective validation study support prior observations of an association between the presence of pretreatment IgE antibodies cross-reactive with cetuximab and SIRs. Further analysis of the test's ability to predict patients at risk of an SIR would be required before this assay could be used reliably in this patient population. © 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

EGFR-targeted therapies in the post-genomic era.

PubMed

Xu, Mary Jue; Johnson, Daniel E; Grandis, Jennifer R

2017-09-01

Over 90% of head and neck cancers overexpress the epidermal growth factor receptor (EGFR). In diverse tumor types, EGFR overexpression has been associated with poorer prognosis and outcomes. Therapies targeting EGFR include monoclonal antibodies, tyrosine kinase inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, and antisense gene therapy. Few EGFR-targeted therapeutics are approved for clinical use. The monoclonal antibody cetuximab is a Food and Drug Administration (FDA)-approved EGFR-targeted therapy, yet has exhibited modest benefit in clinical trials. The humanized monoclonal antibody nimotuzumab is also approved for head and neck cancers in Cuba, Argentina, Colombia, Peru, India, Ukraine, Ivory Coast, and Gabon in addition to nasopharyngeal cancers in China. Few other EGFR-targeted therapeutics for head and neck cancers have led to as significant responses as seen in lung carcinomas, for instance. Recent genome sequencing of head and neck tumors has helped identify patient subgroups with improved response to EGFR inhibitors, for example, cetuximab in patients with the KRAS-variant and the tyrosine kinase inhibitor erlotinib for tumors harboring MAPK1 E322K mutations. Genome sequencing has furthermore broadened our understanding of dysregulated pathways, holding the potential to enhance the benefit derived from therapies targeting EGFR.

Weekly and every 2 weeks cetuximab maintenance therapy after platinum-based chemotherapy plus cetuximab as first-line treatment for non-small cell lung cancer: randomized non-comparative phase IIIb NEXT trial.

PubMed

Heigener, David F; Pereira, José Rodrigues; Felip, Enriqueta; Mazal, Juraj; Manzyuk, Lyudmila; Tan, Eng Huat; Merimsky, Ofer; Sarholz, Barbara; Esser, Regina; Gatzemeier, Ulrich

2015-06-01

The First-Line Erbitux in Lung Cancer (FLEX) trial showed that the addition of cetuximab to chemotherapy followed by weekly cetuximab maintenance significantly improved survival in the first-line treatment of advanced non-small cell lung cancer (NSCLC). The phase IIIb NSCLC Erbitux Trial (NEXT) trial (NCT00820755) investigated the efficacy and safety of weekly and every 2 weeks cetuximab maintenance therapy in this setting. Patients were treated with platinum-based chemotherapy plus cetuximab, and those progression-free after four to six cycles were randomized to every 2 weeks (500 mg/m(2)) or weekly (250 mg/m(2)) cetuximab maintenance. Randomization was stratified for tumor histology and response status. The primary endpoint for a regimen would be reached if the lower boundary of the 95 % confidence interval (CI) for the 1-year survival rate exceeded 55 %. A planned 480 patients were to be randomized. However, enrollment was curtailed following a negative opinion from the European Medicines Agency with regard to the use of cetuximab in this setting. After combination therapy, 311/583 (53.3 %) patients without progression were randomized to maintenance therapy: 157 to every 2 weeks cetuximab and 154 to weekly cetuximab. Baseline characteristics were balanced between these groups and exposure to cetuximab was similar. The 1-year survival rate was 62.8 % (95 % CI, 54.7-70.0) for every 2 weeks cetuximab and 64.4 % (95 % CI, 56.2-71.4) for weekly cetuximab. Safety profiles were similar, manageable, and in line with expectations. Therefore, in patients with advanced NSCLC who were progression-free after four to six cycles of first-line chemotherapy plus cetuximab, weekly and every 2 weeks cetuximab maintenance therapy were associated with similar survival outcomes.

A potential therapy for chordoma via antibody-dependent cell-mediated cytotoxicity employing NK or high-affinity NK cells in combination with cetuximab.

PubMed

Fujii, Rika; Schlom, Jeffrey; Hodge, James W

2018-05-01

OBJECTIVE Chordoma is a rare bone tumor derived from the notochord and is resistant to conventional therapies such as chemotherapy, radiotherapy, and targeting therapeutics. Expression of epidermal growth factor receptor (EGFR) in a large proportion of chordoma specimens indicates a potential target for therapeutic intervention. In this study the authors investigated the potential role of the anti-EGFR antibody cetuximab in immunotherapy for chordoma. METHODS Since cetuximab is a monoclonal antibody of the IgG1 isotype, it has the potential to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) employing natural killer (NK) cells as effectors. Polymorphisms in the CD16 allele expressed on NK cells have been shown to influence the degree of ADCC of tumor cells, with the high-affinity valine (V)/V allele being responsible for more lysis than the V/phenylalanine (F) or FF allele. Unfortunately, however, only approximately 10% of the population expresses the VV allele on NK cells. An NK cell line, NK-92, has now been engineered to endogenously express IL-2 and the high-affinity CD16 allele. These irradiated high-affinity (ha)NK cells were analyzed for lysis of chordoma cells with and without cetuximab, and the levels of lysis observed in ADCC were compared with those of NK cells from donors expressing the VV, VF, and FF alleles. RESULTS Here the authors demonstrate for the first time 1) that cetuximab in combination with NK cells can mediate ADCC of chordoma cells; 2) the influence of the NK CD16 polymorphism in cetuximab-mediated ADCC for chordoma cell lysis; 3) that engineered haNK cells-that is, cells transduced to express the CD16 V158 FcγRIIIa receptor-bind cetuximab with similar affinity to normal NK cells expressing the high-affinity VV allele; and 4) that irradiated haNK cells induce ADCC with cetuximab in chordoma cells. CONCLUSIONS These studies provide rationale for the use of cetuximab in combination with irradiated haNK cells for therapy for

GEM-loaded magnetic albumin nanospheres modified with cetuximab for simultaneous targeting, magnetic resonance imaging, and double-targeted thermochemotherapy of pancreatic cancer cells.

PubMed

Wang, Ling; An, Yanli; Yuan, Chenyan; Zhang, Hao; Liang, Chen; Ding, Fengan; Gao, Qi; Zhang, Dongsheng

2015-01-01

Targeted delivery is a promising strategy to improve the diagnostic imaging and therapeutic effect of cancers. In this paper, novel cetuximab (C225)-conjugated, gemcitabine (GEM)-containing magnetic albumin nanospheres (C225-GEM/MANs) were fabricated and applied as a theranostic nanocarrier to conduct simultaneous targeting, magnetic resonance imaging (MRI), and double-targeted thermochemotherapy against pancreatic cancer cells. Fe3O4 nanoparticles (NPs) and GEM co-loaded albumin nanospheres (GEM/MANs) were prepared, and then C225 was further conjugated to synthesize C225-GEM/MANs. Their morphology, mean particle size, GEM encapsulation ratio, specific cell-binding ability, and thermal dynamic profiles were characterized. The effects of discriminating different EGFR-expressing pancreatic cancer cells (AsPC-1 and MIA PaCa-2) and monitoring cellular targeting effects were assessed by targeted MRI. Lastly, the antitumor efficiency of double/C225/magnetic-targeted and nontargeted thermochemotherapy was compared with chemotherapy alone using 3-(4, 5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and flow cytometry (FCM) assay. When treated with targeted nanospheres, AsPC-1 cells showed a significantly less intense MRI T2 signal than MIA PaCa-2 cells, while both cells had similar signal strength when incubated with nontargeted nanospheres. T2 signal intensity was significantly lower when magnetic and C225 targeting were combined, rather than used alone. The inhibitory and apoptotic rates of each thermochemotherapy group were significantly higher than those of the chemotherapy-alone groups. Additionally, both MTT and FCM analysis verified that double-targeted thermochemotherapy had the highest targeted killing efficiency among all groups. The C225-GEM/MANs can distinguish various EGFR-expressing live pancreatic cancer cells, monitor diverse cellular targeting effects using targeted MRI imaging, and efficiently mediate double-targeted thermochemotherapy

Inhibition of EphB4-ephrin-B2 signaling enhances response to Cetuximab-radiation therapy in head and neck cancers.

PubMed

Bhatia, Shilpa; Sharma, Jaspreet; Bukkapatnam, Sanjana; Oweida, Ayman; Lennon, Shelby; Phan, Andy V; Milner, Dallin; Uyanga, Nomin; Jimeno, Antonio; Raben, David; Somerset, Hilary; Heasley, Lynn; Karam, Sana D

2018-05-30

The clinical success of targeted therapies such as cetuximab and radiation (RT) is hampered by the low response rates and development of therapeutic resistance. In the current study, we investigated the involvement of EphB4-ephrin-B2 pro-tumorigenic signaling in mediating resistance to EGFR inhibition and radiation therapy in head and neck cancers. We used patient-derived xenograft (PDX) models of head and neck squamous cell carcinoma (HNSCC) and HNSCC cell lines to test our hypothesis. Tumor tissues were subjected to PhosphoRTK array, and western blotting to detect changes in EphB4-ephrin-B2 targets. mRNA sequencing and microarray data analysis was performed on PDX tumors and HNSCC cell lines respectively to determine differences in gene expression of molecules involved in tumor cell growth, proliferation, and survival pathways. Effects on cell growth were determined by MTT assay on HNSCC cells downregulated for EphB4/ephrin-B2 expression, with and without EGFR inhibitor and radiation. Our data from locally-advanced HNSCC patients treated with standard of care definitive chemo-RT show elevated EphB4 and ephrin-B2 levels after failure of treatment. We observed significant response towards cetuximab and radiation therapy following EphB4-ephrin-B2 inhibition resulting in improved survival in tumor-bearing mice. Tumor growth inhibition was accompanied by decrease in the levels of proliferation and pro-survival molecules and increased apoptosis. Our findings underscore the importance of adopting rational drug combinations to enhance therapeutic effect. Our study documenting enhanced response of HNSCC to cetuximab-RT therapy with EphB4-ephrin-B2 blockade has the potential to translate into clinic to benefit this patient population. Copyright ©2018, American Association for Cancer Research.

In vivo and ex vivo cetuximab sensitivity assay using three-dimensional primary culture system to stratify KRAS mutant colorectal cancer

PubMed Central

Tashiro, Takahiro; Okuyama, Hiroaki; Endo, Hiroko; Kawada, Kenji; Ashida, Yasuko; Ohue, Masayuki; Sakai, Yoshiharu; Inoue, Masahiro

2017-01-01

In clinic, cetuximab, an anti-EGFR antibody, improves treatment outcomes in colorectal cancer (CRC). KRAS-mutant CRC is generally resistant to cetuximab, although difference of the sensitivity among KRAS-mutants has not been studied in detail. We previously developed the cancer tissue-originated spheroid (CTOS) method, a primary culture method for cancer cells. We applied CTOS method to investigate whether ex vivo cetuximab sensitivity assays reflect the difference in sensitivity in the xenografts. Firstly, in vivo cetuximab treatment was performed with xenografts derived from 10 CTOS lines (3 KRAS-wildtype and 7 KRAS mutants). All two CTOS lines which exhibited tumor regression were KRAS-wildtype, meanwhile all KRAS-mutant CTOS lines grew more than the initial size: were resistant to cetuximab according to the clinical evaluation criteria, although the sensitivity was quite diverse. We divided KRAS-mutants into two groups; partially responsive group in which cetuximab had a substantial growth inhibitory effect, and resistant group which exhibited no effect. The ex vivo signaling assay with EGF stimulation revealed that the partially responsive group, but not the resistant group, exhibited suppressed ERK phosphorylation ex vivo. Furthermore, two lines from the partially responsive group, but none of the lines in the resistant group, exhibited a combinatory effect of cetuximab and trametinib, a MEK inhibitor, ex vivo and in vivo. Taken together, the results indicate that ex vivo signaling assay reflects the difference in sensitivity in vivo and stratifies KRAS mutant CTOS lines by sensitivity. Therefore, coupling the in vivo and ex vivo assays with CTOS can be a useful platform for understanding the mechanism of diversity in drug sensitivity. PMID:28301591

Cetuximab as treatment for head and neck cancer patients with a previous liver transplant: report of two cases.

PubMed

Holguin, Francia; Rubió-Casadevall, Jordi; Saigi, Maria; Marruecos, Jordi; Taberna, Miren; Tobed, Marc; Maños, Manuel; Mesía, Ricard

2017-10-01

Cetuximab is a monoclonal antibody against epidermal growth factor receptor useful in the treatment of patients with Head and Neck Squamous Cell Carcinoma combined with radiotherapy or chemotherapy. Its pharmacokinetics are not influenced by hepatic status and there are no specific warnings concerning its indication in patients with impaired hepatic function. Patients with a previous liver transplant are at risk for hepatic toxicity and use immunosupressants to avoid rejection that can interact with other drugs. We present two cases of patients with a previous liver transplant in which cetuximab was administered to treat head and neck cancer.

Cetuximab treatment in a patient with metastatic colorectal cancer and psoriasis

PubMed Central

Neyns, B.; Meert, V.; Vandenbroucke, F.

2008-01-01

Cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor, has activity against colorectal cancer. Treatment is associated with skin toxicity, and the safety of cetuximab in patients with psoriasis is unknown. We report the case of a male patient with stage iv colorectal cancer (crc) and a life-long history of extensive psoriasis. This patient experienced a durable remission of his crc and major improvement of his psoriasis during single-agent treatment with cetuximab. We conclude that, despite its known skin toxicity, cetuximab treatment can be offered to colorectal patients suffering from psoriasis. PMID:18769609

Activity and Safety of Cetuximab Plus Modified FOLFOXIRI Followed by Maintenance With Cetuximab or Bevacizumab for RAS and BRAF Wild-type Metastatic Colorectal Cancer: A Randomized Phase 2 Clinical Trial.

PubMed

Cremolini, Chiara; Antoniotti, Carlotta; Lonardi, Sara; Aprile, Giuseppe; Bergamo, Francesca; Masi, Gianluca; Grande, Roberta; Tonini, Giuseppe; Mescoli, Claudia; Cardellino, Giovanni Gerardo; Coltelli, Luigi; Salvatore, Lisa; Corsi, Domenico Cristiano; Lupi, Cristiana; Gemma, Donatello; Ronzoni, Monica; Dell'Aquila, Emanuela; Marmorino, Federica; Di Fabio, Francesca; Mancini, Maria Laura; Marcucci, Lorenzo; Fontanini, Gabriella; Zagonel, Vittorina; Boni, Luca; Falcone, Alfredo

2018-04-01

The combination of a triple-drug chemotherapy regimen with an anti-epidermal growth factor receptor (EGFR) agent as a first-line treatment of metastatic colorectal cancer (mCRC) showed promising activity along with safety concerns in single-arm phase 2 trials. The role of maintenance following chemotherapy and anti-EGFR and the optimal regimen to be adopted are not established. To evaluate the activity and safety of cetuximab plus modified FOLFOXIRI (mFOLFOXIRI) and explore the role of maintenance with cetuximab or bevacizumab in RAS and BRAF wild-type mCRC. In a prospective, noncomparative, open-label, multicenter, randomized phase 2 trial, patients aged 18 to 75 years with unresectable, previously untreated RAS and BRAF wild-type (before amendment, KRAS wild-type) mCRC were recruited from 21 oncology units in Italy from October 19, 2011, to March 1, 2015 (followed up through May 31, 2017). In total, 323 patients were screened and 143 were randomized to 2 treatment arms to receive as a first-line induction a regimen of mFOLFOXIRI plus cetuximab followed by cetuximab (arm A) or bevacizumab (arm B) until disease progression. Primary analyses were conducted in a modified intention-to-treat population. mFOLFOXIRI plus cetuximab repeated every 2 weeks for up to 8 cycles, followed by maintenance with cetuximab or bevacizumab until disease progression. The primary end point was the 10-month progression-free rate (PFR); secondary end points included progression-free and overall survival, response rate, rate of metastases resection, and adverse events. Of 143 patients randomized, 116 (81.1%) (median [interquartile range (IQR)] age, 59.5 [53-67] years; 34 [29.3%] women) had RAS and BRAF wild-type mCRC. At a median (IQR) follow-up of 44.0 (30.5-52.1) months, 10-month PFRs were 50.8% (90% CI, 39.5%-62.2%) in arm A and 40.4% (90% CI, 29.4%-52.1%) in arm B. The overall response rate was 71.6% (95% CI, 62.4%-79.5%). Main grade 3/4 adverse events were neutropenia (occurring in 36

Exploring drug-target interaction networks of illicit drugs.

PubMed

Atreya, Ravi V; Sun, Jingchun; Zhao, Zhongming

2013-01-01

Drug addiction is a complex and chronic mental disease, which places a large burden on the American healthcare system due to its negative effects on patients and their families. Recently, network pharmacology is emerging as a promising approach to drug discovery by integrating network biology and polypharmacology, allowing for a deeper understanding of molecular mechanisms of drug actions at the systems level. This study seeks to apply this approach for investigation of illicit drugs and their targets in order to elucidate their interaction patterns and potential secondary drugs that can aid future research and clinical care. In this study, we extracted 188 illicit substances and their related information from the DrugBank database. The data process revealed 86 illicit drugs targeting a total of 73 unique human genes, which forms an illicit drug-target network. Compared to the full drug-target network from DrugBank, illicit drugs and their target genes tend to cluster together and form four subnetworks, corresponding to four major medication categories: depressants, stimulants, analgesics, and steroids. External analysis of Anatomical Therapeutic Chemical (ATC) second sublevel classifications confirmed that the illicit drugs have neurological functions or act via mechanisms of stimulants, opioids, and steroids. To further explore other drugs potentially having associations with illicit drugs, we constructed an illicit-extended drug-target network by adding the drugs that have the same target(s) as illicit drugs to the illicit drug-target network. After analyzing the degree and betweenness of the network, we identified hubs and bridge nodes, which might play important roles in the development and treatment of drug addiction. Among them, 49 non-illicit drugs might have potential to be used to treat addiction or have addictive effects, including some results that are supported by previous studies. This study presents the first systematic review of the network

Exploring drug-target interaction networks of illicit drugs

PubMed Central

2013-01-01

Background Drug addiction is a complex and chronic mental disease, which places a large burden on the American healthcare system due to its negative effects on patients and their families. Recently, network pharmacology is emerging as a promising approach to drug discovery by integrating network biology and polypharmacology, allowing for a deeper understanding of molecular mechanisms of drug actions at the systems level. This study seeks to apply this approach for investigation of illicit drugs and their targets in order to elucidate their interaction patterns and potential secondary drugs that can aid future research and clinical care. Results In this study, we extracted 188 illicit substances and their related information from the DrugBank database. The data process revealed 86 illicit drugs targeting a total of 73 unique human genes, which forms an illicit drug-target network. Compared to the full drug-target network from DrugBank, illicit drugs and their target genes tend to cluster together and form four subnetworks, corresponding to four major medication categories: depressants, stimulants, analgesics, and steroids. External analysis of Anatomical Therapeutic Chemical (ATC) second sublevel classifications confirmed that the illicit drugs have neurological functions or act via mechanisms of stimulants, opioids, and steroids. To further explore other drugs potentially having associations with illicit drugs, we constructed an illicit-extended drug-target network by adding the drugs that have the same target(s) as illicit drugs to the illicit drug-target network. After analyzing the degree and betweenness of the network, we identified hubs and bridge nodes, which might play important roles in the development and treatment of drug addiction. Among them, 49 non-illicit drugs might have potential to be used to treat addiction or have addictive effects, including some results that are supported by previous studies. Conclusions This study presents the first systematic

Cetuximab enhances cisplatin-induced endoplasmic reticulum stress-associated apoptosis in laryngeal squamous cell carcinoma cells by inhibiting expression of TXNDC5.

PubMed

Peng, Fusen; Zhang, Hailin; Du, Youhong; Tan, Pingqing

2018-03-01

; cisplatin and cetuximab had stimulatory and inhibitory effects on the TXNDC5 gene promoter, respectively. The present study offered novel insights into the pharmacological effects of cisplatin and cetuximab on LSCC. It also suggested that TXNDC5 may be a potential therapeutic target for LSCC.

Cetuximab in the treatment of metastatic mucoepidermoid carcinoma of the salivary glands: A case report and review of literature

PubMed Central

Grisanti, Salvatore; Amoroso, Vito; Buglione, Michela; Rosati, Anna; Gatta, Roberto; Pizzocaro, Claudio; Ferrari, Vittorio D; Marini, Giovanni

2008-01-01

Introduction Patients with metastatic mucoepidermoid carcinoma of salivary glands have a poor outcome. The epidermal growth factor receptor protein is overexpressed in approximately 70% of mucoepidermoid carcinoma patients and may represent a therapeutic target. However, whether treatment with anti-epidermal growth factor receptor agents is effective is unclear and clinical trials are difficult due to the rarity of the disease. Here we assessed the activity of cetuximab in mucoepidermoid carcinoma on a molecular basis. Case presentation We present the case of a 40-year old Caucasian man with a mucoepidermoid carcinoma of the major salivary glands who developed distant bone and visceral metastases despite platinum-based chemotherapy. Epidermal growth factor receptor was overexpressed and fluorescence in situ hybridization analysis demonstrated a chromosome 7 polysomy. The patient was treated with the monoclonal antibody cetuximab in combination with cisplatin. After 11 doses of cetuximab, the patient developed brain metastases but evidence of response was documented at all extracranial metastatic sites. Conclusion This case report indicates that cetuximab can be active in mucoepidermoid carcinoma and may restore sensitivity to cisplatin in platinum-treated patients. Cetuximab does not cross the blood brain barrier and may select a metastatic clone to home the central nervous system while responding at other sites. PMID:18826647

HER2 activating mutations are targets for colorectal cancer treatment

PubMed Central

Kavuri, Shyam M.; Jain, Naveen; Galimi, Francesco; Cottino, Francesca; Leto, Simonetta M.; Migliardi, Giorgia; Searleman, Adam C.; Shen, Wei; Monsey, John; Trusolino, Livio; Jacobs, Samuel A.; Bertotti, Andrea; Bose, Ron

2015-01-01

The Cancer Genome Atlas project identified HER2 somatic mutations and gene amplification in 7% of colorectal cancer patients. Introduction of the HER2 mutations, S310F, L755S, V777L, V842I, and L866M, into colon epithelial cells increased signaling pathways and anchorage-independent cell growth, indicating that they are activating mutations. Introduction of these HER2 activating mutations into colorectal cancer cell lines produced resistance to cetuximab and panitumumab by sustaining MAPK phosphorylation. HER2 mutations are potently inhibited by low nanomolar doses of the irreversible tyrosine kinase inhibitors, neratinib and afatinib. HER2 gene sequencing of 48 cetuximab resistant, quadruple (KRAS, NRAS, BRAF, and PIK3CA) WT colorectal cancer patient-derived xenografts (PDX’s) identified 4 PDX’s with HER2 mutations. HER2 targeted therapies were tested on two PDX’s. Treatment with a single HER2 targeted drug (trastuzumab, neratinib, or lapatinib) delayed tumor growth, but dual HER2 targeted therapy with trastuzumab plus tyrosine kinase inhibitors produced regression of these HER2 mutated PDX’s. PMID:26243863

Inhibition of N-acetylglucosaminyltransferase V enhances the cetuximab-induced radiosensitivity of nasopharyngeal carcinoma cells likely through EGFR N-glycan alterations.

PubMed

Huang, Xiaomin; Liu, Ting; Wang, Qiongyao; Zhu, Weiliang; Meng, Hui; Guo, Linlang; Wei, Ting; Zhang, Jian

2017-05-23

N-acetylglucosaminyltransferase V (GnT-V), an enzyme that catalyses the formation of the N-linked β-1-6 branching of oligosaccharides, is related to the radiosensitivity of nasopharyngeal carcinoma (NPC). Cetuximab (C225) is an epidermal growth factor receptor (EGFR) inhibitor used as a radiosensitizer in the treatment of NPC. In this study, we used GnT-V as a molecular target to further sensitize cetuximab-treated NPC cells to radiation. The results from two NPC cell lines (CNE1 and CNE2) revealed that the silencing of GnT-V enhanced cetuximab-induced radiosensitivity by decreasing the β-1-6 branching of oligosaccharides on the EGFR. GnT-V down-regulation combined with cetuximab decreased the survival fraction, healing rate and cell viability and increased the apoptosis rate. Concomitantly, the combination of cetuximab and irradiation did not change the EGFR mRNA and protein levels and decreased the β-1-6 branching on the EGFR. Subsequently, we further explored the signalling downstream of EGF, particularly the PI3K/Akt signalling pathway, and discovered that treatment consisting of GnT-V down-regulation, irradiation and cetuximab was negatively correlated with phospho-Akt and phspho-PI3K. Finally, an in vivo experiment with radiotherapy revealed that the combination of GnT-V down-regulation and cetuximab decelerated tumour growth. In summary, our study demonstrated that the combination of decreased GnT-V activity and cetuximab enhanced NPC radiosensitivity, and the possible mechanism underlying this effect might involve the N-linked β1-6 branching of the EGFR. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Safety of panitumumab-IRDye800CW and cetuximab-IRDye800CW for fluorescence-guided surgical navigation in head and neck cancers.

PubMed

Gao, Rebecca W; Teraphongphom, Nutte; de Boer, Esther; van den Berg, Nynke S; Divi, Vasu; Kaplan, Michael J; Oberhelman, Nicholas J; Hong, Steven S; Capes, Elissa; Colevas, A Dimitrios; Warram, Jason M; Rosenthal, Eben L

2018-01-01

Purpose: To demonstrate the safety and feasibility of leveraging therapeutic antibodies for surgical imaging. Procedures: We conducted two phase I trials for anti-epidermal growth factor receptor antibodies cetuximab-IRDye800CW (n=12) and panitumumab-IRDye800CW (n=15). Adults with biopsy-confirmed head and neck squamous cell carcinoma scheduled for standard-of-care surgery were eligible. For cetuximab-IRDye800CW, cohort 1 was intravenously infused with 2.5 mg/m 2 , cohort 2 received 25 mg/m 2 , and cohort 3 received 62.5 mg/m 2 . For panitumumab-IRDye800CW, cohorts received 0.06 mg/kg, 0.5 mg/kg, and 1 mg/kg, respectively. Electrocardiograms and blood samples were obtained, and patients were followed for 30 days post-study drug infusion. Results: Both fluorescently labeled antibodies had similar pharmacodynamic properties and minimal toxicities. Two infusion reactions occurred with cetuximab and none with panitumumab. There were no grade 2 or higher toxicities attributable to cetuximab-IRDye800CW or panitumumab-IRDye800CW; fifteen grade 1 adverse events occurred with cetuximab-IRDye800CW, and one grade 1 occurred with panitumumab-IRDye800CW. There were no significant differences in QTc prolongation between the two trials (p=0.8). Conclusions: Panitumumab-IRDye800CW and cetuximab-IRDye800CW have toxicity and pharmacodynamic profiles that match the parent compound, suggesting that other therapeutic antibodies may be repurposed as imaging agents with limited preclinical toxicology data.

Safety of panitumumab-IRDye800CW and cetuximab-IRDye800CW for fluorescence-guided surgical navigation in head and neck cancers

PubMed Central

Gao, Rebecca W.; Teraphongphom, Nutte; de Boer, Esther; van den Berg, Nynke S.; Divi, Vasu; Kaplan, Michael J.; Oberhelman, Nicholas J.; Hong, Steven S.; Capes, Elissa; Colevas, A. Dimitrios; Warram, Jason M.; Rosenthal, Eben L.

2018-01-01

Purpose: To demonstrate the safety and feasibility of leveraging therapeutic antibodies for surgical imaging. Procedures: We conducted two phase I trials for anti-epidermal growth factor receptor antibodies cetuximab-IRDye800CW (n=12) and panitumumab-IRDye800CW (n=15). Adults with biopsy-confirmed head and neck squamous cell carcinoma scheduled for standard-of-care surgery were eligible. For cetuximab-IRDye800CW, cohort 1 was intravenously infused with 2.5 mg/m2, cohort 2 received 25 mg/m2, and cohort 3 received 62.5 mg/m2. For panitumumab-IRDye800CW, cohorts received 0.06 mg/kg, 0.5 mg/kg, and 1 mg/kg, respectively. Electrocardiograms and blood samples were obtained, and patients were followed for 30 days post-study drug infusion. Results: Both fluorescently labeled antibodies had similar pharmacodynamic properties and minimal toxicities. Two infusion reactions occurred with cetuximab and none with panitumumab. There were no grade 2 or higher toxicities attributable to cetuximab-IRDye800CW or panitumumab-IRDye800CW; fifteen grade 1 adverse events occurred with cetuximab-IRDye800CW, and one grade 1 occurred with panitumumab-IRDye800CW. There were no significant differences in QTc prolongation between the two trials (p=0.8). Conclusions: Panitumumab-IRDye800CW and cetuximab-IRDye800CW have toxicity and pharmacodynamic profiles that match the parent compound, suggesting that other therapeutic antibodies may be repurposed as imaging agents with limited preclinical toxicology data. PMID:29721094

Biological characterization of cetuximab-conjugated gold nanoparticles in a tumor animal model

NASA Astrophysics Data System (ADS)

Kao, Hao-Wen; Lin, Yi-Yu; Chen, Chao-Cheng; Chi, Kwan-Hwa; Tien, Der-Chi; Hsia, Chien-Chung; Lin, Wuu-Jyh; Chen, Fu-Du; Lin, Ming-Hsien; Wang, Hsin-Ell

2014-07-01

Gold nanoparticles (AuNPs) are widely applied to the diagnosis and treatment of cancer and can be modified to contain target-specific ligands via gold-thiolate bonding. This study investigated the pharmacokinetics and microdistribution of antibody-mediated active targeting gold nanoparticles in mice with subcutaneous lung carcinoma. We conjugated AuNPs with cetuximab (C225), an antibody-targeting epidermal growth factor receptor (EGFR), and then labeled with In-111, which created EGFR-targeted AuNPs. In vitro studies showed that after a 2 h incubation, the uptake of C225-conjugated AuNPs in high EGFR-expression A549 cells was 14.9-fold higher than that of PEGylated AuNPs; furthermore, uptake was also higher at 3.8-fold when MCF7 cells with lower EGFR-expression were used. MicroSPECT/CT imaging and a biodistribution study conducted by using a A549 tumor xenograft mouse model provided evidence of elevated uptake of the C225-conjugated AuNPs into the tumor cells as a result of active targeting. Moreover, the microdistribution of PEGylated AuNPs revealed that a large portion of AuNPs remained in the tumor interstitium, whereas the C225-conjugated AuNPs displayed enhanced internalization via antibody-mediated endocytosis. Our findings suggest that the anti-EGFR antibody-conjugated AuNPs are likely to be a plausible nano-sized vehicle for drug delivery to EGFR-expressing tumors.

The effect of near-infrared fluorescence conjugation on the anti-cancer potential of cetuximab.

PubMed

Yun, Ji Young; Hyun, Byung-Hwa; Nam, Sang Yoon; Yun, Young Won; Lee, Hu-Jang; Lee, Beom-Jun

2018-03-01

This study investigated the anti-cancer potential of a near-infrared fluorescence (NIRF) molecule conjugated with Cetuximab (Cetuximab-NIRF) in six-week-old female BALB/c athymic (nu+/nu+) nude mice. A431 cells were cultured and injected into the animals to induce solid tumors. Paclitaxel (30 mg/kg body weight (BW)), Cetuximab (1 mg/kg BW), and Cetuximab-NIRF (0.25, 0.5 and 1.0 mg/kg BW) were intraperitoneally injected twice a week into the A431 cell xenografts of the nude mice. Changes in BW, tumor volume and weight, fat and lean mass, and diameter of the peri-tumoral blood vessel were determined after two weeks. Tumor volumes and weights were significantly decreased in the Cetuximab-NIRF (1 mg/kg BW) group compared with the control group ( P <0.001). Lean mass and total body water content were also conspicuously reduced in the Cetuximab-NIRF (1 mg/kg BW) group compared with the vehicle control group. Peri-tumoral blood vessel diameters were very thin in the Cetuximab-NIRF groups compared with those of the paclitaxel group. These results indicate that the conjugation of Cetuximab with NIRF does not affect the anti-cancer potential of Cetuximab and NIRF can be used for molecular imaging in cancer treatments.

Salvage Stereotactic Reirradiation With or Without Cetuximab for Locally Recurrent Head-and-Neck Cancer: A Feasibility Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Comet, Benedicte; Kramar, Andrew; Faivre-Pierret, Mathieu

2012-09-01

Purpose: Normal tissues tolerance limits the use of reirradiation for recurrent head-and-neck cancers (HNC). Stereotactic body radiotherapy (SBRT) could offer precise irradiation while sparing healthy tissues. Results of a feasibility study using SBRT with or without cetuximab are reported for reirradiation of recurrent primary HNC. Methods and Materials: Patients with inoperable recurrent, or new primary tumor, in a previously irradiated area were included. Reirradiation dose was 36 Gy in six fractions of 6 Gy to the 85% isodose line covering 95% of the planning target volume. Patients with squamous cell carcinoma received concomitant cetuximab. Results: Between June 2007 and Januarymore » 2010, 40 patients were prospectively treated for 43 lesions. Median age was 60 and median tumor size was 29 mm. Fifteen patients received concomitant cetuximab and 1 received concomitant cisplatin. Median follow-up was 25.6 months with 34 patients evaluable for tumor response. Median overall survival was 13.6 months and response rate was 79.4% (15 complete and 12 partial responses). Grade 3 toxicity occurred in 4 patients. Conclusion: These results suggest that short SBRT with or without cetuximab is an effective salvage treatment with good response rate in this poor prognosis population with previously irradiated HNC. Treatment is feasible and, with appropriate care to limiting critical structure, acute toxicities are acceptable. A prospective multicenter Phase II trial of SRT and concomitant cetuximab in recurrent HNC squamous cell carcinoma is ongoing.« less

Sym004, a Novel EGFR Antibody Mixture, Can Overcome Acquired Resistance to Cetuximab1

PubMed Central

Iida, Mari; Brand, Toni M; Starr, Megan M; Li, Chunrong; Huppert, Evan J; Luthar, Neha; Pedersen, Mikkel W; Horak, Ivan D; Kragh, Michael; Wheeler, Deric L

2013-01-01

The epidermal growth factor receptor (EGFR) is a central regulator of tumor progression in a variety of human cancers. Cetuximab is an anti-EGFR monoclonal antibody that has been approved for head and neck and colorectal cancer treatment, but many patients treated with cetuximab don't respond or eventually acquire resistance. To determine how tumor cells acquire resistance to cetuximab, we previously developed a model of acquired resistance using the non-small cell lung cancer line NCI-H226. These cetuximab-resistant (CtxR) cells exhibit increased steady-state EGFR expression secondary to alterations in EGFR trafficking and degradation and, further, retained dependence on EGFR signaling for enhanced growth potential. Here, we examined Sym004, a novel mixture of antibodies directed against distinct epitopes on the extracellular domain of EGFR, as an alternative therapy for CtxR tumor cells. Sym004 treatment of CtxR clones resulted in rapid EGFR degradation, followed by robust inhibition of cell proliferation and down-regulation of several mitogen-activated protein kinase pathways. To determine whether Sym004 could have therapeutic benefit in vivo, we established de novo CtxR NCI-H226 mouse xenografts and subsequently treated CtxR tumors with Sym004. Sym004 treatment of mice harboring CtxR tumors resulted in growth delay compared to mice continued on cetuximab. Levels of total and phospho-EGFR were robustly decreased in CtxR tumors treated with Sym004. Immunohistochemical analysis of these Sym004-treated xenograft tumors further demonstrated decreased expression of Ki67, and phospho-rpS6, as well as a modest increase in cleaved caspase-3. These results indicate that Sym004 may be an effective targeted therapy for CtxR tumors. PMID:24204198

DrugBank: a knowledgebase for drugs, drug actions and drug targets

PubMed Central

Wishart, David S.; Knox, Craig; Guo, An Chi; Cheng, Dean; Shrivastava, Savita; Tzur, Dan; Gautam, Bijaya; Hassanali, Murtaza

2008-01-01

DrugBank is a richly annotated resource that combines detailed drug data with comprehensive drug target and drug action information. Since its first release in 2006, DrugBank has been widely used to facilitate in silico drug target discovery, drug design, drug docking or screening, drug metabolism prediction, drug interaction prediction and general pharmaceutical education. The latest version of DrugBank (release 2.0) has been expanded significantly over the previous release. With ∼4900 drug entries, it now contains 60% more FDA-approved small molecule and biotech drugs including 10% more ‘experimental’ drugs. Significantly, more protein target data has also been added to the database, with the latest version of DrugBank containing three times as many non-redundant protein or drug target sequences as before (1565 versus 524). Each DrugCard entry now contains more than 100 data fields with half of the information being devoted to drug/chemical data and the other half devoted to pharmacological, pharmacogenomic and molecular biological data. A number of new data fields, including food–drug interactions, drug–drug interactions and experimental ADME data have been added in response to numerous user requests. DrugBank has also significantly improved the power and simplicity of its structure query and text query searches. DrugBank is available at http://www.drugbank.ca PMID:18048412

Complementary Approaches to Existing Target Based Drug Discovery for Identifying Novel Drug Targets.

PubMed

Vasaikar, Suhas; Bhatia, Pooja; Bhatia, Partap G; Chu Yaiw, Koon

2016-11-21

In the past decade, it was observed that the relationship between the emerging New Molecular Entities and the quantum of R&D investment has not been favorable. There might be numerous reasons but few studies stress the introduction of target based drug discovery approach as one of the factors. Although a number of drugs have been developed with an emphasis on a single protein target, yet identification of valid target is complex. The approach focuses on an in vitro single target, which overlooks the complexity of cell and makes process of validation drug targets uncertain. Thus, it is imperative to search for alternatives rather than looking at success stories of target-based drug discovery. It would be beneficial if the drugs were developed to target multiple components. New approaches like reverse engineering and translational research need to take into account both system and target-based approach. This review evaluates the strengths and limitations of known drug discovery approaches and proposes alternative approaches for increasing efficiency against treatment.

Cetuximab-induced skin exanthema: prophylactic and reactive skin therapy are equally effective.

PubMed

Wehler, Thomas C; Graf, Claudine; Möhler, Markus; Herzog, Jutta; Berger, Martin R; Gockel, Ines; Lang, Hauke; Theobald, Matthias; Galle, Peter R; Schimanski, Carl C

2013-10-01

Treatment with cetuximab is accompanied by the development of an acneiform follicular skin exanthema in more than 80 % of patients. Severe exanthema (grade III/IV) develops in about 9-19 % of patients with the necessity of cetuximab dose reduction or cessation. The study presented was a retrospective analysis of 50 gastrointestinal cancer patients treated with cetuximab in combination with either FOLFIRI or FOLFOX. One cohort of 15 patients received an in-house reactive skin protocol upon development of an exanthema. A second cohort of 15 patients received a skin prophylaxis starting with the first dose of cetuximab before clinical signs of toxicity. A third historic group of 20 patients had received no skin prophylaxis or reactive treatment. 19/20 patients of the historic group developed a skin exanthema. Grade III/IV exanthema was observed six times. Forty percent discontinued cetuximab therapy. The average time to exanthema onset was 14.7 days. Applying the reactive skin protocol after the first occurrence of an exanthema, the exanthema was downgraded as follows: No patients developed grade IV° exanthema, and two patients developed a grade II/III exanthema. In the majority of cases, the reactive skin protocol controlled the exanthema (grade 0-I°). No dose reductions in cetuximab were necessary. Applying the prophylactic skin protocol starting at the beginning of cetuximab application was not superior to the reactive skin protocol. Cetuximab-induced skin exanthema can be coped with a reactive protocol equally effective as compared to a prophylactic skin treatment. A prospective study with higher patient numbers is planned.

Afatinib plus cetuximab delays resistance compared to single agent erlotinib or afatinib in mouse models of TKI-naïve EGFR L858R-induced lung adenocarcinoma

PubMed Central

Pirazzoli, Valentina; Ayeni, Deborah; Meador, Catherine B.; Sanganahalli, Basavaraju G.; Hyder, Fahmeed; de Stanchina, Elisa; Goldberg, Sarah; Pao, William; Politi, Katerina

2015-01-01

Purpose The EGFR tyrosine kinase inhibitors (TKIs), erlotinib and afatinib, have transformed the treatment of advanced EGFR mutant lung adenocarcinoma. However, almost all patients who respond develop acquired resistance on average ~1 year after starting therapy. Resistance is commonly due to a secondary mutation in EGFR (EGFRT790M). We previously found that the combination of the EGFR TKI afatinib and the EGFR antibody cetuximab could overcome EGFRT790M-mediated resistance in preclinical models. This combination has shown a 29% response rate in a clinical trial in patients with acquired resistance to first-generation TKIs. An outstanding question is whether this regimen is beneficial when used as front-line therapy. Experimental Design Using mouse models of EGFR mutant lung cancer, we tested whether the combination of afatinib plus cetuximab delivered upfront to mice with TKI-naïve EGFRL858R-induced lung adenocarcinomas delayed tumor relapse and drug-resistance compared to single agent TKI. Results Afatinib plus cetuximab markedly delayed the time to relapse and incidence of drug-resistant tumors, which occurred in only 63% of the mice, in contrast to erlotinib or afatinib treatment where 100% of mice developed resistance. Mechanisms of tumor escape observed in afatinib plus cetuximab resistant tumors include the EGFRT790M mutation and Kras mutations. Experiments in cell lines and xenografts confirmed that the afatinib plus cetuximab combination does not suppress the emergence of EGFRT790M. Conclusions These results highlight the potential of afatinib plus cetuximab as an effective treatment strategy for patients with TKI-naïve EGFR mutant lung cancer and indicate that clinical trial development in this area is warranted. PMID:26341921

Overcoming cetuximab resistance in Ewing's sarcoma by inhibiting lactate dehydrogenase-A.

PubMed

Fu, Jiaxin; Jiang, Han; Wu, Chenxuan; Jiang, Yi; Xiao, Lianping; Tian, Yonggang

2016-07-01

Ewing's sarcoma, the second most common type of malignant bone tumor, generally occurs in children and young adults. The current treatment of Ewing's sarcoma comprises systemic anti‑cancer chemotherapy with complete surgical resection. However, the majority of patients with Ewing's sarcoma develop resistance to chemotherapy. The present study revealed an oncogenic role of lactate dehydrogenase‑A (LDHA) in the resistance of Ewing's sarcoma to cetuximab. LDHA was shown to be upregulated at the protein and mRNA level in cetuximab‑resistant Ewing's sarcoma tissues and a cell line. In addition, a link between LDHA‑induced glycolysis and cetuximab resistance in Ewing's sarcoma cells was revealed. Of note, inhibition of LDHA by either small interfering RNA or LDHA inhibitor oxamate significantly re‑sensitized cetuximab‑resistant cells to cetuximab. Combined treatment with LDHA inhibitor and cetuximab synergistically reduced the viability of cetuximab-resistant cells through the suppression of LDHA. The present study revealed a novel mechanism of cetuximab resistance from the perspective of cancer‑cell metabolism and provided a sensitization approach, which may aid in the development of anti-chemoresistance strategies for the treatment of cetuximab-resistant Ewing's sarcoma.

Economic Analysis of Panitumumab Compared With Cetuximab in Patients With Wild-type KRAS Metastatic Colorectal Cancer That Progressed After Standard Chemotherapy.

PubMed

Graham, Christopher N; Maglinte, Gregory A; Schwartzberg, Lee S; Price, Timothy J; Knox, Hediyyih N; Hechmati, Guy; Hjelmgren, Jonas; Barber, Beth; Fakih, Marwan G

2016-06-01

In this analysis, we compared costs and explored the cost-effectiveness of subsequent-line treatment with cetuximab or panitumumab in patients with wild-type KRAS (exon 2) metastatic colorectal cancer (mCRC) after previous chemotherapy treatment failure. Data were used from ASPECCT (A Study of Panitumumab Efficacy and Safety Compared to Cetuximab in Patients With KRAS Wild-Type Metastatic Colorectal Cancer), a Phase III, head-to-head randomized noninferiority study comparing the efficacy and safety of panitumumab and cetuximab in this population. A decision-analytic model was developed to perform a cost-minimization analysis and a semi-Markov model was created to evaluate the cost-effectiveness of panitumumab monotherapy versus cetuximab monotherapy in chemotherapy-resistant wild-type KRAS (exon 2) mCRC. The cost-minimization model assumed equivalent efficacy (progression-free survival) based on data from ASPECCT. The cost-effectiveness analysis was conducted with the full information (uncertainty) from ASPECCT. Both analyses were conducted from a US third-party payer perspective and calculated average anti-epidermal growth factor receptor doses from ASPECCT. Costs associated with drug acquisition, treatment administration (every 2 weeks for panitumumab, weekly for cetuximab), and incidence of infusion reactions were estimated in both models. The cost-effectiveness model also included physician visits, disease progression monitoring, best supportive care, and end-of-life costs and utility weights estimated from EuroQol 5-Dimension questionnaire responses from ASPECCT. The cost-minimization model results demonstrated lower projected costs for patients who received panitumumab versus cetuximab, with a projected cost savings of $9468 (16.5%) per panitumumab-treated patient. In the cost-effectiveness model, the incremental cost per quality-adjusted life-year gained revealed panitumumab to be less costly, with marginally better outcomes than cetuximab. These economic

Concurrent cetuximab versus platinum-based chemoradiation for the definitive treatment of locoregionally advanced head and neck cancer.

PubMed

Tang, Chad; Chan, Cato; Jiang, Wen; Murphy, James D; von Eyben, Rie; Colevas, A Dimitrios; Pinto, Harlan; Lee-Enriquez, Nancy; Kong, Christina; Le, Quynh-Thu

2015-03-01

The purpose of this study was to present our experience utilizing cetuximab and platinum-based concurrent chemoradiotherapy for the definitive treatment of head and neck squamous cell carcinoma (HNSCC). Patients (n = 177) who received definitive concurrent chemoradiotherapy for HNSCC were stratified into 3 groups: receiving cetuximab monotherapy (n = 24), cetuximab and chemotherapy combination (n = 33), or platinum-based chemotherapy without cetuximab (n = 120). Primary endpoints were freedom from relapse, event-free survival, and overall survival (OS). Patients receiving cetuximab monotherapy were older with lower Karnofsky performance status (KPS) and higher Charlson comorbidity scores compared with those treated with combination cetuximab and chemotherapy or platinum-based concurrent chemoradiotherapy. Patients treated with platinum-based concurrent chemoradiotherapy exhibited significantly better freedom from relapse, event-free survival, and OS compared with those receiving cetuximab monotherapy or cetuximab and chemotherapy combination therapies (all p < .05). Differences between patients receiving cetuximab monotherapy and platinum-based concurrent chemoradiotherapy held on multivariate Cox regression. This study suggests that platinum-based concurrent chemoradiotherapy is superior to cetuximab-based monotherapy for the definitive treatment of HNSCC. © 2014 Wiley Periodicals, Inc.

UniDrug-target: a computational tool to identify unique drug targets in pathogenic bacteria.

PubMed

Chanumolu, Sree Krishna; Rout, Chittaranjan; Chauhan, Rajinder S

2012-01-01

Targeting conserved proteins of bacteria through antibacterial medications has resulted in both the development of resistant strains and changes to human health by destroying beneficial microbes which eventually become breeding grounds for the evolution of resistances. Despite the availability of more than 800 genomes sequences, 430 pathways, 4743 enzymes, 9257 metabolic reactions and protein (three-dimensional) 3D structures in bacteria, no pathogen-specific computational drug target identification tool has been developed. A web server, UniDrug-Target, which combines bacterial biological information and computational methods to stringently identify pathogen-specific proteins as drug targets, has been designed. Besides predicting pathogen-specific proteins essentiality, chokepoint property, etc., three new algorithms were developed and implemented by using protein sequences, domains, structures, and metabolic reactions for construction of partial metabolic networks (PMNs), determination of conservation in critical residues, and variation analysis of residues forming similar cavities in proteins sequences. First, PMNs are constructed to determine the extent of disturbances in metabolite production by targeting a protein as drug target. Conservation of pathogen-specific protein's critical residues involved in cavity formation and biological function determined at domain-level with low-matching sequences. Last, variation analysis of residues forming similar cavities in proteins sequences from pathogenic versus non-pathogenic bacteria and humans is performed. The server is capable of predicting drug targets for any sequenced pathogenic bacteria having fasta sequences and annotated information. The utility of UniDrug-Target server was demonstrated for Mycobacterium tuberculosis (H37Rv). The UniDrug-Target identified 265 mycobacteria pathogen-specific proteins, including 17 essential proteins which can be potential drug targets. UniDrug-Target is expected to accelerate

Decreased SMAD4 expression is associated with induction of epithelial-to-mesenchymal transition and cetuximab resistance in head and neck squamous cell carcinoma

PubMed Central

Cheng, Haixia; Fertig, Elana J; Ozawa, Hiroyuki; Hatakeyama, Hiromitsu; Howard, Jason D; Perez, Jimena; Considine, Michael; Thakar, Manjusha; Ranaweera, Ruchira; Krigsfeld, Gabriel; Chung, Christine H

2015-01-01

Epidermal growth factor receptor (EGFR) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and cetuximab, a monoclonal antibody targeting this receptor, is widely used to treat these patients. In the following investigation, we examined the role of SMAD4 down-regulation in mediating epithelial-to-mesenchymal transition (EMT) and cetuximab resistance in HNSCC. We determined that SMAD4 downregulation was significantly associated with increased cell motility, increased expression of vimentin, and cetuximab resistance in HNSCC cell lines. In the HNSCC genomic dataset obtained from The Cancer Genome Atlas, SMAD4 was altered in 20/279 (7%) of HNSCC via homozygous deletion, and nonsense, missense, and silent mutations. When SMAD4 expression was compared with respect to human papillomavirus (HPV) status, HPV-positive tumors had higher expression compared to HPV-negative tumors. Furthermore, higher SMAD4 expression also correlated with higher CDKN2A (p16) expression. Our data suggest that SMAD4 down-regulation plays an important role in the induction of EMT and cetuximab resistance. Patients with higher SMAD4 expression may benefit from cetuximab use in the clinic. PMID:26046389

Combining cetuximab with killer lymphocytes synergistically inhibits human cholangiocarcinoma cells in vitro.

PubMed

Morisaki, Takashi; Umebayashi, Masayo; Kiyota, Akifumi; Koya, Norihiro; Tanaka, Hiroto; Onishi, Hideya; Katano, Mitsuo

2012-06-01

We explored the possibility of combining adoptive immunotherapy with cytokine-activated killer (CAK) cells and the epidermal growth factor receptor monoclonal antibody, cetuximab, as a treatment for cholangiocarcinoma. CAK cells were cultured with a high-dose of interleukin-2 and anti-CD3 monoclonal antibodies. This cell population contained both activated CD16+/CD56+ (NK) cells and CD3+/NKG2D(high+) T-cells. The effect of CAK cells and cetuximab, alone and in combination, on the viability of human cholangiocarcinoma cells was evaluated. Culture of CAK cells alone, but not cetuximab alone, exhibited modest cytotoxicity toward cholangiocarcinoma cells. However, combining CAK cells with cetuximab significantly enhanced cytotoxicity. This enhancement was inhibited by the addition of excess human immunoglobulins, suggesting that antibody-dependent cytotoxicity, mediated by activated NK cells in the CAK cell culture was involved in this mechanism. Cetuximab may be used to enhance CAK cell therapeutic activity in patients with cholangiocarcinoma, by potentiating antibody-dependent cellular cytotoxicity.

Dual Inhibition of the Epidermal Growth Factor Receptor Pathway with Cetuximab and Erlotinib: A Phase I Study in Patients with Advanced Solid Malignancies

PubMed Central

Guarino, Michael J.; Schneider, Charles J.; Hosford, Martha A.; Brahmer, Julie R.; Rudin, Charles M.; Finckenstein, Friedrich Graf; Philip-Norton, Robyn E.; Lu, Haolan; Weber, Martin R.; Ettinger, David S.

2017-01-01

Purpose To determine the optimal dose of the antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab that can be safely administered in combination with a standard daily dose of erlotinib in patients with advanced solid malignancies. Patients and Methods Patients with advanced solid malignancies who had failed standard chemotherapies received escalating doses of cetuximab without a loading dose (100, 200, 250 mg/m2 i.v. weekly) in combination with a fixed dose of erlotinib (150 mg daily orally) until disease progression or unacceptable toxicity. Results Twenty-two patients were treated, including 14 patients (64%) with non-small cell lung cancer. Twenty patients received combination treatment at the highest dose level for a median of 5.5 weeks (range, 1–31 weeks). One dose-limiting toxicity was observed: grade 3 skin rash. Overall, the most common adverse events (any grade, grade 3/4) were consistent with the safety profiles of the individual drugs: acneform rash (100%, 9%), diarrhea (77%, 5%), and hypomagnesemia (59%, 12%). Seven of 18 evaluable patients (38.9%) had stable disease lasting for a median of 16.6 weeks (range, 6.1–25.1 weeks). Conclusion Dual EGFR inhibition with cetuximab and erlotinib is feasible; the observed toxicities were manageable and consistent with the safety profiles of the individual drugs. The recommended doses for phase II studies are 250 mg/m2 i.v. weekly for cetuximab and 150 mg daily orally for erlotinib. PMID:19182243

Differential histopathologic parameters in colorectal cancer liver metastases resected after triplets plus bevacizumab or cetuximab: a pooled analysis of five prospective trials.

PubMed

Cremolini, Chiara; Milione, Massimo; Marmorino, Federica; Morano, Federica; Zucchelli, Gemma; Mennitto, Alessia; Prisciandaro, Michele; Lonardi, Sara; Pellegrinelli, Alessio; Rossini, Daniele; Bergamo, Francesca; Aprile, Giuseppe; Urbani, Lucio; Morelli, Luca; Schirripa, Marta; Cardellino, Giovanni Gerardo; Fassan, Matteo; Fontanini, Gabriella; de Braud, Filippo; Mazzaferro, Vincenzo; Falcone, Alfredo; Pietrantonio, Filippo

2018-04-01

Many factors, including histopathologic parameters, seem to influence the prognosis of patients undergoing resection of colorectal cancer liver metastases (CRCLM), although their relative weight is unclear. Histopathologic growth patterns (HGPs) of CRCLM may affect sensitivity to antiangiogenics. We aimed at evaluating differences in histopathologic parameters of response according to the use of bevacizumab or cetuximab as first-line targeted agents, and at exploring the prognostic and predictive role of HGPs. We performed a comprehensive histopathologic characterisation of CRCLM from 159 patients who underwent secondary resection, after receiving triplets FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) or COI (capecitabine, oxaliplatin, and irinotecan) plus bevacizumab (N = 103) vs cetuximab (N = 56) in five first-line no-profit clinical trials. Both major histopathologic response (tumour regression grade TRG1-2, 32 vs 14%, p = 0.013) and infarct-like necrosis (80 vs 64%, p = 0.035) were significantly higher in the bevacizumab than in the cetuximab group. Achieving major response positively affected relapse-free survival (RFS) (p = 0.012) and overall survival (OS) (p = 0.045), also in multivariable models (RFS, p = 0.008; OS, p = 0.033). In the desmoplastic HGP (N = 28), a higher percentage of major response was reported (57 vs 17% in pushing and 22% in replacement HGP, p < 0.001) and an unsignificant advantage from cetuximab vs bevacizumab was evident in RFS (p = 0.116). In the pushing HGP (N = 66), a significant benefit from bevacizumab vs cetuximab (p = 0.017) was observed. No difference was described in the replacement HGP (N = 65, p = 0.615). The histopathologic response is the only independent determinant of survival in patients resected after triplets plus a biologic. When associated with triplet chemotherapy, bevacizumab induces a higher histopathologic response rate than

A phase II Study Evaluating Combined Neoadjuvant Cetuximab and Chemotherapy Followed by Chemoradiotherapy and Concomitant Cetuximab in Locoregional Oesophageal Cancer Patients.

PubMed

Alsina, Maria; Rivera, Fernando; Ramos, Francisco Javier; Galán, Maica; López, Rafael; García-Alfonso, Pilar; Alés-Martinez, José Enrique; Queralt, Bernardo; Antón, Antonio; Carrato, Alfredo; Grávalos, Cristina; Méndez-Vidal, Maria José; López, Carlos; de Mena, Inmaculada Ruiz; Tabernero, Josep; Giralt, Jordi; Aranda, Enrique

2018-02-01

Pre-operative chemoradiotherapy using a 5-fluorouracil (5-FU)/cisplatin backbone is widely used to improve surgical outcomes in locoregional oesophageal cancer patients, despite a non-negligible failure rate. We evaluated intensification of this approach to improve patient outcomes by adding cetuximab to induction 5-FU/cisplatin/docetaxel (TPF) and to chemoradiotherapy in a phase II study. Between November 2006 and April 2009, 50 patients with stage II-IVa squamous cell carcinoma (SCC) or adenocarcinoma of the oesophagus or gastro-oesophageal junction initiated three TPF/cetuximab cycles. Six weeks later, patients with response or stabilisation initiated 6 weeks of cisplatin/cetuximab/radiotherapy, followed by surgery. The primary objective was the clinical complete response (cCR) rate after induction therapy plus chemoradiotherapy in intent-to-treat patients. Thirty-eight patients were evaluable after chemoradiotherapy, 84% of whom showed disease control. Six patients (12%) achieved a cCR, with a 54% overall response rate. Twenty-seven patients underwent surgery, 11 of whom (22%; nine SCC, two adenocarcinoma) had a pathological CR (41%). Fifteen patients were alive after a median follow-up of 23.2 months. Median progression-free survival was 12.2 months (95% confidence interval [CI] 1.7-22.8). Median overall survival was 23.4 months (95% CI 12.2-36.6) and was significantly longer among the 22 patients with complete resection than in the five patients without (42.1 vs. 24.9 months; p = 0.02, hazard ratio: 3.6, 95% CI 1.1-11.6). The toxicity profile was acceptable. Neoadjuvant cetuximab/TPF followed by chemoradiotherapy in locoregional oesophageal carcinoma patients is feasible and offers a modest response rate in this trial. The results of combining trimodality neoadjuvant treatment with cetuximab are consistent with the literature. Registration: The study is registered at ClinicalTrials.gov (NCT00733889).

The Human Kinome Targeted by FDA Approved Multi-Target Drugs and Combination Products: A Comparative Study from the Drug-Target Interaction Network Perspective.

PubMed

Li, Ying Hong; Wang, Pan Pan; Li, Xiao Xu; Yu, Chun Yan; Yang, Hong; Zhou, Jin; Xue, Wei Wei; Tan, Jun; Zhu, Feng

2016-01-01

The human kinome is one of the most productive classes of drug target, and there is emerging necessity for treating complex diseases by means of polypharmacology (multi-target drugs and combination products). However, the advantages of the multi-target drugs and the combination products are still under debate. A comparative analysis between FDA approved multi-target drugs and combination products, targeting the human kinome, was conducted by mapping targets onto the phylogenetic tree of the human kinome. The approach of network medicine illustrating the drug-target interactions was applied to identify popular targets of multi-target drugs and combination products. As identified, the multi-target drugs tended to inhibit target pairs in the human kinome, especially the receptor tyrosine kinase family, while the combination products were able to against targets of distant homology relationship. This finding asked for choosing the combination products as a better solution for designing drugs aiming at targets of distant homology relationship. Moreover, sub-networks of drug-target interactions in specific disease were generated, and mechanisms shared by multi-target drugs and combination products were identified. In conclusion, this study performed an analysis between approved multi-target drugs and combination products against the human kinome, which could assist the discovery of next generation polypharmacology.

Preclinical Comparison of Near-Infrared-Labeled Cetuximab and Panitumumab for Optical Imaging of Head and Neck Squamous Cell Carcinoma

PubMed Central

Day, Kristine E.; Sweeny, Larissa; Kulbersh, Brian; Zinn, Kurt R.; Rosenthal, Eben L.

2014-01-01

Purpose: Though various targets have been proposed and evaluated, no agent has yet been investigated in a clinical setting for head and neck cancer. The present study aimed to compare two fluorescently labeled anti-epidermal growth factor receptor (EGFR) antibodies for detection of head and neck squamous cell carcinoma (HNSCC). Procedures: Antigen specificities and in vitro imaging of the fluorescently labeled anti-EGFR antibodies were performed. Next, immunodeficient mice (n=22) bearing HNSCC (OSC-19 and SCC-1) tongue tumors received systemic injections of cetuximab-IRDye800CW, panitumumab-IRDye800CW, or IgG-IRDye800CW (a nonspecific control). Tumors were imaged and resected using two near-infrared imaging systems, SPY and Pearl. Fluorescent lymph nodes were also identified, and all resected tissues were sent for pathology. Results: Panitumumab-IRDye800CW and cetuximab-IRDye800CW had specific and high affinity binding for EGFR (KD=0.12 and 0.31 nM, respectively). Panitumumab-IRDye800CW demonstrated a 2-fold increase in fluorescence intensity compared to cetuximab-IRDye800CW in vitro. In vivo, both fluorescently labeled antibodies produced higher tumor-to-background ratios compared to IgG-IRDye800CW. However, there was no significant difference between the two in either cell line or imaging modality (OSC-19: p=0.08 SPY, p=0.48 Pearl; SCC-1: p=0.77 SPY, p=0.59 Pearl; paired t tests). Conclusions: There was no significant difference between the two fluorescently labeled anti-EGFR monoclonal antibodies in murine models of HNSCC. Both cetuximab and panitumumab can be considered suitable targeting agents for fluorescent intraoperative detection of HNSCC. PMID:23715932

PTEN status in advanced colorectal cancer treated with cetuximab

PubMed Central

Negri, F V; Bozzetti, C; Lagrasta, C A; Crafa, P; Bonasoni, M P; Camisa, R; Pedrazzi, G; Ardizzoni, A

2009-01-01

Background: Loss of phosphatase and tensin homologue deleted in chromosome 10 (PTEN) function in advanced colorectal cancer (CRC) may represent one of the resistance mechanisms to cetuximab by interfering with the epidermal growth factor receptor signal transduction pathway. Methods: PTEN expression tested by indirect immunofluorescence was evaluated both on primary (n=43) and on metastatic (n=24) sites in CRC patients treated with cetuximab. Results: The loss of PTEN expression tested on metastatic sites was negatively associated with response (100% progressive disease (PD) in PTEN-negative cases vs 30% PD in PTEN-positive cases; P<0.05), PFS (0.8 vs 8.2 months; P<0.001) and OS (2.9 vs 14.2 months; P<0.001). Conclusion: A potential role of PTEN in the anti-tumour activity of cetuximab could be hypothesised. PMID:19953097

Multi-target drugs: the trend of drug research and development.

PubMed

Lu, Jin-Jian; Pan, Wei; Hu, Yuan-Jia; Wang, Yi-Tao

2012-01-01

Summarizing the status of drugs in the market and examining the trend of drug research and development is important in drug discovery. In this study, we compared the drug targets and the market sales of the new molecular entities approved by the U.S. Food and Drug Administration from January 2000 to December 2009. Two networks, namely, the target-target and drug-drug networks, have been set up using the network analysis tools. The multi-target drugs have much more potential, as shown by the network visualization and the market trends. We discussed the possible reasons and proposed the rational strategies for drug research and development in the future.

SuperTarget and Matador: resources for exploring drug-target relationships.

PubMed

Günther, Stefan; Kuhn, Michael; Dunkel, Mathias; Campillos, Monica; Senger, Christian; Petsalaki, Evangelia; Ahmed, Jessica; Urdiales, Eduardo Garcia; Gewiess, Andreas; Jensen, Lars Juhl; Schneider, Reinhard; Skoblo, Roman; Russell, Robert B; Bourne, Philip E; Bork, Peer; Preissner, Robert

2008-01-01

The molecular basis of drug action is often not well understood. This is partly because the very abundant and diverse information generated in the past decades on drugs is hidden in millions of medical articles or textbooks. Therefore, we developed a one-stop data warehouse, SuperTarget that integrates drug-related information about medical indication areas, adverse drug effects, drug metabolization, pathways and Gene Ontology terms of the target proteins. An easy-to-use query interface enables the user to pose complex queries, for example to find drugs that target a certain pathway, interacting drugs that are metabolized by the same cytochrome P450 or drugs that target the same protein but are metabolized by different enzymes. Furthermore, we provide tools for 2D drug screening and sequence comparison of the targets. The database contains more than 2500 target proteins, which are annotated with about 7300 relations to 1500 drugs; the vast majority of entries have pointers to the respective literature source. A subset of these drugs has been annotated with additional binding information and indirect interactions and is available as a separate resource called Matador. SuperTarget and Matador are available at http://insilico.charite.de/supertarget and http://matador.embl.de.

Fe3O4@Au composite magnetic nanoparticles modified with cetuximab for targeted magneto-photothermal therapy of glioma cells.

PubMed

Lu, Qianling; Dai, Xinyu; Zhang, Peng; Tan, Xiao; Zhong, Yuejiao; Yao, Cheng; Song, Mei; Song, Guili; Zhang, Zhenghai; Peng, Gang; Guo, Zhirui; Ge, Yaoqi; Zhang, Kangzhen; Li, Yuntao

2018-01-01

Thermoresponsive nanoparticles have become an attractive candidate for designing combined multimodal therapy strategies because of the onset of hyperthermia and their advantages in synergistic cancer treatment. In this paper, novel cetuximab (C225)-encapsulated core-shell Fe 3 O 4 @Au magnetic nanoparticles (Fe 3 O 4 @Au-C225 composite-targeted MNPs) were created and applied as a therapeutic nanocarrier to conduct targeted magneto-photothermal therapy against glioma cells. The core-shell Fe 3 O 4 @Au magnetic nanoparticles (MNPs) were prepared, and then C225 was further absorbed to synthesize Fe 3 O 4 @Au-C225 composite-targeted MNPs. Their morphology, mean particle size, zeta potential, optical property, magnetic property and thermal dynamic profiles were characterized. After that, the glioma-destructive effect of magnetic fluid hyperthermia (MFH) combined with near-infrared (NIR) hyperthermia mediated by Fe 3 O 4 @Au-C225 composite-targeted MNPs was evaluated through in vitro and in vivo experiments. The inhibitory and apoptotic rates of Fe 3 O 4 @Au-C225 composite-targeted MNPs-mediated combined hyperthermia (MFH+NIR) group were significantly higher than other groups in vitro and the marked upregulation of caspase-3, caspase-8, and caspase-9 expression indicated excellent antitumor effect by inducing intrinsic apoptosis. Furthermore, Fe 3 O 4 @Au-C225 composite-targeted MNPs-mediated combined hyperthermia (MFH+NIR) group exhibited significant tumor growth suppression compared with other groups in vivo. Our studies illustrated that Fe 3 O 4 @Au-C225 composite-targeted MNPs have great potential as a promising nanoplatform for human glioma therapy and could be of great value in medical use in the future.

Fe3O4@Au composite magnetic nanoparticles modified with cetuximab for targeted magneto-photothermal therapy of glioma cells

PubMed Central

Tan, Xiao; Zhong, Yuejiao; Yao, Cheng; Song, Mei; Song, Guili; Zhang, Zhenghai; Peng, Gang; Guo, Zhirui; Ge, Yaoqi; Zhang, Kangzhen; Li, Yuntao

2018-01-01

Background Thermoresponsive nanoparticles have become an attractive candidate for designing combined multimodal therapy strategies because of the onset of hyperthermia and their advantages in synergistic cancer treatment. In this paper, novel cetuximab (C225)-encapsulated core-shell Fe3O4@Au magnetic nanoparticles (Fe3O4@Au-C225 composite-targeted MNPs) were created and applied as a therapeutic nanocarrier to conduct targeted magneto-photothermal therapy against glioma cells. Methods The core-shell Fe3O4@Au magnetic nanoparticles (MNPs) were prepared, and then C225 was further absorbed to synthesize Fe3O4@Au-C225 composite-targeted MNPs. Their morphology, mean particle size, zeta potential, optical property, magnetic property and thermal dynamic profiles were characterized. After that, the glioma-destructive effect of magnetic fluid hyperthermia (MFH) combined with near-infrared (NIR) hyperthermia mediated by Fe3O4@Au-C225 composite-targeted MNPs was evaluated through in vitro and in vivo experiments. Results The inhibitory and apoptotic rates of Fe3O4@Au-C225 composite-targeted MNPs-mediated combined hyperthermia (MFH+NIR) group were significantly higher than other groups in vitro and the marked upregulation of caspase-3, caspase-8, and caspase-9 expression indicated excellent antitumor effect by inducing intrinsic apoptosis. Furthermore, Fe3O4@Au-C225 composite-targeted MNPs-mediated combined hyperthermia (MFH+NIR) group exhibited significant tumor growth suppression compared with other groups in vivo. Conclusion Our studies illustrated that Fe3O4@Au-C225 composite-targeted MNPs have great potential as a promising nanoplatform for human glioma therapy and could be of great value in medical use in the future. PMID:29719396

Predicting drug-target interaction for new drugs using enhanced similarity measures and super-target clustering.

PubMed

Shi, Jian-Yu; Yiu, Siu-Ming; Li, Yiming; Leung, Henry C M; Chin, Francis Y L

2015-07-15

Predicting drug-target interaction using computational approaches is an important step in drug discovery and repositioning. To predict whether there will be an interaction between a drug and a target, most existing methods identify similar drugs and targets in the database. The prediction is then made based on the known interactions of these drugs and targets. This idea is promising. However, there are two shortcomings that have not yet been addressed appropriately. Firstly, most of the methods only use 2D chemical structures and protein sequences to measure the similarity of drugs and targets respectively. However, this information may not fully capture the characteristics determining whether a drug will interact with a target. Secondly, there are very few known interactions, i.e. many interactions are "missing" in the database. Existing approaches are biased towards known interactions and have no good solutions to handle possibly missing interactions which affect the accuracy of the prediction. In this paper, we enhance the similarity measures to include non-structural (and non-sequence-based) information and introduce the concept of a "super-target" to handle the problem of possibly missing interactions. Based on evaluations on real data, we show that our similarity measure is better than the existing measures and our approach is able to achieve higher accuracy than the two best existing algorithms, WNN-GIP and KBMF2K. Our approach is available at http://web.hku.hk/∼liym1018/projects/drug/drug.html or http://www.bmlnwpu.org/us/tools/PredictingDTI_S2/METHODS.html. Copyright © 2015 Elsevier Inc. All rights reserved.

The drug target genes show higher evolutionary conservation than non-target genes.

PubMed

Lv, Wenhua; Xu, Yongdeng; Guo, Yiying; Yu, Ziqi; Feng, Guanglong; Liu, Panpan; Luan, Meiwei; Zhu, Hongjie; Liu, Guiyou; Zhang, Mingming; Lv, Hongchao; Duan, Lian; Shang, Zhenwei; Li, Jin; Jiang, Yongshuai; Zhang, Ruijie

2016-01-26

Although evidence indicates that drug target genes share some common evolutionary features, there have been few studies analyzing evolutionary features of drug targets from an overall level. Therefore, we conducted an analysis which aimed to investigate the evolutionary characteristics of drug target genes. We compared the evolutionary conservation between human drug target genes and non-target genes by combining both the evolutionary features and network topological properties in human protein-protein interaction network. The evolution rate, conservation score and the percentage of orthologous genes of 21 species were included in our study. Meanwhile, four topological features including the average shortest path length, betweenness centrality, clustering coefficient and degree were considered for comparison analysis. Then we got four results as following: compared with non-drug target genes, 1) drug target genes had lower evolutionary rates; 2) drug target genes had higher conservation scores; 3) drug target genes had higher percentages of orthologous genes and 4) drug target genes had a tighter network structure including higher degrees, betweenness centrality, clustering coefficients and lower average shortest path lengths. These results demonstrate that drug target genes are more evolutionarily conserved than non-drug target genes. We hope that our study will provide valuable information for other researchers who are interested in evolutionary conservation of drug targets.

Properties of Protein Drug Target Classes

PubMed Central

Bull, Simon C.; Doig, Andrew J.

2015-01-01

Accurate identification of drug targets is a crucial part of any drug development program. We mined the human proteome to discover properties of proteins that may be important in determining their suitability for pharmaceutical modulation. Data was gathered concerning each protein’s sequence, post-translational modifications, secondary structure, germline variants, expression profile and drug target status. The data was then analysed to determine features for which the target and non-target proteins had significantly different values. This analysis was repeated for subsets of the proteome consisting of all G-protein coupled receptors, ion channels, kinases and proteases, as well as proteins that are implicated in cancer. Machine learning was used to quantify the proteins in each dataset in terms of their potential to serve as a drug target. This was accomplished by first inducing a random forest that could distinguish between its targets and non-targets, and then using the random forest to quantify the drug target likeness of the non-targets. The properties that can best differentiate targets from non-targets were primarily those that are directly related to a protein’s sequence (e.g. secondary structure). Germline variants, expression levels and interactions between proteins had minimal discriminative power. Overall, the best indicators of drug target likeness were found to be the proteins’ hydrophobicities, in vivo half-lives, propensity for being membrane bound and the fraction of non-polar amino acids in their sequences. In terms of predicting potential targets, datasets of proteases, ion channels and cancer proteins were able to induce random forests that were highly capable of distinguishing between targets and non-targets. The non-target proteins predicted to be targets by these random forests comprise the set of the most suitable potential future drug targets, and should therefore be prioritised when building a drug development programme. PMID

Cost-effectiveness analysis of KRAS testing and cetuximab as last-line therapy for colorectal cancer.

PubMed

Shiroiwa, Takeru; Motoo, Yoshiharu; Tsutani, Kiichiro

2010-12-01

Cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor, improves progression-free survival and overall survival in patients with metastatic colorectal cancer (mCRC). However, patients with a KRAS gene mutation do not benefit from cetuximab therapy. We performed a cost-effectiveness analysis of KRAS testing and cetuximab treatment as last-line therapy for patients with mCRC in Japan. In our analysis, we considered three treatment strategies. In the 'KRAS-testing strategy' (strategy A), KRAS testing was performed to guide treatment: patients with wild-type KRAS received cetuximab, and those with mutant KRAS received best supportive care (BSC). In the 'no-KRAS-testing strategy' (strategy B), genetic testing was not conducted and all patients received cetuximab. In the 'no-cetuximab strategy' (strategy C), genetic testing was not conducted and all patients received BSC. To evaluate the cost effectiveness of KRAS testing, the KRAS-testing strategy was compared with the no-KRAS-testing strategy; to evaluate the cost effectiveness of KRAS testing and cetuximab, the KRAS-testing strategy was compared with the no-cetuximab strategy; and to evaluate the cost effectiveness of cetuximab treatment without KRAS testing, the no-KRAS-testing strategy was compared with the no-cetuximab strategy. A three-state Markov model was used to predict expected costs and outcomes for each group. Outcomes in the model were based on those reported in a retrospective analysis of data from the National Cancer Institute of Canada Clinical Trials Group CO.17 study. We included only direct medical costs from the perspective of the Japanese healthcare payer. A 3% discount rate was used for both costs and outcome. Two outcomes, life-years (LYs) gained and quality-adjusted life-years (QALYs) gained, were used to calculate the incremental cost-effectiveness ratio (ICER). Our cost-effectiveness analysis revealed that the KRAS-testing strategy was dominant compared with the

Drug-Target Interactions: Prediction Methods and Applications.

PubMed

Anusuya, Shanmugam; Kesherwani, Manish; Priya, K Vishnu; Vimala, Antonydhason; Shanmugam, Gnanendra; Velmurugan, Devadasan; Gromiha, M Michael

2018-01-01

Identifying the interactions between drugs and target proteins is a key step in drug discovery. This not only aids to understand the disease mechanism, but also helps to identify unexpected therapeutic activity or adverse side effects of drugs. Hence, drug-target interaction prediction becomes an essential tool in the field of drug repurposing. The availability of heterogeneous biological data on known drug-target interactions enabled many researchers to develop various computational methods to decipher unknown drug-target interactions. This review provides an overview on these computational methods for predicting drug-target interactions along with available webservers and databases for drug-target interactions. Further, the applicability of drug-target interactions in various diseases for identifying lead compounds has been outlined. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Drug-targeting methodologies with applications: A review

PubMed Central

Kleinstreuer, Clement; Feng, Yu; Childress, Emily

2014-01-01

Targeted drug delivery to solid tumors is a very active research area, focusing mainly on improved drug formulation and associated best delivery methods/devices. Drug-targeting has the potential to greatly improve drug-delivery efficacy, reduce side effects, and lower the treatment costs. However, the vast majority of drug-targeting studies assume that the drug-particles are already at the target site or at least in its direct vicinity. In this review, drug-delivery methodologies, drug types and drug-delivery devices are discussed with examples in two major application areas: (1) inhaled drug-aerosol delivery into human lung-airways; and (2) intravascular drug-delivery for solid tumor targeting. The major problem addressed is how to deliver efficiently the drug-particles from the entry/infusion point to the target site. So far, most experimental results are based on animal studies. Concerning pulmonary drug delivery, the focus is on the pros and cons of three inhaler types, i.e., pressurized metered dose inhaler, dry powder inhaler and nebulizer, in addition to drug-aerosol formulations. Computational fluid-particle dynamics techniques and the underlying methodology for a smart inhaler system are discussed as well. Concerning intravascular drug-delivery for solid tumor targeting, passive and active targeting are reviewed as well as direct drug-targeting, using optimal delivery of radioactive microspheres to liver tumors as an example. The review concludes with suggestions for future work, considereing both pulmonary drug targeting and direct drug delivery to solid tumors in the vascular system. PMID:25516850

Development of Bone Targeting Drugs.

PubMed

Stapleton, Molly; Sawamoto, Kazuki; Alméciga-Díaz, Carlos J; Mackenzie, William G; Mason, Robert W; Orii, Tadao; Tomatsu, Shunji

2017-06-23

The skeletal system, comprising bones, ligaments, cartilage and their connective tissues, is critical for the structure and support of the body. Diseases that affect the skeletal system can be difficult to treat, mainly because of the avascular cartilage region. Targeting drugs to the site of action can not only increase efficacy but also reduce toxicity. Bone-targeting drugs are designed with either of two general targeting moieties, aimed at the entire skeletal system or a specific cell type. Most bone-targeting drugs utilize an affinity to hydroxyapatite, a major component of the bone matrix that includes a high concentration of positively-charged Ca 2+ . The strategies for designing such targeting moieties can involve synthetic and/or biological components including negatively-charged amino acid peptides or bisphosphonates. Efficient delivery of bone-specific drugs provides significant impact in the treatment of skeletal related disorders including infectious diseases (osteoarthritis, osteomyelitis, etc.), osteoporosis, and metabolic skeletal dysplasia. Despite recent advances, however, both delivering the drug to its target without losing activity and avoiding adverse local effects remain a challenge. In this review, we investigate the current development of bone-targeting moieties, their efficacy and limitations, and discuss future directions for the development of these specific targeted treatments.

Development of Bone Targeting Drugs

PubMed Central

Stapleton, Molly; Sawamoto, Kazuki; Alméciga-Díaz, Carlos J.; Mackenzie, William G.; Mason, Robert W.; Orii, Tadao; Tomatsu, Shunji

2017-01-01

The skeletal system, comprising bones, ligaments, cartilage and their connective tissues, is critical for the structure and support of the body. Diseases that affect the skeletal system can be difficult to treat, mainly because of the avascular cartilage region. Targeting drugs to the site of action can not only increase efficacy but also reduce toxicity. Bone-targeting drugs are designed with either of two general targeting moieties, aimed at the entire skeletal system or a specific cell type. Most bone-targeting drugs utilize an affinity to hydroxyapatite, a major component of the bone matrix that includes a high concentration of positively-charged Ca2+. The strategies for designing such targeting moieties can involve synthetic and/or biological components including negatively-charged amino acid peptides or bisphosphonates. Efficient delivery of bone-specific drugs provides significant impact in the treatment of skeletal related disorders including infectious diseases (osteoarthritis, osteomyelitis, etc.), osteoporosis, and metabolic skeletal dysplasia. Despite recent advances, however, both delivering the drug to its target without losing activity and avoiding adverse local effects remain a challenge. In this review, we investigate the current development of bone-targeting moieties, their efficacy and limitations, and discuss future directions for the development of these specific targeted treatments. PMID:28644392

Severe Acneiform Eruption Induced by Cetuximab (Erbitux®)

PubMed Central

Lee, Jung Eun; Lee, Sang Ju; Lee, Hee Jung; Lee, Ju Hee

2008-01-01

Epidermal growth factor has an important role in the regulation of proliferation and differentiation in epidermal keratinocytes, as well as in the survival, angiogenesis and metastasis of cancer cells. Cetuximab is a chimeric monoclonal antibody selective for the epidermal growth factor receptor that induces a broad range of cellular responses that enhance tumor sensitivity to radiotherapy and chemotherapeutic agents. However, it can cause adverse events in the patient including acneiform eruption, asthenia, abdominal pain and nausea/vomiting. We report a case of severe acneiform eruption induced by cetuximab in a 56-year-old man with colorectal cancer and liver metastases. PMID:18972607

A novel anti-EGFR monoclonal antibody inhibiting tumor cell growth by recognizing different epitopes from cetuximab.

PubMed

Hong, Kwang-Won; Kim, Chang-Goo; Lee, Seung-Hyun; Chang, Ki-Hwan; Shin, Yong Won; Ryoo, Kyung-Hwan; Kim, Se-Ho; Kim, Yong-Sung

2010-01-01

The epidermal growth factor receptor (EGFR) overexpressed in many epithelial tumors is an attractive target for tumor therapy since numerous blocking agents of EGFR signaling have proven their anti-tumor activity. Here we report a novel monoclonal antibody (mAb), A13, which was generated from mice immunized with human cervical carcinoma A431 cells. In addition to binding to soluble EGFR with affinity of K(D) approximately 5.8nM, mAb A13 specifically bound to a variety of tumor cells and human placenta tissues expressing EGFR. A13 efficiently inhibited both EGF-dependant EGFR tyrosine phosphorylation in cervical and breast tumor cells and also in vitro colony formation of EGFR-overexpressing lung tumors. Competition and sandwich ELISAs, competitive surface plasmon resonance, and domain-level epitope mapping analyses demonstrated that mAb A13 competitively bound to the domain III (amino acids 302-503) of EGFR with EGF, but recognized distinct epitopes from those of cetuximab (Erbitux). Our results demonstrated that anti-EGFR mAb A13 interfered with EGFR proliferation signaling by blocking EGF binding to EGFR with different epitopes from those of cetuximab, suggesting that combination therapies of mAb A13 with cetuximab may prove beneficial for anti-tumor therapy.

Drug target identification in protozoan parasites.

PubMed

Müller, Joachim; Hemphill, Andrew

2016-08-01

Despite the fact that diseases caused by protozoan parasites represent serious challenges for public health, animal production and welfare, only a limited panel of drugs has been marketed for clinical applications. Herein, the authors investigate two strategies, namely whole organism screening and target-based drug design. The present pharmacopoeia has resulted from whole organism screening, and the mode of action and targets of selected drugs are discussed. However, the more recent extensive genome sequencing efforts and the development of dry and wet lab genomics and proteomics that allow high-throughput screening of interactions between micromolecules and recombinant proteins has resulted in target-based drug design as the predominant focus in anti-parasitic drug development. Selected examples of target-based drug design studies are presented, and calcium-dependent protein kinases, important drug targets in apicomplexan parasites, are discussed in more detail. Despite the enormous efforts in target-based drug development, this approach has not yet generated market-ready antiprotozoal drugs. However, whole-organism screening approaches, comprising of both in vitro and in vivo investigations, should not be disregarded. The repurposing of already approved and marketed drugs could be a suitable strategy to avoid fastidious approval procedures, especially in the case of neglected or veterinary parasitoses.

Drug target identification in protozoan parasites

PubMed Central

Müller, Joachim; Hemphill, Andrew

2016-01-01

Introduction Despite the fact that diseases caused by protozoan parasites represent serious challenges for public health, animal production and welfare, only a limited panel of drugs has been marketed for clinical applications. Areas covered Herein, the authors investigate two strategies, namely whole organism screening and target-based drug design. The present pharmacopoeia has resulted from whole organism screening, and the mode of action and targets of selected drugs are discussed. However, the more recent extensive genome sequencing efforts and the development of dry and wet lab genomics and proteomics that allow high-throughput screening of interactions between micromolecules and recombinant proteins has resulted in target-based drug design as the predominant focus in anti-parasitic drug development. Selected examples of target-based drug design studies are presented, and calcium-dependent protein kinases, important drug targets in apicomplexan parasites, are discussed in more detail. Expert opinion Despite the enormous efforts in target-based drug development, this approach has not yet generated market-ready antiprotozoal drugs. However, whole-organism screening approaches, comprising of both in vitro and in vivo investigations, should not be disregarded. The repurposing of already approved and marketed drugs could be a suitable strategy to avoid fastidious approval procedures, especially in the case of neglected or veterinary parasitoses. PMID:27238605

Deep-Learning-Based Drug-Target Interaction Prediction.

PubMed

Wen, Ming; Zhang, Zhimin; Niu, Shaoyu; Sha, Haozhi; Yang, Ruihan; Yun, Yonghuan; Lu, Hongmei

2017-04-07

Identifying interactions between known drugs and targets is a major challenge in drug repositioning. In silico prediction of drug-target interaction (DTI) can speed up the expensive and time-consuming experimental work by providing the most potent DTIs. In silico prediction of DTI can also provide insights about the potential drug-drug interaction and promote the exploration of drug side effects. Traditionally, the performance of DTI prediction depends heavily on the descriptors used to represent the drugs and the target proteins. In this paper, to accurately predict new DTIs between approved drugs and targets without separating the targets into different classes, we developed a deep-learning-based algorithmic framework named DeepDTIs. It first abstracts representations from raw input descriptors using unsupervised pretraining and then applies known label pairs of interaction to build a classification model. Compared with other methods, it is found that DeepDTIs reaches or outperforms other state-of-the-art methods. The DeepDTIs can be further used to predict whether a new drug targets to some existing targets or whether a new target interacts with some existing drugs.

DrugE-Rank: improving drug-target interaction prediction of new candidate drugs or targets by ensemble learning to rank.

PubMed

Yuan, Qingjun; Gao, Junning; Wu, Dongliang; Zhang, Shihua; Mamitsuka, Hiroshi; Zhu, Shanfeng

2016-06-15

Identifying drug-target interactions is an important task in drug discovery. To reduce heavy time and financial cost in experimental way, many computational approaches have been proposed. Although these approaches have used many different principles, their performance is far from satisfactory, especially in predicting drug-target interactions of new candidate drugs or targets. Approaches based on machine learning for this problem can be divided into two types: feature-based and similarity-based methods. Learning to rank is the most powerful technique in the feature-based methods. Similarity-based methods are well accepted, due to their idea of connecting the chemical and genomic spaces, represented by drug and target similarities, respectively. We propose a new method, DrugE-Rank, to improve the prediction performance by nicely combining the advantages of the two different types of methods. That is, DrugE-Rank uses LTR, for which multiple well-known similarity-based methods can be used as components of ensemble learning. The performance of DrugE-Rank is thoroughly examined by three main experiments using data from DrugBank: (i) cross-validation on FDA (US Food and Drug Administration) approved drugs before March 2014; (ii) independent test on FDA approved drugs after March 2014; and (iii) independent test on FDA experimental drugs. Experimental results show that DrugE-Rank outperforms competing methods significantly, especially achieving more than 30% improvement in Area under Prediction Recall curve for FDA approved new drugs and FDA experimental drugs. http://datamining-iip.fudan.edu.cn/service/DrugE-Rank zhusf@fudan.edu.cn Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press.

HER2 activating mutations are targets for colorectal cancer treatment.

PubMed

Kavuri, Shyam M; Jain, Naveen; Galimi, Francesco; Cottino, Francesca; Leto, Simonetta M; Migliardi, Giorgia; Searleman, Adam C; Shen, Wei; Monsey, John; Trusolino, Livio; Jacobs, Samuel A; Bertotti, Andrea; Bose, Ron

2015-08-01

The Cancer Genome Atlas project identified HER2 somatic mutations and gene amplification in 7% of patients with colorectal cancer. Introduction of the HER2 mutations S310F, L755S, V777L, V842I, and L866M into colon epithelial cells increased signaling pathways and anchorage-independent cell growth, indicating that they are activating mutations. Introduction of these HER2 activating mutations into colorectal cancer cell lines produced resistance to cetuximab and panitumumab by sustaining MAPK phosphorylation. HER2 mutants are potently inhibited by low nanomolar doses of the irreversible tyrosine kinase inhibitors neratinib and afatinib. HER2 gene sequencing of 48 cetuximab-resistant, quadruple (KRAS, NRAS, BRAF, and PIK3CA) wild-type (WT) colorectal cancer patient-derived xenografts (PDX) identified 4 PDXs with HER2 mutations. HER2-targeted therapies were tested on two PDXs. Treatment with a single HER2-targeted drug (trastuzumab, neratinib, or lapatinib) delayed tumor growth, but dual HER2-targeted therapy with trastuzumab plus tyrosine kinase inhibitors produced regression of these HER2-mutated PDXs. HER2 activating mutations cause EGFR antibody resistance in colorectal cell lines, and PDXs with HER2 mutations show durable tumor regression when treated with dual HER2-targeted therapy. These data provide a strong preclinical rationale for clinical trials targeting HER2 activating mutations in metastatic colorectal cancer. ©2015 American Association for Cancer Research.

Drug–Target Kinetics in Drug Discovery

PubMed Central

2017-01-01

The development of therapies for the treatment of neurological cancer faces a number of major challenges including the synthesis of small molecule agents that can penetrate the blood-brain barrier (BBB). Given the likelihood that in many cases drug exposure will be lower in the CNS than in systemic circulation, it follows that strategies should be employed that can sustain target engagement at low drug concentration. Time dependent target occupancy is a function of both the drug and target concentration as well as the thermodynamic and kinetic parameters that describe the binding reaction coordinate, and sustained target occupancy can be achieved through structural modifications that increase target (re)binding and/or that decrease the rate of drug dissociation. The discovery and deployment of compounds with optimized kinetic effects requires information on the structure–kinetic relationships that modulate the kinetics of binding, and the molecular factors that control the translation of drug–target kinetics to time-dependent drug activity in the disease state. This Review first introduces the potential benefits of drug-target kinetics, such as the ability to delineate both thermodynamic and kinetic selectivity, and then describes factors, such as target vulnerability, that impact the utility of kinetic selectivity. The Review concludes with a description of a mechanistic PK/PD model that integrates drug–target kinetics into predictions of drug activity. PMID:28640596

Severe skin reaction secondary to concomitant radiotherapy plus cetuximab

PubMed Central

Berger, Bernhard; Belka, Claus

2008-01-01

The therapeutic use of monoclonal antibodies against the epidermal growth factor receptor (EGFR) is specifically associated with dermatologic reactions of variable severity. Recent evidence suggests superiority of the EGFR inhibitor (EGFRI) cetuximab plus radiotherapy compared to radiotherapy alone in patients with squamous cell carcinoma of the head and neck. Although not documented in a study population, several reports indicate a possible overlap between radiation dermatitis and the EGFRI-induced skin rash. We here present a case of severe skin reaction secondary to the addition of cetuximab to radiotherapy. PMID:18226196

Cetuximab-induced skin exanthema: Improvement by a reactive skin therapy.

PubMed

Schimanski, Carl C; Moehler, Markus; Zimmermann, Tim; Wörns, Markus A; Steinbach, Alma; Baum, Michael; Galle, Peter R

2010-01-01

More than 80% of patients treated with cetuximab develop an acneiform follicular skin exanthema. Grade 3 exanthema develops in 9-19% of these cases, bearing the risk of cetuximab dose-reduction or cessation. We retrospectively analysed a cohort of 20 patients treated with cetuximab and an in-house reactive skin protocol upon development of an exanthema. The reactive skin protocol was built up as follows: grade 1 exanthema: topical cleansing syndet (Dermowas®) + topical metronidazole cream (Rosiced®); grade 2 exanthema: grade 1 treatment + oral minocycline 50 mg twice per day; grade 3 exanthema: grade 2 treatment + topical corticoid (Dermatop®) + topical nadifloxacin (Nadixa®). As soon as a grade 3 had improved to a grade less than or equal to 2, the application of the topical corticoid was ceased. During the initial 12 weeks of therapy with cetuximab, all patients developed a skin exanthema (20/20; 100%). Of these, 2 patients (10%) developed a grade 3 exanthema, 10 patients (50%) experienced a grade 2 and 8 patients (40%) a grade 1 exanthema. Time to onset ranged from 1 to 4 weeks, with the average time to onset being 2.8 weeks. Applying the reactive skin protocol after the first occurrence of an exanthema, the grade of exanthema was downgraded as follows: no patients (0%) had a persisting grade 3 exanthema, while only 2 patients (10%) experienced a persisting grade 2 exanthema and 8 patients (40%) a persisting grade 1 exanthema. In the majority of cases (10 patients; 50%), the reactive skin protocol completely controlled the exanthema (grade 0). The average time to exanthema reduction by one grade was 9.5 days. No dose reductions of cetuximab were necessary. Cetuximab-induced skin exanthema is effectively managed by applying our reactive protocol. The simple protocol is based on a topical cleansing syndet and topical metronidazole and is to be intensified by the addition of oral minocycline, a topical corticoid and topical nadifloxacine, in cases of high

EphA2 receptor activation with ephrin-A1 ligand restores cetuximab efficacy in NRAS-mutant colorectal cancer cells.

PubMed

Cuyàs, Elisabet; Queralt, Bernardo; Martin-Castillo, Begoña; Bosch-Barrera, Joaquim; Menendez, Javier A

2017-07-01

Patients with wild-type KRAS metastatic colorectal cancer (mCRC) that harbors NRAS activating mutations do not benefit from anti-EGFR therapies. Very little is known about oncogenic NRAS signaling driving mCRC unresponsiveness to the EGFR-directed antibody cetuximab. Using a system of paired NRAS-mutant and wild-type isogenic mCRC cell lines to explore signaling pathways engaged by the common oncogenic NRAS Q61K variant upon challenge with cetuximab, we uncovered an unexpected mechanism of resistance to cetuximab involving dysregulation of the ephrin-A1/EphA2 signaling axis. Parental NRAS+/+ cells, but not NRASQ61K/+ cells, activated the ephrin receptor ephA1 in response to cetuximab treatment. Moreover, whereas cetuximab treatment significantly downregulated EPHA2 gene expression in NRAS+/+ cells, EPHA2 expression in NRASQ61K/+ cells was refractory to cetuximab. Remarkably, pharmacologically mimicked ephrin-A1 engagement to ephA2 converted NRAS-mutant into RAS wild-type mCRC cells in terms of cetuximab efficacy. Accordingly, activation of the ephA2 receptor by bioactive recombinant human ephrin-A1/Fc-fusion protein suppressed the cetuximab-unresponsive hyperactivation of MAPK and AKT and fully restored cetuximab activity in NRAS-mutant colorectal cells. Collectively, these findings reveal that the clinical benefit of cetuximab in mCRC might necessarily involve the suppression of the ligandless oncogenic signaling of the ephA2 receptor. Hence, ligand-dependent tumor suppressor signaling using therapeutic ephA2 agonists might offer new therapeutic opportunities to clinically widen the use of cetuximab in NRAS-mutated and/or ephA2-dependent mCRC tumors.

Clinical and economic impact of infusion reactions in patients with colorectal cancer treated with cetuximab

PubMed Central

Foley, K. A.; Wang, P. F.; Barber, B. L.; Long, S. R.; Bagalman, J. E.; Wagner, V.; Song, X.; Zhao, Z.

2010-01-01

Background: Systemic agents in cancer treatment were often associated with possible infusion reactions (IRs). This study estimated the incidence of IRs requiring medical intervention and assessed the clinical and economic impacts of IRs in patients with colorectal cancer (CRC) treated with cetuximab. Patients and methods: Details on patients with CRC receiving cetuximab in 2004–2006 were extracted from a large USA administrative claims database. IRs were identified based on the occurrence of outpatient treatment, emergency room (ER) visit, and/or hospitalization for hypersensitivity and allergic reactions. Multivariate regressions were used to examine potential risk factors and quantify the economic impact of IRs. Results: A total of 1122 CRC patients receiving cetuximab were identified. The incidence of IRs requiring medical intervention was 8.4%. Sixty-eight percent of the patients had treatment disruptions and 34% discontinued cetuximab treatment. Mean adjusted costs were $13 863 for cetuximab administrations with an IR requiring ER visit or hospitalization and $6280 for those with an IR requiring outpatient treatment, compared with $4555 for those without an IR. Conclusions: The incidence rate of cetuximab-related IRs requiring medical intervention in clinical practice was found to be higher than rates reported in the product label and clinical trials. The clinical and economic impacts of these IRs are substantial. PMID:20100773

Neoadjuvant Treatment With Single-Agent Cetuximab Followed by 5-FU, Cetuximab, and Pelvic Radiotherapy: A Phase II Study in Locally Advanced Rectal Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bertolini, Federica; Chiara, Silvana; Bengala, Carmelo

2009-02-01

Purpose: Preoperative chemoradiotherapy followed by surgery represents the standard of care for locally advanced rectal cancer (LARC). Cetuximab has proved activity in advanced colorectal cancer, and its incorporation in preoperative treatment may increase tumor downstaging. Methods and Materials: After biopsy and staging, uT3/uT4 N0/+ LARC received single-agent cetuximab in three doses, followed by weekly cetuximab plus 5-fluorouracil (5-FU), concomitantly with RT. Sample size was calculated according to Bryant and Day test, a two-stage design with at least 10 pathologic complete remissions observed in 60 patients (pts) able to complete the treatment plan. Results: Forty pts with LARC were entered: male/femalemore » = 34/6; median age: 61 (range, 28-77); 12 uT3N0 Ed(30%); 25 uT3N1 (62%); 3 uT4N1 (8%); all Eastern Cooperative Oncology Group = 0. Thirty-five pts completed neoadjuvant treatment; 5 (12%) withdrew therapy after one cetuximab administration: three for hypersensitivity reactions, one for rapid progression, and one for purulent arthritis. They continued 5-FU in continuous infusion in association with RT. Thirty-one pts (77%) presented with acnelike rash; dose reduction/interruption of treatment was necessary in six pts (15%): two for Grade 3 acnelike rash, two for Grade 3 gastrointestinal toxicity, and two for refusal. Thirty-eight pts were evaluable for pathological response (one patient refused surgery, and one was progressed during neoadjuvant treatment). Pathological staging was: pT0N0 three pts (8%), pT1N0 1 pt (3%); pT2N0 13 pts (34%), and pT3 19 pts (50%) (N0:9, N1:5; N2:5); pT4 2 pts (5%). Conclusions: Preoperative treatment with 5-FU, cetuximab, and pelvic RT is feasible with acceptable toxicities; however, the rate of pathologic responses is disappointingly low.« less

Identifying Drug-Target Interactions with Decision Templates.

PubMed

Yan, Xiao-Ying; Zhang, Shao-Wu

2018-01-01

During the development process of new drugs, identification of the drug-target interactions wins primary concerns. However, the chemical or biological experiments bear the limitation in coverage as well as the huge cost of both time and money. Based on drug similarity and target similarity, chemogenomic methods can be able to predict potential drug-target interactions (DTIs) on a large scale and have no luxurious need about target structures or ligand entries. In order to reflect the cases that the drugs having variant structures interact with common targets and the targets having dissimilar sequences interact with same drugs. In addition, though several other similarity metrics have been developed to predict DTIs, the combination of multiple similarity metrics (especially heterogeneous similarities) is too naïve to sufficiently explore the multiple similarities. In this paper, based on Gene Ontology and pathway annotation, we introduce two novel target similarity metrics to address above issues. More importantly, we propose a more effective strategy via decision template to integrate multiple classifiers designed with multiple similarity metrics. In the scenarios that predict existing targets for new drugs and predict approved drugs for new protein targets, the results on the DTI benchmark datasets show that our target similarity metrics are able to enhance the predictive accuracies in two scenarios. And the elaborate fusion strategy of multiple classifiers has better predictive power than the naïve combination of multiple similarity metrics. Compared with other two state-of-the-art approaches on the four popular benchmark datasets of binary drug-target interactions, our method achieves the best results in terms of AUC and AUPR for predicting available targets for new drugs (S2), and predicting approved drugs for new protein targets (S3).These results demonstrate that our method can effectively predict the drug-target interactions. The software package can

Ultrasound-stimulated drug delivery for treatment of residual disease after incomplete resection of head and neck cancer.

PubMed

Sorace, Anna G; Korb, Melissa; Warram, Jason M; Umphrey, Heidi; Zinn, Kurt R; Rosenthal, Eben; Hoyt, Kenneth

2014-04-01

Microbubbles triggered with localized ultrasound (US) can improve tumor drug delivery and retention. Termed US-stimulated drug delivery, this strategy was applied to head and neck cancer (HNC) in a post-surgical tumor resection model. Luciferase-positive HNC squamous cell carcinoma (SCC) was implanted in the flanks of nude athymic mice (N = 24) that underwent various degrees of surgical tumor resection (0%, 50% or 100%). After surgery, animals received adjuvant therapy with cetuximab-IRDye alone, or cetuximab-IRDye in combination with US-stimulated drug delivery or saline injections (control) on days 4, 7 and 10. Tumor drug delivery was assessed on days 0, 4, 7, 10, 14 and 17 with an in vivo fluorescence imaging system, and tumor viability was evaluated at the same times with in vivo bioluminescence imaging. Tumor caliper measurements occurred two times per week for 24 d. Optical imaging revealed that in the 50% tumor resection group, US-stimulated drug delivery resulted in a significant increase in cetuximab delivery compared with administration of drug alone on day 10 (day of peak fluorescence) (p = 0.03). Tumor viability decreased in all groups that received cetuximab-IRDye in combination with US-stimulated drug delivery, compared with the group that received only the drug. After various degrees of surgical resection, this novel study reports positive improvements in drug uptake in the residual cancer cells when drug delivery is stimulated with US. Copyright © 2014 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Rechallenge and maintenance therapy using cetuximab and chemotherapy administered to a patient with metastatic colorectal cancer.

PubMed

Ma, Jian; Yang, Quan-Liang; Ling, Yang

2017-02-14

Cetuximab combined with chemotherapy is one of the first-line treatments of metastatic colorectal cancer. Although disease progression inevitably occurs, rechallenge and maintenance therapies using cetuximab-based regimens may be beneficial, particularly for patients with wild-type (WT) KRAS. A 47-year-old female patient who underwent right hemicolectomy presented with an ulcerative adenocarcinoma (grade 2) revealed by histopathological analysis. The patient received three cycles of adjuvant chemotherapy, but disease recurred 15 months later. Cetuximab and a FOLFOX-4 regimen were administered, followed by surgery and adjuvant chemotherapy that was administered for approximately one year. Three years after completing adjuvant therapy, her serum carcinoembryonic antigen levels rapidly increased, and enhanced computed tomography showed widespread metastases. Rechallenge with cetuximab and the FOLFIRI regimen was then initiated, and after 12 cycles, lesions in the lung and liver shrank significantly, and serum CEA levels dramatically declined. Maintenance therapy with cetuximab and capecitabine was then administered for 10 months until the metastatic lesions in the lung and liver enlarged. Rechallenge and maintenance therapy with cetuximab-based chemotherapy were relatively effective for managing a female patient with WT KRAS. Optimization of this strategy requires further in-depth investigations of more patients.

miR-143 or miR-145 overexpression increases cetuximab-mediated antibody-dependent cellular cytotoxicity in human colon cancer cells

PubMed Central

Gomes, Sofia E.; Simões, André E. S.; Pereira, Diane M.; Castro, Rui E.; Rodrigues, Cecília M. P.; Borralho, Pedro M.

2016-01-01

miR-143 and miR-145 are downregulated in colon cancer. Here, we tested the effect of restoring these miRNAs on sensitization to cetuximab in mutant KRAS (HCT116 and SW480) and wild-type KRAS (SW48) colon cancer cells. We evaluated cetuximab-mediated antibody-dependent cellular cytotoxicity (ADCC) and the modulation of signaling pathways involved in immune effector cell-mediated elimination of cancer cells. Stable miR-143 or miR-145 overexpression increased cell sensitivity to cetuximab, resulting in a significant increase of cetuximab-mediated ADCC independently of KRAS status. Importantly, HCT116 cells overexpressing these miRNAs triggered apoptosis in result of cetuximab-mediated ADCC, effected by peripheral blood mononuclear cells (p < 0.01). This was associated with increased apoptosis and caspase-3/7 activity, and reduced Bcl-2 protein expression (p < 0.01). In addition, caspase inhibition abrogated cetuximab-mediated ADCC in HCT116 cells overexpressing either miR-143 or miR-145 (p < 0.01). Furthermore, Bcl-2 silencing led to high level of cetuximab-mediated ADCC, compared to control siRNA (p < 0.05). Importantly, granzyme B inhibition, abrogated cetuximab-mediated ADCC, reducing caspase-3/7 activity (p < 0.01). Collectively, our data suggests that re-introduction of miR-143 or miR-145 may provide a new approach for development of therapeutic strategies to re-sensitize colon cancer cells to cetuximab by stimulating cetuximab-dependent ADCC to induce cell death. PMID:26824186

Rapid palliation of symptoms with platinum-based chemotherapy plus cetuximab in recurrent oral cancer: a case report

PubMed Central

2010-01-01

Background Symptom control is an important consideration in the choice of treatment for patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). Patients who demonstrate objective tumour responses to platinum-based chemotherapy are more likely to have symptom relief than those who do not have such responses. A phase III trial (EXTREME) showed that adding the epidermal growth factor receptor (EGFR)-targeting IgG1 monoclonal antibody cetuximab to first-line platinum-based chemotherapy significantly prolongs progression-free and overall survival and increases response rate compared with platinum-based chemotherapy alone. We report here the case of a 60-year old female with recurrent squamous cell carcinoma of the gum who had rapid palliation of symptoms and reduction of facial disease mass following treatment with a combination of carboplatin/5-fluorouracil (5-FU) and cetuximab. Case presentation The patient was diagnosed with T4N0 M0 disease of the oral cavity in November 2006 and underwent surgery, with R0 resection, followed by adjuvant radiotherapy and concomitant cisplatin chemotherapy. Around 3 months later, the disease recurred and the patient had severe pain (9/10 on a visual pain scale), marked facial oedema and a palpable facial mass of 89 mm. The patient received 4 21-day cycles of carboplatin (AUC 5), 5-FU (1,000 mg/m2/day for 4 days) and cetuximab (400 mg/m2 initial dose followed by subsequently weekly doses of 250 mg/m2), with continuation of cetuximab monotherapy at the end of this time, and pain relief with topical fentanyl and oral morphine. After 7 days of treatment, pain had reduced to 2/10, with discontinuation of morphine after 4 days, and the facial mass had reduced to 70 mm. After 2 cycles of treatment, the facial mass had decreased to 40 mm. After 3 cycles of treatment, pain and facial oedema had resolved completely and a cervical computed tomography scan showed a marked reduction in tumour mass. Cetuximab

Gemcitabine in combination with EGF-Receptor antibody (Cetuximab) as a treatment of cholangiocarcinoma: a case report

PubMed Central

Sprinzl, Martin F; Schimanski, Carl C; Moehler, Markus; Schadmand-Fischer, Simin; Galle, Peter R; Kanzler, Stephan

2006-01-01

Background Extensive disease of cholangiocarcinoma (CC) determines the overall outcome and limits curative resection. Despite chemotherapy, which has been introduced to improve the outcome of biliary tract malignancies, the benefit in survival is still marginal. Case presentation We report a 69-year-old patient with non-resectable CC showing hepatic metastasis and peritoneal carcinomatosis. Diagnosis was based on computed tomography, mini-laparoscopy and bioptic specimens. Histology revealed an adenocarcinoma of the biliary tract with expression of epithelial growth factor receptor. After informed consent the patient received experimental gemcitabine (1000 mg/m2) every other week and cetuximab (250 mg/m2) weekly for palliative chemotherapy. During the reported follow up (since time of first presentation) 20 cycles of chemotherapy were administered. Relevant chemotherapy-related toxicity was limited on gemcitabine-associated side effects. Predominantly, haematological toxicity (CTC, grade 3) and neutropenic fever (CTC, grade 3) promoted by catheter-related sepsis were observed. Cetuximab caused only mild skin toxicity (CTC, grade 1). Chemotherapy led to a partial response (> 30% reduction, according to RECIST) of the target lesions and disappearance of the peritoneal carcinomatosis as shown by computed tomography. Partial response occurred after 17 weeks of treatment and remained stable during the entire course of chemotherapy for 9.7 months. In parallel, Ca 19-9 serum levels, which were elevated 5-fold at time of diagnosis, returned to normal after 16 weeks of treatment. The performance status stabilized and intravenous alimentation could be discontinued. Conclusion Our experience from one patient with CC suggests, that a combination of cytotoxic chemotherapy together with cetuximab may show promising efficacy in respect to survival and quality of life. Therefore cetuximab, as a component of palliative chemotherapy in biliary tract cancer, needs further evaluation

Matching the Decay Half-Life with the Biological Half-Life: ImmunoPET Imaging with 44Sc-Labeled Cetuximab Fab Fragment

PubMed Central

2015-01-01

Scandium-44 (t1/2 = 3.9 h) is a relatively new radioisotope of potential interest for use in clinical positron emission tomography (PET). Herein, we report, for the first time, the room-temperature radiolabeling of proteins with 44Sc for in vivo PET imaging. For this purpose, the Fab fragment of Cetuximab, a monoclonal antibody that binds with high affinity to epidermal growth factor receptor (EGFR), was generated and conjugated with N-[(R)-2-amino-3-(para-isothiocyanato-phenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-N,N,N′,N″,N″-pentaacetic acid (CHX-A″-DTPA). The high purity of Cetuximab-Fab was confirmed by SDS-PAGE and mass spectrometry. The potential of the bioconjugate for PET imaging of EGFR expression in human glioblastoma (U87MG) tumor-bearing mice was investigated after 44Sc labeling. PET imaging revealed rapid tumor uptake (maximum uptake of ∼12% ID/g at 4 h postinjection) of 44Sc–CHX-A″-DTPA–Cetuximab-Fab with excellent tumor-to-background ratio, which might allow for same day PET imaging in future clinical studies. Immunofluorescence staining was conducted to correlate tracer uptake in the tumor and normal tissues with EGFR expression. This successful strategy for immunoPET imaging of EGFR expression using 44Sc–CHX-A″-DTPA–Cetuximab-Fab can make clinically translatable advances to select the right population of patients for EGFR-targeted therapy and also to monitor the therapeutic efficacy of anti-EGFR treatments. PMID:25389697

Drug target ontology to classify and integrate drug discovery data.

PubMed

Lin, Yu; Mehta, Saurabh; Küçük-McGinty, Hande; Turner, John Paul; Vidovic, Dusica; Forlin, Michele; Koleti, Amar; Nguyen, Dac-Trung; Jensen, Lars Juhl; Guha, Rajarshi; Mathias, Stephen L; Ursu, Oleg; Stathias, Vasileios; Duan, Jianbin; Nabizadeh, Nooshin; Chung, Caty; Mader, Christopher; Visser, Ubbo; Yang, Jeremy J; Bologa, Cristian G; Oprea, Tudor I; Schürer, Stephan C

2017-11-09

One of the most successful approaches to develop new small molecule therapeutics has been to start from a validated druggable protein target. However, only a small subset of potentially druggable targets has attracted significant research and development resources. The Illuminating the Druggable Genome (IDG) project develops resources to catalyze the development of likely targetable, yet currently understudied prospective drug targets. A central component of the IDG program is a comprehensive knowledge resource of the druggable genome. As part of that effort, we have developed a framework to integrate, navigate, and analyze drug discovery data based on formalized and standardized classifications and annotations of druggable protein targets, the Drug Target Ontology (DTO). DTO was constructed by extensive curation and consolidation of various resources. DTO classifies the four major drug target protein families, GPCRs, kinases, ion channels and nuclear receptors, based on phylogenecity, function, target development level, disease association, tissue expression, chemical ligand and substrate characteristics, and target-family specific characteristics. The formal ontology was built using a new software tool to auto-generate most axioms from a database while supporting manual knowledge acquisition. A modular, hierarchical implementation facilitate ontology development and maintenance and makes use of various external ontologies, thus integrating the DTO into the ecosystem of biomedical ontologies. As a formal OWL-DL ontology, DTO contains asserted and inferred axioms. Modeling data from the Library of Integrated Network-based Cellular Signatures (LINCS) program illustrates the potential of DTO for contextual data integration and nuanced definition of important drug target characteristics. DTO has been implemented in the IDG user interface Portal, Pharos and the TIN-X explorer of protein target disease relationships. DTO was built based on the need for a formal semantic

Predicting new molecular targets for known drugs

PubMed Central

Keiser, Michael J.; Setola, Vincent; Irwin, John J.; Laggner, Christian; Abbas, Atheir; Hufeisen, Sandra J.; Jensen, Niels H.; Kuijer, Michael B.; Matos, Roberto C.; Tran, Thuy B.; Whaley, Ryan; Glennon, Richard A.; Hert, Jérôme; Thomas, Kelan L.H.; Edwards, Douglas D.; Shoichet, Brian K.; Roth, Bryan L.

2009-01-01

Whereas drugs are intended to be selective, at least some bind to several physiologic targets, explaining both side effects and efficacy. As many drug-target combinations exist, it would be useful to explore possible interactions computationally. Here, we compared 3,665 FDA-approved and investigational drugs against hundreds of targets, defining each target by its ligands. Chemical similarities between drugs and ligand sets predicted thousands of unanticipated associations. Thirty were tested experimentally, including the antagonism of the β1 receptor by the transporter inhibitor Prozac, the inhibition of the 5-HT transporter by the ion channel drug Vadilex, and antagonism of the histamine H4 receptor by the enzyme inhibitor Rescriptor. Overall, 23 new drug-target associations were confirmed, five of which were potent (< 100 nM). The physiological relevance of one such, the drug DMT on serotonergic receptors, was confirmed in a knock-out mouse. The chemical similarity approach is systematic and comprehensive, and may suggest side-effects and new indications for many drugs. PMID:19881490

Sensitivity and Specificity of Cetuximab-IRDye800CW to Identify Regional Metastatic Disease in Head and Neck Cancer.

PubMed

Rosenthal, Eben L; Moore, Lindsay S; Tipirneni, Kiranya; de Boer, Esther; Stevens, Todd M; Hartman, Yolanda E; Carroll, William R; Zinn, Kurt R; Warram, Jason M

2017-08-15

Purpose: Comprehensive cervical lymphadenectomy can be associated with significant morbidity and poor quality of life. This study evaluated the sensitivity and specificity of cetuximab-IRDye800CW to identify metastatic disease in patients with head and neck cancer. Experimental Design: Consenting patients scheduled for curative resection were enrolled in a clinical trial to evaluate the safety and specificity of cetuximab-IRDye800CW. Patients ( n = 12) received escalating doses of the study drug. Where indicated, cervical lymphadenectomy accompanied primary tumor resection, which occurred 3 to 7 days following intravenous infusion of cetuximab-IRDye800CW. All 471 dissected lymph nodes were imaged with a closed-field, near-infrared imaging device during gross processing of the fresh specimens. Intraoperative imaging of exposed neck levels was performed with an open-field fluorescence imaging device. Blinded assessments of the fluorescence data were compared to histopathology to calculate sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV). Results: Of the 35 nodes diagnosed pathologically positive, 34 were correctly identified with fluorescence imaging, yielding a sensitivity of 97.2%. Of the 435 pathologically negative nodes, 401 were correctly assessed using fluorescence imaging, yielding a specificity of 92.7%. The NPV was determined to be 99.7%, and the PPV was 50.7%. When 37 fluorescently false-positive nodes were sectioned deeper (1 mm) into their respective blocks, metastatic cancer was found in 8.1% of the recut nodal specimens, which altered staging in two of those cases. Conclusions: Fluorescence imaging of lymph nodes after systemic cetuximab-IRDye800CW administration demonstrated high sensitivity and was capable of identifying additional positive nodes on deep sectioning. Clin Cancer Res; 23(16); 4744-52. ©2017 AACR . ©2017 American Association for Cancer Research.

Drug resistance mechanisms and novel drug targets for tuberculosis therapy.

PubMed

Islam, Md Mahmudul; Hameed, H M Adnan; Mugweru, Julius; Chhotaray, Chiranjibi; Wang, Changwei; Tan, Yaoju; Liu, Jianxiong; Li, Xinjie; Tan, Shouyong; Ojima, Iwao; Yew, Wing Wai; Nuermberger, Eric; Lamichhane, Gyanu; Zhang, Tianyu

2017-01-20

Drug-resistant tuberculosis (TB) poses a significant challenge to the successful treatment and control of TB worldwide. Resistance to anti-TB drugs has existed since the beginning of the chemotherapy era. New insights into the resistant mechanisms of anti-TB drugs have been provided. Better understanding of drug resistance mechanisms helps in the development of new tools for the rapid diagnosis of drug-resistant TB. There is also a pressing need in the development of new drugs with novel targets to improve the current treatment of TB and to prevent the emergence of drug resistance in Mycobacterium tuberculosis. This review summarizes the anti-TB drug resistance mechanisms, furnishes some possible novel drug targets in the development of new agents for TB therapy and discusses the usefulness using known targets to develop new anti-TB drugs. Whole genome sequencing is currently an advanced technology to uncover drug resistance mechanisms in M. tuberculosis. However, further research is required to unravel the significance of some newly discovered gene mutations in their contribution to drug resistance. Copyright © 2016 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Ltd. All rights reserved.

Nanocarriers for cancer-targeted drug delivery.

PubMed

Kumari, Preeti; Ghosh, Balaram; Biswas, Swati

2016-01-01

Nanoparticles as drug delivery system have received much attention in recent years, especially for cancer treatment. In addition to improving the pharmacokinetics of the loaded poorly soluble hydrophobic drugs by solubilizing them in the hydrophobic compartments, nanoparticles allowed cancer specific drug delivery by inherent passive targeting phenomena and adopted active targeting strategies. For this reason, nanoparticles-drug formulations are capable of enhancing the safety, pharmacokinetic profiles and bioavailability of the administered drugs leading to improved therapeutic efficacy compared to conventional therapy. The focus of this review is to provide an overview of various nanoparticle formulations in both research and clinical applications with a focus on various chemotherapeutic drug delivery systems for the treatment of cancer. The use of various nanoparticles, including liposomes, polymeric nanoparticles, dendrimers, magnetic and other inorganic nanoparticles for targeted drug delivery in cancer is detailed.

Cetuximab Plus Various Chemotherapy Regimens for Patients with KRAS Wild-Type Metastatic Colorectal Cancer.

PubMed

Azadeh, Payam; Mortazavi, Nafiseh; Tahmasebi, Arezoo; Hosseini Kamal, Farnaz; Novin, Kambiz

2016-01-01

The aim of this study was to compare the efficacy and hematologic toxicity of cetuximab combined with various types of chemotherapy regimens in patients with KRAS wild-type metastatic colorectal cancer (mCRC). The response rate, progression-free survival (PFS) and overall survival of the patients were analyzed. In total, 45 patients were included in the study. The overall response rate for the combination of cetuximab and FOLFOX, FOLFIRI and CAPOX was 20, 46 and 30%, respectively, but the differences were not statistically significant. The median PFS for the three groups were 8, 6 and 3.5 months, respectively, but again these differences were not significant. All-grade leukopenia and anemia for the cetuximab plus FOLFOX group were significantly higher than for the other chemotherapy regimens. Our findings suggest that the combination of cetuximab and the three standard chemotherapy regimens resulted in the same outcomes in our patient population of mCRC, with higher hematologic toxicities among the FOLFOX subgroup. © 2015 S. Karger AG, Basel.

A pediatric trial of radiation/cetuximab followed by irinotecan/cetuximab in newly diagnosed diffuse pontine gliomas and high-grade astrocytomas: A Pediatric Oncology Experimental Therapeutics Investigators' Consortium study.

PubMed

Macy, Margaret E; Kieran, Mark W; Chi, Susan N; Cohen, Kenneth J; MacDonald, Tobey J; Smith, Amy A; Etzl, Michael M; Kuei, Michele C; Donson, Andrew M; Gore, Lia; DiRenzo, Jennifer; Trippett, Tanya M; Ostrovnaya, Irina; Narendran, Aru; Foreman, Nicholas K; Dunkel, Ira J

2017-11-01

Diffuse intrinsic pontine gliomas (DIPGs) and high-grade astrocytomas (HGA) continue to have dismal prognoses. The combination of cetuximab and irinotecan was demonstrated to be safe and tolerable in a previous pediatric phase 1 combination study. We developed this phase 2 trial to investigate the safety and efficacy of cetuximab given with radiation therapy followed by adjuvant cetuximab and irinotecan. Eligible patients of age 3-21 years had newly diagnosed DIPG or HGA. Patients received radiation therapy (5,940 cGy) with concurrent cetuximab. Following radiation, patients received cetuximab weekly and irinotecan daily for 5 days per week for 2 weeks every 21 days for 30 weeks. Correlative studies were performed. The regimen was considered to be promising if the number of patients with 1-year progression-free survival (PFS) for DIPG and HGA was at least six of 25 and 14 of 26, respectively. Forty-five evaluable patients were enrolled (25 DIPG and 20 HGA). Six patients with DIPG and five with HGA were progression free at 1 year from the start of therapy with 1-year PFS of 29.6% and 18%, respectively. Fatigue, gastrointestinal complaints, electrolyte abnormalities, and rash were the most common adverse events and generally of grade 1 and 2. Increased epidermal growth factor receptor copy number but no K-ras mutations were identified in available samples. The trial did not meet the predetermined endpoint to deem this regimen successful for HGA. While the trial met the predetermined endpoint for DIPG, overall survival was not markedly improved from historical controls, therefore does not merit further study in this population. © 2017 Wiley Periodicals, Inc.

Target assessment for antiparasitic drug discovery

PubMed Central

Frearson, Julie A.; Wyatt, Paul G.; Gilbert, Ian H.; Fairlamb, Alan H.

2010-01-01

Drug discovery is a high-risk, expensive and lengthy process taking at least 12 years and costing upwards of US$500 million per drug to reach the clinic. For neglected diseases, the drug discovery process is driven by medical need and guided by pre-defined target product profiles. Assessment and prioritisation of the most promising targets for entry into screening programmes is crucial for maximising chances of success. Here we describe criteria used in our drug discovery unit for target assessment and introduce the ‘traffic light’ system as a prioritisation and management tool. We hope this brief review will stimulate basic scientists to acquire additional information necessary for drug discovery. PMID:17962072

THE ECSTACY OF GOLD Patent Expirations for Trastuzumab, Bevacizumab, Rituximab, and Cetuximab.

PubMed

Serna-Gallegos, Tasha R; LaFargue, Christopher J; Tewari, Krishnansu S

2017-11-22

Fully humanized monoclonal antibodies have revolutionized the treatment of many solid tumors, including breast, lung, colorectal, and ovarian cancer. Among the most widely used monoclonal antibodies in clinical oncology are cetuximab, trastuzumab, rituximab, and bevacizumab. This article will review these four notable monoclonal antibodies, their role in clinical oncology, and the drug patents that are nearing expiration. They are used in both first and second line treatment regimens for multiple common malignancies. With recent patent expirations, pharmaceutical companies involved in biosimilar manufacture are looking to establish ownership over these financial monopolies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Use of early tumor shrinkage to predict long-term outcome in metastatic colorectal cancer treated with cetuximab.

PubMed

Piessevaux, Hubert; Buyse, Marc; Schlichting, Michael; Van Cutsem, Eric; Bokemeyer, Carsten; Heeger, Steffen; Tejpar, Sabine

2013-10-20

Early tumor shrinkage (ETS) is associated with long-term outcome in patients with chemorefractory metastatic colorectal cancer (mCRC) receiving cetuximab. This association was investigated in the first-line setting in the randomized CRYSTAL and OPUS mCRC trials, after controlling for KRAS tumor mutation status. Radiologic assessments at week 8 were used to calculate the relative change in the sum of the longest diameters of the target lesions. Time-dependent receiver operating characteristics provided Cτ-indices (time-dependent c-index). Cox regression models and subpopulation treatment effect pattern plot analysis investigated associations between ETS (radiologic tumor size decrease at week 8) and survival and progression-free survival (PFS). In both trials, in patients with KRAS wild-type mCRC, Cτ values for PFS and survival were higher (P < .001) in those receiving chemotherapy plus cetuximab versus chemotherapy alone, indicating a stronger predictive value of ETS for long-term outcome in these patients. In the CRYSTAL and OPUS trials, respectively, the cutoff value of ETS ≥ 20% (v < 20%) identified patients with KRAS wild-type mCRC receiving chemotherapy plus cetuximab with longer PFS (medians 14.1 v 7.3 months, hazard ratio [HR] = 0.32; P < .001, and medians 11.9 v 5.7 months, HR = 0.22; P < .001) and survival (medians 30.0 v 18.6 months, HR = 0.53; P < .001 and medians 26.0 v 15.7 months, HR = 0.43; P = .006). ETS was significantly associated with long-term outcome in patients with KRAS wild-type mCRC treated first-line with chemotherapy plus cetuximab. Validation in prospective trials is required to assess the value of this on-treatment marker in the clinical decision-making process.

Lower gingival squamous cell carcinoma with brain metastasis during long-term cetuximab treatment: A case report.

PubMed

Naruse, Tomofumi; Tokuhisa, Mitsuko; Yanamoto, Souichi; Sakamoto, Yuki; Okuyama, Kohei; Tsuchihashi, Hiroki; Umeda, Masahiro

2018-05-01

Long-term cetuximab treatment can lead to acquired resistance, and tumor progression and/or new lesions often occur. The present report describes a case of lower gingival squamous cell carcinoma with brain metastasis during long-term cetuximab treatment in a 60-year-old man, including findings of an immunohistochemical study. The resected primary tumors, biopsy of the lung metastasis before administration of cetuximab, and brain metastasis specimens mediated by cetuximab were immunohistochemically examined. Histologically, the metastatic brain lesion showed hyperkeratinizing tumor cells with deeply stained irregular nuclei with necrotizing tumor cells, and a decrease in cell density was exhibited in part of the tumor nest. Moreover, the brain lesion was less malignant compared with the primary tumor and metastatic lung lesions. Immunohistochemically, the metastatic brain lesions showed low expression of epidermal growth factor receptor (EGFR) and high expression of N-cadherin compared with the primary tumor and metastatic lung lesions. These results suggest that acquired resistance to cetuximab may be associated with low EGFR expression and increased epithelial-to-mesenchymal transition potential.

Convection-enhanced delivery of cetuximab conjugated iron-oxide nanoparticles for treatment of spontaneous canine intracranial gliomas.

PubMed

Freeman, A Courtenay; Platt, Simon R; Holmes, Shannon; Kent, M; Robinson, Kelsey; Howerth, Elizabeth; Eagleson, Joe; Bouras, Alexandros; Kaluzova, Milota; Hadjipanayis, Constantinos G

2018-05-01

Cetuximab conjugated iron-oxide nanoparticles (cetuximab-IONPs) have shown both in-vitro and in-vivo anti-tumor efficacy against gliomas. The purpose of this pilot study was to evaluate the safety and potential efficacy of cetuximab-IONPs for treatment of spontaneously occurring intracranial gliomas in canines after convection-enhanced delivery (CED). The use of CED allowed for direct infusion of the cetuximab-IONPs both intratumorally and peritumorally avoiding the blood brain barrier (BBB) and limiting systemic effects. A total of eight dogs participated in the study and only two developed mild post-operative complications, which resolved with medical therapy. All canines underwent a single CED treatment of the cetuximab-IONPs over 3 days and did not receive any further adjuvant treatments. Volumetric analysis showed a median reduction in tumor size of 54.9% by MRI at 1-month (4-6 weeks) follow-up. Five dogs were euthanized due to recurrence of neurological signs other than seizures, two due to recurrent seizures, and one dog died in his sleep. Median survival time after surgery was 248 days (mean 367 days).

Severe cutaneous toxicity following treatment with radiotherapy and cetuximab: a case report

PubMed Central

2009-01-01

While the addition of cetuximab to radiotherapy improves clinical outcomes in locoregionally advanced head and neck squamous cell cancers, there are a small number of reports of severe radiation dermatitis occurring with this therapeutic combination. We present the case of a 69 year old male who developed severe radiation dermatitis following treatment with cetuximab and radiotherapy for a locoregionally advanced head and neck squamous cell cancer. PMID:19128507

Targets of drugs are generally, and targets of drugs having side effects are specifically good spreaders of human interactome perturbations.

PubMed

Perez-Lopez, Áron R; Szalay, Kristóf Z; Türei, Dénes; Módos, Dezső; Lenti, Katalin; Korcsmáros, Tamás; Csermely, Peter

2015-05-11

Network-based methods are playing an increasingly important role in drug design. Our main question in this paper was whether the efficiency of drug target proteins to spread perturbations in the human interactome is larger if the binding drugs have side effects, as compared to those which have no reported side effects. Our results showed that in general, drug targets were better spreaders of perturbations than non-target proteins, and in particular, targets of drugs with side effects were also better spreaders of perturbations than targets of drugs having no reported side effects in human protein-protein interaction networks. Colorectal cancer-related proteins were good spreaders and had a high centrality, while type 2 diabetes-related proteins showed an average spreading efficiency and had an average centrality in the human interactome. Moreover, the interactome-distance between drug targets and disease-related proteins was higher in diabetes than in colorectal cancer. Our results may help a better understanding of the network position and dynamics of drug targets and disease-related proteins, and may contribute to develop additional, network-based tests to increase the potential safety of drug candidates.

Targets of drugs are generally, and targets of drugs having side effects are specifically good spreaders of human interactome perturbations

NASA Astrophysics Data System (ADS)

Perez-Lopez, Áron R.; Szalay, Kristóf Z.; Türei, Dénes; Módos, Dezső; Lenti, Katalin; Korcsmáros, Tamás; Csermely, Peter

2015-05-01

Network-based methods are playing an increasingly important role in drug design. Our main question in this paper was whether the efficiency of drug target proteins to spread perturbations in the human interactome is larger if the binding drugs have side effects, as compared to those which have no reported side effects. Our results showed that in general, drug targets were better spreaders of perturbations than non-target proteins, and in particular, targets of drugs with side effects were also better spreaders of perturbations than targets of drugs having no reported side effects in human protein-protein interaction networks. Colorectal cancer-related proteins were good spreaders and had a high centrality, while type 2 diabetes-related proteins showed an average spreading efficiency and had an average centrality in the human interactome. Moreover, the interactome-distance between drug targets and disease-related proteins was higher in diabetes than in colorectal cancer. Our results may help a better understanding of the network position and dynamics of drug targets and disease-related proteins, and may contribute to develop additional, network-based tests to increase the potential safety of drug candidates.

Targets of drugs are generally, and targets of drugs having side effects are specifically good spreaders of human interactome perturbations

PubMed Central

Perez-Lopez, Áron R.; Szalay, Kristóf Z.; Türei, Dénes; Módos, Dezső; Lenti, Katalin; Korcsmáros, Tamás; Csermely, Peter

2015-01-01

Network-based methods are playing an increasingly important role in drug design. Our main question in this paper was whether the efficiency of drug target proteins to spread perturbations in the human interactome is larger if the binding drugs have side effects, as compared to those which have no reported side effects. Our results showed that in general, drug targets were better spreaders of perturbations than non-target proteins, and in particular, targets of drugs with side effects were also better spreaders of perturbations than targets of drugs having no reported side effects in human protein-protein interaction networks. Colorectal cancer-related proteins were good spreaders and had a high centrality, while type 2 diabetes-related proteins showed an average spreading efficiency and had an average centrality in the human interactome. Moreover, the interactome-distance between drug targets and disease-related proteins was higher in diabetes than in colorectal cancer. Our results may help a better understanding of the network position and dynamics of drug targets and disease-related proteins, and may contribute to develop additional, network-based tests to increase the potential safety of drug candidates. PMID:25960144

Matching the decay half-life with the biological half-life: ImmunoPET imaging with 44 Sc-labeled Cetuximab Fab fragment

DOE PAGES

Chakravarty, Rubel; Goel, Shreya; Valdovinos, Hector F.; ...

2014-11-11

Scandium-44 (t 1/2 = 3.9 h) is a relatively new radioisotope of potential interest for use in clinical positron emission tomography (PET). Herein, we report, for the first time, the room-temperature radiolabeling of proteins with 44Sc for in vivo PET imaging. For this purpose, the Fab fragment of Cetuximab, a monoclonal antibody that binds with high affinity to epidermal growth factor receptor (EGFR), was generated and conjugated with N-[(R)-2-amino-3-( para-isothiocyanato-phenyl)propyl]- trans-(S,S)-cyclohexane-1,2-diamine- N,N,N',N'',N''-pentaacetic acid (CHX-A"-DTPA). The high purity of Cetuximab-Fab was confirmed by SDS-PAGE and mass spectrometry. The potential of the bioconjugate for PET imaging of EGFR expression in human glioblastomamore » (U87MG) tumor-bearing mice was investigated after 44Sc labeling. PET imaging revealed rapid tumor uptake (maximum uptake of ~12% ID/g at 4 h postinjection) of 44Sc–CHX-A"-DTPA–Cetuximab-Fab with excellent tumor-to-background ratio, which might allow for same day PET imaging in future clinical studies. Immunofluorescence staining was conducted to correlate tracer uptake in the tumor and normal tissues with EGFR expression. As a result, this successful strategy for immunoPET imaging of EGFR expression using 44Sc–CHX-''-DTPA–Cetuximab-Fab can make clinically translatable advances to select the right population of patients for EGFR-targeted therapy and also to monitor the therapeutic efficacy of anti-EGFR treatments.« less

Simple and rapid LC-MS/MS method for the absolute determination of cetuximab in human serum using an immobilized trypsin.

PubMed

Shibata, Kaito; Naito, Takafumi; Okamura, Jun; Hosokawa, Seiji; Mineta, Hiroyuki; Kawakami, Junichi

2017-11-30

Proteomic approaches using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) without an immunopurification technique have not been applied to the determination of serum cetuximab. This study developed a simple and rapid LC-MS/MS method for the absolute determination of cetuximab in human serum and applied it to clinical settings. Surrogate peptides derived from cetuximab digests were selected using a Fourier transform mass spectrometer. Reduced-alkylated serum cetuximab without immunopurification was digested for 20minutes using immobilized trypsin, and the digestion products were purified by solid-phase extraction. The LC-MS/MS was run in positive ion multiple reaction monitoring mode. This method was applied to the determination of serum samples in head and neck cancer patients treated with cetuximab. The chromatographic run time was 10minutes and no peaks interfering with surrogate peptides in serum digestion products were observed. The calibration curve of absolute cetuximab in serum was linear over the concentration range of 4-200μg/mL. The lower limit of quantification of cetuximab in human serum was 4μg/mL. The intra-assay and inter-assay precision and accuracy were less than 13.2% and 88.0-100.7%, respectively. The serum concentration range of cetuximab was 19-140μg/mL in patients. The serum cetuximab concentrations in LC-MS/MS were correlated with those in ELISA (r=0.899, P <0.01) and the mean bias was 1.5% in cancer patients. In conclusion, the present simple and rapid method with acceptable analytical performance can be helpful for evaluating the absolute concentration of serum cetuximab in clinical settings. Copyright © 2017 Elsevier B.V. All rights reserved.

Effectiveness of bevacizumab and cetuximab in metastatic colorectal cancer across selected public hospitals in Queensland.

PubMed

Chapman, Suzannah J; McKavanagh, Daniel; Burge, Matthew E; McPherson, Ian; Walpole, Euan; Hollingworth, Samantha A

2017-10-01

Metastatic colorectal cancer has a large burden of disease in Australia. Medical therapy is fundamental to extending survival and improving quality of life. The benefits of two costly medicines, bevacizumab and cetuximab, used in Australia remain unclear. The aim of this study was to retrospectively examine the use of these two medicines in metastatic colorectal cancer across five public hospitals in south east Queensland and to compare clinical outcomes to those of published clinical trials. We extracted data from the chemotherapy prescribing database for patients planned for bevacizumab or cetuximab therapy between 2009 and 2013. Median overall survival was estimated using Kaplan-Meier methods. There were 490 bevacizumab-containing protocols planned and 292 patients received at least one dose of bevacizumab. Median overall survival was 17.2 months (95% confidence interval [CI], 15.4-19.3). Of 208 planned cetuximab-containing protocols, 134 patients received at least one dose of cetuximab. Median overall survival was 9.1 months (95% CI, 7.6-12.0). Thirty-day mortality rates from date of first dose were 0.7% for bevacizumab and 7.5% for cetuximab. Overall survival of patients receiving bevacizumab and cetuximab was consistent with clinical trials, providing some assurance that benefits seen in trials are observed in usual practice. This study provides a methodology of using routinely collected health data for clinical monitoring and research. Because of the high cost of these medicines and the lack of toxicity data in this study, further analysis in the postmarketing setting should be explored. © 2016 John Wiley & Sons Australia, Ltd.

Cetuximab treatment for metastatic colorectal cancer with KRAS p.G13D mutations improves progression-free survival

PubMed Central

OSUMI, HIROKI; SHINOZAKI, EIJI; OSAKO, MASAHIKO; KAWAZOE, YOSHIMASA; OBA, MASARU; MISAKA, TAKAHARU; GOTO, TAKASHI; KAMO, HITOMI; SUENAGA, MITSUKUNI; KUMEKAWA, YOSUKE; OGURA, MARIKO; OZAKA, MASATO; MATSUSAKA, SATOSHI; CHIN, KEISHO; HATAKE, KIYOHIKO; MIZUNUMA, NOBUYUKI

2015-01-01

A number of previous studies have reported that 30–50% of patients with colorectal cancer (CRC) harbor Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations, which is a major predictive biomarker of resistance to epidermal growth factor (EGFR)-targeted therapy. Treatment with an anti-EGFR inhibitor is recommended for patients with KRAS wild-type metastatic colorectal cancer (mCRC). A recent retrospective study of cetuximab reported that patients with KRAS p.G13D mutations had better outcomes compared with those with other mutations. The aim of this retrospective study was to assess the prevalence of KRAS p.G13D mutations and evaluate the effectiveness of cetuximab in mCRC patients with KRAS p.G13D or other KRAS mutations. We reviewed the clinical records of 98 mCRC patients with KRAS mutations who were treated between August, 2004 and January, 2011 in four hospitals located in Tokyo and Kyushu Island. We also investigated KRAS mutation subtypes and patient characteristics. In the patients who received cetuximab, univariate and multivariate analyses were performed to assess the effect of KRAS p.G13D mutations on progression-free survival (PFS) and overall survival (OS). Of the 98 patients, 23 (23.5%) had KRAS p.G13D-mutated tumors, whereas 75 (76.5%) had tumors harboring other mutations. Of the 31 patients who received cetuximab, 9 (29.0%) had KRAS p.G13D mutations and 22 (71.0%) had other mutations. There were no significant differences in age, gender, primary site, pathological type, history of chemotherapy, or the combined use of irinotecan between either of the patient subgroups. The univariate analysis revealed no significant difference in PFS or OS between the patients with KRAS p.G13D mutations and those with other mutations (median PFS, 4.5 vs. 2.8 months, respectively; P=0.65; and median OS, 15.3 vs. 8.9 months, respectively; P=0.51). However, the multivariate analysis revealed a trend toward better PFS among patients harboring p.G13D mutations (PFS

Systems genetics for drug target discovery

PubMed Central

Penrod, Nadia M.; Cowper-Sal_lari, Richard; Moore, Jason H.

2011-01-01

The collection and analysis of genomic data has the potential to reveal novel druggable targets by providing insight into the genetic basis of disease. However, the number of drugs, targeting new molecular entities, approved by the US Food and Drug Administration (FDA) has not increased in the years since the collection of genomic data has become commonplace. The paucity of translatable results can be partly attributed to conventional analysis methods that test one gene at a time in an effort to identify disease-associated factors as candidate drug targets. By disengaging genetic factors from their position within the genetic regulatory system, much of the information stored within the genomic data set is lost. Here we discuss how genomic data is used to identify disease-associated genes or genomic regions, how disease-associated regions are validated as functional targets, and the role network analysis can play in bridging the gap between data generation and effective drug target identification. PMID:21862141

Drug Target Protein-Protein Interaction Networks: A Systematic Perspective

PubMed Central

2017-01-01

The identification and validation of drug targets are crucial in biomedical research and many studies have been conducted on analyzing drug target features for getting a better understanding on principles of their mechanisms. But most of them are based on either strong biological hypotheses or the chemical and physical properties of those targets separately. In this paper, we investigated three main ways to understand the functional biomolecules based on the topological features of drug targets. There are no significant differences between targets and common proteins in the protein-protein interactions network, indicating the drug targets are neither hub proteins which are dominant nor the bridge proteins. According to some special topological structures of the drug targets, there are significant differences between known targets and other proteins. Furthermore, the drug targets mainly belong to three typical communities based on their modularity. These topological features are helpful to understand how the drug targets work in the PPI network. Particularly, it is an alternative way to predict potential targets or extract nontargets to test a new drug target efficiently and economically. By this way, a drug target's homologue set containing 102 potential target proteins is predicted in the paper. PMID:28691014

Radiotherapy and "new" drugs-new side effects?

PubMed Central

2011-01-01

Background and purpose Targeted drugs have augmented the cancer treatment armamentarium. Based on the molecular specificity, it was initially believed that these drugs had significantly less side effects. However, currently it is accepted that all of these agents have their specific side effects. Based on the given multimodal approach, special emphasis has to be placed on putative interactions of conventional cytostatic drugs, targeted agents and other modalities. The interaction of targeted drugs with radiation harbours special risks, since the awareness for interactions and even synergistic toxicities is lacking. At present, only limited is data available regarding combinations of targeted drugs and radiotherapy. This review gives an overview on the current knowledge on such combined treatments. Materials and methods Using the following MESH headings and combinations of these terms pubmed database was searched: Radiotherapy AND cetuximab/trastuzumab/panitumumab/nimotuzumab, bevacizumab, sunitinib/sorafenib/lapatinib/gefitinib/erlotinib/sirolimus, thalidomide/lenalidomide as well as erythropoietin. For citation crosscheck the ISI web of science database was used employing the same search terms. Results Several classes of targeted substances may be distinguished: Small molecules including kinase inhibitors and specific inhibitors, antibodies, and anti-angiogenic agents. Combination of these agents with radiotherapy may lead to specific toxicities or negatively influence the efficacy of RT. Though there is only little information on the interaction of molecular targeted radiation and radiotherapy in clinical settings, several critical incidents are reported. Conclusions The addition of molecular targeted drugs to conventional radiotherapy outside of approved regimens or clinical trials warrants a careful consideration especially when used in conjunction in hypo-fractionated regimens. Clinical trials are urgently needed in order to address the open question in regard

Heterocyclic Drug-polymer Conjugates for Cancer Targeted Drug Delivery.

PubMed

Kaur, Harmeet; Desai, Sapna D; Kumar, Virender; Rathi, Pooja; Singh, Jasbir

2016-01-01

New polymer therapeutics like polymer-drug conjugates (PDCs) are developing day by day. Heterocyclic drugs with excellent cytotoxic properties are available, but lack of their specificity makes them available to the normal cells also, which is the main cause of their toxicity. Drugs in the form of PDCs make delivery possible to the specific sites. Most of the PDCs are designed with the aim to either target and/or to get activated in specific cancer microenvironments. Therefore, the most exploited targets for cancer drug delivery are; cancer cell enzymes, heat shock protein 90 (HSP90), multi-drug resistance (MDR) proteins, angiogenesis, apoptosis and cell membrane receptors (e.g., folates, transferrin, etc.). In this review, we will summarize PDCs of heterocyclic drugs, like doxorubicin (DOX), daunorubicin, paclitaxel (PTX), docetaxel (DTX), cisplatin, camptothecin (CPT), geldanamycin (GDM), etc., and some of their analogs for efficient delivery of drugs to cancer cells.

Clinical outcomes and prognostic factors in cisplatin versus cetuximab chemoradiation for locally advanced p16 positive oropharyngeal carcinoma.

PubMed

Barney, Christian L; Walston, Steve; Zamora, Pedro; Healy, Erin H; Nolan, Nicole; Diavolitsis, Virginia M; Neki, Anterpreet; Rupert, Robert; Savvides, Panos; Agrawal, Amit; Old, Matthew; Ozer, Enver; Carrau, Ricardo; Kang, Stephen; Rocco, James; Teknos, Theodoros; Grecula, John C; Wobb, Jessica; Mitchell, Darrion; Blakaj, Dukagjin; Bhatt, Aashish D

2018-04-01

Randomized trials evaluating cisplatin versus cetuximab chemoradiation (CRT) for p16+ oropharyngeal cancer (OPC) have yet to report preliminary data. Meanwhile, as a preemptive step toward morbidity reduction, the off-trial use of cetuximab in p16+ patients is increasing, even in those who could potentially tolerate cisplatin. The purpose of this study was to compare the efficacy of cisplatin versus cetuximab CRT in the treatment of p16+ OPC and to identify prognostic factors and predictors of tumor response. Cases of p16+ OPC treated with cisplatin or cetuximab CRT at our institution from 2010 to 2014 were identified. Recursive partitioning analysis (RPA) classification was used to determine low-risk (LR-RPA) and intermediate-risk (IR-RPA) groups. Log-rank/Kaplan-Meier and Cox Regression methods were used to compare groups. We identified 205 patients who received cisplatin (n = 137) or cetuximab (n = 68) CRT in the definitive (n = 178) or postoperative (n = 27) setting. Median follow-up was 3 years. Cisplatin improved 3-year locoregional control (LRC) [92.7 vs 65.4%], distant metastasis-free survival (DMFS) [88.3 vs 71.2%], recurrence-free survival (RFS) [86.6 vs 50.6%], and overall survival (OS) [92.6 vs 72.2%] compared to cetuximab [all p < .001]. Concurrent cisplatin improved 3-year OS for LR-RPA (97.1 vs 80.3%, p < .001) and IR-RPA (97.1 vs 80.3%, p < .001) groupings. When treating p16+ OPC with CRT, the threshold for substitution of cisplatin with cetuximab should be maintained appropriately high in order to prolong survival times and optimize locoregional and distant tumor control. When cetuximab is used in cisplatin-ineligible patients, altered fractionation RT should be considered in an effort to improve LRC. Copyright © 2018 Elsevier Ltd. All rights reserved.

Predicting Drug-Target Interactions for New Drug Compounds Using a Weighted Nearest Neighbor Profile.

PubMed

van Laarhoven, Twan; Marchiori, Elena

2013-01-01

In silico discovery of interactions between drug compounds and target proteins is of core importance for improving the efficiency of the laborious and costly experimental determination of drug-target interaction. Drug-target interaction data are available for many classes of pharmaceutically useful target proteins including enzymes, ion channels, GPCRs and nuclear receptors. However, current drug-target interaction databases contain a small number of drug-target pairs which are experimentally validated interactions. In particular, for some drug compounds (or targets) there is no available interaction. This motivates the need for developing methods that predict interacting pairs with high accuracy also for these 'new' drug compounds (or targets). We show that a simple weighted nearest neighbor procedure is highly effective for this task. We integrate this procedure into a recent machine learning method for drug-target interaction we developed in previous work. Results of experiments indicate that the resulting method predicts true interactions with high accuracy also for new drug compounds and achieves results comparable or better than those of recent state-of-the-art algorithms. Software is publicly available at http://cs.ru.nl/~tvanlaarhoven/drugtarget2013/.

Genomes2Drugs: Identifies Target Proteins and Lead Drugs from Proteome Data

PubMed Central

Toomey, David; Hoppe, Heinrich C.; Brennan, Marian P.; Nolan, Kevin B.; Chubb, Anthony J.

2009-01-01

Background Genome sequencing and bioinformatics have provided the full hypothetical proteome of many pathogenic organisms. Advances in microarray and mass spectrometry have also yielded large output datasets of possible target proteins/genes. However, the challenge remains to identify new targets for drug discovery from this wealth of information. Further analysis includes bioinformatics and/or molecular biology tools to validate the findings. This is time consuming and expensive, and could fail to yield novel drugs if protein purification and crystallography is impossible. To pre-empt this, a researcher may want to rapidly filter the output datasets for proteins that show good homology to proteins that have already been structurally characterised or proteins that are already targets for known drugs. Critically, those researchers developing novel antibiotics need to select out the proteins that show close homology to any human proteins, as future inhibitors are likely to cross-react with the host protein, causing off-target toxicity effects later in clinical trials. Methodology/Principal Findings To solve many of these issues, we have developed a free online resource called Genomes2Drugs which ranks sequences to identify proteins that are (i) homologous to previously crystallized proteins or (ii) targets of known drugs, but are (iii) not homologous to human proteins. When tested using the Plasmodium falciparum malarial genome the program correctly enriched the ranked list of proteins with known drug target proteins. Conclusions/Significance Genomes2Drugs rapidly identifies proteins that are likely to succeed in drug discovery pipelines. This free online resource helps in the identification of potential drug targets. Importantly, the program further highlights proteins that are likely to be inhibited by FDA-approved drugs. These drugs can then be rapidly moved into Phase IV clinical studies under ‘change-of-application’ patents. PMID:19593435

Inferring protein domains associated with drug side effects based on drug-target interaction network.

PubMed

Iwata, Hiroaki; Mizutani, Sayaka; Tabei, Yasuo; Kotera, Masaaki; Goto, Susumu; Yamanishi, Yoshihiro

2013-01-01

Most phenotypic effects of drugs are involved in the interactions between drugs and their target proteins, however, our knowledge about the molecular mechanism of the drug-target interactions is very limited. One of challenging issues in recent pharmaceutical science is to identify the underlying molecular features which govern drug-target interactions. In this paper, we make a systematic analysis of the correlation between drug side effects and protein domains, which we call "pharmacogenomic features," based on the drug-target interaction network. We detect drug side effects and protein domains that appear jointly in known drug-target interactions, which is made possible by using classifiers with sparse models. It is shown that the inferred pharmacogenomic features can be used for predicting potential drug-target interactions. We also discuss advantages and limitations of the pharmacogenomic features, compared with the chemogenomic features that are the associations between drug chemical substructures and protein domains. The inferred side effect-domain association network is expected to be useful for estimating common drug side effects for different protein families and characteristic drug side effects for specific protein domains.

CD137 Stimulation Enhances Cetuximab-Induced Natural Killer: Dendritic Cell Priming of Antitumor T-Cell Immunity in Patients with Head and Neck Cancer.

PubMed

Srivastava, Raghvendra M; Trivedi, Sumita; Concha-Benavente, Fernando; Gibson, Sandra P; Reeder, Carly; Ferrone, Soldano; Ferris, Robert L

2017-02-01

Cetuximab, an EGFR-specific antibody (mAb), modestly improves clinical outcome in patients with head and neck cancer (HNC). Cetuximab mediates natural killer (NK) cell:dendritic cell (DC) cross-talk by cross-linking FcγRIIIa, which is important for inducing antitumor cellular immunity. Cetuximab-activated NK cells upregulate the costimulatory receptor CD137 (4-1BB), which, when triggered by agonistic mAb urelumab, might enhance NK-cell functions, to promote T-cell-based immunity. CD137 expression on tumor-infiltrating lymphocytes was evaluated in a prospective cetuximab neoadjuvant trial, and CD137 stimulation was evaluated in a phase Ib trial, in combining agonistic urelumab with cetuximab. Flow cytometry and cytokine release assays using NK cells and DC were used in vitro, testing the addition of urelumab to cetuximab-activated NK, DC, and cross presentation to T cells. CD137 agonist mAb urelumab enhanced cetuximab-activated NK-cell survival, DC maturation, and tumor antigen cross-presentation. Urelumab boosted DC maturation markers, CD86 and HLA DR, and antigen-processing machinery (APM) components TAP1/2, leading to increased tumor antigen cross-presentation. In neoadjuvant cetuximab-treated patients with HNC, upregulation of CD137 by intratumoral, cetuximab-activated NK cells correlated with FcγRIIIa V/F polymorphism and predicted clinical response. Moreover, immune biomarker modulation was observed in an open label, phase Ib clinical trial, of patients with HNC treated with cetuximab plus urelumab. These results suggest a beneficial effect of combination immunotherapy using cetuximab and CD137 agonist in HNC. Clin Cancer Res; 23(3); 707-16. ©2016 AACR. ©2016 American Association for Cancer Research.

Early skin toxicity predicts better outcomes, and early tumor shrinkage predicts better response after cetuximab treatment in advanced colorectal cancer.

PubMed

Kogawa, T; Doi, A; Shimokawa, M; Fouad, T M; Osuga, T; Tamura, F; Mizushima, T; Kimura, T; Abe, S; Ihara, H; Kukitsu, T; Sumiyoshi, T; Yoshizaki, N; Hirayama, M; Sasaki, T; Kawarada, Y; Kitashiro, S; Okushiba, S; Kondo, H; Tsuji, Y

2015-03-01

Cetuximab-containing treatments for metastatic colorectal cancer have been shown to have higher overall response rates and longer progression-free and overall survival than other systemic therapies. Cetuximab-related manifestations, including severe skin toxicity and early tumor shrinkage, have been shown to be predictors of response to cetuximab. We hypothesized that early skin toxicity is a predictor of response and better outcomes in patients with advanced colorectal carcinoma. We retrospectively evaluated 62 patients with colorectal adenocarcinoma who had unresectable tumors and were treated with cetuximab in our institution. Skin toxicity grade was evaluated on each treatment day. Tumor size was evaluated using computed tomography prior to treatment and 4-8 weeks after the start of treatment with cetuximab.Patients with early tumor shrinkage after starting treatment with cetuximab had a significantly higher overall response rate (P = 0.0001). Patients with early skin toxicity showed significantly longer overall survival (P = 0.0305), and patients with higher skin toxicity grades had longer progression-free survival (P = 0.0168).We have shown that early tumor shrinkage, early onset of skin toxicity, and high skin toxicity grade are predictors of treatment efficacy and/or outcome in patients with advanced colorectal carcinoma treated with cetuximab.

Drug Target Discovery Methods In Targeting Neurotropic Parasitic Amoebae.

PubMed

Baig, Abdul Mannan; Waliani, Nuzair; Karim, Saiqa

2018-02-21

Neurotropic parasitic amoebal infections have imposed an enormous challenge to chemotherapy in patients who fall victims to the infections caused by them. Conventional antibiotics that are given to treat these infections have a low patient compliance because of the serious adverse effects that are associated with their use. Additionally, the growing incidence of the development of drug resistance by the neurotropic parasites like Naegleria fowleri, Balamuthia mandrillaris, and Acanthamoeba spp has made the drug therapy more challenging. Recent studies have reported some cellular targets in the neurotropic parasitic Acanthamoeba that are used as receptors by human neurotransmitters like acetylcholine. This Viewpoint attempts to highlight the novel methodologies that use drug assays and structural modeling to uncover cellular targets of diverse groups of drugs and the safety issues of the drugs proposed for their use in brain infections caused by the neurotropic parasitic amoebae.

Cetuximab Combined With Induction Oxaliplatin and Capecitabine, Followed by Neoadjuvant Chemoradiation for Locally Advanced Rectal Cancer: SWOG 0713.

PubMed

Leichman, Cynthia Gail; McDonough, Shannon L; Smalley, Stephen R; Billingsley, Kevin G; Lenz, Heinz-Josef; Beldner, Matthew A; Hezel, Aram F; Velasco, Mario R; Guthrie, Katherine A; Blanke, Charles D; Hochster, Howard S

2018-03-01

Neoadjuvant chemoradiation (NCRT) is standard treatment for locally advanced rectal cancer. Pathologic complete response (pCR) has associated with improved survival. In modern phase III trials of NCRT, pCR ranges from 10% to 20%. Cetuximab improves response in KRAS (KRAS proto-oncogene) wild type (wt) metastatic colorectal cancer. S0713 was designed to assess improvement in pCR with additional use of cetuximab with induction chemotherapy and NCRT for locally advanced, KRAS-wt rectal cancer. Patient eligibility: stage II to III biopsy-proven, KRAS-wt rectal adenocarcinoma; no bowel obstruction; adequate hematologic, hepatic and renal function; performance status of 0 to 2. Target enrollment: 80 patients. induction chemotherapy with wCAPOX (weekly capecitabine and oxaliplatin) and cetuximab followed by the same regimen concurrent with radiation (omitting day 15 oxaliplatin). If fewer than 7 pCRs were observed at planned interim analysis after 40 patients received all therapy, the study would close. Eighty eligible patients would provide 90% power given a true pCR rate > 35% at a significance of 0.04. The regimen would lack future interest if pCR probability was ≤ 20%. Between February 2009 and April 2013, 83 patients registered. Four were ineligible and 4 not treated, leaving 75 evaluable for clinical outcomes and toxicity, of whom 65 had surgery. Of 75 patients, 20 had pCR (27%; 95% confidence interval [CI], 17%-38%); 19 (25%) had microscopic cancer; 36 (48%) had minor/no response (including 10 without surgery). Three-year disease-free survival was 73% (95% CI, 63%-83%). Our trial did not meet the pCR target of 35%. Toxicity was generally acceptable. This regimen cannot be recommended outside the clinical trial setting. Copyright © 2017 Elsevier Inc. All rights reserved.

Targeted Drug-Carrying Bacteriophages as Antibacterial Nanomedicines▿

PubMed Central

Yacoby, Iftach; Bar, Hagit; Benhar, Itai

2007-01-01

While the resistance of bacteria to traditional antibiotics is a major public health concern, the use of extremely potent antibacterial agents is limited by their lack of selectivity. As in cancer therapy, antibacterial targeted therapy could provide an opportunity to reintroduce toxic substances to the antibacterial arsenal. A desirable targeted antibacterial agent should combine binding specificity, a large drug payload per binding event, and a programmed drug release mechanism. Recently, we presented a novel application of filamentous bacteriophages as targeted drug carriers that could partially inhibit the growth of Staphylococcus aureus bacteria. This partial success was due to limitations of drug-loading capacity that resulted from the hydrophobicity of the drug. Here we present a novel drug conjugation chemistry which is based on connecting hydrophobic drugs to the phage via aminoglycoside antibiotics that serve as solubility-enhancing branched linkers. This new formulation allowed a significantly larger drug-carrying capacity of the phages, resulting in a drastic improvement in their performance as targeted drug-carrying nanoparticles. As an example for a potential systemic use for potent agents that are limited for topical use, we present antibody-targeted phage nanoparticles that carry a large payload of the hemolytic antibiotic chloramphenicol connected through the aminoglycoside neomycin. We demonstrate complete growth inhibition toward the pathogens Staphylococcus aureus, Streptococcus pyogenes, and Escherichia coli with an improvement in potency by a factor of ∼20,000 compared to the free drug. PMID:17404004

Blood-based markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance).

PubMed

Hatch, Ace J; Sibley, Alexander B; Starr, Mark D; Brady, J Chris; Jiang, Chen; Jia, Jingquan; Bowers, Daniel L; Pang, Herbert; Owzar, Kouros; Niedzwiecki, Donna; Innocenti, Federico; Venook, Alan P; Hurwitz, Herbert I; Nixon, Andrew B

2016-09-01

Circulating protein markers were assessed in patients with colorectal cancer (CRC) treated with cetuximab in CALGB 80203 to identify prognostic and predictive biomarkers. Patients with locally advanced or metastatic CRC received FOLFOX or FOLFIRI chemotherapy (chemo) or chemo in combination with cetuximab. Baseline plasma samples from 152 patients were analyzed for six candidate markers [epidermal growth factor (EGF), heparin-binding EGF (HBEGF), epidermal growth factor receptor (EGFR), HER2, HER3, and CD73]. Analyte levels were associated with survival endpoints using univariate Cox proportional hazards models. Predictive markers were identified using a treatment-by-marker interaction term in the Cox model. Plasma levels of EGF, HBEGF, HER3, and CD73 were prognostic for overall survival (OS) across all patients (KRAS mutant and wild-type). High levels of EGF predicted for lack of OS benefit from cetuximab in KRAS wild-type (WT) patients (chemo HR = 0.98, 95% CI = 0.74-1.29; chemo+cetuximab HR = 1.54, 95% CI = 1.05-2.25; interaction P = 0.045) and benefit from cetuximab in KRAS mutant patients (chemo HR = 1.72, 95% CI = 1.02-2.92; chemo+cetuximab HR = 0.90, 95% CI = 0.67-1.21; interaction P = 0.026). Across all patients, higher HER3 levels were associated with significant OS benefit from cetuximab treatment (chemo HR = 4.82, 95% CI = 1.68-13.84; chemo+cetuximab HR = 0.95, 95% CI = 0.31-2.95; interaction P = 0.046). CD73 was also identified as predictive of OS benefit in KRAS WT patients (chemo HR = 1.28, 95% CI = 0.88-1.84; chemo+cetuximab HR = 0.60, 95% CI = 0.32-1.13; interaction P = 0.049). Although these results are preliminary, and confirmatory studies are necessary before clinical application, the data suggest that HER3 and CD73 may play important roles in the biological response to cetuximab. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Interstitial photodynamic therapy in combination with Cetuximab for recurrent head and neck squamous cell carcinoma

NASA Astrophysics Data System (ADS)

Rigual, Nestor; Dildeep, Ambujakshan; Shafirstein, Gal

2013-03-01

Background and Purpose: Combination therapy of interstitial photodynamic therapy (iPDT) with Cetuximab to attain symptomatic control of recurrent head and neck cancer. Methods: Two patients with Unresectable recurrent Head and Neck SCC were treated with iPDT alone and iPDT and cetuximab. Treatments were administered in an outpatient setting. A single dose of Photofrin at 2 mg per kilogram of body weight was administered intravenously two days prior to laser illumination. The iPDT was accomplished by delivering 630-nm laser light through two laser fibers with 2.5 and 5 cm long diffusive ends. Light irradiance of 400 mW/cm for 250 seconds was used to deliver a total of 100 J/cm, during the iPDT. Light applications were conducted, twice, at 3-4 days interval. One of the patients was treated with cetuximab along with iPDT. Results: Near total resolution of tumor was observed in the patient treated with iPDT and cetuximab, and partial resolution was seen in the patient treated with iPDT alone. Conclusion: Interstitial photodynamic therapy may be used to treat patients with recurrent unresectable head and neck cancer. The combination of iPDT with Cetuximab has the potential to improve tumor response in the patient population for whom there is no effective therapies. This observation merits further studies.

Bacterial production and structure-functional validation of a recombinant antigen-binding fragment (Fab) of an anti-cancer therapeutic antibody targeting epidermal growth factor receptor.

PubMed

Kim, Ji-Hun; Sim, Dae-Won; Park, Dongsun; Jung, Tai-Geun; Lee, Seonghwan; Oh, Taeheun; Ha, Jong-Ryul; Seok, Seung-Hyeon; Seo, Min-Duk; Kang, Ho Chul; Kim, Young Pil; Won, Hyung-Sik

2016-12-01

Fragment engineering of monoclonal antibodies (mAbs) has emerged as an excellent paradigm to develop highly efficient therapeutic and/or diagnostic agents. Engineered mAb fragments can be economically produced in bacterial systems using recombinant DNA technologies. In this work, we established recombinant production in Escherichia coli for monovalent antigen-binding fragment (Fab) adopted from a clinically used anticancer mAB drug cetuximab targeting epidermal growth factor receptor (EGFR). Recombinant DNA constructs were designed to express both polypeptide chains comprising Fab in a single vector and to secrete them to bacterial periplasmic space for efficient folding. Particularly, a C-terminal engineering to confer an interchain disulfide bond appeared to be able to enhance its heterodimeric integrity and EGFR-binding activity. Conformational relevance of the purified final product was validated by mass spectrometry and crystal structure at 1.9 Å resolution. Finally, our recombinant cetuximab-Fab was found to have strong binding affinity to EGFR overexpressed in human squamous carcinoma model (A431) cells. Its binding ability was comparable to that of cetuximab. Its EGFR-binding affinity was estimated at approximately 0.7 nM of Kd in vitro, which was quite stronger than the binding affinity of natural ligand EGF. Hence, the results validate that our construction could serve as an efficient platform to produce a recombinant cetuximab-Fab with a retained antigen-binding functionality.

Primary tumor location predicts poor clinical outcome with cetuximab in RAS wild-type metastatic colorectal cancer.

PubMed

Kim, Dalyong; Kim, Sun Young; Lee, Ji Sung; Hong, Yong Sang; Kim, Jeong Eun; Kim, Kyu-Pyo; Kim, Jihun; Jang, Se Jin; Yoon, Young-Kwang; Kim, Tae Won

2017-11-23

In metastatic colorectal cancer, the location of the primary tumor has been suggested to have biological significance. In this study, we investigated whether primary tumor location affects cetuximab efficacy in patients with RAS wild-type metastatic colorectal cancer. Genotyping by the SequenomMassARRAY technology platform (OncoMap) targeting KRAS, NRAS, PIK3CA, and BRAF was performed in tumors from 307 patients who had been given cetuximab as salvage treatment. Tumors with mutated RAS (KRAS or NRAS; n = 127) and those with multiple primary location (n = 10) were excluded. Right colon cancer was defined as a tumor located in the proximal part to splenic flexure. A total of 170 patients were included in the study (right versus left, 23 and 147, respectively). Patients with right colon cancer showed more mutated BRAF (39.1% vs. 5.4%), mutated PIK3CA (13% vs. 1.4%), poorly differentiated tumor (17.4% vs. 3.4%), and peritoneal involvement (26.1% vs. 8.8%) than those with left colon and rectal cancer. Right colon cancer showed poorer progression-free survival (2.0 vs.5.0 months, P = 0.002) and overall survival (4.1 months and 13.0 months, P < 0.001) than the left colon and rectal cancer. By multivariable analysis, BRAF mutation, right colon primary, poorly differentiated histology, and peritoneal involvement were associated with risk of death. In RAS wild-type colon cancer treated with cetuximab as salvage treatment, right colon primary was associated with poorer survival outcomes than left colon and rectal cancer.

Inferring protein domains associated with drug side effects based on drug-target interaction network

PubMed Central

2013-01-01

Background Most phenotypic effects of drugs are involved in the interactions between drugs and their target proteins, however, our knowledge about the molecular mechanism of the drug-target interactions is very limited. One of challenging issues in recent pharmaceutical science is to identify the underlying molecular features which govern drug-target interactions. Results In this paper, we make a systematic analysis of the correlation between drug side effects and protein domains, which we call "pharmacogenomic features," based on the drug-target interaction network. We detect drug side effects and protein domains that appear jointly in known drug-target interactions, which is made possible by using classifiers with sparse models. It is shown that the inferred pharmacogenomic features can be used for predicting potential drug-target interactions. We also discuss advantages and limitations of the pharmacogenomic features, compared with the chemogenomic features that are the associations between drug chemical substructures and protein domains. Conclusion The inferred side effect-domain association network is expected to be useful for estimating common drug side effects for different protein families and characteristic drug side effects for specific protein domains. PMID:24565527

Drugs and Targets in Fibrosis

PubMed Central

Li, Xiaoyi; Zhu, Lixin; Wang, Beibei; Yuan, Meifei; Zhu, Ruixin

2017-01-01

Fibrosis contributes to the development of many diseases and many target molecules are involved in fibrosis. Currently, the majority of fibrosis treatment strategies are limited to specific diseases or organs. However, accumulating evidence demonstrates great similarities among fibroproliferative diseases, and more and more drugs are proved to be effective anti-fibrotic therapies across different diseases and organs. Here we comprehensively review the current knowledge on the pathological mechanisms of fibrosis, and divide factors mediating fibrosis progression into extracellular and intracellular groups. Furthermore, we systematically summarize both single and multiple component drugs that target fibrosis. Future directions of fibrosis drug discovery are also proposed. PMID:29218009

Discovery of Anthelmintic Drug Targets and Drugs Using Chokepoints in Nematode Metabolic Pathways

PubMed Central

Taylor, Christina M.; Wang, Qi; Rosa, Bruce A.; Huang, Stanley Ching-Cheng; Powell, Kerrie; Schedl, Tim; Pearce, Edward J.; Abubucker, Sahar; Mitreva, Makedonka

2013-01-01

Parasitic roundworm infections plague more than 2 billion people (1/3 of humanity) and cause drastic losses in crops and livestock. New anthelmintic drugs are urgently needed as new drug resistance and environmental concerns arise. A “chokepoint reaction” is defined as a reaction that either consumes a unique substrate or produces a unique product. A chokepoint analysis provides a systematic method of identifying novel potential drug targets. Chokepoint enzymes were identified in the genomes of 10 nematode species, and the intersection and union of all chokepoint enzymes were found. By studying and experimentally testing available compounds known to target proteins orthologous to nematode chokepoint proteins in public databases, this study uncovers features of chokepoints that make them successful drug targets. Chemogenomic screening was performed on drug-like compounds from public drug databases to find existing compounds that target homologs of nematode chokepoints. The compounds were prioritized based on chemical properties frequently found in successful drugs and were experimentally tested using Caenorhabditis elegans. Several drugs that are already known anthelmintic drugs and novel candidate targets were identified. Seven of the compounds were tested in Caenorhabditis elegans and three yielded a detrimental phenotype. One of these three drug-like compounds, Perhexiline, also yielded a deleterious effect in Haemonchus contortus and Onchocerca lienalis, two nematodes with divergent forms of parasitism. Perhexiline, known to affect the fatty acid oxidation pathway in mammals, caused a reduction in oxygen consumption rates in C. elegans and genome-wide gene expression profiles provided an additional confirmation of its mode of action. Computational modeling of Perhexiline and its target provided structural insights regarding its binding mode and specificity. Our lists of prioritized drug targets and drug-like compounds have potential to expedite the discovery

The Research Progress of Targeted Drug Delivery Systems

NASA Astrophysics Data System (ADS)

Zhan, Jiayin; Ting, Xizi Liang; Zhu, Junjie

2017-06-01

Targeted drug delivery system (DDS) means to selectively transport drugs to targeted tissues, organs, and cells through a variety of drugs carrier. It is usually designed to improve the pharmacological and therapeutic properties of conventional drugs and to overcome problems such as limited solubility, drug aggregation, poor bio distribution and lack of selectivity, controlling drug release carrier and to reduce normal tissue damage. With the characteristics of nontoxic and biodegradable, it can increase the retention of drug in lesion site and the permeability, improve the concentration of the drug in lesion site. at present, there are some kinds of DDS using at test phase, such as slow controlled release drug delivery system, targeted drug delivery systems, transdermal drug delivery system, adhesion dosing system and so on. This paper makes a review for DDS.

Killing cancer cells by targeted drug-carrying phage nanomedicines

PubMed Central

Bar, Hagit; Yacoby, Iftach; Benhar, Itai

2008-01-01

Background Systemic administration of chemotherapeutic agents, in addition to its anti-tumor benefits, results in indiscriminate drug distribution and severe toxicity. This shortcoming may be overcome by targeted drug-carrying platforms that ferry the drug to the tumor site while limiting exposure to non-target tissues and organs. Results We present a new form of targeted anti-cancer therapy in the form of targeted drug-carrying phage nanoparticles. Our approach is based on genetically-modified and chemically manipulated filamentous bacteriophages. The genetic manipulation endows the phages with the ability to display a host-specificity-conferring ligand. The phages are loaded with a large payload of a cytotoxic drug by chemical conjugation. In the presented examples we used anti ErbB2 and anti ERGR antibodies as targeting moieties, the drug hygromycin conjugated to the phages by a covalent amide bond, or the drug doxorubicin conjugated to genetically-engineered cathepsin-B sites on the phage coat. We show that targeting of phage nanomedicines via specific antibodies to receptors on cancer cell membranes results in endocytosis, intracellular degradation, and drug release, resulting in growth inhibition of the target cells in vitro with a potentiation factor of >1000 over the corresponding free drugs. Conclusion The results of the proof-of concept study presented here reveal important features regarding the potential of filamentous phages to serve as drug-delivery platform, on the affect of drug solubility or hydrophobicity on the target specificity of the platform and on the effect of drug release mechanism on the potency of the platform. These results define targeted drug-carrying filamentous phage nanoparticles as a unique type of antibody-drug conjugates. PMID:18387177

Identifying mechanism-of-action targets for drugs and probes

PubMed Central

Gregori-Puigjané, Elisabet; Setola, Vincent; Hert, Jérôme; Crews, Brenda A.; Irwin, John J.; Lounkine, Eugen; Marnett, Lawrence; Roth, Bryan L.; Shoichet, Brian K.

2012-01-01

Notwithstanding their key roles in therapy and as biological probes, 7% of approved drugs are purported to have no known primary target, and up to 18% lack a well-defined mechanism of action. Using a chemoinformatics approach, we sought to “de-orphanize” drugs that lack primary targets. Surprisingly, targets could be easily predicted for many: Whereas these targets were not known to us nor to the common databases, most could be confirmed by literature search, leaving only 13 Food and Drug Administration—approved drugs with unknown targets; the number of drugs without molecular targets likely is far fewer than reported. The number of worldwide drugs without reasonable molecular targets similarly dropped, from 352 (25%) to 44 (4%). Nevertheless, there remained at least seven drugs for which reasonable mechanism-of-action targets were unknown but could be predicted, including the antitussives clemastine, cloperastine, and nepinalone; the antiemetic benzquinamide; the muscle relaxant cyclobenzaprine; the analgesic nefopam; and the immunomodulator lobenzarit. For each, predicted targets were confirmed experimentally, with affinities within their physiological concentration ranges. Turning this question on its head, we next asked which drugs were specific enough to act as chemical probes. Over 100 drugs met the standard criteria for probes, and 40 did so by more stringent criteria. A chemical information approach to drug-target association can guide therapeutic development and reveal applications to probe biology, a focus of much current interest. PMID:22711801

Enhanced cell killing and apoptosis of oral squamous cell carcinoma cells with ultrasound in combination with cetuximab coated albumin microbubbles.

PubMed

Narihira, Kyoichi; Watanabe, Akiko; Sheng, Hong; Endo, Hitomi; Feril, Loreto B; Irie, Yutaka; Ogawa, Koichi; Moosavi-Nejad, Seyedeh; Kondo, Seiji; Kikuta, Toshihiro; Tachibana, Katsuro

2018-03-01

Targeted microbubbles have the potential to be used for ultrasound (US) therapy and diagnosis of various cancers. In the present study, US was irradiated to oral squamous cell carcinoma cells (HSC-2) in the presence of cetuximab-coated albumin microbubbles (CCAM). Cell killing rate with US treatment at 0.9 W/cm 2 and 1.0 W/cm 2 in the presence of CCAM was greater compared to non-targeted albumin microbubbles (p < .05). On the other hand, selective cell killing was not observed in human myelomonocytic lymphoma cell line (U937) that had no affinity to cetuximab. Furthermore, US irradiation in the presence of CCAM showed a fivefold increase of cell apoptotic rate for HSC-2 cells (21.0 ± 3.8%) as compared to U937 cells (4.0 ± 0.8%). Time-signal intensity curve in a tissue phantom demonstrated clear visualisation of CCAM with conventional US imaging device. Our experiment verifies the hypothesis that CCAM was selective to HSC-2 cells and may be applied as a novel therapeutic/diagnostic microbubble for oral squamous cell carcinoma.

PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response

PubMed Central

Liao, Hsin-Wei; Hsu, Jung-Mao; Xia, Weiya; Wang, Hung-Ling; Wang, Ying-Nai; Chang, Wei-Chao; Arold, Stefan T.; Chou, Chao-Kai; Tsou, Pei-Hsiang; Yamaguchi, Hirohito; Fang, Yueh-Fu; Lee, Hong-Jen; Lee, Heng-Huan; Tai, Shyh-Kuan; Yang, Mhu-Hwa; Morelli, Maria P.; Sen, Malabika; Ladbury, John E.; Chen, Chung-Hsuan; Grandis, Jennifer R.; Kopetz, Scott; Hung, Mien-Chie

2015-01-01

Posttranslational modifications to the intracellular domain of the EGFR are known to regulate EGFR functions; however, modifications to the extracellular domain and their effects remain relatively unexplored. Here, we determined that methylation at R198 and R200 of the EGFR extracellular domain by protein arginine methyltransferase 1 (PRMT1) enhances binding to EGF and subsequent receptor dimerization and signaling activation. In a mouse orthotopic colorectal cancer xenograft model, expression of a methylation-defective EGFR reduced tumor growth. Moreover, increased EGFR methylation sustained signaling activation and cell proliferation in the presence of the therapeutic EGFR monoclonal antibody cetuximab. In colorectal cancer patients, EGFR methylation level also correlated with a higher recurrence rate after cetuximab treatment and reduced overall survival. Together, these data indicate that R198/R200 methylation of the EGFR plays an important role in regulating EGFR functionality and resistance to cetuximab treatment. PMID:26571401

Prediction of Drug-Target Interactions and Drug Repositioning via Network-Based Inference

PubMed Central

Jiang, Jing; Lu, Weiqiang; Li, Weihua; Liu, Guixia; Zhou, Weixing; Huang, Jin; Tang, Yun

2012-01-01

Drug-target interaction (DTI) is the basis of drug discovery and design. It is time consuming and costly to determine DTI experimentally. Hence, it is necessary to develop computational methods for the prediction of potential DTI. Based on complex network theory, three supervised inference methods were developed here to predict DTI and used for drug repositioning, namely drug-based similarity inference (DBSI), target-based similarity inference (TBSI) and network-based inference (NBI). Among them, NBI performed best on four benchmark data sets. Then a drug-target network was created with NBI based on 12,483 FDA-approved and experimental drug-target binary links, and some new DTIs were further predicted. In vitro assays confirmed that five old drugs, namely montelukast, diclofenac, simvastatin, ketoconazole, and itraconazole, showed polypharmacological features on estrogen receptors or dipeptidyl peptidase-IV with half maximal inhibitory or effective concentration ranged from 0.2 to 10 µM. Moreover, simvastatin and ketoconazole showed potent antiproliferative activities on human MDA-MB-231 breast cancer cell line in MTT assays. The results indicated that these methods could be powerful tools in prediction of DTIs and drug repositioning. PMID:22589709

In silico re-identification of properties of drug target proteins.

PubMed

Kim, Baeksoo; Jo, Jihoon; Han, Jonghyun; Park, Chungoo; Lee, Hyunju

2017-05-31

Computational approaches in the identification of drug targets are expected to reduce time and effort in drug development. Advances in genomics and proteomics provide the opportunity to uncover properties of druggable genomes. Although several studies have been conducted for distinguishing drug targets from non-drug targets, they mainly focus on the sequences and functional roles of proteins. Many other properties of proteins have not been fully investigated. Using the DrugBank (version 3.0) database containing nearly 6,816 drug entries including 760 FDA-approved drugs and 1822 of their targets and human UniProt/Swiss-Prot databases, we defined 1578 non-redundant drug target and 17,575 non-drug target proteins. To select these non-redundant protein datasets, we built four datasets (A, B, C, and D) by considering clustering of paralogous proteins. We first reassessed the widely used properties of drug target proteins. We confirmed and extended that drug target proteins (1) are likely to have more hydrophobic, less polar, less PEST sequences, and more signal peptide sequences higher and (2) are more involved in enzyme catalysis, oxidation and reduction in cellular respiration, and operational genes. In this study, we proposed new properties (essentiality, expression pattern, PTMs, and solvent accessibility) for effectively identifying drug target proteins. We found that (1) drug targetability and protein essentiality are decoupled, (2) druggability of proteins has high expression level and tissue specificity, and (3) functional post-translational modification residues are enriched in drug target proteins. In addition, to predict the drug targetability of proteins, we exploited two machine learning methods (Support Vector Machine and Random Forest). When we predicted drug targets by combining previously known protein properties and proposed new properties, an F-score of 0.8307 was obtained. When the newly proposed properties are integrated, the prediction performance

RAS testing and cetuximab treatment for metastatic colorectal cancer: a cost-effectiveness analysis in a setting with limited health resources.

PubMed

Wu, Bin; Yao, Yuan; Zhang, Ke; Ma, Xuezhen

2017-09-19

To test the cost-effectiveness of cetuximab plus irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment in patients with metastatic colorectal cancer (mCRC) from a Chinese medical insurance perspective. Baseline analysis showed that the addition of cetuximab increased quality-adjusted life-years (QALYs) by 0.63, an increase of $17,086 relative to FOLFIRI chemotherapy, resulting in an incremental cost-effectiveness ratio (ICER) of $27,145/QALY. When the patient assistance program (PAP) was available, the ICER decreased to $14,049/QALY, which indicated that the cetuximab is cost-effective at a willingness-to-pay threshold of China ($22,200/QALY). One-way sensitivity analyses showed that the median overall survival time for the cetuximab was the most influential parameter. A Markov model by incorporating clinical, utility and cost data was developed to evaluate the economic outcome of cetuximab in mCRC. The lifetime horizon was used, and sensitivity analyses were carried out to test the robustness of the model results. The impact of PAP was also evaluated in scenario analyses. RAS testing with cetuximab treatment is likely to be cost-effective for patients with mCRC when PAP is available in China.

DrugECs: An Ensemble System with Feature Subspaces for Accurate Drug-Target Interaction Prediction

PubMed Central

Jiang, Jinjian; Wang, Nian; Zhang, Jun

2017-01-01

Background Drug-target interaction is key in drug discovery, especially in the design of new lead compound. However, the work to find a new lead compound for a specific target is complicated and hard, and it always leads to many mistakes. Therefore computational techniques are commonly adopted in drug design, which can save time and costs to a significant extent. Results To address the issue, a new prediction system is proposed in this work to identify drug-target interaction. First, drug-target pairs are encoded with a fragment technique and the software “PaDEL-Descriptor.” The fragment technique is for encoding target proteins, which divides each protein sequence into several fragments in order and encodes each fragment with several physiochemical properties of amino acids. The software “PaDEL-Descriptor” creates encoding vectors for drug molecules. Second, the dataset of drug-target pairs is resampled and several overlapped subsets are obtained, which are then input into kNN (k-Nearest Neighbor) classifier to build an ensemble system. Conclusion Experimental results on the drug-target dataset showed that our method performs better and runs faster than the state-of-the-art predictors. PMID:28744468

Updates on drug-target network; facilitating polypharmacology and data integration by growth of DrugBank database.

PubMed

Barneh, Farnaz; Jafari, Mohieddin; Mirzaie, Mehdi

2016-11-01

Network pharmacology elucidates the relationship between drugs and targets. As the identified targets for each drug increases, the corresponding drug-target network (DTN) evolves from solely reflection of the pharmaceutical industry trend to a portrait of polypharmacology. The aim of this study was to evaluate the potentials of DrugBank database in advancing systems pharmacology. We constructed and analyzed DTN from drugs and targets associations in the DrugBank 4.0 database. Our results showed that in bipartite DTN, increased ratio of identified targets for drugs augmented density and connectivity of drugs and targets and decreased modular structure. To clear up the details in the network structure, the DTNs were projected into two networks namely, drug similarity network (DSN) and target similarity network (TSN). In DSN, various classes of Food and Drug Administration-approved drugs with distinct therapeutic categories were linked together based on shared targets. Projected TSN also showed complexity because of promiscuity of the drugs. By including investigational drugs that are currently being tested in clinical trials, the networks manifested more connectivity and pictured the upcoming pharmacological space in the future years. Diverse biological processes and protein-protein interactions were manipulated by new drugs, which can extend possible target combinations. We conclude that network-based organization of DrugBank 4.0 data not only reveals the potential for repurposing of existing drugs, also allows generating novel predictions about drugs off-targets, drug-drug interactions and their side effects. Our results also encourage further effort for high-throughput identification of targets to build networks that can be integrated into disease networks. © The Author 2015. Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

DrugE-Rank: improving drug–target interaction prediction of new candidate drugs or targets by ensemble learning to rank

PubMed Central

Yuan, Qingjun; Gao, Junning; Wu, Dongliang; Zhang, Shihua; Mamitsuka, Hiroshi; Zhu, Shanfeng

2016-01-01

Motivation: Identifying drug–target interactions is an important task in drug discovery. To reduce heavy time and financial cost in experimental way, many computational approaches have been proposed. Although these approaches have used many different principles, their performance is far from satisfactory, especially in predicting drug–target interactions of new candidate drugs or targets. Methods: Approaches based on machine learning for this problem can be divided into two types: feature-based and similarity-based methods. Learning to rank is the most powerful technique in the feature-based methods. Similarity-based methods are well accepted, due to their idea of connecting the chemical and genomic spaces, represented by drug and target similarities, respectively. We propose a new method, DrugE-Rank, to improve the prediction performance by nicely combining the advantages of the two different types of methods. That is, DrugE-Rank uses LTR, for which multiple well-known similarity-based methods can be used as components of ensemble learning. Results: The performance of DrugE-Rank is thoroughly examined by three main experiments using data from DrugBank: (i) cross-validation on FDA (US Food and Drug Administration) approved drugs before March 2014; (ii) independent test on FDA approved drugs after March 2014; and (iii) independent test on FDA experimental drugs. Experimental results show that DrugE-Rank outperforms competing methods significantly, especially achieving more than 30% improvement in Area under Prediction Recall curve for FDA approved new drugs and FDA experimental drugs. Availability: http://datamining-iip.fudan.edu.cn/service/DrugE-Rank Contact: zhusf@fudan.edu.cn Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27307615

TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models.

PubMed

Yao, Zhi-Jiang; Dong, Jie; Che, Yu-Jing; Zhu, Min-Feng; Wen, Ming; Wang, Ning-Ning; Wang, Shan; Lu, Ai-Ping; Cao, Dong-Sheng

2016-05-01

Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at http://targetnet.scbdd.com .

TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models

NASA Astrophysics Data System (ADS)

Yao, Zhi-Jiang; Dong, Jie; Che, Yu-Jing; Zhu, Min-Feng; Wen, Ming; Wang, Ning-Ning; Wang, Shan; Lu, Ai-Ping; Cao, Dong-Sheng

2016-05-01

Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at http://targetnet.scbdd.com.

Cetuximab-activated natural killer (NK) and dendritic cells (DC) collaborate to trigger tumor antigen-specific T cell immunity in head and neck cancer patients

PubMed Central

Srivastava, Raghvendra M.; Lee, Steve C.; Filho, Pedro A. Andrade; Lord, Christopher A.; Jie, Hyun-bae; Davidson, H. Carter; López-Albaitero, Andrés; Gibson, Sandra P.; Gooding, William E.; Ferrone, Soldano; Ferris, Robert L.

2013-01-01

Purpose Tumor antigen (TA)-specific monoclonal antibodies (mAb) block oncogenic signaling and induce Fcγ receptor (FcγR)-mediated cytotoxicity. However, the role of CD8+ cytotoxic T lymphocyte (CTL) and FcγR in initiating innate and adaptive immune responses in mAb-treated human cancer patients is still emerging. Experimental Design FcγRIIIa codon 158 polymorphism was correlated with survival in 107 cetuximab-treated head and neck cancer (HNC) patients. Flow cytometry was performed to quantify EGFR-specific T cells in cetuximab-treated HNC patients. The effect of cetuximab on NK cell, dendritic cell (DC), and T cell activation was measured using IFN-γ release assays and flow cytometry. Results FcγR IIIa polymorphism did not predict clinical outcome in cetuximab-treated HNC patients, however elevated circulating EGFR -specific CD8+ 853-861 T cells were found in cetuximab-treated HNC patients (p<0.005). Cetuximab promoted EGFR-specific cellular immunity through the interaction of EGFR+ tumor cells and FcγRIIIa on NK cells, but not on the polymorphism per se. Cetuximab-activated NK cells induced IFN-γ dependent expression of DC maturation markers, antigen presentation machinery (APM) components such as TAP-1/2, and Th1 chemokines through NKG2D/MICA binding. Cetuximab initiated adaptive immune responses via NK-cell induced DC maturation, which enhanced cross-presentation to CTL specific for EGFR as well as another TA, MAGE-3. Conclusion Cetuximab-activated NK cells promote DC maturation and CD8+ T cell priming, leading to TA spreading and Th1 cytokine release through ‘NK-DC cross-talk.’ FcγRIIIa polymorphism did not predict clinical response to cetuximab, but was necessary for NK-DC interaction and mAb induced cross-presentation. EGFR-specific T cells in cetuximab treated HNC patients may contribute to clinical response. PMID:23444227

STAT1-Induced HLA class I Upregulation Enhances Immunogenicity and Clinical Response to anti-EGFR mAb Cetuximab Therapy in HNC Patients

PubMed Central

Srivastava, Raghvendra M.; Trivedi, Sumita; Concha-Benavente, Fernando; Hyun-bae, Jie; Wang, Lin; Seethala, Raja R.; Branstetter, Barton F.; Ferrone, Soldano; Ferris, Robert L.

2015-01-01

The goal of this study was to characterize the molecular mechanisms underlying cetuximab-mediated upregulation of HLA class I antigen-processing machinery components in head and neck cancer (HNC) cells and to determine the clinical significance of these changes in cetuximab-treated HNC patients. Flow cytometry, signaling studies and chromatin immunoprecipitation (ChIP) assays were performed using HNC cells treated with cetuximab alone or with Fcγ receptor (FcγR)-bearing lymphocytes to establish the mechanism of EGFR-dependent regulation of HLA APM expression. A prospective phase II clinical trial of neoadjuvant cetuximab was utilized to correlate HLA class I expression with clinical response in HNC patients. EGFR blockade triggered STAT1 activation and HLA upregulation, in a src homology-containing protein (SHP)-2-dependent fashion, more prominently in HLA-B/C than in HLA-A alleles. EGFR signaling blockade also enhanced IFNγ receptor 1 (IFNAR) expression, augmenting induction of HLA class I and TAP1/2 expression by IFNγ, which was abrogated in STAT1−/− cells. Cetuximab enhanced HNC cell recognition by EGFR853–861-specific CTLs, and notably enhanced surface presentation of a non-EGFR peptide (MAGE-3271–279). HLA class I upregulation was significantly associated with clinical response in cetuximab-treated HNC patients. EGFR induces HLA downregulation through SHP-2/STAT1 suppression. Reversal of HLA class I downregulation was more prominent in clinical responders to cetuximab therapy, supporting an important role for adaptive immunity in cetuximab antitumor activity. Abrogating EGFR-induced immune escape mechanisms and restoring STAT1 signaling to reverse HLA downregulation using cetuximab should be combined with strategies to enhance adaptive cellular immunity. PMID:25972070

The Role of p53 in Combination Radioimmunotherapy with 64Cu-DOTA-Cetuximab and Cisplatin in a Mouse Model of Colorectal Cancer

PubMed Central

Guo, Yunjun; Parry, Jesse J.; Laforest, Richard; Rogers, Buck E.; Anderson, Carolyn J.

2014-01-01

Radioimmunotherapy has been successfully used in the treatment of lymphoma but thus far has not demonstrated significant efficacy in humans beyond disease stabilization in solid tumors. Radioimmunotherapy with 64Cu was highly effective in a hamster model of colorectal cancer, but targeted radiotherapies with this radionuclide have since not shown as much success. It is widely known that mutations in key proteins play a role in the success or failure of cancer therapies. For example, the KRAS mutation is predictive of poor response to anti–epidermal growth factor receptor therapies in colorectal cancer, whereas p53 is frequently mutated in tumors, causing resistance to multiple therapeutic regimens. Methods We previously showed that nuclear localization of 64Cu-labeled DOTA-cetuximab was enhanced in p53 wild-type tumor cells. Here, we examine the role of p53 in the response to radioimmunotherapy with 64Cu-DOTA-cetuximab in KRAS-mutated HCT116 tumor–bearing mice, with and without cisplatin, which upregulates wild-type p53. Results Experiments with HCT116 cells that are p53 +/+ (p53 wild-type) and −/− (p53 null) grown in cell culture demonstrated that preincubation with cisplatin increased expression of p53 and subsequently enhanced localization of 64Cu from 64Cuacetate and 64Cu-DOTA-cetuximab to the tumor cell nuclei. Radioimmunotherapy studies in p53-positive HCT116 tumor–bearing mice, receiving either radioimmunotherapy alone or in combination with cisplatin, showed significantly longer survival in mice receiving unlabeled cetuximab or cisplatin alone or in combination (all, P < 0.01). In contrast, the p53-negative tumor-bearing mice treated with radioimmunotherapy alone or combined with cisplatin showed no survival advantage, compared with control groups (all, P > 0.05). Conclusion Together, these data suggest that 64Cu specifically delivered to epidermal growth factor receptor–positive tumors by cetuximab can suppress tumor growth despite the KRAS

The role of p53 in combination radioimmunotherapy with 64Cu-DOTA-cetuximab and cisplatin in a mouse model of colorectal cancer.

PubMed

Guo, Yunjun; Parry, Jesse J; Laforest, Richard; Rogers, Buck E; Anderson, Carolyn J

2013-09-01

Radioimmunotherapy has been successfully used in the treatment of lymphoma but thus far has not demonstrated significant efficacy in humans beyond disease stabilization in solid tumors. Radioimmunotherapy with (64)Cu was highly effective in a hamster model of colorectal cancer, but targeted radiotherapies with this radionuclide have since not shown as much success. It is widely known that mutations in key proteins play a role in the success or failure of cancer therapies. For example, the KRAS mutation is predictive of poor response to anti-epidermal growth factor receptor therapies in colorectal cancer, whereas p53 is frequently mutated in tumors, causing resistance to multiple therapeutic regimens. We previously showed that nuclear localization of (64)Cu-labeled DOTA-cetuximab was enhanced in p53 wild-type tumor cells. Here, we examine the role of p53 in the response to radioimmunotherapy with (64)Cu-DOTA-cetuximab in KRAS-mutated HCT116 tumor-bearing mice, with and without cisplatin, which upregulates wild-type p53. Experiments with HCT116 cells that are p53 +/+ (p53 wild-type) and -/- (p53 null) grown in cell culture demonstrated that preincubation with cisplatin increased expression of p53 and subsequently enhanced localization of (64)Cu from (64)Cu-acetate and (64)Cu-DOTA-cetuximab to the tumor cell nuclei. Radioimmunotherapy studies in p53-positive HCT116 tumor-bearing mice, receiving either radioimmunotherapy alone or in combination with cisplatin, showed significantly longer survival in mice receiving unlabeled cetuximab or cisplatin alone or in combination (all, P < 0.01). In contrast, the p53-negative tumor-bearing mice treated with radioimmunotherapy alone or combined with cisplatin showed no survival advantage, compared with control groups (all, P > 0.05). Together, these data suggest that (64)Cu specifically delivered to epidermal growth factor receptor-positive tumors by cetuximab can suppress tumor growth despite the KRAS status and present

Targeted Cellular Drug Delivery using Tailored Dendritic Nanostructures

NASA Astrophysics Data System (ADS)

Kannan, Rangaramanujam; Kolhe, Parag; Kannan, Sujatha; Lieh-Lai, Mary

2002-03-01

Dendrimers and hyperbranched polymers possess highly branched architectures, with a large number of controllable, tailorble, ‘peripheral’ functionalities. Since the surface chemistry of these materials can be modified with relative ease, these materials have tremendous potential in targeted drug and gene delivery. The large number of end groups can also be tailored to create special affinity to targeted cells, and can also encapsulate drugs and deliver them in a controlled manner. We are developing tailor-modified dendritic systems for drug delivery. Synthesis, in-vitro drug loading, in-vitro drug delivery, and the targeting efficiency to the cell are being studied systematically using a wide variety of experimental tools. Polyamidoamine and Polyol dendrimers, with different generations and end-groups are studied, with drugs such as Ibuprofen and Methotrexate. Our results indicate that a large number of drug molecules can be encapsulated/attached to the dendrimers, depending on the end groups. The drug-encapsulated dendrimer is able to enter the cells rapidly and deliver the drug. Targeting strategies being explored

Phase I study of bortezomib and cetuximab in patients with solid tumours expressing epidermal growth factor receptor

PubMed Central

Dudek, A Z; Lesniewski-Kmak, K; Shehadeh, N J; Pandey, O N; Franklin, M; Kratzke, R A; Greeno, E W; Kumar, P

2009-01-01

Bortezomib inhibits nuclear factor-κB (NF-κB). Cetuximab is a chimeric mouse–human antibody targeted against epidermal growth factor receptor (EGFR). We hypothesised that concomitant blockade of NF-κB and EGFR signalling would overcome EGFR-mediated resistance to single-agent bortezomib and induce apoptosis through two molecular pathways. The aim of this phase I trial was to establish the maximum tolerated dose (MTD) for bortezomib plus cetuximab in patients with EGFR-expressing epithelial tumours. The 21-day treatment cycle consisted of bortezomib administered on days 1 and 8 through dose escalation (1.3–2 mg m−2). Cetuximab was delivered at a dose of 250 mg m−2 on days 1, 8 and 15 (400 mg m−2 day 1 cycle 1). A total of 37 patients were enroled and given a total 91 cycles. No grade ⩾3 haematological toxicity was noted. Non-hematological grade ⩾3 toxicities included fatigue (22% of patients), dyspnoea (16%) and infection (11%). The MTD was not reached at the highest tested bortezomib dose (2.0 mg m−2). Efficacy outcomes included disease progression in 21 patients (56.7%) and stable disease (SD) at 6 weeks in 16 patients (43.3%). Five of the six patients with SD at 12 weeks were diagnosed with cancers of the lungs or head and neck. This combination therapy was moderately effective in extensively pretreated patients with non-small cell lung or head and neck cancers and warrants further investigation. PMID:19401697

Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial

PubMed Central

Maughan, Timothy S; Adams, Richard A; Smith, Christopher G; Meade, Angela M; Seymour, Matthew T; Wilson, Richard H; Idziaszczyk, Shelley; Harris, Rebecca; Fisher, David; Kenny, Sarah L; Kay, Edward; Mitchell, Jenna K; Madi, Ayman; Jasani, Bharat; James, Michelle D; Bridgewater, John; Kennedy, M John; Claes, Bart; Lambrechts, Diether; Kaplan, Richard; Cheadle, Jeremy P

2011-01-01

Summary Background In the Medical Research Council (MRC) COIN trial, the epidermal growth factor receptor (EGFR)-targeted antibody cetuximab was added to standard chemotherapy in first-line treatment of advanced colorectal cancer with the aim of assessing effect on overall survival. Methods In this randomised controlled trial, patients who were fit for but had not received previous chemotherapy for advanced colorectal cancer were randomly assigned to oxaliplatin and fluoropyrimidine chemotherapy (arm A), the same combination plus cetuximab (arm B), or intermittent chemotherapy (arm C). The choice of fluoropyrimidine therapy (capecitabine or infused fluouroracil plus leucovorin) was decided before randomisation. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and C is described in a companion paper. Here, we present the comparison of arm A and B, for which the primary outcome was overall survival in patients with KRAS wild-type tumours. Analysis was by intention to treat. Further analyses with respect to NRAS, BRAF, and EGFR status were done. The trial is registered, ISRCTN27286448. Findings 1630 patients were randomly assigned to treatment groups (815 to standard therapy and 815 to addition of cetuximab). Tumour samples from 1316 (81%) patients were used for somatic molecular analyses; 565 (43%) had KRAS mutations. In patients with KRAS wild-type tumours (arm A, n=367; arm B, n=362), overall survival did not differ between treatment groups (median survival 17·9 months [IQR 10·3–29·2] in the control group vs 17·0 months [9·4–30·1] in the cetuximab group; HR 1·04, 95% CI 0·87–1·23, p=0·67). Similarly, there was no effect on progression-free survival (8·6 months [IQR 5·0–12·5] in the control group vs 8·6 months [5·1–13·8] in the cetuximab group; HR 0·96, 0·82–1·12, p=0·60). Overall response rate increased from 57% (n=209

Drug-therapy networks and the prediction of novel drug targets

PubMed Central

Spiro, Zoltan; Kovacs, Istvan A; Csermely, Peter

2008-01-01

A recent study in BMC Pharmacology presents a network of drugs and the therapies in which they are used. Network approaches open new ways of predicting novel drug targets and overcoming the cellular robustness that can prevent drugs from working. PMID:18710588

Nanogel Carrier Design for Targeted Drug Delivery

PubMed Central

Eckmann, D. M.; Composto, R. J.; Tsourkas, A.; Muzykantov, V. R.

2014-01-01

Polymer-based nanogel formulations offer features attractive for drug delivery, including ease of synthesis, controllable swelling and viscoelasticity as well as drug loading and release characteristics, passive and active targeting, and the ability to formulate nanogel carriers that can respond to biological stimuli. These unique features and low toxicity make the nanogels a favorable option for vascular drug targeting. In this review, we address key chemical and biological aspects of nanogel drug carrier design. In particular, we highlight published studies of nanogel design, descriptions of nanogel functional characteristics and their behavior in biological models. These studies form a compendium of information that supports the scientific and clinical rationale for development of this carrier for targeted therapeutic interventions. PMID:25485112

Limited Efficiency of Drug Delivery to Specific Intracellular Organelles Using Subcellularly "Targeted" Drug Delivery Systems.

PubMed

Maity, Amit Ranjan; Stepensky, David

2016-01-04

Many drugs have been designed to act on intracellular targets and to affect intracellular processes inside target cells. For the desired effects to be exerted, these drugs should permeate target cells and reach specific intracellular organelles. This subcellular drug targeting approach has been proposed for enhancement of accumulation of these drugs in target organelles and improved efficiency. This approach is based on drug encapsulation in drug delivery systems (DDSs) and/or their decoration with specific targeting moieties that are intended to enhance the drug/DDS accumulation in the intracellular organelle of interest. During recent years, there has been a constant increase in interest in DDSs targeted to specific intracellular organelles, and many different approaches have been proposed for attaining efficient drug delivery to specific organelles of interest. However, it appears that in many studies insufficient efforts have been devoted to quantitative analysis of the major formulation parameters of the DDSs disposition (efficiency of DDS endocytosis and endosomal escape, intracellular trafficking, and efficiency of DDS delivery to the target organelle) and of the resulting pharmacological effects. Thus, in many cases, claims regarding efficient delivery of drug/DDS to a specific organelle and efficient subcellular targeting appear to be exaggerated. On the basis of the available experimental data, it appears that drugs/DDS decoration with specific targeting residues can affect their intracellular fate and result in preferential drug accumulation within an organelle of interest. However, it is not clear whether these approaches will be efficient in in vivo settings and be translated into preclinical and clinical applications. Studies that quantitatively assess the mechanisms, barriers, and efficiencies of subcellular drug delivery and of the associated toxic effects are required to determine the therapeutic potential of subcellular DDS targeting.

Drug-target interaction prediction: A Bayesian ranking approach.

PubMed

Peska, Ladislav; Buza, Krisztian; Koller, Júlia

2017-12-01

In silico prediction of drug-target interactions (DTI) could provide valuable information and speed-up the process of drug repositioning - finding novel usage for existing drugs. In our work, we focus on machine learning algorithms supporting drug-centric repositioning approach, which aims to find novel usage for existing or abandoned drugs. We aim at proposing a per-drug ranking-based method, which reflects the needs of drug-centric repositioning research better than conventional drug-target prediction approaches. We propose Bayesian Ranking Prediction of Drug-Target Interactions (BRDTI). The method is based on Bayesian Personalized Ranking matrix factorization (BPR) which has been shown to be an excellent approach for various preference learning tasks, however, it has not been used for DTI prediction previously. In order to successfully deal with DTI challenges, we extended BPR by proposing: (i) the incorporation of target bias, (ii) a technique to handle new drugs and (iii) content alignment to take structural similarities of drugs and targets into account. Evaluation on five benchmark datasets shows that BRDTI outperforms several state-of-the-art approaches in terms of per-drug nDCG and AUC. BRDTI results w.r.t. nDCG are 0.929, 0.953, 0.948, 0.897 and 0.690 for G-Protein Coupled Receptors (GPCR), Ion Channels (IC), Nuclear Receptors (NR), Enzymes (E) and Kinase (K) datasets respectively. Additionally, BRDTI significantly outperformed other methods (BLM-NII, WNN-GIP, NetLapRLS and CMF) w.r.t. nDCG in 17 out of 20 cases. Furthermore, BRDTI was also shown to be able to predict novel drug-target interactions not contained in the original datasets. The average recall at top-10 predicted targets for each drug was 0.762, 0.560, 1.000 and 0.404 for GPCR, IC, NR, and E datasets respectively. Based on the evaluation, we can conclude that BRDTI is an appropriate choice for researchers looking for an in silico DTI prediction technique to be used in drug

Targeting Antibacterial Agents by Using Drug-Carrying Filamentous Bacteriophages

PubMed Central

Yacoby, Iftach; Shamis, Marina; Bar, Hagit; Shabat, Doron; Benhar, Itai

2006-01-01

Bacteriophages have been used for more than a century for (unconventional) therapy of bacterial infections, for half a century as tools in genetic research, for 2 decades as tools for discovery of specific target-binding proteins, and for nearly a decade as tools for vaccination or as gene delivery vehicles. Here we present a novel application of filamentous bacteriophages (phages) as targeted drug carriers for the eradication of (pathogenic) bacteria. The phages are genetically modified to display a targeting moiety on their surface and are used to deliver a large payload of a cytotoxic drug to the target bacteria. The drug is linked to the phages by means of chemical conjugation through a labile linker subject to controlled release. In the conjugated state, the drug is in fact a prodrug devoid of cytotoxic activity and is activated following its dissociation from the phage at the target site in a temporally and spatially controlled manner. Our model target was Staphylococcus aureus, and the model drug was the antibiotic chloramphenicol. We demonstrated the potential of using filamentous phages as universal drug carriers for targetable cells involved in disease. Our approach replaces the selectivity of the drug itself with target selectivity borne by the targeting moiety, which may allow the reintroduction of nonspecific drugs that have thus far been excluded from antibacterial use (because of toxicity or low selectivity). Reintroduction of such drugs into the arsenal of useful tools may help to combat emerging bacterial antibiotic resistance. PMID:16723570

Promising Targets in Anti-cancer Drug Development: Recent Updates.

PubMed

Kumar, Bhupinder; Singh, Sandeep; Skvortsova, Ira; Kumar, Vinod

2017-01-01

Cancer is a multifactorial disease and its genesis and progression are extremely complex. The biggest problem in the anticancer drug development is acquiring of multidrug resistance and relapse. Classical chemotherapeutics directly target the DNA of the cell, while the contemporary anticancer drugs involve molecular-targeted therapy such as targeting the proteins possessing abnormal expression inside the cancer cells. Conventional strategies for the complete eradication of the cancer cells proved ineffective. Targeted chemotherapy was successful in certain malignancies however, the effectiveness has often been limited by drug resistance and side effects on normal tissues and cells. Since last few years, many promising drug targets have been identified for the effective treatment of cancer. The current review article describes some of these promising anticancer targets that include kinases, tubulin, cancer stem cells, monoclonal antibodies and vascular targeting agents. In addition, promising drug candidates under various phases of clinical trials are also described. Multi-acting drugs that simultaneously target different cancer cell signaling pathways may facilitate the process of effective anti-cancer drug development. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Cetuximab in treatment of metastatic colorectal cancer: final survival analyses and extended RAS data from the NORDIC-VII study.

PubMed

Guren, Tormod Kyrre; Thomsen, Maria; Kure, Elin H; Sorbye, Halfdan; Glimelius, Bengt; Pfeiffer, Per; Österlund, Pia; Sigurdsson, Fridbjörn; Lothe, Inger Marie Bowitz; Dalsgaard, Astrid Marie; Skovlund, Eva; Christoffersen, Thoralf; Tveit, Kjell Magne

2017-05-09

The NORDIC-VII study is a randomised phase III trial of cetuximab plus continuous or intermittent fluorouracil, folinic acid, and oxaliplatin (Nordic FLOX) vs FLOX alone in first-line treatment of metastatic colorectal cancer. The present report presents an updated and final survival analysis with BRAF and extended RAS mutational status, 5 years after the primary analysis. A total of 566 patients were included in the intention-to-treat (ITT) population of the NORDIC-VII study. Updated survival status was obtained from 176 patients who were alive in the primary survival analyses. Samples from 223 tumours previously found to be KRAS (exon 2) and BRAF (V600E) wild-type, were re-analysed for KRAS (exons 3 and 4) and NRAS (exons 2-4) mutations. Including the extended RAS analyses, RAS and BRAF mutational status was available from 457 patients (81% of the ITT population). RAS was mutated in 46% and BRAF in 12% of the tumours. RAS and BRAF, if mutated, were negative prognostic factors. The updated analyses confirmed the finding of the primary report that cetuximab did not provide any additional benefit when added to FLOX in patients with RAS/BRAF wild-type tumours, neither on progression-free nor overall survival. However, the outcomes in a subset of patients, which, after the first eight treatment cycles, received cetuximab alone, suggested a beneficial effect of cetuximab monotherapy. Adding cetuximab to Nordic FLOX did not provide any clinical benefit, but the data suggested an effect of cetuximab monotherapy in patients with RAS/BRAF wild-type tumours in the NORDIC-VII cohort. The data were compatible with a negative interaction between cetuximab and the Nordic FLOX chemotherapy backbone.

Predicting Drug-Target Interactions With Multi-Information Fusion.

PubMed

Peng, Lihong; Liao, Bo; Zhu, Wen; Li, Zejun; Li, Keqin

2017-03-01

Identifying potential associations between drugs and targets is a critical prerequisite for modern drug discovery and repurposing. However, predicting these associations is difficult because of the limitations of existing computational methods. Most models only consider chemical structures and protein sequences, and other models are oversimplified. Moreover, datasets used for analysis contain only true-positive interactions, and experimentally validated negative samples are unavailable. To overcome these limitations, we developed a semi-supervised based learning framework called NormMulInf through collaborative filtering theory by using labeled and unlabeled interaction information. The proposed method initially determines similarity measures, such as similarities among samples and local correlations among the labels of the samples, by integrating biological information. The similarity information is then integrated into a robust principal component analysis model, which is solved using augmented Lagrange multipliers. Experimental results on four classes of drug-target interaction networks suggest that the proposed approach can accurately classify and predict drug-target interactions. Part of the predicted interactions are reported in public databases. The proposed method can also predict possible targets for new drugs and can be used to determine whether atropine may interact with alpha1B- and beta1- adrenergic receptors. Furthermore, the developed technique identifies potential drugs for new targets and can be used to assess whether olanzapine and propiomazine may target 5HT2B. Finally, the proposed method can potentially address limitations on studies of multitarget drugs and multidrug targets.

Depicting changes in tumor biology in response to cetuximab mono- or combination therapy by apoptosis and proliferation imaging using 18F-ICMT-11 and 3'-Deoxy-3'-[18F]Fluorothymidine (18F-FLT) PET.

PubMed

Heinzmann, Kathrin; Nguyen, Quang-De; Honess, Davina Jean; Smith, Donna-Michelle; Stribbling, Stephen; Brickute, Diana; Barnes, Christopher; Griffiths, John Richard; Aboagye, Eric Ofori

2018-05-24

Imaging biomarkers must demonstrate their value in monitoring treatment. Two PET tracers, the caspase-3/7-specific isatin-5-sulfonamide 18 F-ICMT-11 and 3'-Deoxy-3'-[ 18 F]Fluorothymidine ( 18 F-FLT), were employed to detect early treatment-induced changes in tumor biology and whether any changes indicate response to cetuximab, administered as mono- or combination therapy with gemcitabine. Methods: Effects of single or repeated doses of the anti-Epidermal Growth Factor Receptor (EGFR) antibody cetuximab (10mg/kg on day 1 only or day 1 and 2) and/or a single dose of gemcitabine (125mg/kg; day 2) were investigated in mice bearing cetuximab-sensitive H1975 tumors (non-small cell lung cancer) by 18 F-ICMT-11 or 18 F-FLT-PET (day 3). Imaging was also performed in mice bearing cetuximab-insensitive HCT116 tumors (colorectal cancer) after two doses of cetuximab (day 1 and 2). For imaging/histology comparison, tumors were evaluated for proliferation (Ki67; thymidine kinase 1, TK1), cell death (cleaved caspase-3, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL)) and target engagement (EGFR expression) by immunohistochemistry, immunofluorescence and immunoblot, respectively. Tumor and plasma were analysed for thymidine and gemcitabine metabolites by liquid chromatography-mass spectrometry. Results: Retention of both tracers was sensitive to cetuximab in H1975 tumors. 18 F-ICMT-11 uptake and ex vivo cleaved caspase-3 staining notably increased in tumors treated with repeated doses of cetuximab- (75%) and combination-treatment (46%). While one dose of cetuximab was insufficient to induce apoptosis it did affect proliferation. Significant reduction in tumor 18 F-FLT uptake (44 to 50%; P < 0.001) induced by cetuximab mono- and combination-therapy were paralleled with a clear decrease in proliferation (%Ki67 decrease: 72 to 95%; P < 0.0001) and followed by marked tumor growth delay. TK1 expression and tumor thymidine concentrations were profoundly

Multicenter retrospective study of cetuximab plus platinum-based chemotherapy for recurrent or metastatic oral squamous cell carcinoma.

PubMed

Yanamoto, Souichi; Umeda, Masahiro; Kioi, Mitomu; Kirita, Tadaaki; Yamashita, Tetsuro; Hiratsuka, Hiroyoshi; Yokoo, Satoshi; Tanzawa, Hideki; Uzawa, Narikazu; Shibahara, Takahiko; Ota, Yoshihide; Kurita, Hiroshi; Okura, Masaya; Hamakawa, Hiroyuki; Kusukawa, Jingo; Tohnai, Iwai

2018-03-01

The purpose of this study was to assess the efficacy and safety of cetuximab plus platinum-based chemotherapy for patients specifically diagnosed with recurrent or metastatic oral squamous cell carcinoma (OSCC). We conducted a multicenter retrospective observational study of patients who underwent first-line cetuximab plus platinum-based chemotherapy between December 2012 and June 2015. 65 patients received weekly cetuximab (week 1, 400 mg/m 2 ; subsequent weeks, 250 mg/m 2 ) plus a maximum of six 3-weekly cycles of cisplatin (80 or 100 mg/m 2 , day 1) or carboplatin (at an area under the curve of 5 mg/mL/min as a 1-h intravenous infusion on day 1) and 5-fluorouracil (800 or 1000 mg/m 2 /day, days 1-4). Patients with stable disease who received cetuximab plus platinum-based chemotherapy continued to receive cetuximab until disease progression or unacceptable toxicities, whichever occurred first. The median follow-up was 10.5 (range 1.2-34.2) months. The best overall response and the disease control rates were 46.2 and 67.7%, respectively. The median overall survival and progression-free survival rates were 12.1 and 7.8 months, respectively. The most common grades 3-4 adverse events were skin rash (9.2%) followed by leukopenia (6.2%). None of the adverse events were fatal. The results of our multicenter retrospective study, which was the largest of its kind to date, suggest that first-line cetuximab plus platinum-based chemotherapy is suitable and well-tolerated for the systemic therapy of recurrent or metastatic OSCC.

Impact of Primary Tumor Location on First-line Bevacizumab or Cetuximab in Metastatic Colorectal Cancer.

PubMed

Snyder, Matthew; Bottiglieri, Sal; Almhanna, Khaldoun

2018-01-01

Colorectal cancer is one of the most common malignancies in the United States, with a large proportion of patients presenting with metastatic disease or developing a recurrence. Systemic chemotherapy is the mainstay of therapy in this setting. There is a clear benefit in the addition of bevacizumab or cetuximab (for rat sarcoma [RAS] wild type tumors) to oxaliplatin- and irinotecan-based regimens which can be considered for first-line therapy. However, many significant questions remain as to which agent reflects best practice. Our review aimed to elucidate the benefit of adding bevacizumab and cetuximab to initial therapy for metastatic colorectal cancer based on primary tumor location and a variety of other disease- and patient-related factors, addressing the paucity of evidence that currently exists in this area and contributing to current literature and clinical practices. The primary endpoints of the study were first Progression-Free Survival (PFS) and Overall Survival (OS). Secondary endpoints included best response to first- and second-line therapies, Treatment- Related Adverse Events (TRAEs), second PFS, cost of therapy, and an assessment of other patient- and disease-related factors affecting PFS and OS. While there were trends towards improved OS in patients with left-sided primary tumors (n=57) compared to those with right-sided disease (n=23), there were no significant differences between the two groups in either primary endpoint. While no differences were found for patients with left- or right- sided tumors stratified by add-on agent, these analyses were limited by the small number of patients receiving cetuximab with first-line therapy (n=4). However, the bevacizumab cohort (n=76) was sizable enough to provide ample data and produce clinically relevant results. Add-on therapy with bevacizumab in our study achieved impressive survival outcomes in both left-sided (median first PFS = 13 months, 95% CI 11-15 months; median OS = 37 months, 95% CI 21

Combination of post-operative radiotherapy and cetuximab for high-risk cutaneous squamous cell cancer of the head and neck: A propensity score analysis.

PubMed

Palmer, Joshua D; Schneider, Charles J; Hockstein, Neil; Hanlon, Alexandra L; Silberg, Jordan; Strasser, Jon; Mauer, Elizabeth A; Dzeda, Michael; Witt, Robert; Raben, Adam

2018-03-01

The objective of this study was to investigate the safety, tolerability and preliminary efficacy of radiotherapy plus cetuximab in high risk CSCC patients. Patients with high-risk CSCC diagnosed between 2006 and 2013 were analyzed. Patients were divided into two groups: radiotherapy alone versus radiotherapy plus cetuximab. Among 68 patients meeting study criteria, we identified 29 treated with cetuximab plus RT and 39 with RT alone. Primary analysis examined disease-free and overall survival, freedom from local and distant recurrence in the propensity score matched cohort. Propensity score analysis was performed with weighted factors including: Charlson Comorbidity Index score, age. KPS, primary location, T and N stage, recurrent status, margin status, LVSI, PNI and grade. Toxicity was assessed using the CTCAE v4.0. Median follow-up for living patients was 30 months. Patients in the cetuximab group were more likely to have advanced N stage, positive margins and recurrent disease. After propensity score matching the groups were well balanced. Six patients experienced ≥ grade 3 acute toxicity in the cetuximab group. The 1-year, 2-year and 5-year progression free survival (PFS) for patients in the cetuximab group were 86%, 72% and 66%, respectively. The 1-year, 2-year and 5-year overall survival (OS) for patients in the cetuximab group was 98%, 80% and 80%, respectively. Although limited by small numbers, the combination of cetuximab and radiotherapy in CSCC appears well tolerated there were more long-term survivors and less distant metastasis in the cetuximab group. These promising finding warrant further studies. Copyright © 2018 Elsevier Ltd. All rights reserved.

Biodegradable polymers for targeted delivery of anti-cancer drugs.

PubMed

Doppalapudi, Sindhu; Jain, Anjali; Domb, Abraham J; Khan, Wahid

2016-06-01

Biodegradable polymers have been used for more than three decades in cancer treatment and have received increased interest in recent years. A range of biodegradable polymeric drug delivery systems designed for localized and systemic administration of therapeutic agents as well as tumor-targeting macromolecules has entered into the clinical phase of development, indicating the significance of biodegradable polymers in cancer therapy. This review elaborates upon applications of biodegradable polymers in the delivery and targeting of anti-cancer agents. Design of various drug delivery systems based on biodegradable polymers has been described. Moreover, the indication of polymers in the targeted delivery of chemotherapeutic drugs via passive, active targeting, and localized drug delivery are also covered. Biodegradable polymer-based drug delivery systems have the potential to deliver the payload to the target and can enhance drug availability at desired sites. Systemic toxicity and serious side effects observed with conventional cancer therapeutics can be significantly reduced with targeted polymeric systems. Still, there are many challenges that need to be met with respect to the degradation kinetics of the system, diffusion of drug payload within solid tumors, targeting tumoral tissue and tumor heterogeneity.

Dual responsive PNIPAM-chitosan targeted magnetic nanopolymers for targeted drug delivery

NASA Astrophysics Data System (ADS)

Yadavalli, Tejabhiram; Ramasamy, Shivaraman; Chandrasekaran, Gopalakrishnan; Michael, Isaac; Therese, Helen Annal; Chennakesavulu, Ramasamy

2015-04-01

A dual stimuli sensitive magnetic hyperthermia based drug delivery system has been developed for targeted cancer treatment. Thermosensitive amine terminated poly-N-isopropylacrylamide complexed with pH sensitive chitosan nanoparticles was prepared as the drug carrier. Folic acid and fluorescein were tagged to the nanopolymer complex via N-hydroxysuccinimide and ethyl-3-(3-dimethylaminopropyl)carbodiimide reaction to form a fluorescent and cancer targeting magnetic carrier system. The formation of the polymer complex was confirmed using infrared spectroscopy. Gadolinium doped nickel ferrite nanoparticles prepared by a hydrothermal method were encapsulated in the polymer complex to form a magnetic drug carrier system. The proton relaxation studies on the magnetic carrier system revealed a 200% increase in the T1 proton relaxation rate. These magnetic carriers were loaded with curcumin using solvent evaporation method with a drug loading efficiency of 86%. Drug loaded nanoparticles were tested for their targeting and anticancer properties on four cancer cell lines with the help of MTT assay. The results indicated apoptosis of cancer cell lines within 3 h of incubation.

Anti-EGFR Targeted Monoclonal Antibody Isotype Influences Antitumor Cellular Immunity in Head and Neck Cancer Patients.

PubMed

Trivedi, Sumita; Srivastava, Raghvendra M; Concha-Benavente, Fernando; Ferrone, Soldano; Garcia-Bates, Tatiana M; Li, Jing; Ferris, Robert L

2016-11-01

EGF receptor (EGFR) is highly overexpressed on several cancers and two targeted anti-EGFR antibodies which differ by isotype are FDA-approved for clinical use. Cetuximab (IgG1 isotype) inhibits downstream signaling of EGFR and activates antitumor, cellular immune mechanisms. As panitumumab (IgG2 isotype) may inhibit downstream EGFR signaling similar to cetuximab, it might also induce adaptive immunity. We measured in vitro activation of cellular components of the innate and adaptive immune systems. We also studied the in vivo activation of components of the adaptive immune system in patient specimens from two recent clinical trials using cetuximab or panitumumab. Both monoclonal antibodies (mAb) primarily activate natural killer (NK) cells, although cetuximab is significantly more potent than panitumumab. Cetuximab-activated neutrophils mediate antibody-dependent cellular cytotoxicity (ADCC) against head and neck squamous cell carcinomas (HNSCC) tumor cells, and interestingly, this effect was FcγRIIa- and FcγRIIIa genotype-dependent. Panitumumab may activate monocytes through CD32 (FcγRIIa); however, monocytes activated by either mAb are not able to mediate ADCC. Cetuximab enhanced dendritic cell (DC) maturation to a greater extent than panitumumab, which was associated with improved tumor antigen cross-presentation by cetuximab compared with panitumumab. This correlated with increased EGFR-specific cytotoxic CD8 + T cells in patients treated with cetuximab compared with those treated with panitumumab. Although panitumumab effectively inhibits EGFR signaling to a similar extent as cetuximab, it is less effective at triggering antitumor, cellular immune mechanisms which may be crucial for effective therapy of HNSCC. Clin Cancer Res; 22(21); 5229-37. ©2016 AACR. ©2016 American Association for Cancer Research.

New Equilibrium Models of Drug-Receptor Interactions Derived from Target-Mediated Drug Disposition.

PubMed

Peletier, Lambertus A; Gabrielsson, Johan

2018-05-14

In vivo analyses of pharmacological data are traditionally based on a closed system approach not incorporating turnover of target and ligand-target kinetics, but mainly focussing on ligand-target binding properties. This study incorporates information about target and ligand-target kinetics parallel to binding. In a previous paper, steady-state relationships between target- and ligand-target complex versus ligand exposure were derived and a new expression of in vivo potency was derived for a circulating target. This communication is extending the equilibrium relationships and in vivo potency expression for (i) two separate targets competing for one ligand, (ii) two different ligands competing for a single target and (iii) a single ligand-target interaction located in tissue. The derived expressions of the in vivo potencies will be useful both in drug-related discovery projects and mechanistic studies. The equilibrium states of two targets and one ligand may have implications in safety assessment, whilst the equilibrium states of two competing ligands for one target may cast light on when pharmacodynamic drug-drug interactions are important. The proposed equilibrium expressions for a peripherally located target may also be useful for small molecule interactions with extravascularly located targets. Including target turnover, ligand-target complex kinetics and binding properties in expressions of potency and efficacy will improve our understanding of within and between-individual (and across species) variability. The new expressions of potencies highlight the fact that the level of drug-induced target suppression is very much governed by target turnover properties rather than by the target expression level as such.

Association of Primary Tumor Site With Mortality in Patients Receiving Bevacizumab and Cetuximab for Metastatic Colorectal Cancer.

PubMed

Aljehani, Mayada A; Morgan, John W; Guthrie, Laurel A; Jabo, Brice; Ramadan, Majed; Bahjri, Khaled; Lum, Sharon S; Selleck, Matthew; Reeves, Mark E; Garberoglio, Carlos; Senthil, Maheswari

2018-01-01

Biologic therapy (BT) (eg, bevacizumab or cetuximab) is increasingly used to treat metastatic colorectal cancer (mCRC). Recent investigations have suggested that right- or left-sided primary tumor origin affects survival and response to BT. To evaluate the association of tumor origin with mortality in a diverse population-based data set of patients receiving systemic chemotherapy (SC) and bevacizumab or cetuximab for mCRC. This population-based nonconcurrent cohort study of statewide California Cancer Registry data included all patients aged 40 to 85 years diagnosed with mCRC and treated with SC only or SC plus bevacizumab or cetuximab from January 1, 2004, through December 31, 2014. Patients were stratified by tumor origin in the left vs right sides. Treatment with SC or SC plus bevacizumab or cetuximab. Mortality hazards by tumor origin (right vs left sides) were assessed for patients receiving SC alone or SC plus bevacizumab or cetuximab. Subgroup analysis for patients with wild-type KRAS tumors was also performed. A total of 11 905 patients with mCRC (6713 men [56.4%] and 5192 women [43.6%]; mean [SD] age, 60.0 [10.9] years) were eligible for the study. Among these, 4632 patients received SC and BT. Compared with SC alone, SC plus bevacizumab reduced mortality among patients with right- and left-sided mCRC, whereas SC plus cetuximab reduced mortality only among patients with left-sided tumors and was associated with significantly higher mortality for right-sided tumors (hazard ratio [HR], 1.31; 95% CI, 1.14-1.51; P < .001). Among patients treated with SC plus BT, right-sided tumor origin was associated with higher mortality among patients receiving bevacizumab (HR, 1.31; 95% CI, 1.25-1.36; P < .001) and cetuximab (HR, 1.88; 95% CI, 1.68-2.12; P < .001) BT, compared with left-sided tumor origin. In patients with wild-type KRAS tumors (n = 668), cetuximab was associated with reduced mortality among only patients with left-sided mCRC compared

The efficacy of Pistacia Terebinthus soap in the treatment of cetuximab-induced skin toxicity.

PubMed

Tastekin, Didem; Tambas, Makbule; Kilic, Kemal; Erturk, Kayhan; Arslan, Deniz

2014-12-01

This open-labeled phase II, efficacy-finding study evaluated the efficiency and safety of Pistacia terebinthus soap in metastatic colorectal cancer patients who developed cetuximab induced skin toxicity. Patients who received cetuximab plus chemotherapy and developed Grade 2 or 3 skin toxicity were treated twice daily with a soap made of oil extracted from Pistacia terebinthus. During treatment, no topical or oral antibiotics, corticosteroids or other moisturizers were used. Patients were examined 1 week later and their photographs were taken. Fifteen mCRC patients who developed skin toxicity while receiving first-line CTX in combination with chemotherapy were included into the study. Eight patients were male and the median age was 58 (25-70). Sixty percent of the patients (n:9) had Grade 3 skin toxicity. Complete response rates in patients with Grade 2 and Grade 3 skin toxicities were 100 and 33%, respectively. In the remaining patients with Grade 3 toxicity the skin toxicity regressed to Grade 1. The objective response rate was 100%, and no delay, dose reduction or discontinuation of CTX treatment due to skin toxicity was necessary. Skin toxicity reoccurred in all patients when patients stopped administering the soap and therefore they used it throughout the cetuximab treatment. Pistacia terebinthus soap seemed to be used safely and effectively in the treatment of skin toxicity induced by Cetuximab.

Understanding drug targets: no such thing as bad news.

PubMed

Roberts, Ruth A

2018-05-24

How can small-to-medium pharma and biotech companies enhance the chances of running a successful drug project and maximise the return on a limited number of assets? Having a full appreciation of the safety risks associated with proposed drug targets is a crucial element in understanding the unwanted side-effects that might stop a project in its tracks. Having this information is necessary to complement knowledge about the probable efficacy of a future drug. However, the lack of data-rich insight into drug-target safety is one of the major causes of drug-project failure today. Conducting comprehensive target-safety reviews early in the drug discovery process enables project teams to make the right decisions about which drug targets to take forward. Copyright © 2018 Elsevier Ltd. All rights reserved.

Pathological response after neoadjuvant bevacizumab- or cetuximab-based chemotherapy in resected colorectal cancer liver metastases.

PubMed

Pietrantonio, Filippo; Mazzaferro, Vincenzo; Miceli, Rosalba; Cotsoglou, Christian; Melotti, Flavia; Fanetti, Giuseppe; Perrone, Federica; Biondani, Pamela; Muscarà, Cecilia; Di Bartolomeo, Maria; Coppa, Jorgelina; Maggi, Claudia; Milione, Massimo; Tamborini, Elena; de Braud, Filippo

2015-07-01

Neoadjuvant chemotherapy (NACT) prior to liver resection is advantageous for patients with colorectal cancer liver metastases (CLM). Bevacizumab- or cetuximab-based NACT may affect patient outcome and curative resection rate, but comparative studies on differential tumour regression grade (TRG) associated with distinct antibodies-associated regimens are lacking. Ninety-three consecutive patients received NACT plus bevacizumab (n = 46) or cetuximab (n = 47) followed by CLM resection. Pathological response was determined in each resected metastasis as TRG rated from 1 (complete) to 5 (no response). Except for KRAS mutations prevailing in bevacizumab versus cetuximab (57 vs. 21 %, p = 0.001), patients characteristics were well balanced. Median follow-up was 31 months (IQR 17-48). Bevacizumab induced significantly better pathological response rates (TRG1-3: 78 vs. 34 %, p < 0.001) as well as complete responses (TRG1: 13 vs. 0 %, p = 0.012) with respect to cetuximab. Three-year progression-free survival (PFS) and overall survival (OS) were not significantly different in the two cohorts. At multivariable analysis, significant association with pathological response was found for number of resected metastases (p = 0.015) and bevacizumab allocation (p < 0.001), while KRAS mutation showed only a trend. Significant association with poorer PFS and OS was found for low grades of pathological response (p = 0.009 and p < 0.001, respectively), R2 resection or presence of extrahepatic disease (both p < 0.001) and presence of KRAS mutation (p = 0.007 and p < 0.001, respectively). Bevacizumab-based regimens, although influenced by the number of metastases and KRAS status, improve significantly pathological response if compared to cetuximab-based NACT. Possible differential impact among regimens on patient outcome has still to be elucidated.

Breast Cancer-Targeted Nuclear Drug Delivery Overcoming Drug Resistance for Breast Cancer Chemotherapy

DTIC Science & Technology

2011-09-01

breast-cancer-targeted nuclear drug delivery carriers , but we found that the ability of the PEI to disrupt the endosome/lysosome membrane was not...AD_________________ Award Number: W81XWH-09-1-0502 TITLE: Breast Cancer-Targeted Nuclear Drug ...Delivery Overcoming Drug Resistance for Breast Cancer Chemotherapy PRINCIPAL INVESTIGATOR: Youqing Shen, Ph.D

Targeted delivery of anti-tuberculosis drugs to macrophages: targeting mannose receptors

NASA Astrophysics Data System (ADS)

Filatova, L. Yu; Klyachko, N. L.; Kudryashova, E. V.

2018-04-01

The development of systems for targeted delivery of anti-tuberculosis drugs is a challenge of modern biotechnology. Currently, these drugs are encapsulated in a variety of carriers such as liposomes, polymers, emulsions and so on. Despite successful in vitro testing of these systems, virtually no success was achieved in vivo, because of low accessibility of the foci of infection located in alveolar macrophage cells. A promising strategy for increasing the efficiency of therapeutic action of anti-tuberculosis drugs is to encapsulate the agents into mannosylated carriers targeting the mannose receptors of alveolar macrophages. The review addresses the methods for modification of drug substance carriers, such as liposomes and biodegradable polymers, with mannose residues. The use of mannosylated carriers to deliver anti-tuberculosis agents increases the drug circulation time in the blood stream and increases the drug concentration in alveolar macrophage cells. The bibliography includes 113 references.

Systematic review and economic evaluation of bevacizumab and cetuximab for the treatment of metastatic colorectal cancer.

PubMed

Tappenden, P; Jones, R; Paisley, S; Carroll, C

2007-03-01

To assess the clinical effectiveness and cost-effectiveness of bevacizumab and cetuximab in the treatment of individuals with metastatic colorectal cancer (CRC). Searches of main electronic databases were conducted in April and May 2005. For the assessment of bevacizumab, trials were included if they recruited participants with untreated metastatic CRC for first-line treatment. Only trials comparing bevacizumab in combination with irinotecan and/or established fluorouracil (5-FU)-containing or releasing regimens given as first-line therapy were included. For the assessment of cetuximab, trials were included if they recruited participants with epidermal growth-factor receptor-expressing metastatic CRC who had previously failed irinotecan-including therapy. Independent cost-effectiveness models of bevacizumab and cetuximab were developed using survival modelling methods. Adding bevacizumab to irinotecan in combination with 5-FU/folic acid (FA) plus irinotecan resulted in a statistically significant increase in median overall survival (OS) of 4.7 months. Adding bevacizumab to 5-FU/FA resulted in a non-significant increase in median OS of 3.7 months within one study and 7.7 months in another. Adding bevacizumab to irinotecan, fluorouracil and leucovorin (IFL) resulted in a statistically significant increase in median progression-free survival (PFS) of 4.4 months. Adding bevacizumab to 5-FU/FA resulted in a statistically significant increase in median PFS of 3.7 months, and a statistically significant increase in time to disease progression of 3.8 months compared to FU/FA alone. An overall tumour response rate of 44.8% was reported for bevacizumab plus IFL compared to 34.8% for IFL plus placebo. This addition was statistically significant. The addition of bevacizumab to 5-FU/FA resulted in a significant difference in tumour response rate within one study, but not another. Bevacizumab in combination with IFL or 5-FU/FA was observed to result in an increase of grade 3

A General Strategy for Targeting Drugs to Bone.

PubMed

Jahnke, Wolfgang; Bold, Guido; Marzinzik, Andreas L; Ofner, Silvio; Pellé, Xavier; Cotesta, Simona; Bourgier, Emmanuelle; Lehmann, Sylvie; Henry, Chrystelle; Hemmig, René; Stauffer, Frédéric; Hartwieg, J Constanze D; Green, Jonathan R; Rondeau, Jean-Michel

2015-11-23

Targeting drugs to their desired site of action can increase their safety and efficacy. Bisphosphonates are prototypical examples of drugs targeted to bone. However, bisphosphonate bone affinity is often considered too strong and cannot be significantly modulated without losing activity on the enzymatic target, farnesyl pyrophosphate synthase (FPPS). Furthermore, bisphosphonate bone affinity comes at the expense of very low and variable oral bioavailability. FPPS inhibitors were developed with a monophosphonate as a bone-affinity tag that confers moderate affinity to bone, which can furthermore be tuned to the desired level, and the relationship between structure and bone affinity was evaluated by using an NMR-based bone-binding assay. The concept of targeting drugs to bone with moderate affinity, while retaining oral bioavailability, has broad application to a variety of other bone-targeted drugs. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Importance of target-mediated drug disposition for small molecules.

PubMed

Smith, Dennis A; van Waterschoot, Robert A B; Parrott, Neil J; Olivares-Morales, Andrés; Lavé, Thierry; Rowland, Malcolm

2018-06-18

Target concentration is typically not considered in drug discovery. However, if targets are expressed at relatively high concentrations and compounds have high affinity, such that most of the drug is bound to its target, in vitro screens can give unreliable information on compound affinity. In vivo, a similar situation will generate pharmacokinetic (PK) profiles that deviate greatly from those normally expected, owing to target binding affecting drug distribution and clearance. Such target-mediated drug disposition (TMDD) effects on small molecules have received little attention and might only become apparent during clinical trials, with the potential for data misinterpretation. TMDD also confounds human microdosing approaches by providing therapeutically unrepresentative PK profiles. Being aware of these phenomena will improve the likelihood of successful drug discovery and development. Copyright © 2018. Published by Elsevier Ltd.

Targeting bacterial central metabolism for drug development.

PubMed

Murima, Paul; McKinney, John D; Pethe, Kevin

2014-11-20

Current antibiotics, derived mainly from natural sources, inhibit a narrow spectrum of cellular processes, namely DNA replication, protein synthesis, and cell wall biosynthesis. With the worldwide explosion of drug resistance, there is renewed interest in the investigation of alternate essential cellular processes, including bacterial central metabolic pathways, as a drug target space for the next generation of antibiotics. However, the validation of targets in central metabolism is more complex, as essentiality of such targets can be conditional and/or contextual. Bearing in mind our enhanced understanding of prokaryotic central metabolism, a key question arises: can central metabolism be bacteria's Achilles' heel and a therapeutic target for the development of new classes of antibiotics? In this review, we draw lessons from oncology and attempt to address some of the open questions related to feasibility of targeting bacterial central metabolism as a strategy for developing new antibacterial drugs. Copyright © 2014 Elsevier Ltd. All rights reserved.

Drug2Gene: an exhaustive resource to explore effectively the drug-target relation network.

PubMed

Roider, Helge G; Pavlova, Nadia; Kirov, Ivaylo; Slavov, Stoyan; Slavov, Todor; Uzunov, Zlatyo; Weiss, Bertram

2014-03-11

Information about drug-target relations is at the heart of drug discovery. There are now dozens of databases providing drug-target interaction data with varying scope, and focus. Therefore, and due to the large chemical space, the overlap of the different data sets is surprisingly small. As searching through these sources manually is cumbersome, time-consuming and error-prone, integrating all the data is highly desirable. Despite a few attempts, integration has been hampered by the diversity of descriptions of compounds, and by the fact that the reported activity values, coming from different data sets, are not always directly comparable due to usage of different metrics or data formats. We have built Drug2Gene, a knowledge base, which combines the compound/drug-gene/protein information from 19 publicly available databases. A key feature is our rigorous unification and standardization process which makes the data truly comparable on a large scale, allowing for the first time effective data mining in such a large knowledge corpus. As of version 3.2, Drug2Gene contains 4,372,290 unified relations between compounds and their targets most of which include reported bioactivity data. We extend this set with putative (i.e. homology-inferred) relations where sufficient sequence homology between proteins suggests they may bind to similar compounds. Drug2Gene provides powerful search functionalities, very flexible export procedures, and a user-friendly web interface. Drug2Gene v3.2 has become a mature and comprehensive knowledge base providing unified, standardized drug-target related information gathered from publicly available data sources. It can be used to integrate proprietary data sets with publicly available data sets. Its main goal is to be a 'one-stop shop' to identify tool compounds targeting a given gene product or for finding all known targets of a drug. Drug2Gene with its integrated data set of public compound-target relations is freely accessible without

Predicting drug-target interactions using restricted Boltzmann machines.

PubMed

Wang, Yuhao; Zeng, Jianyang

2013-07-01

In silico prediction of drug-target interactions plays an important role toward identifying and developing new uses of existing or abandoned drugs. Network-based approaches have recently become a popular tool for discovering new drug-target interactions (DTIs). Unfortunately, most of these network-based approaches can only predict binary interactions between drugs and targets, and information about different types of interactions has not been well exploited for DTI prediction in previous studies. On the other hand, incorporating additional information about drug-target relationships or drug modes of action can improve prediction of DTIs. Furthermore, the predicted types of DTIs can broaden our understanding about the molecular basis of drug action. We propose a first machine learning approach to integrate multiple types of DTIs and predict unknown drug-target relationships or drug modes of action. We cast the new DTI prediction problem into a two-layer graphical model, called restricted Boltzmann machine, and apply a practical learning algorithm to train our model and make predictions. Tests on two public databases show that our restricted Boltzmann machine model can effectively capture the latent features of a DTI network and achieve excellent performance on predicting different types of DTIs, with the area under precision-recall curve up to 89.6. In addition, we demonstrate that integrating multiple types of DTIs can significantly outperform other predictions either by simply mixing multiple types of interactions without distinction or using only a single interaction type. Further tests show that our approach can infer a high fraction of novel DTIs that has been validated by known experiments in the literature or other databases. These results indicate that our approach can have highly practical relevance to DTI prediction and drug repositioning, and hence advance the drug discovery process. Software and datasets are available on request. Supplementary data are

Aging Biology and Novel Targets for Drug Discovery

PubMed Central

McLachlan, Andrew J.; Quinn, Ronald J.; Simpson, Stephen J.; de Cabo, Rafael

2012-01-01

Despite remarkable technological advances in genetics and drug screening, the discovery of new pharmacotherapies has slowed and new approaches to drug development are needed. Research into the biology of aging is generating many novel targets for drug development that may delay all age-related diseases and be used long term by the entire population. Drugs that successfully delay the aging process will clearly become “blockbusters.” To date, the most promising leads have come from studies of the cellular pathways mediating the longevity effects of caloric restriction (CR), particularly target of rapamycin and the sirtuins. Similar research into pathways governing other hormetic responses that influence aging is likely to yield even more targets. As aging becomes a more attractive target for drug development, there will be increasing demand to develop biomarkers of aging as surrogate outcomes for the testing of the effects of new agents on the aging process. PMID:21693687

Chloride channels as drug targets

PubMed Central

Verkman, Alan S.; Galietta, Luis J. V.

2013-01-01

Chloride channels represent a relatively under-explored target class for drug discovery as elucidation of their identity and physiological roles has lagged behind that of many other drug targets. Chloride channels are involved in a wide range of biological functions, including epithelial fluid secretion, cell-volume regulation, neuroexcitation, smooth-muscle contraction and acidification of intracellular organelles. Mutations in several chloride channels cause human diseases, including cystic fibrosis, macular degeneration, myotonia, kidney stones, renal salt wasting and hyperekplexia. Chloride-channel modulators have potential applications in the treatment of some of these disorders, as well as in secretory diarrhoeas, polycystic kidney disease, osteoporosis and hypertension. Modulators of GABAA (γ-aminobutyric acid A) receptor chloride channels are in clinical use and several small-molecule chloride-channel modulators are in preclinical development and clinical trials. Here, we discuss the broad opportunities that remain in chloride-channel-based drug discovery. PMID:19153558

Placebo-controlled phase II study of vitamin K3 cream for the treatment of cetuximab-induced rash.

PubMed

Eriksen, Jesper Grau; Kaalund, Inger; Clemmensen, Ole; Overgaard, Jens; Pfeiffer, Per

2017-07-01

Cetuximab inhibits the epidermal growth factor receptor (EGFR), and papulopustular eruptions is a frequent side effect. Vitamin K3 (menadione) has preclinically shown to be a potential activator of the EGFR by phosphorylating the receptor (pEGFR). The present randomised study investigated the effect of a vitamin K3 cream on cetuximab-induced rash. Thirty patients were included in this double-blinded placebo-controlled trial. Patients receiving cetuximab 500 mg/m 2 every second week plus chemotherapy for metastatic cancer were included. In each patient, vitamin K3 cream and placebo were applied twice daily on two separate areas of the skin of minimum 10 × 10 cm for up to 2 months. Papulopustular eruptions were evaluated clinically and monitored by clinical photos. Skin biopsies, from ten patients taken before and after 1 month of treatment from each treatment area, were stained for EGFR and pEGFR. Application of vitamin K3 cream twice daily during treatment with cetuximab did not reduce the number of papulopustular eruptions, and this was independent of the use of systemic tetracycline. No significant changes in the staining of EGFR or pEGFR were observed in the skin of the vitamin K3-treated area compared to the placebo area. The present data do not support any clinical or immunohistochemical benefit of using vitamin K3 cream for cetuximab-induced rash.

Drug-Target Interaction Prediction through Label Propagation with Linear Neighborhood Information.

PubMed

Zhang, Wen; Chen, Yanlin; Li, Dingfang

2017-11-25

Interactions between drugs and target proteins provide important information for the drug discovery. Currently, experiments identified only a small number of drug-target interactions. Therefore, the development of computational methods for drug-target interaction prediction is an urgent task of theoretical interest and practical significance. In this paper, we propose a label propagation method with linear neighborhood information (LPLNI) for predicting unobserved drug-target interactions. Firstly, we calculate drug-drug linear neighborhood similarity in the feature spaces, by considering how to reconstruct data points from neighbors. Then, we take similarities as the manifold of drugs, and assume the manifold unchanged in the interaction space. At last, we predict unobserved interactions between known drugs and targets by using drug-drug linear neighborhood similarity and known drug-target interactions. The experiments show that LPLNI can utilize only known drug-target interactions to make high-accuracy predictions on four benchmark datasets. Furthermore, we consider incorporating chemical structures into LPLNI models. Experimental results demonstrate that the model with integrated information (LPLNI-II) can produce improved performances, better than other state-of-the-art methods. The known drug-target interactions are an important information source for computational predictions. The usefulness of the proposed method is demonstrated by cross validation and the case study.

Increased PD-1+ and TIM-3+ TILs during cetuximab therapy inversely correlates with response in head and neck cancer patients

PubMed Central

Jie, Hyun-Bae; Srivastava, Raghvendra M.; Argiris, Athanassios; Bauman, Julie E.; Kane, Lawrence P.; Ferris, Robert L.

2017-01-01

Despite emerging appreciation for the important role of immune checkpoint receptors in regulating the effector functions of T cells, it is unknown whether their expression is involved in determining the clinical outcome in response to cetuximab therapy. We examined the expression patterns of immune checkpoint receptors (including PD-1, CTLA-4, and TIM-3) and cytolytic molecules (including granzyme B and perforin) of CD8+ tumor-infiltrating lymphocytes (TILs) and compared them to those of peripheral blood T lymphocytes (PBLs) in patients with head and neck cancer (HNSCC) during cetuximab therapy. The frequency of PD-1 and TIM-3 expression was significantly increased in CD8+ TILs compared to CD8+ PBLs (P = 0.008 and P = 0.02, respectively). This increased CD8+ TIL population co-expressed granzyme B/perforin and PD-1/TIM-3, which suggests a regulatory role for these immune checkpoint receptors in cetuximab-promoting cytolytic activities of CD8+ TIL. Indeed, the increased frequency of PD-1+ and TIM-3+ CD8+ TILs was inversely correlated with clinical outcome of cetuximab therapy. These findings support the use of PD-1 and TIM-3 as biomarkers to reflect immune status of CD8+ T cells in the tumor microenvironment during cetuximab therapy. Blockade of these immune checkpoint receptors might enhance cetuximab-based cancer immunotherapy to reverse CD8+ TIL dysfunction, thus potentially improving clinical outcomes of HNSCC patients. PMID:28408386

A Computational Approach to Finding Novel Targets for Existing Drugs

PubMed Central

Li, Yvonne Y.; An, Jianghong; Jones, Steven J. M.

2011-01-01

Repositioning existing drugs for new therapeutic uses is an efficient approach to drug discovery. We have developed a computational drug repositioning pipeline to perform large-scale molecular docking of small molecule drugs against protein drug targets, in order to map the drug-target interaction space and find novel interactions. Our method emphasizes removing false positive interaction predictions using criteria from known interaction docking, consensus scoring, and specificity. In all, our database contains 252 human protein drug targets that we classify as reliable-for-docking as well as 4621 approved and experimental small molecule drugs from DrugBank. These were cross-docked, then filtered through stringent scoring criteria to select top drug-target interactions. In particular, we used MAPK14 and the kinase inhibitor BIM-8 as examples where our stringent thresholds enriched the predicted drug-target interactions with known interactions up to 20 times compared to standard score thresholds. We validated nilotinib as a potent MAPK14 inhibitor in vitro (IC50 40 nM), suggesting a potential use for this drug in treating inflammatory diseases. The published literature indicated experimental evidence for 31 of the top predicted interactions, highlighting the promising nature of our approach. Novel interactions discovered may lead to the drug being repositioned as a therapeutic treatment for its off-target's associated disease, added insight into the drug's mechanism of action, and added insight into the drug's side effects. PMID:21909252

Self-Assembled Smart Nanocarriers for Targeted Drug Delivery.

PubMed

Cui, Wei; Li, Junbai; Decher, Gero

2016-02-10

Nanostructured drug-carrier systems promise numerous benefits for drug delivery. They can be engineered to precisely control drug-release rates or to target specific sites within the body with a specific amount of therapeutic agent. However, to achieve the best therapeutic effects, the systems should be designed for carrying the optimum amount of a drug to the desired target where it should be released at the optimum rate for a specified time. Despite numerous attempts, fulfilling all of these requirements in a synergistic way remains a huge challenge. The trend in drug delivery is consequently directed toward integrated multifunctional carrier systems, providing selective recognition in combination with sustained or triggered release. Capsules as vesicular systems enable drugs to be confined for controlled release. Furthermore, carriers modified with recognition groups can enhance the capability of encapsulated drug efficacy. Here, recent advances are reviewed regarding designing and preparing assembled capsules with targeting ligands or size controllable for selective recognition in drug delivery. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Solution NMR Spectroscopy in Target-Based Drug Discovery.

PubMed

Li, Yan; Kang, Congbao

2017-08-23

Solution NMR spectroscopy is a powerful tool to study protein structures and dynamics under physiological conditions. This technique is particularly useful in target-based drug discovery projects as it provides protein-ligand binding information in solution. Accumulated studies have shown that NMR will play more and more important roles in multiple steps of the drug discovery process. In a fragment-based drug discovery process, ligand-observed and protein-observed NMR spectroscopy can be applied to screen fragments with low binding affinities. The screened fragments can be further optimized into drug-like molecules. In combination with other biophysical techniques, NMR will guide structure-based drug discovery. In this review, we describe the possible roles of NMR spectroscopy in drug discovery. We also illustrate the challenges encountered in the drug discovery process. We include several examples demonstrating the roles of NMR in target-based drug discoveries such as hit identification, ranking ligand binding affinities, and mapping the ligand binding site. We also speculate the possible roles of NMR in target engagement based on recent processes in in-cell NMR spectroscopy.

Experimental Drug Metarrestin Targets Metastatic Tumors

Cancer.gov

An experimental drug called metarrestin appears to selectively target tumors that have spread to other parts of the body. As this Cancer Currents blog post reports, the drug shrank metastatic tumors and extended survival in in mouse models of pancreatic cancer.

Discovery of peptide drug carrier candidates for targeted multi-drug delivery into prostate cancer cells.

PubMed

Bashari, O; Redko, B; Cohen, A; Luboshits, G; Gellerman, G; Firer, M A

2017-11-01

Metastatic castration-resistant prostate cancer (mCRPC) remains essentially incurable. Targeted Drug Delivery (TDD) systems may overcome the limitations of current mCRPC therapies. We describe the use of strict criteria to isolate novel prostate cancer cell targeting peptides that specifically deliver drugs into target cells. Phage from a libraries displaying 7mer peptides were exposed to PC-3 cells and only internalized phage were recovered. The ability of these phage to internalize into other prostate cancer cells (LNCaP, DU-145) was validated. The displayed peptides of selected phage clones were synthesized and their specificity for target cells was validated in vitro and in vivo. One peptide (P12) which specifically targeted PC-3 tumors in vivo was incorporated into mono-drug (Chlorambucil, Combretastatin or Camptothecin) and dual-drug (Chlorambucil/Combretastatin or Chlorambucil/Camptothecin) PDCs and the cytotoxic efficacy of these conjugates for target cells was tested. Conjugation of P12 into dual-drug PDCs allowed discovery of new drug combinations with synergistic effects. The use of strict selection criteria can lead to discovery of novel peptides for use as drug carriers for TDD. PDCs represent an effective alternative to current modes of free drug chemotherapy for prostate cancer. Copyright © 2017. Published by Elsevier B.V.

A review on proniosomal drug delivery system for targeted drug action.

PubMed

Radha, G V; Rani, T Sudha; Sarvani, B

2013-03-01

Proniosomes are dry formulation of water soluble carrier particles that are coated with surfactant. They are rehydrated to form niosomal dispersion immediately before use on agitation in hot aqueous media within minutes. Proniosomes are physically stable during the storage and transport. Drug encapsulated in the vesicular structure of proniosomes prolong the existence of drug in the systematic circulation and enhances the penetration into target tissue and reduce toxicity. From a technical point of view, niosomes are promising drug carriers as they possess greater chemical stability and lack of many disadvantages associated with liposomes, such as high- cost and variable purity problems of phospholipids. The present review emphasizes on overall methods of preparation characterization and applicability of proniosomes in targeted drug action.

Multifunctional particles for melanoma-targeted drug delivery.

PubMed

Wadajkar, Aniket S; Bhavsar, Zarna; Ko, Cheng-Yu; Koppolu, Bhanuprasanth; Cui, Weina; Tang, Liping; Nguyen, Kytai T

2012-08-01

New magnetic-based core-shell particles (MBCSPs) were developed to target skin cancer cells while delivering chemotherapeutic drugs in a controlled fashion. MBCSPs consist of a thermo-responsive shell of poly(N-isopropylacrylamide-acrylamide-allylamine) and a core of poly(lactic-co-glycolic acid) (PLGA) embedded with magnetite nanoparticles. To target melanoma cancer cells, MBCSPs were conjugated with Gly-Arg-Gly-Asp-Ser (GRGDS) peptides that specifically bind to the α(5)β(3) receptors of melanoma cells. MBCSPs consist of unique multifunctional and controlled drug delivery characteristics. Specially, they can provide dual drug release mechanisms (a sustained release of drugs through degradation of PLGA core and a controlled release in response to changes in temperature via thermo-responsive polymer shell), and dual targeting mechanisms (magnetic localization and receptor-mediated targeting). Results from in vitro studies indicate that GRGDS-conjugated MBCSPs have an average diameter of 296 nm and exhibit no cytotoxicity towards human dermal fibroblasts up to 500 μg ml(-1). Further, a sustained release of curcumin from the core and a temperature-dependent release of doxorubicin from the shell of MBCSPs were observed. The particles also produced a dark contrast signal in magnetic resonance imaging. Finally, the particles were accumulated at the tumor site in a B16F10 melanoma orthotopic mouse model, especially in the presence of a magnet. Results indicate great potential of MBCSPs as a platform technology to target, treat and monitor melanoma for targeted drug delivery to reduce side effects of chemotherapeutic reagents. Copyright © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Drug Discovery for Neglected Diseases: Molecular Target-Based and Phenotypic Approaches

PubMed Central

2013-01-01

Drug discovery for neglected tropical diseases is carried out using both target-based and phenotypic approaches. In this paper, target-based approaches are discussed, with a particular focus on human African trypanosomiasis. Target-based drug discovery can be successful, but careful selection of targets is required. There are still very few fully validated drug targets in neglected diseases, and there is a high attrition rate in target-based drug discovery for these diseases. Phenotypic screening is a powerful method in both neglected and non-neglected diseases and has been very successfully used. Identification of molecular targets from phenotypic approaches can be a way to identify potential new drug targets. PMID:24015767

DrugPath: a database for academic investigators to match oncology molecular targets with drugs in development.

PubMed

Shah, Eric D; Fisch, Brandon M A; Arceci, Robert J; Buckley, Jonathan D; Reaman, Gregory H; Sorensen, Poul H; Triche, Timothy J; Reynolds, C Patrick

2014-05-01

Academic laboratories are developing increasingly large amounts of data that describe the genomic landscape and gene expression patterns of various types of cancers. Such data can potentially identify novel oncology molecular targets in cancer types that may not be the primary focus of a drug sponsor's initial research for an investigational new drug. Obtaining preclinical data that point toward the potential for a given molecularly targeted agent, or a novel combination of agents requires knowledge of drugs currently in development in both the academic and commercial sectors. We have developed the DrugPath database ( http://www.drugpath.org ) as a comprehensive, free-of-charge resource for academic investigators to identify agents being developed in academics or industry that may act against molecular targets of interest. DrugPath data on molecular targets overlay the Michigan Molecular Interactions ( http://mimi.ncibi.org ) gene-gene interaction map to facilitate identification of related agents in the same pathway. The database catalogs 2,081 drug development programs representing 751 drug sponsors and 722 molecular and genetic targets. DrugPath should assist investigators in identifying and obtaining drugs acting on specific molecular targets for biological and preclinical therapeutic studies.

Discovery of novel drugs for promising targets.

PubMed

Martell, Robert E; Brooks, David G; Wang, Yan; Wilcoxen, Keith

2013-09-01

Once a promising drug target is identified, the steps to actually discover and optimize a drug are diverse and challenging. The goal of this study was to provide a road map to navigate drug discovery. Review general steps for drug discovery and provide illustrating references. A number of approaches are available to enhance and accelerate target identification and validation. Consideration of a variety of potential mechanisms of action of potential drugs can guide discovery efforts. The hit to lead stage may involve techniques such as high-throughput screening, fragment-based screening, and structure-based design, with informatics playing an ever-increasing role. Biologically relevant screening models are discussed, including cell lines, 3-dimensional culture, and in vivo screening. The process of enabling human studies for an investigational drug is also discussed. Drug discovery is a complex process that has significantly evolved in recent years. © 2013 Elsevier HS Journals, Inc. All rights reserved.

Drug targets for resistant malaria: Historic to future perspectives.

PubMed

Kumar, Sahil; Bhardwaj, T R; Prasad, D N; Singh, Rajesh K

2018-05-11

New antimalarial targets are the prime need for the discovery of potent drug candidates. In order to fulfill this objective, antimalarial drug researches are focusing on promising targets in order to develop new drug candidates. Basic metabolism and biochemical process in the malaria parasite, i.e. Plasmodium falciparum can play an indispensable role in the identification of these targets. But, the emergence of resistance to antimalarial drugs is an escalating comprehensive problem with the progress of antimalarial drug development. The development of resistance has highlighted the need for the search of novel antimalarial molecules. The pharmaceutical industries are committed to new drug development due to the global recognition of this life threatening resistance to the currently available antimalarial therapy. The recent developments in the understanding of parasite biology are exhilarating this resistance issue which is further being ignited by malaria genome project. With this background of information, this review was aimed to highlights and provides useful information on various present and promising treatment approaches for resistant malaria, new progresses, pursued by some innovative targets that have been explored till date. This review also discusses modern and futuristic multiple approaches to antimalarial drug discovery and development with pictorial presentations highlighting the various targets, that could be exploited for generating promising new drugs in the future for drug resistant malaria. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Enhanced cellular transport and drug targeting using dendritic nanostructures

NASA Astrophysics Data System (ADS)

Kannan, R. M.; Kolhe, Parag; Kannan, Sujatha; Lieh-Lai, Mary

2003-03-01

Dendrimers and hyperbranched polymers possess highly branched architectures, with a large number of controllable, tailorable, peripheral' functionalities. Since the surface chemistry of these materials can be modified with relative ease, these materials have tremendous potential in targeted drug delivery. The large density of end groups can also be tailored to create enhanced affinity to targeted cells, and can also encapsulate drugs and deliver them in a controlled manner. We are developing tailor-modified dendritic systems for drug delivery. Synthesis, drug/ligand conjugation, in vitro cellular and in vivo drug delivery, and the targeting efficiency to the cell are being studied systematically using a wide variety of experimental tools. Results on PAMAM dendrimers and polyol hyperbranched polymers suggest that: (1) These materials complex/encapsulate a large number of drug molecules and release them at tailorable rates; (2) The drug-dendrimer complex is transported very rapidly through a A549 lung epithelial cancel cell line, compared to free drug, perhaps by endocytosis. The ability of the drug-dendrimer-ligand complexes to target specific asthma and cancer cells is currently being explored using in vitro and in vivo animal models.

Cetuximab with radiotherapy as an alternative treatment for advanced squamous cell carcinoma of the temporal bone.

PubMed

Ebisumoto, Koji; Okami, Kenji; Hamada, Masashi; Maki, Daisuke; Sakai, Akihiro; Saito, Kosuke; Shimizu, Fukuko; Kaneda, Shoji; Iida, Masahiro

2018-06-01

The prognosis of advanced temporal bone cancer is poor, because complete surgical resection is difficult to achieve. Chemoradiotherapy is one of the available curative treatment options; however, its systemic effects on the patient restrict the use of this treatment. A 69-year-old female (who needed peritoneal dialysis) presented at our clinic with T4 left external auditory canal cancer and was treated with cetuximab plus radiotherapy (RT). The primary lesion showed complete response. The patient is currently alive with no evidence of disease two years after completion of the treatment and does not show any late toxicity. This is the first advanced temporal bone cancer patient treated with RT plus cetuximab. Cetuximab plus RT might be a treatment alternative for patients with advanced temporal bone cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

Different Toxicity of Cetuximab and Panitumumab in Metastatic Colorectal Cancer Treatment: A Systematic Review and Meta-Analysis.

PubMed

Petrelli, Fausto; Ardito, Raffaele; Ghidini, Antonio; Zaniboni, Alberto; Ghidini, Michele; Barni, Sandro; Tomasello, Gianluca

2018-01-01

Over the last few years only one large randomized phase III study has tried to prospectively assess the safety of cetuximab and panitumumab in a head-to-head comparison. Despite the similar overall toxicity profile, cetuximab and panitumumab retain peculiar safety characteristics that deserve to be deeply investigated. We conducted a systematic review for randomized trials in PubMed, the Cochrane Central Register of Controlled Trials, SCOPUS, Web of Science, and EMBASE using the terms ("cetuximab" or "panitumumab") AND ("colorectal cancer" OR "colorectal carcinoma"). Data of adverse events were aggregated to obtain pooled incidence rates of prespecified adverse events. Incidence of skin toxicities was the primary outcome. A χ2 test was used for comparisons of proportions and an odds ratio (OR) was calculated for comparison. A total of 38 studies were included for analysis. Cetuximab was associated with fewer G3-4 skin toxicities (OR = 0.62, 95% CI 0.53-0.62; p < 0.001), slightly more frequent G3-4 acne-like rash (OR = 1.24, 95% CI 1.04-1.48; p = 0.04), and paronychia (OR 1.36, 95% CI 1.1-1.7), but fewer cases of skin fissures (OR = 0.64, 95% CI 0.44-0.93; p = 0.02) and pruritus (OR = 0.45, 95% CI 0.35-0.58; p < 0.001) than PANI. In conclusion, this meta-analysis shows that cetuximab- and panitumumab-based chemotherapy have different toxicity profiles in terms of the rate of severe adverse events. © 2018 S. Karger AG, Basel.

Drug Target Interference in Immunogenicity Assays: Recommendations and Mitigation Strategies.

PubMed

Zhong, Zhandong Don; Clements-Egan, Adrienne; Gorovits, Boris; Maia, Mauricio; Sumner, Giane; Theobald, Valerie; Wu, Yuling; Rajadhyaksha, Manoj

2017-11-01

Sensitive and specific methodology is required for the detection and characterization of anti-drug antibodies (ADAs). High-quality ADA data enables the evaluation of potential impact of ADAs on the drug pharmacokinetic profile, patient safety, and efficacious response to the drug. Immunogenicity assessments are typically initiated at early stages in preclinical studies and continue throughout the drug development program. One of the potential bioanalytical challenges encountered with ADA testing is the need to identify and mitigate the interference mediated by the presence of soluble drug target. A drug target, when present at sufficiently high circulating concentrations, can potentially interfere with the performance of ADA and neutralizing antibody (NAb) assays, leading to either false-positive or, in some cases, false-negative ADA and NAb assay results. This publication describes various mechanisms of assay interference by soluble drug target, as well as strategies to recognize and mitigate such target interference. Pertinent examples are presented to illustrate the impact of target interference on ADA and NAb assays as well as several mitigation strategies, including the use of anti-target antibodies, soluble versions of the receptors, target-binding proteins, lectins, and solid-phase removal of targets. Furthermore, recommendations for detection and mitigation of such interference in different formats of ADA and NAb assays are provided.

Drug Target Prediction and Repositioning Using an Integrated Network-Based Approach

PubMed Central

Emig, Dorothea; Ivliev, Alexander; Pustovalova, Olga; Lancashire, Lee; Bureeva, Svetlana; Nikolsky, Yuri; Bessarabova, Marina

2013-01-01

The discovery of novel drug targets is a significant challenge in drug development. Although the human genome comprises approximately 30,000 genes, proteins encoded by fewer than 400 are used as drug targets in the treatment of diseases. Therefore, novel drug targets are extremely valuable as the source for first in class drugs. On the other hand, many of the currently known drug targets are functionally pleiotropic and involved in multiple pathologies. Several of them are exploited for treating multiple diseases, which highlights the need for methods to reliably reposition drug targets to new indications. Network-based methods have been successfully applied to prioritize novel disease-associated genes. In recent years, several such algorithms have been developed, some focusing on local network properties only, and others taking the complete network topology into account. Common to all approaches is the understanding that novel disease-associated candidates are in close overall proximity to known disease genes. However, the relevance of these methods to the prediction of novel drug targets has not yet been assessed. Here, we present a network-based approach for the prediction of drug targets for a given disease. The method allows both repositioning drug targets known for other diseases to the given disease and the prediction of unexploited drug targets which are not used for treatment of any disease. Our approach takes as input a disease gene expression signature and a high-quality interaction network and outputs a prioritized list of drug targets. We demonstrate the high performance of our method and highlight the usefulness of the predictions in three case studies. We present novel drug targets for scleroderma and different types of cancer with their underlying biological processes. Furthermore, we demonstrate the ability of our method to identify non-suspected repositioning candidates using diabetes type 1 as an example. PMID:23593264

Fluid mechanics aspects of magnetic drug targeting.

PubMed

Odenbach, Stefan

2015-10-01

Experiments and numerical simulations using a flow phantom for magnetic drug targeting have been undertaken. The flow phantom is a half y-branched tube configuration where the main tube represents an artery from which a tumour-supplying artery, which is simulated by the side branch of the flow phantom, branches off. In the experiments a quantification of the amount of magnetic particles targeted towards the branch by a magnetic field applied via a permanent magnet is achieved by impedance measurement using sensor coils. Measuring the targeting efficiency, i.e. the relative amount of particles targeted to the side branch, for different field configurations one obtains targeting maps which combine the targeting efficiency with the magnetic force densities in characteristic points in the flow phantom. It could be shown that targeting efficiency depends strongly on the magnetic field configuration. A corresponding numerical model has been set up, which allows the simulation of targeting efficiency for variable field configuration. With this simulation good agreement of targeting efficiency with experimental data has been found. Thus, the basis has been laid for future calculations of optimal field configurations in clinical applications of magnetic drug targeting. Moreover, the numerical model allows the variation of additional parameters of the drug targeting process and thus an estimation of the influence, e.g. of the fluid properties on the targeting efficiency. Corresponding calculations have shown that the non-Newtonian behaviour of the fluid will significantly influence the targeting process, an aspect which has to be taken into account, especially recalling the fact that the viscosity of magnetic suspensions depends strongly on the magnetic field strength and the mechanical load.

Leukocytes as carriers for targeted cancer drug delivery.

PubMed

Mitchell, Michael J; King, Michael R

2015-03-01

Metastasis contributes to over 90% of cancer-related deaths. Numerous nanoparticle platforms have been developed to target and treat cancer, yet efficient delivery of these systems to the appropriate site remains challenging. Leukocytes, which share similarities to tumor cells in terms of their transport and migration through the body, are well suited to serve as carriers of drug delivery systems to target cancer sites. This review focuses on the use and functionalization of leukocytes for therapeutic targeting of metastatic cancer. Tumor cell and leukocyte extravasation, margination in the bloodstream, and migration into soft tissue are discussed, along with the potential to exploit these functional similarities to effectively deliver drugs. Current nanoparticle-based drug formulations for the treatment of cancer are reviewed, along with methods to functionalize delivery vehicles to leukocytes, either on the surface and/or within the cell. Recent progress in this area, both in vitro and in vivo, is also discussed, with a particular emphasis on targeting cancer cells in the bloodstream as a means to interrupt the metastatic process. Leukocytes interact with cancer cells both in the bloodstream and at the site of solid tumors. These interactions can be utilized to effectively deliver drugs to targeted areas, which can reduce both the amount of drug required and various nonspecific cytotoxic effects within the body. If drug delivery vehicle functionalization does not interfere with leukocyte function, this approach may be utilized to neutralize tumor cells in the bloodstream to prevent the formation of new metastases, and also to deliver drugs to metastatic sites within tissues.

Targeted delivery of drugs for liver fibrosis.

PubMed

Li, Feng; Wang, Ji-yao

2009-05-01

Liver fibrosis and its end stage disease cirrhosis are a major cause of mortality and morbidity around the world. There is no effective pharmaceutical intervention for liver fibrosis at present. Many drugs that show potent antifibrotic activities in vitro often show only minor effects in vivo because of insufficient concentrations of drugs accumulating around the target cell and their adverse effects as a result of affecting other non-target cells. Hepatic stellate cells (HSC) play a critical role in the fibrogenesis of liver, so they are the target cells of antifibrotic therapy. Several kinds of targeted delivery system that could target the receptors expressed on HSC have been designed, and have shown an attractive targeted potential in vivo. After being carried by these delivery systems, many agents showed a powerful antifibrotic effect in animal models of liver fibrosis. These targeted delivery systems provide a new pathway for the therapy of liver fibrosis. The characteristics of theses targeted carriers are reviewed in this paper.

Preoperative Radiotherapy of Advanced Rectal Cancer With Capecitabine and Oxaliplatin With or Without Cetuximab: A Pooled Analysis of Three Prospective Phase I-II Trials

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weiss, Christian, E-mail: christian.weiss@kgu.d; Arnold, Dirk; Dellas, Kathrin

2010-10-01

Purpose: A pooled analysis of three prospective trials of preoperative radiochemotherapy (RCT) for rectal cancer by using oxaliplatin and capecitabine with or without cetuximab was performed to evaluate the impact of additional cetuximab on pathologic complete response (pCR) rates and tumor regression (TRG) grades. Methods and Materials: Of 202 patients, 172 patients met the inclusion criteria (primary tumor stage II/III, M0). All patients received concurrent RCT, and 46 patients received additional cetuximab therapy. A correlation of pretreatment clinicopathologic factors and cetuximab treatment with early pCR rates (TRG > 50%) was performed with univariate and multivariate analyses. Toxicity data were recordedmore » for all patients. Results: Of 172 patients, 24 (14%) patients achieved a pCR, and 84 of 172 (71%) patients showed a TRG of >50% in the surgical specimen assessment after preoperative treatment. Age, gender, and T/N stages, as well as localization of the tumor, were not associated with pCR or good TRG. The pCR rate was 16% after preoperative RCT alone and 9% with concurrent cetuximab therapy (p = 0.32). A significantly reduced TRG of >50% was found after RCT with cetuximab compared to RCT alone (p = 0.0035). This was validated by a multivariate analysis with all available clinical factors (p = 0.0037). Acute toxicity and surgical complications were not increased with additional cetuximab. Conclusions: Triple therapy with RCT and cetuximab seems to be feasible, with no unexpected toxicity. Early response assessment (TRG), however, suggests subadditive interaction. A longer follow-up (and finally randomized trials) is needed to draw any firm conclusions with respect to local and distant failure rates.« less

The addition of celecoxib improves the antitumor effect of cetuximab in colorectal cancer: role of EGFR-RAS-FOXM1-β-catenin signaling axis

PubMed Central

Valverde, Araceli; Peñarando, Jon; Cañas, Amanda; López-Sánchez, Laura M.; Conde, Francisco; Guil-Luna, Silvia; Hernández, Vanessa; Villar, Carlos; Morales-Estévez, Cristina; de la Haba-Rodríguez, Juan; Arand o, Enrique; Rodríguez-Ariza, Antonio

2017-01-01

Here we showed that the addition of the COX-2 inhibitor celecoxib improved the antitumor efficacy in colorectal cancer (CRC) of the monoclonal anti-EGFR antibody cetuximab. The addition of celecoxib augmented the efficacy of cetuximab to inhibit cell proliferation and to induce apoptosis in CRC cells. Moreover, the combination of celecoxib and cetuximab was more effective than either treatment alone in reducing the tumor volume in a mouse xenograft model. The combined treatment enhanced the inhibition of EGFR signaling and altered the subcellular distribution of β-catenin. Moreover, knockdown of FOXM1 showed that this transcription factor participates in this enhanced antitumoral response. Besides, the combined treatment decreased β-catenin/FOXM1 interaction and reduced the cancer stem cell subpopulation in CRC cells, as indicated their diminished capacity to form colonospheres. Notably, the inmunodetection of FOXM1 in the nuclei of tumor cells in human colorectal adenocarcinomas was significantly associated with response of patients to cetuximab. In summary, our study shows that the addition of celecoxib enhances the antitumor efficacy of cetuximab in CRC due to impairment of EGFR-RAS-FOXM1-β-catenin signaling axis. Results also support that FOXM1 could be a predictive marker of response of mCRC patients to cetuximab therapy. PMID:28423516

The Tuberculosis Drug Discovery and Development Pipeline and Emerging Drug Targets

PubMed Central

Mdluli, Khisimuzi; Kaneko, Takushi; Upton, Anna

2015-01-01

The recent accelerated approval for use in extensively drug-resistant and multidrug-resistant-tuberculosis (MDR-TB) of two first-in-class TB drugs, bedaquiline and delamanid, has reinvigorated the TB drug discovery and development field. However, although several promising clinical development programs are ongoing to evaluate new TB drugs and regimens, the number of novel series represented is few. The global early-development pipeline is also woefully thin. To have a chance of achieving the goal of better, shorter, safer TB drug regimens with utility against drug-sensitive and drug-resistant disease, a robust and diverse global TB drug discovery pipeline is key, including innovative approaches that make use of recently acquired knowledge on the biology of TB. Fortunately, drug discovery for TB has resurged in recent years, generating compounds with varying potential for progression into developable leads. In parallel, advances have been made in understanding TB pathogenesis. It is now possible to apply the lessons learned from recent TB hit generation efforts and newly validated TB drug targets to generate the next wave of TB drug leads. Use of currently underexploited sources of chemical matter and lead-optimization strategies may also improve the efficiency of future TB drug discovery. Novel TB drug regimens with shorter treatment durations must target all subpopulations of Mycobacterium tuberculosis existing in an infection, including those responsible for the protracted TB treatment duration. This review summarizes the current TB drug development pipeline and proposes strategies for generating improved hits and leads in the discovery phase that could help achieve this goal. PMID:25635061

Mechanistic models enable the rational use of in vitro drug-target binding kinetics for better drug effects in patients.

PubMed

de Witte, Wilhelmus E A; Wong, Yin Cheong; Nederpelt, Indira; Heitman, Laura H; Danhof, Meindert; van der Graaf, Piet H; Gilissen, Ron A H J; de Lange, Elizabeth C M

2016-01-01

Drug-target binding kinetics are major determinants of the time course of drug action for several drugs, as clearly described for the irreversible binders omeprazole and aspirin. This supports the increasing interest to incorporate newly developed high-throughput assays for drug-target binding kinetics in drug discovery. A meaningful application of in vitro drug-target binding kinetics in drug discovery requires insight into the relation between in vivo drug effect and in vitro measured drug-target binding kinetics. In this review, the authors discuss both the relation between in vitro and in vivo measured binding kinetics and the relation between in vivo binding kinetics, target occupancy and effect profiles. More scientific evidence is required for the rational selection and development of drug-candidates on the basis of in vitro estimates of drug-target binding kinetics. To elucidate the value of in vitro binding kinetics measurements, it is necessary to obtain information on system-specific properties which influence the kinetics of target occupancy and drug effect. Mathematical integration of this information enables the identification of drug-specific properties which lead to optimal target occupancy and drug effect in patients.

Phase II Trial of Cetuximab With or Without Paclitaxel in Patients With Advanced Urothelial Tract Carcinoma

PubMed Central

Wong, Yu-Ning; Litwin, Samuel; Vaughn, David; Cohen, Seth; Plimack, Elizabeth R.; Lee, James; Song, Wei; Dabrow, Michael; Brody, Marion; Tuttle, Holly; Hudes, Gary

2012-01-01

Purpose The benefit of salvage chemotherapy is modest in metastatic urothelial cancer. We conducted a randomized, noncomparative phase II study to measure the efficacy of cetuximab with or without paclitaxel in patients with previously treated urothelial cancer. Patients and Methods Patients with metastatic urothelial cancer who received one line of chemotherapy in the perioperative or metastatic setting were randomly assigned to 4-week cycles of cetuximab 250 mg/m2 with or without paclitaxel 80 mg/m2 per week. We used early progression as an indicator of futility. Either arm would close if seven of the initial 15 patients in that arm progressed at the first disease evaluation at 8 weeks. Results We enrolled 39 evaluable patients. The single-agent cetuximab arm closed after nine of the first 11 patients progressed by 8 weeks. The combination arm completed the full accrual of 28 patients, of whom 22 patients (78.5%) had visceral disease. Twelve of 28 patients had progression-free survival greater than 16 weeks. The overall response rate was 25% (95% CI, 11% to 45%; three complete responses and four partial responses). The median progression-free survival was 16.4 weeks (95% CI, 12 to 25.1 weeks), and the median overall survival was 42 weeks (95% CI, 30.4 to 78 weeks). Treatment-related grade 3 and 4 adverse events that occurred in at least two patients were rash (six cases), fatigue (five cases), and low magnesium (three cases). Conclusion Although it had limited activity as a single agent, cetuximab appears to augment the antitumor activity of paclitaxel in previously treated urothelial cancers. The cetuximab and paclitaxel combination merits additional study to establish its role in the treatment of urothelial cancers. PMID:22927525

Radiochemotherapy With Cetuximab, Cisplatin, and Amifostine for Locally Advanced Head and Neck Cancer: A Feasibility Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Koukourakis, Michael I., E-mail: targ@her.forthnet.g; Tsoutsou, Pelagia G.; Karpouzis, Antonios

2010-05-01

Purpose: Radiotherapy (RT) combined with cisplatin or cetuximab is the standard of care for patients with locally advanced head/neck cancer (LA-HNC). The feasibility of radiochemotherapy with cisplatin and cetuximab, supported with amifostine, was herein investigated. Methods and Materials: Forty-three patients with LA-HNC were recruited. Conformal hypofractionated/accelerated RT with amifostine cytoprotection (2.7 Gy/fraction, 21 fractions in 4 weeks) was combined with cisplatin (30 mg/m{sup 2}/week) and cetuximab (standard weekly regimen) therapy. The dose of amifostine was individualized according to tolerance. Results: A high daily amifostine dose (750-1,000 mg) was tolerated by 41.8% of patients, and a standard dose (500 mg) wasmore » tolerated by 34.9% of patients. A high amifostine dose was linked to reduced RT delays (p = 0.0003). Grade 3 to 4 (3-4) mucositis occurred in 7/43 (16.2%) patients, and fungal infections occurred in 18/43 (41.8%) patients. Radiation dermatitis was not aggravated. Interruption of cetuximab due to acneiform rash was necessary in 23.3% of patients, while amifostine-related fever and rash were not observed. Severe late radiation sequelae consisted of laryngeal edema (9% laryngeal cases) and cervical strictures (33% of hypopharyngeal cases). Good salivary function was preserved in 6/11 (54.5%) nasopharyngeal cancer patients. The complete response rate was 68.5%, reaching 77.2% in patients with minor radiotherapy delays. The 24-month local control and survival rates were 72.3% and 91%, respectively (median follow-up was 13 months.). Conclusions: In this feasibility study, weekly administration of cisplatin and cetuximab was safely combined with accelerated RT, supported with amifostine, at the cost of a high incidence of acneiform rash but a reduced incidence of amifostine-related fever/rash. A high daily dose of amifostine allows completion of therapy with minor delays.« less

Effect of HK2, PKM2 and LDHA on Cetuximab efficacy in metastatic colorectal cancer.

PubMed

Wang, Haohua; Peng, Roujun; Chen, Xiuxing; Jia, Rui; Huang, Chunyue; Huang, Yuanyuan; Xia, Liangping; Guo, Guifang

2018-04-01

Although hexokinase (HK) 2, pyruvate kinase muscle (PKM) isozyme 2 and lactate dehydrogenase (LDH) A predict the efficacy of medicines in various solid tumors, their ability to predict the efficacy of cetuximab in metastatic colorectal cancer (mCRC) remains unclear. mCRC patients with pathological specimens who received cetuximab and chemotherapy from 2005 to 2015 in the present institution were enrolled. Immunohistochemistry was used to detect HK2, PKM2 and LDHA expression. SPSS20 was used for statistical analysis. A total of 68 patients were included; 33 received cetuximab plus chemotherapy as first-line therapy, and the rest, as second- or later-line therapy. HK2 expression levels were increased in cancer compared with normal tissue (75.4% vs. 40%; P<0.001), however PKM2 (P=0.243) and LDHA (P=0.067) expression levels were not. For progression-free survival (PFS) with first-line cetuximab plus chemotherapy, patients with high HK2 expression exhibited longer PFS compared with those with low HK2 expression (23.9 months vs. 6.9 months; P=0.021). However, this positive association was absent in 35 cases administered first-line chemotherapy alone (13.4 months vs. 13.5 months; P=0.539). LDHA expression was associated with the PFS of patients receiving first-line chemotherapy (18.3 and 10.1 months for high and low expression, respectively; P=0.005), whereas this association was absent in cetuximab plus chemotherapy cases (19.9 months vs. 12 months; P=0.522). Furthermore, high LDHA expression correlated with high overall response rate (ORR) (72.2% vs. 15.4%, P=0.006) for chemotherapy, however not disease control rate (DCR) (P=0.074). Neither DCR nor ORR were associated with HK2 expression. PKM2 expression did not affect PFS, DCR or ORR. LDHA expression (P=0.005), pathological differentiation (P=0.019) and synchronous/metachronous metastasis (P=0.014) were independent predictive factors of PFS for all first-line patients, and tumor differentiation (P=0.002) was associated

The Expanding Diversity of Mycobacterium tuberculosis Drug Targets.

PubMed

Wellington, Samantha; Hung, Deborah T

2018-05-11

After decades of relative inactivity, a large increase in efforts to discover antitubercular therapeutics has brought insights into the biology of Mycobacterium tuberculosis (Mtb) and promising new drugs such as bedaquiline, which inhibits ATP synthase, and the nitroimidazoles delamanid and pretomanid, which inhibit both mycolic acid synthesis and energy production. Despite these advances, the drug discovery pipeline remains underpopulated. The field desperately needs compounds with novel mechanisms of action capable of inhibiting multi- and extensively drug -resistant Mtb (M/XDR-TB) and, potentially, nonreplicating Mtb with the hope of shortening the duration of required therapy. New knowledge about Mtb, along with new methods and technologies, has driven exploration into novel target areas, such as energy production and central metabolism, that diverge from the classical targets in macromolecular synthesis. Here, we review new small molecule drug candidates that act on these novel targets to highlight the methods and perspectives advancing the field. These new targets bring with them the aspiration of shortening treatment duration as well as a pipeline of effective regimens against XDR-TB, positioning Mtb drug discovery to become a model for anti-infective discovery.

Analysis of A Drug Target-based Classification System using Molecular Descriptors.

PubMed

Lu, Jing; Zhang, Pin; Bi, Yi; Luo, Xiaomin

2016-01-01

Drug-target interaction is an important topic in drug discovery and drug repositioning. KEGG database offers a drug annotation and classification using a target-based classification system. In this study, we gave an investigation on five target-based classes: (I) G protein-coupled receptors; (II) Nuclear receptors; (III) Ion channels; (IV) Enzymes; (V) Pathogens, using molecular descriptors to represent each drug compound. Two popular feature selection methods, maximum relevance minimum redundancy and incremental feature selection, were adopted to extract the important descriptors. Meanwhile, an optimal prediction model based on nearest neighbor algorithm was constructed, which got the best result in identifying drug target-based classes. Finally, some key descriptors were discussed to uncover their important roles in the identification of drug-target classes.

Leukocytes as carriers for targeted cancer drug delivery

PubMed Central

Mitchell, Michael J

2017-01-01

Introduction Metastasis contributes to over 90% of cancer-related deaths. Numerous nanoparticle platforms have been developed to target and treat cancer, yet efficient delivery of these systems to the appropriate site remains challenging. Leukocytes, which share similarities to tumor cells in terms of their transport and migration through the body, are well suited to serve as carriers of drug delivery systems to target cancer sites. Areas covered This review focuses on the use and functionalization of leukocytes for therapeutic targeting of metastatic cancer. Tumor cell and leukocyte extravasation, margination in the bloodstream, and migration into soft tissue are discussed, along with the potential to exploit these functional similarities to effectively deliver drugs. Current nanoparticle-based drug formulations for the treatment of cancer are reviewed, along with methods to functionalize delivery vehicles to leukocytes, either on the surface and/or within the cell. Recent progress in this area, both in vitro and in vivo, is also discussed, with a particular emphasis on targeting cancer cells in the bloodstream as a means to interrupt the metastatic process. Expert opinion Leukocytes interact with cancer cells both in the bloodstream and at the site of solid tumors. These interactions can be utilized to effectively deliver drugs to targeted areas, which can reduce both the amount of drug required and various nonspecific cytotoxic effects within the body. If drug delivery vehicle functionalization does not interfere with leukocyte function, this approach may be utilized to neutralize tumor cells in the bloodstream to prevent the formation of new metastases, and also to deliver drugs to metastatic sites within tissues. PMID:25270379

Leveraging 3D chemical similarity, target and phenotypic data in the identification of drug-protein and drug-adverse effect associations.

PubMed

Vilar, Santiago; Hripcsak, George

2016-01-01

Drug-target identification is crucial to discover novel applications for existing drugs and provide more insights about mechanisms of biological actions, such as adverse drug effects (ADEs). Computational methods along with the integration of current big data sources provide a useful framework for drug-target and drug-adverse effect discovery. In this article, we propose a method based on the integration of 3D chemical similarity, target and adverse effect data to generate a drug-target-adverse effect predictor along with a simple leveraging system to improve identification of drug-targets and drug-adverse effects. In the first step, we generated a system for multiple drug-target identification based on the application of 3D drug similarity into a large target dataset extracted from the ChEMBL. Next, we developed a target-adverse effect predictor combining targets from ChEMBL with phenotypic information provided by SIDER data source. Both modules were linked to generate a final predictor that establishes hypothesis about new drug-target-adverse effect candidates. Additionally, we showed that leveraging drug-target candidates with phenotypic data is very useful to improve the identification of drug-targets. The integration of phenotypic data into drug-target candidates yielded up to twofold precision improvement. In the opposite direction, leveraging drug-phenotype candidates with target data also yielded a significant enhancement in the performance. The modeling described in the current study is simple and efficient and has applications at large scale in drug repurposing and drug safety through the identification of mechanism of action of biological effects.

Increased Expression of HER2, HER3, and HER2:HER3 Heterodimers in HPV-Positive HNSCC Using a Novel Proximity-Based Assay: Implications for Targeted Therapies.

PubMed

Pollock, Netanya I; Wang, Lin; Wallweber, Gerald; Gooding, William E; Huang, Weidong; Chenna, Ahmed; Winslow, John; Sen, Malabika; DeGrave, Kara A; Li, Hua; Zeng, Yan; Grandis, Jennifer R

2015-10-15

In other cancer types, HPV infection has been reported to coincide with overexpression of HER2 (ERBB2) and HER3 (ERBB3); however, the association between HER2 or HER3 expression and dimer formation in HNSCC has not been reported. Overexpression of HER2 and HER3 may contribute to resistance to EGFR inhibitors, including cetuximab, although the contribution of HPV in modulating cetuximab response remains unknown. Determination of heterodimerization of HER receptors is challenging and has not been reported in HNSCC. The present study aimed to determine the expression of HER proteins in HPV(+) versus HPV(-) HNSCC tumors using a proximity-based protein expression assay (VeraTag), and to determine the efficacy of HER-targeting agents in HPV(+) and HPV(-) HNSCC cell lines. Expression of total HER1, HER2, and HER3, p95HER2, p-HER3, HER1:HER1 homodimers, HER2:HER3 heterodimers, and the HER3-PI3K complex in 88 HNSCC was determined using VeraTag, including 33 baseline tumors from individuals treated in a trial including cetuximab. Inhibition of cell growth and protein activation with cetuximab and afatinib was compared in HPV(+) and HPV(-) cetuximab-resistant cell lines. Expression of total HER2, total HER3, HER2:HER3 heterodimers, and the HER3:PI3K complex were significantly elevated in HPV(+) HNSCC. Total EGFR was significantly increased in HPV(-) HNSCC where VeraTag assay results correlated with IHC. Afatinib significantly inhibited cell growth when compared with cetuximab in the HPV(+) and HPV(-) cetuximab-resistant HNSCC cell lines. These findings suggest that agents targeting multiple HER proteins may be effective in the setting of HPV(+) HNSCC and/or cetuximab resistance. ©2015 American Association for Cancer Research.

Drug discovery in tuberculosis. New drug targets and antimycobacterial agents.

PubMed

Campaniço, André; Moreira, Rui; Lopes, Francisca

2018-04-25

Tuberculosis (TB) remains a major health problem worldwide. The infectious agent, Mycobacterium tuberculosis, has a unique ability to survive within the host, alternating between active and latent disease states, and escaping the immune system defences. The extended duration of anti-TB regimens and the increasing prevalence of multidrug- (MDR) and extensively drug-resistant (XDR) M. tuberculosis strains have created an urgent need for new antibiotics active against drug-resistant organisms and that can shorten standard therapy. However, despite success in identifying active compounds through phenotypic screens, the conversion of hits into novel chemical series and ultimately into clinical candidates is hampered by the poor efficacy in eliminating M. tuberculosis within different host compartments, including macrophages, as well as a lack of knowledge about the specific target(s) inhibited and/or upregulated. The current status of anti-TB lead generation has much improved over the last decade, as exemplified by the recent approval of bedaquiline and delamanid to treat MDR-TB and XDR-TB. This review provides a critical analysis on the strategies used to progress hit compounds into viable lead candidates, and how emerging targets may play a role in TB drug discovery in the near future. Four new relevant targets are addressed: the enoyl-acyl carrier protein reductase, InhA; the transmembrane transport protein large, MmpL3; the decaprenylphospho-beta-d-ribofuranose 2-oxidase, DprE1; and the ubiquinol-cytochrome C reductase, QcrB. Validated hit compounds for each target are presented and explored, and the medicinal chemistry strategies to expand SAR around novel chemotypes analyzed. In addition, very recent emerging targets are also discussed. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Target-Pathogen: a structural bioinformatic approach to prioritize drug targets in pathogens.

PubMed

Sosa, Ezequiel J; Burguener, Germán; Lanzarotti, Esteban; Defelipe, Lucas; Radusky, Leandro; Pardo, Agustín M; Marti, Marcelo; Turjanski, Adrián G; Fernández Do Porto, Darío

2018-01-04

Available genomic data for pathogens has created new opportunities for drug discovery and development to fight them, including new resistant and multiresistant strains. In particular structural data must be integrated with both, gene information and experimental results. In this sense, there is a lack of an online resource that allows genome wide-based data consolidation from diverse sources together with thorough bioinformatic analysis that allows easy filtering and scoring for fast target selection for drug discovery. Here, we present Target-Pathogen database (http://target.sbg.qb.fcen.uba.ar/patho), designed and developed as an online resource that allows the integration and weighting of protein information such as: function, metabolic role, off-targeting, structural properties including druggability, essentiality and omic experiments, to facilitate the identification and prioritization of candidate drug targets in pathogens. We include in the database 10 genomes of some of the most relevant microorganisms for human health (Mycobacterium tuberculosis, Mycobacterium leprae, Klebsiella pneumoniae, Plasmodium vivax, Toxoplasma gondii, Leishmania major, Wolbachia bancrofti, Trypanosoma brucei, Shigella dysenteriae and Schistosoma Smanosoni) and show its applicability. New genomes can be uploaded upon request. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Target-Pathogen: a structural bioinformatic approach to prioritize drug targets in pathogens

PubMed Central

Sosa, Ezequiel J; Burguener, Germán; Lanzarotti, Esteban; Radusky, Leandro; Pardo, Agustín M; Marti, Marcelo

2018-01-01

Abstract Available genomic data for pathogens has created new opportunities for drug discovery and development to fight them, including new resistant and multiresistant strains. In particular structural data must be integrated with both, gene information and experimental results. In this sense, there is a lack of an online resource that allows genome wide-based data consolidation from diverse sources together with thorough bioinformatic analysis that allows easy filtering and scoring for fast target selection for drug discovery. Here, we present Target-Pathogen database (http://target.sbg.qb.fcen.uba.ar/patho), designed and developed as an online resource that allows the integration and weighting of protein information such as: function, metabolic role, off-targeting, structural properties including druggability, essentiality and omic experiments, to facilitate the identification and prioritization of candidate drug targets in pathogens. We include in the database 10 genomes of some of the most relevant microorganisms for human health (Mycobacterium tuberculosis, Mycobacterium leprae, Klebsiella pneumoniae, Plasmodium vivax, Toxoplasma gondii, Leishmania major, Wolbachia bancrofti, Trypanosoma brucei, Shigella dysenteriae and Schistosoma Smanosoni) and show its applicability. New genomes can be uploaded upon request. PMID:29106651

Drug target inference through pathway analysis of genomics data

PubMed Central

Ma, Haisu; Zhao, Hongyu

2013-01-01

Statistical modeling coupled with bioinformatics is commonly used for drug discovery. Although there exist many approaches for single target based drug design and target inference, recent years have seen a paradigm shift to system-level pharmacological research. Pathway analysis of genomics data represents one promising direction for computational inference of drug targets. This article aims at providing a comprehensive review on the evolving issues is this field, covering methodological developments, their pros and cons, as well as future research directions. PMID:23369829

A phase I study of selumetinib (AZD6244/ARRY-142866), a MEK1/2 inhibitor, in combination with cetuximab in refractory solid tumors and KRAS mutant colorectal cancer

PubMed Central

Deming, Dustin A.; Cavalcante, Ludmila L.; Lubner, Sam J.; Mulkerin, Daniel L.; LoConte, Noelle K.; Eickhoff, Jens C.; Kolesar, Jill M.; Fioravanti, Suzanne; Greten, Tim F.; Compton, Kathryn; Doyle, Austin G.; Wilding, George; Duffy, Austin; Liu, Glenn

2015-01-01

Background KRAS mutations are clinically important predictors of resistance to EGFR-directed therapies in colorectal cancer (CRC). Oncogenic activation of the RAS/RAF/MEK/ERK signaling cascade mediates proliferation independent of growth factor signaling. We hypothesized that targeting MEK with selumetinib could overcome resistance to cetuximab in KRAS mutant CRC. Methods A phase I study (NCT01287130) was undertaken to determine the tolerability, and pharmacokinetic profiles of the combination of selumetinib and cetuximab, with an expanded cohort in KRAS-mutant CRC. Results 15 patients were treated in the dose escalation cohort and 18 patients were treated in the expansion cohort. Two dose-limiting toxicities were observed. One grade 3 acneiform rash and one grade 4 hypomagnesemia occurred. The most common grade 1 and 2 adverse events included rash, nausea/vomiting, diarrhea, and fatigue. The maximum tolerated dose was established at selumetinib 75 mg PO BID and cetuximab 250 mg/m2 weekly following a 400 mg/m2 load. Best clinical response in the dose escalation group included 1 unconfirmed partial response in a patient with CRC and stable disease (SD) in 5 patients (1 squamous cell carcinoma of the tonsil, 1 non-small cell lung cancer, and 3 CRC), and in the KRAS-mutant CRC dose expansion cohort, of the 14 patients who were evaluable for response, 5 patients had SD and 9 patients had progressive disease. Conclusions The combination of selumetinib and cetuximab is safe and well tolerated. Minimal anti-tumor activity was observed in KRAS-mutant refractory metastatic CRC. Further investigations might be warranted in other cancer subtypes. PMID:26666244

A phase I study of selumetinib (AZD6244/ARRY-142866), a MEK1/2 inhibitor, in combination with cetuximab in refractory solid tumors and KRAS mutant colorectal cancer.

PubMed

Deming, Dustin A; Cavalcante, Ludmila L; Lubner, Sam J; Mulkerin, Daniel L; LoConte, Noelle K; Eickhoff, Jens C; Kolesar, Jill M; Fioravanti, Suzanne; Greten, Tim F; Compton, Kathryn; Doyle, Austin G; Wilding, George; Duffy, Austin; Liu, Glenn

2016-04-01

KRAS mutations are clinically important predictors of resistance to EGFR-directed therapies in colorectal cancer (CRC). Oncogenic activation of the RAS/RAF/MEK/ERK signaling cascade mediates proliferation independent of growth factor signaling. We hypothesized that targeting MEK with selumetinib could overcome resistance to cetuximab in KRAS mutant CRC. A phase I study (NCT01287130) was undertaken to determine the tolerability, and pharmacokinetic profiles of the combination of selumetinib and cetuximab, with an expanded cohort in KRAS-mutant CRC. 15 patients were treated in the dose escalation cohort and 18 patients were treated in the expansion cohort. Two dose-limiting toxicities were observed. One grade 3 acneiform rash and one grade 4 hypomagnesemia occurred. The most common grade 1 and 2 adverse events included rash, nausea/vomiting, diarrhea, and fatigue. The maximum tolerated dose was established at selumetinib 75 mg p.o. BID and cetuximab 250 mg/m(2) weekly following a 400 mg/m(2) load. Best clinical response in the dose escalation group included 1 unconfirmed partial response in a patient with CRC and stable disease (SD) in 5 patients (1 squamous cell carcinoma of the tonsil, 1 non-small cell lung cancer, and 3 CRC), and in the KRAS-mutant CRC dose expansion cohort, of the 14 patients who were evaluable for response, 5 patients had SD and 9 patients had progressive disease. The combination of selumetinib and cetuximab is safe and well tolerated. Minimal anti-tumor activity was observed in KRAS-mutant refractory metastatic CRC. Further investigations might be warranted in other cancer subtypes.

KCa 3.1-a microglial target ready for drug repurposing?

PubMed

Dale, Elena; Staal, Roland G W; Eder, Claudia; Möller, Thomas

2016-10-01

Over the past decade, glial cells have attracted attention for harboring unexploited targets for drug discovery. Several glial targets have attracted de novo drug discovery programs, as highlighted in this GLIA Special Issue. Drug repurposing, which has the objective of utilizing existing drugs as well as abandoned, failed, or not yet pursued clinical development candidates for new indications, might provide a faster opportunity to bring drugs for glial targets to patients with unmet needs. Here, we review the potential of the intermediate-conductance calcium-activated potassium channels KCa 3.1 as the target for such a repurposing effort. We discuss the data on KCa 3.1 expression on microglia in vitro and in vivo and review the relevant literature on the two KCa 3.1 inhibitors TRAM-34 and Senicapoc. Finally, we provide an outlook of what it might take to harness the potential of KCa 3.1 as a bona fide microglial drug target. GLIA 2016;64:1733-1741. © 2016 Wiley Periodicals, Inc.

A small molecule nanodrug consisting of amphiphilic targeting ligand-chemotherapy drug conjugate for targeted cancer therapy.

PubMed

Mou, Quanbing; Ma, Yuan; Zhu, Xinyuan; Yan, Deyue

2016-05-28

Targeted drug delivery is a broadly applicable approach for cancer therapy. However, the nanocarrier-based targeted delivery system suffers from batch-to-batch variation, quality concerns and carrier-related toxicity issues. Thus, to develop a carrier-free targeted delivery system with nanoscale characteristics is very attractive. Here, a novel targeting small molecule nanodrug self-delivery system consisting of targeting ligand and chemotherapy drug was constructed, which combined the advantages of small molecules and nano-assemblies together and showed excellent targeting ability and long blood circulation time with well-defined structure, high drug loading ratio and on-demand drug release behavior. As a proof-of-concept, lactose (Lac) and doxorubicin (DOX) were chosen as the targeting ligand and chemotherapy drug, respectively. Lac and DOX were conjugated through a pH-responsive hydrazone group. For its intrinsic amphiphilic property, Lac-DOX conjugate could self-assemble into nanoparticles in water. Both in vitro and in vivo assays indicated that Lac-DOX nanoparticles exhibited enhanced anticancer activity and weak side effects. This novel active targeting nanodrug delivery system shows great potential in cancer therapy. Copyright © 2016 Elsevier B.V. All rights reserved.

Predicting selective drug targets in cancer through metabolic networks

PubMed Central

Folger, Ori; Jerby, Livnat; Frezza, Christian; Gottlieb, Eyal; Ruppin, Eytan; Shlomi, Tomer

2011-01-01

The interest in studying metabolic alterations in cancer and their potential role as novel targets for therapy has been rejuvenated in recent years. Here, we report the development of the first genome-scale network model of cancer metabolism, validated by correctly identifying genes essential for cellular proliferation in cancer cell lines. The model predicts 52 cytostatic drug targets, of which 40% are targeted by known, approved or experimental anticancer drugs, and the rest are new. It further predicts combinations of synthetic lethal drug targets, whose synergy is validated using available drug efficacy and gene expression measurements across the NCI-60 cancer cell line collection. Finally, potential selective treatments for specific cancers that depend on cancer type-specific downregulation of gene expression and somatic mutations are compiled. PMID:21694718

Trends in GPCR drug discovery: new agents, targets and indications.

PubMed

Hauser, Alexander S; Attwood, Misty M; Rask-Andersen, Mathias; Schiöth, Helgi B; Gloriam, David E

2017-12-01

G protein-coupled receptors (GPCRs) are the most intensively studied drug targets, mostly due to their substantial involvement in human pathophysiology and their pharmacological tractability. Here, we report an up-to-date analysis of all GPCR drugs and agents in clinical trials, which reveals current trends across molecule types, drug targets and therapeutic indications, including showing that 475 drugs (~34% of all drugs approved by the US Food and Drug Administration (FDA)) act at 108 unique GPCRs. Approximately 321 agents are currently in clinical trials, of which ~20% target 66 potentially novel GPCR targets without an approved drug, and the number of biological drugs, allosteric modulators and biased agonists has increased. The major disease indications for GPCR modulators show a shift towards diabetes, obesity and Alzheimer disease, although several central nervous system disorders are also highly represented. The 224 (56%) non-olfactory GPCRs that have not yet been explored in clinical trials have broad untapped therapeutic potential, particularly in genetic and immune system disorders. Finally, we provide an interactive online resource to analyse and infer trends in GPCR drug discovery.

NCI-MATCH Trial Links Targeted Drugs to Mutations

Cancer.gov

Investigators for the nationwide trial, NCI-MATCH: Molecular Analysis for Therapy Choice, announced that the trial will seek to determine whether targeted therapies for people whose tumors have specific gene mutations will be effective regardless of their cancer type. NCI-MATCH will incorporate more than 20 different study drugs or drug combinations, each targeting a specific gene mutation, in order to match each patient in the trial with a therapy that targets a molecular abnormality in their tumor.

Enhancement of antibody-dependent cellular cytotoxicity of cetuximab by a chimeric protein encompassing interleukin-15.

PubMed

Ochoa, Maria Carmen; Minute, Luna; López, Ascensión; Pérez-Ruiz, Elisabeth; Gomar, Celia; Vasquez, Marcos; Inoges, Susana; Etxeberria, Iñaki; Rodriguez, Inmaculada; Garasa, Saray; Mayer, Jan-Peter Andreas; Wirtz, Peter; Melero, Ignacio; Berraondo, Pedro

2018-01-01

Enhancement of antibody-dependent cellular cytotoxicity (ADCC) may potentiate the antitumor efficacy of tumor-targeted monoclonal antibodies. Increasing the numbers and antitumor activity of NK cells is a promising strategy to maximize the ADCC of standard-of-care tumor-targeted antibodies. For this purpose, we have preclinically tested a recombinant chimeric protein encompassing the sushi domain of the IL15Rα, IL-15, and apolipoprotein A-I (Sushi-IL15-Apo) as produced in CHO cells. The size-exclusion purified monomeric fraction of this chimeric protein was stable and retained the IL-15 and the sushi domain bioactivity as measured by CTLL-2 and Mo-7e cell proliferation and STAT5 phosphorylation in freshly isolated human NK and CD8 + T cells. On cell cultures, Sushi-IL15-Apo increases NK cell proliferation and survival as well as spontaneous and antibody-mediated cytotoxicity. Scavenger receptor class B type I (SR-B1) is the receptor for ApoA-I and is expressed on the surface of tumor cells. SR-B1 can adsorb the chimeric protein on tumor cells and can transpresent IL-15 to NK and CD8 + T cells. A transient NK-humanized murine model was developed to test the increase of ADCC attained by the chimeric protein in vivo . The EGFR + human colon cancer cell line HT-29 was intraperitoneally inoculated in immune-deficient Rag2 -/- γc -/- mice that were reconstituted with freshly isolated PBMCs and treated with the anti-EGFR mAb cetuximab. The combination of the Sushi-IL15-Apo protein and cetuximab reduced the number of remaining tumor cells in the peritoneal cavity and delayed tumor engraftment in the peritoneum. Furthermore, Sushi-IL15-Apo increased the anti-tumor effect of a murine anti-EGFR mAb in Rag1 -/- mice bearing subcutaneous MC38 colon cancer transfected to express EGFR. Thus, Sushi-IL15-Apo is a potent tool to increase the number and the activation of NK cells to promote the ADCC activity of antibodies targeting tumor antigens.

Phase 2 Study of Concurrent Cetuximab Plus Definitive Thoracic Radiation Therapy Followed by Consolidation Docetaxel Plus Cetuximab in Poor Prognosis or Elderly Patients With Locally Advanced Non-Small Cell Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dilling, Thomas J.; Extermann, Martine; Kim, Jongphil

Background: Recursive partitioning analysis has shown that Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≥2, male sex, and age ≥70 years are prognostic of poor outcome in locally advanced non-small cell lung cancer (LA-NSCLC) patients. Concurrent chemoradiation therapy (CRT) improves survival, but toxicity is a concern in this frail patient cohort. We therefore opened this trial of concurrent definitive thoracic radiation therapy (XRT) and cetuximab, followed by consolidation docetaxel plus cetuximab. Methods and Materials: Eligible patients had pathologically proven, unresectable LA-NSCLC (stage IIA-“dry” IIIB). They had ECOG PS 2 or weight loss ≥5% in 3 months or were aged ≥70 years. Themore » primary objective was progression-free survival (PFS). Secondary objectives included overall survival (OS) and overall response rate (ORR). Results: From May 2008 to November 2010, a total of 32 patients were evaluated in our single-institution, institutional review board–approved prospective clinical trial. Three patients were screen failures and 2 more withdrew consent before treatment, leaving 27 evaluable patients. One was removed because of poor therapy compliance, and 2 were taken off trial because of grade 3 cetuximab-related toxicities but were followed up under intent-to-treat analysis. The median follow-up and OS were 10.5 months. The median PFS was 7.5 months. The ORR was 59.3%. Eight early/sudden deaths were reported. Upon review, 6 patients developed severe pulmonary complications. Conclusions: Patients enrolled in this trial had improved OS compared with poor-PS historical controls (10.5 vs 6.4 months) and comparable OS to good-PS historical controls (10.5 vs 11.9 months) treated with XRT alone. However, pulmonary toxicity is a concern. Consolidative cetuximab/docetaxel, in conjunction with high-dose radiation therapy, is a putative cause.« less

Drug-target residence time--a case for G protein-coupled receptors.

PubMed

Guo, Dong; Hillger, Julia M; IJzerman, Adriaan P; Heitman, Laura H

2014-07-01

A vast number of marketed drugs act on G protein-coupled receptors (GPCRs), the most successful category of drug targets to date. These drugs usually possess high target affinity and selectivity, and such combined features have been the driving force in the early phases of drug discovery. However, attrition has also been high. Many investigational new drugs eventually fail in clinical trials due to a demonstrated lack of efficacy. A retrospective assessment of successfully launched drugs revealed that their beneficial effects in patients may be attributed to their long drug-target residence times (RTs). Likewise, for some other GPCR drugs short RT could be beneficial to reduce the potential for on-target side effects. Hence, the compounds' kinetics behavior might in fact be the guiding principle to obtain a desired and durable effect in vivo. We therefore propose that drug-target RT should be taken into account as an additional parameter in the lead selection and optimization process. This should ultimately lead to an increased number of candidate drugs moving to the preclinical development phase and on to the market. This review contains examples of the kinetics behavior of GPCR ligands with improved in vivo efficacy and summarizes methods for assessing drug-target RT. © 2014 Wiley Periodicals, Inc.

Structural systems pharmacology: a new frontier in discovering novel drug targets.

PubMed

Tan, Hepan; Ge, Xiaoxia; Xie, Lei

2013-08-01

The modern target-based drug discovery process, characterized by the one-drug-one-gene paradigm, has been of limited success. In contrast, phenotype-based screening produces thousands of active compounds but gives no hint as to what their molecular targets are or which ones merit further research. This presents a question: What is a suitable target for an efficient and safe drug? In this paper, we argue that target selection should take into account the proteome-wide energetic and kinetic landscape of drug-target interactions, as well as their cellular and organismal consequences. We propose a new paradigm of structural systems pharmacology to deconvolute the molecular targets of successful drugs as well as to identify druggable targets and their drug-like binders. Here we face two major challenges in structural systems pharmacology: How do we characterize and analyze the structural and energetic origins of drug-target interactions on a proteome scale? How do we correlate the dynamic molecular interactions to their in vivo activity? We will review recent advances in developing new computational tools for biophysics, bioinformatics, chemoinformatics, and systems biology related to the identification of genome-wide target profiles. We believe that the integration of these tools will realize structural systems pharmacology, enabling us to both efficiently develop effective therapeutics for complex diseases and combat drug resistance.

Market uptake of biologic and small-molecule--targeted oncology drugs in Europe.

PubMed

Obradovic, Marko; Mrhar, Ales; Kos, Mitja

2009-12-01

The aim of this study was to investigate the market uptake of biologic and small-molecule-targeted oncology drugs in Europe. Targeted oncology drugs that were used in one of the selected European countries before the end of 2007 were eligible for inclusion in the analysis. The following European countries were included: Austria, Croatia, France, Germany, Hungary, Italy, Slovenia, and the United Kingdom. Monetary market uptake of targeted oncology drugs was assessed by using sales data (in euros) obtained from 2 large data- bases for the period 1997-2007. Market uptake was assessed in terms of expenditures for specific drugs in euros per capita and in market shares. The monetary market uptake of targeted oncology drugs had an exponential growth from 1997 to 2007 in all comparison countries and reached 40% of the total oncology drug market in 2007. Although the various European countries allocate substantially different amounts of resources per capita for oncology drugs, the share of expenditures attributed to targeted oncology drugs did not differ substantially among the countries. Biologic molecules were used in clinical practice before the small-molecule-targeted oncology drugs. Targeted oncology drugs that were introduced first to clinical practice in most of the comparison countries (ie, rituximab, trastuzumab, imatinib mesylate) maintained the leading positions on the market throughout the period of the analysis. In 2007, approximately 25% of all expenditures for oncology drugs were attributed to biologic oncology drugs, and approximately 15% were spent on small-molecule-targeted oncology drugs. Expenditures on targeted oncology drugs have been increasing exponentially in Europe throughout the past decade and have reached a 40% share of the oncology drug market. As of 2007, the market share of biologic oncology drugs was higher than the market share of small-molecule-targeted oncology drugs. Copyright 2009 Excerpta Medica Inc. All rights reserved.

Reduced Cytokine Release in Ex Vivo Response to Cilengitide and Cetuximab Is a Marker for Improved Survival of Head and Neck Cancer Patients

PubMed Central

Cedra, Susan; Wiegand, Susanne; Kolb, Marlen; Dietz, Andreas; Wichmann, Gunnar

2017-01-01

Targeting of αVβ3 and αVβ5 integrins by cilengitide may reduce growth of solid tumors including head and neck squamous cell carcinoma (HNSCC). Preclinical investigations suggest increased activity of cilengitide in combination with other treatment modalities. The only published trial in HNSCC (ADVANTAGE) investigated cisplatin, 5-fluorouracil, and cetuximab (PFE) without or with once (PFE+CIL1W) or twice weekly cilengitide (PFE+CIL2W) in recurrent/metastatic HNSCC. ADVANTAGE showed good tolerability of the cilengitide arms and even lower adverse events (AEs) compared to PFE but not the benefit in overall survival expected based on preclinical data. As we found in the FLAVINO assay, a short-time ex vivo assay for prediction of chemosensitivity, only a subgroup of HNSCC had an increased suppressive effect of cilengitide containing combination therapies on colony formation of epithelial cells (CFec) and release of pro-angiogenetic and pro-inflammatory cytokines, whereas other HNSCC failed to respond. Response to αVβ3 and αVβ5 integrin targeting by cilengitide classifies HNSCC regarding outcome. We present FLAVINO data arguing for further development of cilengitide plus cetuximab in treatment of a subgroup of HNSCC potentially identified by the FLAVINO assay using a set of biomarkers for response evaluation. PMID:28872582

Targeted Vascular Drug Delivery in Cerebral Cancer.

PubMed

Humle, Nanna; Johnsen, Kasper Bendix; Arendt, Gitte Abildgaard; Nielsen, Rikke Paludan; Moos, Torben; Thomsen, Louiza Bohn

2016-01-01

This review presents the present-day literature on the anatomy and physiological mechanisms of the blood-brain barrier and the problematic of cerebral drug delivery in relation to malignant brain tumors. First step in treatment of malignant brain tumors is resection, but there is a high risk of single remnant infiltrative tumor cells in the outer zone of the brain tumor. These infiltrative single-cells will be supplied by capillaries with an intact BBB as opposed to the partly leaky BBB found in the tumor tissue before resection. Even though BBB penetrance of a chemotherapeutic agent is considered irrelevant though the limited success rate for chemotherapeutic treatability of GBM tumors indicate otherwise. Therefore drug delivery strategies to cerebral cancer after resection should be tailored to being able to both penetrate the intact BBB and target the cancer cells. In this review the intact bloodbrain barrier and cerebral cancer with main focus on glioblastoma multiforme (GBM) is introduced. The GBM induced formation of a blood-tumor barrier and the consequences hereof is described and discussed with emphasis on the impact these changes of the BBB has on drug delivery to GBM. The most commonly used drug carriers for drug delivery to GBM is described and the current drug delivery strategies for glioblastoma multiforme including possible routes through the BBB and epitopes, which can be targeted on the GBM cells is outlined. Overall, this review aims to address targeted drug delivery in GBM treatment when taking the differing permeability of the BBB into consideration.

Recommendation Techniques for Drug-Target Interaction Prediction and Drug Repositioning.

PubMed

Alaimo, Salvatore; Giugno, Rosalba; Pulvirenti, Alfredo

2016-01-01

The usage of computational methods in drug discovery is a common practice. More recently, by exploiting the wealth of biological knowledge bases, a novel approach called drug repositioning has raised. Several computational methods are available, and these try to make a high-level integration of all the knowledge in order to discover unknown mechanisms. In this chapter, we review drug-target interaction prediction methods based on a recommendation system. We also give some extensions which go beyond the bipartite network case.

Development In Drug Targeting And Delivery In Cervical Cancer.

PubMed

Aggarwal, Urvashi; Goyal, Amit Kumar; Rath, Goutam

2017-10-09

Cervical cancer is the second most common cancer in women. Standard treatment options available for cervical cancer including chemotherapy, surgery and radiation therapy associated with their own side effects and toxicities. Tumor-targeted delivery of anticancer drugs is perhaps one of the most appropriate strategies to achieve optimal outcomes from treatment and improve quality of life. Recently nanocarriers based drug delivery systems owing to their unique properties have been extensively investigated for anticancer drug delivery. In addition to that addressing the anatomical significance of cervical cancer, various local drug delivery strategies for the cancer treatment are introduced like: gels, nanoparticles, polymeric films, rods and wafers, lipid based nanocarrier. Localized drug delivery systems allows passive drug targeting results in high drug concentration at the target site. Further they can be tailor made to achieve both sustained and controlled release behavior, substantially improving therapeutic outcomes and minimizing side effects. This review summarizes the meaningful advances in drug delivery strategies to treat cervical cancer. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Fe₃O₄ Nanoparticles in Targeted Drug/Gene Delivery Systems.

PubMed

Shen, Lazhen; Li, Bei; Qiao, Yongsheng

2018-02-23

Fe₃O₄ nanoparticles (NPs), the most traditional magnetic nanoparticles, have received a great deal of attention in the biomedical field, especially for targeted drug/gene delivery systems, due to their outstanding magnetism, biocompatibility, lower toxicity, biodegradability, and other features. Naked Fe₃O₄ NPs are easy to aggregate and oxidize, and thus are often made with various coatings to realize superior properties for targeted drug/gene delivery. In this review, we first list the three commonly utilized synthesis methods of Fe₃O₄ NPs, and their advantages and disadvantages. In the second part, we describe coating materials that exhibit noticeable features that allow functionalization of Fe₃O₄ NPs and summarize their methods of drug targeting/gene delivery. Then our efforts will be devoted to the research status and progress of several different functionalized Fe₃O₄ NP delivery systems loaded with chemotherapeutic agents, and we present targeted gene transitive carriers in detail. In the following section, we illuminate the most effective treatment systems of the combined drug and gene therapy. Finally, we propose opportunities and challenges of the clinical transformation of Fe₃O₄ NPs targeting drug/gene delivery systems.

Graphene quantum dots for cancer targeted drug delivery.

PubMed

Iannazzo, Daniela; Pistone, Alessandro; Salamò, Marina; Galvagno, Signorino; Romeo, Roberto; Giofré, Salvatore V; Branca, Caterina; Visalli, Giuseppa; Di Pietro, Angela

2017-02-25

A biocompatible and cell traceable drug delivery system Graphene Quantum Dots (GQD) based, for the targeted delivery of the DNA intercalating drug doxorubicin (DOX) to cancer cells, is here reported. Highly dispersible and water soluble GQD, synthesized by acidic oxidation and exfoliation of multi-walled carbon nanotubes (MWCNT), were covalently linked to the tumor targeting module biotin (BTN), able to efficiently recognize biotin receptors over-expressed on cancer cells and loaded with DOX. Biological test performed on A549 cells reported a very low toxicity of the synthesized carrier (GQD and GQD-BTN). In GQD-BTN-DOX treated cancer cells, the cytotoxicity was strongly dependent from cell uptake which was greater and delayed after treatment with GQD-BTN-DOX system with respect to what observed for cells treated with the same system lacking of the targeting module BTN (GQD-DOX) or with the free drug alone. A delayed nuclear internalization of the drug is reported, due to the drug detachment from the nanosystem, triggered by the acidic environment of cancer cells. Copyright © 2017 Elsevier B.V. All rights reserved.

Increasing the Structural Coverage of Tuberculosis Drug Targets

PubMed Central

Baugh, Loren; Phan, Isabelle; Begley, Darren W.; Clifton, Matthew C.; Armour, Brianna; Dranow, David M.; Taylor, Brandy M.; Muruthi, Marvin M.; Abendroth, Jan; Fairman, James W.; Fox, David; Dieterich, Shellie H.; Staker, Bart L.; Gardberg, Anna S.; Choi, Ryan; Hewitt, Stephen N.; Napuli, Alberto J.; Myers, Janette; Barrett, Lynn K.; Zhang, Yang; Ferrell, Micah; Mundt, Elizabeth; Thompkins, Katie; Tran, Ngoc; Lyons-Abbott, Sally; Abramov, Ariel; Sekar, Aarthi; Serbzhinskiy, Dmitri; Lorimer, Don; Buchko, Garry W.; Stacy, Robin; Stewart, Lance J.; Edwards, Thomas E.; Van Voorhis, Wesley C.; Myler, Peter J.

2015-01-01

High-resolution three-dimensional structures of essential Mycobacterium tuberculosis (Mtb) proteins provide templates for TB drug design, but are available for only a small fraction of the Mtb proteome. Here we evaluate an intra-genus “homolog-rescue” strategy to increase the structural information available for TB drug discovery by using mycobacterial homologs with conserved active sites. Of 179 potential TB drug targets selected for x-ray structure determination, only 16 yielded a crystal structure. By adding 1675 homologs from nine other mycobacterial species to the pipeline, structures representing an additional 52 otherwise intractable targets were solved. To determine whether these homolog structures would be useful surrogates in TB drug design, we compared the active sites of 106 pairs of Mtb and non-TB mycobacterial (NTM) enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. Pair-wise structural comparisons revealed that 19/22 pairs with >55% overall sequence identity had active site Cα RMSD <1Å, >85% side chain identity, and ≥80% PSAPF (similarity based on pharmacophoric properties) indicating highly conserved active site shape and chemistry. Applying these results to the 52 NTM structures described above, 41 shared >55% sequence identity with the Mtb target, thus increasing the effective structural coverage of the 179 Mtb targets over three-fold (from 9% to 32%). The utility of these structures in TB drug design can be tested by designing inhibitors using the homolog structure and assaying the cognate Mtb enzyme; a promising test case, Mtb cytidylate kinase, is described. The homolog-rescue strategy evaluated here for TB is also generalizable to drug targets for other diseases. PMID:25613812

Hierarchical pulmonary target nanoparticles via inhaled administration for anticancer drug delivery.

PubMed

Chen, Rui; Xu, Liu; Fan, Qin; Li, Man; Wang, Jingjing; Wu, Li; Li, Weidong; Duan, Jinao; Chen, Zhipeng

2017-11-01

Inhalation administration, compared with intravenous administration, significantly enhances chemotherapeutic drug exposure to the lung tissue and may increase the therapeutic effect for pulmonary anticancer. However, further identification of cancer cells after lung deposition of inhaled drugs is necessary to avoid side effects on normal lung tissue and to maximize drug efficacy. Moreover, as the action site of the major drug was intracellular organelles, drug target to the specific organelle is the final key for accurate drug delivery. Here, we designed a novel multifunctional nanoparticles (MNPs) for pulmonary antitumor and the material was well-designed for hierarchical target involved lung tissue target, cancer cell target, and mitochondrial target. The biodistribution in vivo determined by UHPLC-MS/MS method was employed to verify the drug concentration overwhelmingly increasing in lung tissue through inhaled administration compared with intravenous administration. Cellular uptake assay using A549 cells proved the efficient receptor-mediated cell endocytosis. Confocal laser scanning microscopy observation showed the location of MNPs in cells was mitochondria. All results confirmed the intelligent material can progressively play hierarchical target functions, which could induce more cell apoptosis related to mitochondrial damage. It provides a smart and efficient nanocarrier platform for hierarchical targeting of pulmonary anticancer drug. So far, this kind of material for pulmonary mitochondrial-target has not been seen in other reports.

Cetuximab improves AZD6244 antitumor activity in colorectal cancer HT29 cells in vitro and in nude mice by attenuating HER3/Akt pathway activation.

PubMed

Zhang, Qin; Xiao, He; Jin, Feng; Li, Mengxia; Luo, Jia; Wang, Ge

2018-07-01

The present study investigated the molecular mechanism by which the epidermal growth factor receptor (EGFR) inhibitor cetuximab enhances the antitumor activity of the mitogen-activated protein kinase kinase (MEK) inhibitor AZD6244 in colorectal cancer HT29 cells. HT29 cells were treated with AZD6244 plus cetuximab and then subjected to the following assays: Cell Counting kit-8, BrdU-incorporation, flow cytometric cell cycle distribution and apoptosis analysis, western blot analysis, and nude mouse xenografts. The combination of AZD6244 and cetuximab significantly reduced HT29 cell viability and proliferation compared with AZD6244 alone. The combination treatment reduced the IC 50 value from 108.12±10.05 to 28.45±1.92 nM. AZD6244 and cetuximab also induced cell cycle arrest at G1 phase and reduced S phase (88.53% vs. 93.39%, P=0.080; 8.73% vs. 4.24%, P=0.082, respectively). Combination of AZD6244 with cetuximab significantly induced tumor cells apoptosis (14.61% vs. 8.99%, P=0.046). Inhibition of EGFR activity using cetuximab partially abrogated the feedback-activation of phosphorylated receptor tyrosine-protein kinase erB-3 (p-HER3) and p-AKT serine/threonine kinase (AKT), as well as prevented reactivation of p-extracellular regulated kinase (ERK) conferred by AZD6244 treatment. Combination of AZD6244 and cetuximab also inhibited HT29 cell xenograft growth in nude mice and suppressed HER3 and p-AKT levels in xenografts. The EGFR inhibitor cetuximab enhanced the antitumor activity of the MEK inhibitor AZD6244 in colorectal cells in vitro and in vivo . Co-inhibition of MEK and EGFR may be a promising treatment strategy in colorectal cancers.

Molecular targets for flavivirus drug discovery

PubMed Central

Sampath, Aruna; Padmanabhan, R.

2009-01-01

Flaviviruses are a major cause of infectious disease in humans. Dengue virus causes an estimated 50 million cases of febrile illness each year, including an increasing number of cases of hemorrhagic fever. West Nile virus, which recently spread from the Mediterranean basin to the Western Hemisphere, now causes thousands of sporadic cases of encephalitis annually. Despite the existence of licensed vaccines, yellow fever, Japanese encephalitis and tick-borne encephalitis also claim many thousands of victims each year across their vast endemic areas. Antiviral therapy could potentially reduce morbidity and mortality from flavivirus infections, but no effective drugs are currently available. This article introduces a collection of papers in Antiviral Research on molecular targets for flavivirus antiviral drug design and murine models of dengue virus disease that aims to encourage drug development efforts. After reviewing the flavivirus replication cycle, we discuss the envelope glycoprotein, NS3 protease, NS3 helicase, NS5 methyltransferase and NS5 RNA-dependent RNA polymerase as potential drug targets, with special attention being given to the viral protease. The other viral proteins are the subject of individual articles in the journal. Together, these papers highlight current status of drug discovery efforts for flavivirus diseases and suggest promising areas for further research. PMID:18796313

SMAD4 Loss Is Associated with Cetuximab Resistance and Induction of MAPK/JNK Activation in Head and Neck Cancer Cells.

PubMed

Ozawa, Hiroyuki; Ranaweera, Ruchira S; Izumchenko, Evgeny; Makarev, Eugene; Zhavoronkov, Alex; Fertig, Elana J; Howard, Jason D; Markovic, Ana; Bedi, Atul; Ravi, Rajani; Perez, Jimena; Le, Quynh-Thu; Kong, Christina S; Jordan, Richard C; Wang, Hao; Kang, Hyunseok; Quon, Harry; Sidransky, David; Chung, Christine H

2017-09-01

Purpose: We previously demonstrated an association between decreased SMAD4 expression and cetuximab resistance in head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to further elucidate the clinical relevance of SMAD4 loss in HNSCC. Experimental Design: SMAD4 expression was assessed by IHC in 130 newly diagnosed and 43 patients with recurrent HNSCC. Correlative statistical analysis with clinicopathologic data was also performed. OncoFinder, a bioinformatics tool, was used to analyze molecular signaling in TCGA tumors with low or high SMAD4 mRNA levels. The role of SMAD4 was investigated by shRNA knockdown and gene reconstitution of HPV-negative HNSCC cell lines in vitro and in vivo Results: Our analysis revealed that SMAD4 loss was associated with an aggressive, HPV-negative, cetuximab-resistant phenotype. We found a signature of prosurvival and antiapoptotic pathways that were commonly dysregulated in SMAD4 -low cases derived from TCGA-HNSCC dataset and an independent oral cavity squamous cell carcinoma (OSCC) cohort obtained from GEO. We show that SMAD4 depletion in an HNSCC cell line induces cetuximab resistance and results in worse survival in an orthotopic mouse model in vivo We implicate JNK and MAPK activation as mediators of cetuximab resistance and provide the foundation for the concomitant EGFR and JNK/MAPK inhibition as a potential strategy for overcoming cetuximab resistance in HNSCCs with SMAD4 loss. Conclusions: Our study demonstrates that loss of SMAD4 expression is a signature characterizing the cetuximab-resistant phenotype and suggests that SMAD4 expression may be a determinant of sensitivity/resistance to EGFR/MAPK or EGFR/JNK inhibition in HPV-negative HNSCC tumors. Clin Cancer Res; 23(17); 5162-75. ©2017 AACR . ©2017 American Association for Cancer Research.

Polysaccharide-based micro/nanocarriers for oral colon-targeted drug delivery.

PubMed

Zhang, Lin; Sang, Yuan; Feng, Jing; Li, Zhaoming; Zhao, Aili

2016-08-01

Oral colon-targeted drug delivery has attracted many researchers because of its distinct advantages of increasing the bioavailability of the drug at the target site and reducing the side effects. Polysaccharides that are precisely activated by the physiological environment of the colon hold greater promise for colon targeting. Considerable research efforts have been directed towards developing polysaccharide-based micro/nanocarriers. Types of polysaccharides for colon targeting and in vitro/in vivo assessments of polysaccharide-based carriers for oral colon-targeted drug delivery are summarised. Polysaccharide-based microspheres have gained increased importance not just for the delivery of the drugs for the treatment of local diseases associated with the colon (colon cancer, inflammatory bowel disease (IBD), amoebiasis and irritable bowel syndrome (IBS)), but also for it's potential for the delivery of anti-rheumatoid arthritis and anti-chronic stable angina drugs. Besides, Polysaccharide-based micro/nanocarriers such as microbeads, microcapsules, microparticles, nanoparticles, nanogels and nanospheres are also introduced in this review.

In vivo characteristics of targeted drug-carrying filamentous bacteriophage nanomedicines

PubMed Central

2011-01-01

Background Targeted drug-carrying phage nanomedicines are a new class of nanomedicines that combines biological and chemical components into a modular nanometric drug delivery system. The core of the system is a filamentous phage particle that is produced in the bacterial host Escherichia coli. Target specificity is provided by a targeting moiety, usually an antibody that is displayed on the tip of the phage particle. A large drug payload is chemically conjugated to the protein coat of the phage via a chemically or genetically engineered linker that provides for controlled release of the drug after the particle homed to the target cell. Recently we have shown that targeted drug-carrying phage nanomedicines can be used to eradicate pathogenic bacteria and cultured tumor cells with great potentiation over the activity of the free untargeted drug. We have also shown that poorly water soluble drugs can be efficiently conjugated to the phage coat by applying hydrophilic aminoglycosides as branched solubility-enhancing linkers. Results With an intention to move to animal experimentation of efficacy, we tested anti-bacterial drug-carrying phage nanomedicines for toxicity and immunogenicity and blood pharmacokinetics upon injection into mice. Here we show that anti-bacterial drug-carrying phage nanomedicines that carry the antibiotic chloramphenicol conjugated via an aminoglycoside linker are non-toxic to mice and are greatly reduced in immunogenicity in comparison to native phage particles or particles to which the drug is conjugated directly and are cleared from the blood more slowly in comparison to native phage particles. Conclusion Our results suggest that aminoglycosides may serve as branched solubility enhancing linkers for drug conjugation that also provide for a better safety profile of the targeted nanomedicine. PMID:22185583

Chemical signatures and new drug targets for gametocytocidal drug development

NASA Astrophysics Data System (ADS)

Sun, Wei; Tanaka, Takeshi Q.; Magle, Crystal T.; Huang, Wenwei; Southall, Noel; Huang, Ruili; Dehdashti, Seameen J.; McKew, John C.; Williamson, Kim C.; Zheng, Wei

2014-01-01

Control of parasite transmission is critical for the eradication of malaria. However, most antimalarial drugs are not active against P. falciparum gametocytes, responsible for the spread of malaria. Consequently, patients can remain infectious for weeks after the clearance of asexual parasites and clinical symptoms. Here we report the identification of 27 potent gametocytocidal compounds (IC50 < 1 μM) from screening 5,215 known drugs and compounds. All these compounds were active against three strains of gametocytes with different drug sensitivities and geographical origins, 3D7, HB3 and Dd2. Cheminformatic analysis revealed chemical signatures for P. falciparum sexual and asexual stages indicative of druggability and suggesting potential targets. Torin 2, a top lead compound (IC50 = 8 nM against gametocytes in vitro), completely blocked oocyst formation in a mouse model of transmission. These results provide critical new leads and potential targets to expand the repertoire of malaria transmission-blocking reagents.

Targeted cancer drug delivery with aptamer-functionalized polymeric nanoparticles.

PubMed

Zununi Vahed, Sepideh; Fathi, Nazanin; Samiei, Mohammad; Maleki Dizaj, Solmaz; Sharifi, Simin

2018-06-21

Based on exceptional advantages of aptamers, increasing attention has been presented in the utilize of them as targeted ligands for cancer drug delivery. Recently, the progress of aptamer- targeted nanoparticles has presented new therapeutic systems for several types of cancer with decreased toxicity and improved efficacy. We highlight some of the promising formulations of aptamer-conjugated polymeric nanoparticles for specific targeted drug delivery to cancer cells. This review paper focuses on the current progresses in the use of the novel strategies to aptamer-targeted drug delivery for chemotherapy. An extensive literature review was performed using internet database, mainly PubMed based on MeSH keywords. The searches included full-text publications written in English without any limitation in date. The abstracts, reviews, books as well as studies without obvious relating of aptamers as targeted ligands for cancer drug delivery were excluded from the study. The reviewed literature revealed that aptamers with ability to modify and conjugate to various molecules can be used as targeted cancer therapy agents. However, development of aptamers unique to each individual's tumor to the development of personalized medicine seems to be needed.

Cetuximab plus carboplatin and paclitaxel with or without bevacizumab versus carboplatin and paclitaxel with or without bevacizumab in advanced NSCLC (SWOG S0819): a randomised, phase 3 study.

PubMed

Herbst, Roy S; Redman, Mary W; Kim, Edward S; Semrad, Thomas J; Bazhenova, Lyudmila; Masters, Gregory; Oettel, Kurt; Guaglianone, Perry; Reynolds, Christopher; Karnad, Anand; Arnold, Susanne M; Varella-Garcia, Marileila; Moon, James; Mack, Philip C; Blanke, Charles D; Hirsch, Fred R; Kelly, Karen; Gandara, David R

2018-01-01

EGFR antibodies have shown promise in patients with advanced non-small-cell lung cancer (NSCLC), particularly with squamous cell histology. We hypothesised that EGFR copy number by fluorescence in-situ hybridisation (FISH) can identify patients most likely to benefit from these drugs combined with chemotherapy and we aimed to explore the activity of cetuximab with chemotherapy in patients with advanced NSCLC who are EGFR FISH-positive. We did this open-label, phase 3 study (SWOG S0819) at 277 sites in the USA and Mexico. We randomly assigned (1:1) eligible patients with treatment-naive stage IV NSCLC to receive paclitaxel (200 mg/m 2 ; every 21 days) plus carboplatin (area under the curve of 6 by modified Calvert formula; every 21 days) or carboplatin plus paclitaxel and bevacizumab (15 mg/kg; every 21 days), either with cetuximab (250 mg/m 2 weekly after loading dose; cetuximab group) or without (control group), stratified by bevacizumab treatment, smoking status, and M-substage using a dynamic-balancing algorithm. Co-primary endpoints were progression-free survival in patients with EGFR FISH-positive cancer and overall survival in the entire study population. We analysed clinical outcomes with the intention-to-treat principle and analysis of safety outcomes included patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (number NCT00946712). Between Aug 13, 2009, and May 30, 2014, we randomly assigned 1313 patients to the control group (n=657; 277 with bevacizumab and 380 without bevacizumab in the intention-to-treat population) or the cetuximab group (n=656; 283 with bevacizumab and 373 without bevacizumab in the intention-to-treat population). EGFR FISH was assessable in 976 patients and 400 patients (41%) were EGFR FISH-positive. The median follow-up for patients last known to be alive was 35·2 months (IQR 22·9-39·9). After 194 progression-free survival events in the cetuximab group and 198 in the control

Target-similarity search using Plasmodium falciparum proteome identifies approved drugs with anti-malarial activity and their possible targets

PubMed Central

Akala, Hoseah M.; Macharia, Rosaline W.; Juma, Dennis W.; Cheruiyot, Agnes C.; Andagalu, Ben; Brown, Mathew L.; El-Shemy, Hany A.; Nyanjom, Steven G.

2017-01-01

Malaria causes about half a million deaths annually, with Plasmodium falciparum being responsible for 90% of all the cases. Recent reports on artemisinin resistance in Southeast Asia warrant urgent discovery of novel drugs for the treatment of malaria. However, most bioactive compounds fail to progress to treatments due to safety concerns. Drug repositioning offers an alternative strategy where drugs that have already been approved as safe for other diseases could be used to treat malaria. This study screened approved drugs for antimalarial activity using an in silico chemogenomics approach prior to in vitro verification. All the P. falciparum proteins sequences available in NCBI RefSeq were mined and used to perform a similarity search against DrugBank, TTD and STITCH databases to identify similar putative drug targets. Druggability indices of the potential P. falciparum drug targets were obtained from TDR targets database. Functional amino acid residues of the drug targets were determined using ConSurf server which was used to fine tune the similarity search. This study predicted 133 approved drugs that could target 34 P. falciparum proteins. A literature search done at PubMed and Google Scholar showed 105 out of the 133 drugs to have been previously tested against malaria, with most showing activity. For further validation, drug susceptibility assays using SYBR Green I method were done on a representative group of 10 predicted drugs, eight of which did show activity against P. falciparum 3D7 clone. Seven had IC50 values ranging from 1 μM to 50 μM. This study also suggests drug-target association and hence possible mechanisms of action of drugs that did show antiplasmodial activity. The study results validate the use of proteome-wide target similarity approach in identifying approved drugs with activity against P. falciparum and could be adapted for other pathogens. PMID:29088219

Targeted drug delivery using genetically engineered diatom biosilica.

PubMed

Delalat, Bahman; Sheppard, Vonda C; Rasi Ghaemi, Soraya; Rao, Shasha; Prestidge, Clive A; McPhee, Gordon; Rogers, Mary-Louise; Donoghue, Jacqueline F; Pillay, Vinochani; Johns, Terrance G; Kröger, Nils; Voelcker, Nicolas H

2015-11-10

The ability to selectively kill cancerous cell populations while leaving healthy cells unaffected is a key goal in anticancer therapeutics. The use of nanoporous silica-based materials as drug-delivery vehicles has recently proven successful, yet production of these materials requires costly and toxic chemicals. Here we use diatom microalgae-derived nanoporous biosilica to deliver chemotherapeutic drugs to cancer cells. The diatom Thalassiosira pseudonana is genetically engineered to display an IgG-binding domain of protein G on the biosilica surface, enabling attachment of cell-targeting antibodies. Neuroblastoma and B-lymphoma cells are selectively targeted and killed by biosilica displaying specific antibodies sorbed with drug-loaded nanoparticles. Treatment with the same biosilica leads to tumour growth regression in a subcutaneous mouse xenograft model of neuroblastoma. These data indicate that genetically engineered biosilica frustules may be used as versatile 'backpacks' for the targeted delivery of poorly water-soluble anticancer drugs to tumour sites.

Drug-induced amplification of nanoparticle targeting to tumors

PubMed Central

Lin, Kevin Y.; Kwon, Ester J.; Lo, Justin H.; Bhatia, Sangeeta N.

2018-01-01

Summary Nanomedicines have the potential to significantly impact cancer therapy by improving drug efficacy and decreasing off-target effects, yet our ability to efficiently home nanoparticles to disease sites remains limited. One frequently overlooked constraint of current active targeting schemes is the relative dearth of targetable antigens within tumors, which restricts the amount of cargo that can be delivered in a tumor-specific manner. To address this limitation, we exploit tumor-specific responses to drugs to construct a cooperative targeting system where a small molecule therapeutic modulates the disease microenvironment to amplify nanoparticle recruitment in vivo. We first administer a vascular disrupting agent, ombrabulin, which selectively affects tumors and leads to locally elevated presentation of the stress-related protein, p32. This increase in p32 levels provides more binding sites for circulating p32-targeted nanoparticles, enhancing their delivery of diagnostic or therapeutic cargos to tumors. We show that this cooperative targeting system recruits over five times higher doses of nanoparticles to tumors and decreases tumor burden when compared with non-cooperative controls. These results suggest that using nanomedicine in conjunction with drugs that enhance the presentation of target antigens in the tumor environment may be an effective strategy for improving the diagnosis and treatment of cancer. PMID:29731806

Neo-adjuvant chemotherapy followed by chemoradiation and surgery with and without cetuximab in patients with resectable esophageal cancer: a randomized, open-label, phase III trial (SAKK 75/08).

PubMed

Ruhstaller, T; Thuss-Patience, P; Hayoz, S; Schacher, S; Knorrenschild, J R; Schnider, A; Plasswilm, L; Budach, W; Eisterer, W; Hawle, H; Mariette, C; Hess, V; Mingrone, W; Montemurro, M; Girschikofsky, M; Schmidt, S C; Bitzer, M; Bedenne, L; Brauchli, P; Stahl, M

2018-04-04

This open-label, phase lll trial compared chemoradiation followed by surgery with or without neoadjuvant and adjuvant cetuximab in patients with resectable esophageal carcinoma. Patients were randomly assigned (1:1) to 2 cycles of chemotherapy (docetaxel 75 mg/m2, cisplatin 75 mg/m2) followed by chemoradiation (45 Gy, docetaxel 20 mg/m2 and cisplatin 25 mg/m2, weekly for 5 weeks) and surgery, with or without neoadjuvant cetuximab 250 mg/m2 weekly and adjuvant cetuximab 500 mg/m2 fortnightly for 3 months. The primary endpoint was progression-free survival (PFS). In total, 300 patients (median age, 61 years; 88% male; 63% adenocarcinoma; 85% cT3/4a, 90% cN+) were assigned to cetuximab (n = 149) or control (n = 151). The R0-resection rate was 95% for cetuximab versus 97% for control. Postoperative treatment-related mortality was 6% in both arms. Median PFS was 2.9 years (95% CI, 2.0 to not reached) with cetuximab and 2.0 years (95% CI, 1.5 to 2.8) with control (HR, 0.79; 95% CI, 0.58 to 1.07; P = .13). Median overall survival (OS) time was 5.1 years (95% CI, 3.7 to not reached) versus 3.0 years (95% CI, 2.2 to 4.2) for cetuximab and control, respectively (HR, 0.73; 95% CI, 0.52 to 1.01; P = .055). Time to loco-regional failure after R0-resection was significantly longer for cetuximab (HR 0.53; 95% CI, 0.31 to 0.90; P = .017); time to distant failure did not differ between arms (HR, 1.01; 95% CI, 0.64 to 1.59, P = .97). Cetuximab did not increase adverse events in neoadjuvant or postoperative settings. Adding cetuximab to multimodal therapy significantly improved loco-regional control, and led to clinically relevant, but not-significant improvements in PFS and OS in resectable esophageal carcinoma. NCT01107639.

Drug-target interaction prediction from PSSM based evolutionary information.

PubMed

Mousavian, Zaynab; Khakabimamaghani, Sahand; Kavousi, Kaveh; Masoudi-Nejad, Ali

2016-01-01

The labor-intensive and expensive experimental process of drug-target interaction prediction has motivated many researchers to focus on in silico prediction, which leads to the helpful information in supporting the experimental interaction data. Therefore, they have proposed several computational approaches for discovering new drug-target interactions. Several learning-based methods have been increasingly developed which can be categorized into two main groups: similarity-based and feature-based. In this paper, we firstly use the bi-gram features extracted from the Position Specific Scoring Matrix (PSSM) of proteins in predicting drug-target interactions. Our results demonstrate the high-confidence prediction ability of the Bigram-PSSM model in terms of several performance indicators specifically for enzymes and ion channels. Moreover, we investigate the impact of negative selection strategy on the performance of the prediction, which is not widely taken into account in the other relevant studies. This is important, as the number of non-interacting drug-target pairs are usually extremely large in comparison with the number of interacting ones in existing drug-target interaction data. An interesting observation is that different levels of performance reduction have been attained for four datasets when we change the sampling method from the random sampling to the balanced sampling. Copyright © 2015 Elsevier Inc. All rights reserved.

Drug-target interaction prediction via class imbalance-aware ensemble learning.

PubMed

Ezzat, Ali; Wu, Min; Li, Xiao-Li; Kwoh, Chee-Keong

2016-12-22

Multiple computational methods for predicting drug-target interactions have been developed to facilitate the drug discovery process. These methods use available data on known drug-target interactions to train classifiers with the purpose of predicting new undiscovered interactions. However, a key challenge regarding this data that has not yet been addressed by these methods, namely class imbalance, is potentially degrading the prediction performance. Class imbalance can be divided into two sub-problems. Firstly, the number of known interacting drug-target pairs is much smaller than that of non-interacting drug-target pairs. This imbalance ratio between interacting and non-interacting drug-target pairs is referred to as the between-class imbalance. Between-class imbalance degrades prediction performance due to the bias in prediction results towards the majority class (i.e. the non-interacting pairs), leading to more prediction errors in the minority class (i.e. the interacting pairs). Secondly, there are multiple types of drug-target interactions in the data with some types having relatively fewer members (or are less represented) than others. This variation in representation of the different interaction types leads to another kind of imbalance referred to as the within-class imbalance. In within-class imbalance, prediction results are biased towards the better represented interaction types, leading to more prediction errors in the less represented interaction types. We propose an ensemble learning method that incorporates techniques to address the issues of between-class imbalance and within-class imbalance. Experiments show that the proposed method improves results over 4 state-of-the-art methods. In addition, we simulated cases for new drugs and targets to see how our method would perform in predicting their interactions. New drugs and targets are those for which no prior interactions are known. Our method displayed satisfactory prediction performance and was

Current Molecular Targeted Therapy in Advanced Gastric Cancer: A Comprehensive Review of Therapeutic Mechanism, Clinical Trials, and Practical Application

PubMed Central

Li, Kaichun; Li, Jin

2016-01-01

Despite the great progress in the treatment of gastric cancer, it is still the third leading cause of cancer death worldwide. Patients often miss the opportunity for a surgical cure, because the cancer has already developed into advanced cancer when identified. Compared to best supportive care, chemotherapy can improve quality of life and prolong survival time, but the overall survival is often short. Due to the molecular study of gastric cancer, new molecular targeted drugs have entered the clinical use. Trastuzumab, an antibody targeting human epidermal growth factor receptor 2 (HER2), can significantly improve survival in advanced gastric cancer patients with HER2 overexpression. Second-line treatment of advanced gastric cancer with ramucirumab, an antibody targeting VEGFR-2, alone or in combination with paclitaxel, has been proved to provide a beneficial effect. The VEGFR-2 tyrosine kinase inhibitor, apatinib, can improve the survival of advanced gastric cancer patients after second-line chemotherapy failure. Unfortunately, none of the EGFR targeting antibodies (cetuximab or panitumumab), VEGF targeting monoclonal antibodies (bevacizumab), mTOR inhibitor (everolimus), or HGF/MET pathway targeting drugs has a significant survival benefit. Many other clinical trials based on molecular markers are underway. This review will summarize targeted therapies for advanced gastric cancer. PMID:26880889

A side-effect free method for identifying cancer drug targets.

PubMed

Ashraf, Md Izhar; Ong, Seng-Kai; Mujawar, Shama; Pawar, Shrikant; More, Pallavi; Paul, Somnath; Lahiri, Chandrajit

2018-04-27

Identifying effective drug targets, with little or no side effects, remains an ever challenging task. A potential pitfall of failing to uncover the correct drug targets, due to side effect of pleiotropic genes, might lead the potential drugs to be illicit and withdrawn. Simplifying disease complexity, for the investigation of the mechanistic aspects and identification of effective drug targets, have been done through several approaches of protein interactome analysis. Of these, centrality measures have always gained importance in identifying candidate drug targets. Here, we put forward an integrated method of analysing a complex network of cancer and depict the importance of k-core, functional connectivity and centrality (KFC) for identifying effective drug targets. Essentially, we have extracted the proteins involved in the pathways leading to cancer from the pathway databases which enlist real experimental datasets. The interactions between these proteins were mapped to build an interactome. Integrative analyses of the interactome enabled us to unearth plausible reasons for drugs being rendered withdrawn, thereby giving future scope to pharmaceutical industries to potentially avoid them (e.g. ESR1, HDAC2, F2, PLG, PPARA, RXRA, etc). Based upon our KFC criteria, we have shortlisted ten proteins (GRB2, FYN, PIK3R1, CBL, JAK2, LCK, LYN, SYK, JAK1 and SOCS3) as effective candidates for drug development.

KRAS Mutation Status and Clinical Outcome of Preoperative Chemoradiation With Cetuximab in Locally Advanced Rectal Cancer: A Pooled Analysis of 2 Phase II Trials

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Sun Young; Shim, Eun Kyung; Yeo, Hyun Yang

2013-01-01

Purpose: Cetuximab-containing chemotherapy is known to be effective for KRAS wild-type metastatic colorectal cancer; however, it is not clear whether cetuximab-based preoperative chemoradiation confers an additional benefit compared with chemoradiation without cetuximab in patients with locally advanced rectal cancer. Methods and Materials: We analyzed EGFR, KRAS, BRAF, and PIK3CA mutation status with direct sequencing and epidermal growth factor receptor (EGFR) and Phosphatase and tensin homolog (PTEN) expression status with immunohistochemistry in tumor samples of 82 patients with locally advanced rectal cancer who were enrolled in the IRIX trial (preoperative chemoradiation with irinotecan and capecitabine; n=44) or the ERBIRIX trial (preoperativemore » chemoradiation with irinotecan and capecitabine plus cetuximab; n=38). Both trials were similarly designed except for the administration of cetuximab; radiation therapy was administered at a dose of 50.4 Gy/28 fractions and irinotecan and capecitabine were given at doses of 40 mg/m{sup 2} weekly and 1650 mg/m{sup 2}/day, respectively, for 5 days per week. In the ERBIRIX trial, cetuximab was additionally given with a loading dose of 400 mg/m{sup 2} on 1 week before radiation, and 250 mg/m{sup 2} weekly thereafter. Results: Baseline characteristics before chemoradiation were similar between the 2 trial cohorts. A KRAS mutation in codon 12, 13, and 61 was noted in 15 (34%) patients in the IRIX cohort and 5 (13%) in the ERBIRIX cohort (P=.028). Among 62 KRAS wild-type cancer patients, major pathologic response rate, disease-free survival and pathologic stage did not differ significantly between the 2 cohorts. No mutations were detected in BRAF exon 11 and 15, PIK3CA exon 9 and 20, or EGFR exon 18-24 in any of the 82 patients, and PTEN and EGFR expression were not predictive of clinical outcome. Conclusions: In patients with KRAS wild-type locally advanced rectal cancer, the addition of cetuximab to the

Increasing the structural coverage of tuberculosis drug targets.

PubMed

Baugh, Loren; Phan, Isabelle; Begley, Darren W; Clifton, Matthew C; Armour, Brianna; Dranow, David M; Taylor, Brandy M; Muruthi, Marvin M; Abendroth, Jan; Fairman, James W; Fox, David; Dieterich, Shellie H; Staker, Bart L; Gardberg, Anna S; Choi, Ryan; Hewitt, Stephen N; Napuli, Alberto J; Myers, Janette; Barrett, Lynn K; Zhang, Yang; Ferrell, Micah; Mundt, Elizabeth; Thompkins, Katie; Tran, Ngoc; Lyons-Abbott, Sally; Abramov, Ariel; Sekar, Aarthi; Serbzhinskiy, Dmitri; Lorimer, Don; Buchko, Garry W; Stacy, Robin; Stewart, Lance J; Edwards, Thomas E; Van Voorhis, Wesley C; Myler, Peter J

2015-03-01

High-resolution three-dimensional structures of essential Mycobacterium tuberculosis (Mtb) proteins provide templates for TB drug design, but are available for only a small fraction of the Mtb proteome. Here we evaluate an intra-genus "homolog-rescue" strategy to increase the structural information available for TB drug discovery by using mycobacterial homologs with conserved active sites. Of 179 potential TB drug targets selected for x-ray structure determination, only 16 yielded a crystal structure. By adding 1675 homologs from nine other mycobacterial species to the pipeline, structures representing an additional 52 otherwise intractable targets were solved. To determine whether these homolog structures would be useful surrogates in TB drug design, we compared the active sites of 106 pairs of Mtb and non-TB mycobacterial (NTM) enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. Pair-wise structural comparisons revealed that 19/22 pairs with >55% overall sequence identity had active site Cα RMSD <1 Å, >85% side chain identity, and ≥80% PSAPF (similarity based on pharmacophoric properties) indicating highly conserved active site shape and chemistry. Applying these results to the 52 NTM structures described above, 41 shared >55% sequence identity with the Mtb target, thus increasing the effective structural coverage of the 179 Mtb targets over three-fold (from 9% to 32%). The utility of these structures in TB drug design can be tested by designing inhibitors using the homolog structure and assaying the cognate Mtb enzyme; a promising test case, Mtb cytidylate kinase, is described. The homolog-rescue strategy evaluated here for TB is also generalizable to drug targets for other diseases. Copyright © 2014 Elsevier Ltd. All rights reserved.

Increasing the structural coverage of tuberculosis drug targets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baugh, Loren; Phan, Isabelle; Begley, Darren W.

High-resolution three-dimensional structures of essential Mycobacterium tuberculosis (Mtb) proteins provide templates for TB drug design, but are available for only a small fraction of the Mtb proteome. Here we evaluate an intra-genus “homolog-rescue” strategy to increase the structural information available for TB drug discovery by using mycobacterial homologs with conserved active sites. We found that of 179 potential TB drug targets selected for x-ray structure determination, only 16 yielded a crystal structure. By adding 1675 homologs from nine other mycobacterial species to the pipeline, structures representing an additional 52 otherwise intractable targets were solved. To determine whether these homolog structuresmore » would be useful surrogates in TB drug design, we compared the active sites of 106 pairs of Mtb and non-TB mycobacterial (NTM) enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. Pair-wise structural comparisons revealed that 19/22 pairs with >55% overall sequence identity had active site Cα RMSD <1 Å, >85% side chain identity, and ≥80% PS APF (similarity based on pharmacophoric properties) indicating highly conserved active site shape and chemistry. Applying these results to the 52 NTM structures described above, 41 shared >55% sequence identity with the Mtb target, thus increasing the effective structural coverage of the 179 Mtb targets over three-fold (from 9% to 32%). The utility of these structures in TB drug design can be tested by designing inhibitors using the homolog structure and assaying the cognate Mtb enzyme; a promising test case, Mtb cytidylate kinase, is described. The homolog-rescue strategy evaluated here for TB is also generalizable to drug targets for other diseases.« less

Increasing the structural coverage of tuberculosis drug targets

DOE PAGES

Baugh, Loren; Phan, Isabelle; Begley, Darren W.; ...

2014-12-19

High-resolution three-dimensional structures of essential Mycobacterium tuberculosis (Mtb) proteins provide templates for TB drug design, but are available for only a small fraction of the Mtb proteome. Here we evaluate an intra-genus “homolog-rescue” strategy to increase the structural information available for TB drug discovery by using mycobacterial homologs with conserved active sites. We found that of 179 potential TB drug targets selected for x-ray structure determination, only 16 yielded a crystal structure. By adding 1675 homologs from nine other mycobacterial species to the pipeline, structures representing an additional 52 otherwise intractable targets were solved. To determine whether these homolog structuresmore » would be useful surrogates in TB drug design, we compared the active sites of 106 pairs of Mtb and non-TB mycobacterial (NTM) enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. Pair-wise structural comparisons revealed that 19/22 pairs with >55% overall sequence identity had active site Cα RMSD <1 Å, >85% side chain identity, and ≥80% PS APF (similarity based on pharmacophoric properties) indicating highly conserved active site shape and chemistry. Applying these results to the 52 NTM structures described above, 41 shared >55% sequence identity with the Mtb target, thus increasing the effective structural coverage of the 179 Mtb targets over three-fold (from 9% to 32%). The utility of these structures in TB drug design can be tested by designing inhibitors using the homolog structure and assaying the cognate Mtb enzyme; a promising test case, Mtb cytidylate kinase, is described. The homolog-rescue strategy evaluated here for TB is also generalizable to drug targets for other diseases.« less

Randomized, Phase II Study of the Insulin-Like Growth Factor-1 Receptor Inhibitor IMC-A12, With or Without Cetuximab, in Patients With Cetuximab- or Panitumumab-Refractory Metastatic Colorectal Cancer

PubMed Central

Reidy, Diane Lauren; Vakiani, Efsevia; Fakih, Marwan G.; Saif, Muhammad Wasif; Hecht, Joel Randolph; Goodman-Davis, Noah; Hollywood, Ellen; Shia, Jinru; Schwartz, Jonathan; Chandrawansa, Kumari; Dontabhaktuni, Aruna; Youssoufian, Hagop; Solit, David B.; Saltz, Leonard B.

2010-01-01

Purpose To evaluate the safety and efficacy of IMC-A12, a human monoclonal antibody (mAb) that blocks insulin-like growth factor receptor-1 (IGF-1R), as monotherapy or in combination with cetuximab in patients with metastatic refractory anti–epidermal growth factor receptor (EGFR) mAb colorectal cancer. Methods A randomized, phase II study was performed in which patients in arm A received IMC-A12 10 mg/kg intravenously (IV) every 2 weeks, while patients in arm B received this same dose of IMC-A12 plus cetuximab 500 mg/m2 IV every 2 weeks. Subsequently, arm C (same combination treatment as arm B) was added to include patients who had disease control on a prior anti-EGFR mAb and wild-type KRAS tumors. Archived pretreatment tumor tissue was obtained when possible for KRAS, PIK3CA, and BRAF genotyping, and immunohistochemistry was obtained for pAKT as well as IGF-1R. Results Overall, 64 patients were treated (median age, 61 years; range, 40 to 84 years): 23 patients in arm A, 21 in arm B, and 20 in arm C. No antitumor activity was seen in the 23 patients treated with IMC-A12 monotherapy. Of the 21 patients randomly assigned to IMC-A12 plus cetuximab, one patient (with KRAS wild type) achieved a partial response, with disease control lasting 6.5 months. Arm C (all patients with KRAS wild type), however, showed no additional antitumor activity. Serious adverse events thought possibly related to IMC-A12 included a grade 2 infusion-related reaction (2%; one of 64 patients), thrombocytopenia (2%; one of 64 patients), grade 3 hyperglycemia (2%; one of 64 patients), and grade 1 pyrexia (2%, one of 64 patients). Conclusion IMC-A12 alone or in combination with cetuximab was insufficient to warrant additional study in patients with colorectal cancer refractory to EGFR inhibitors. PMID:20713879

Untethered magnetic millirobot for targeted drug delivery.

PubMed

Iacovacci, Veronica; Lucarini, Gioia; Ricotti, Leonardo; Dario, Paolo; Dupont, Pierre E; Menciassi, Arianna

2015-01-01

This paper reports the design and development of a novel millimeter-sized robotic system for targeted therapy. The proposed medical robot is conceived to perform therapy in relatively small diameter body canals (spine, urinary system, ovary, etc.), and to release several kinds of therapeutics, depending on the pathology to be treated. The robot is a nearly-buoyant bi-component system consisting of a carrier, in which the therapeutic agent is embedded, and a piston. The piston, by exploiting magnetic effects, docks with the carrier and compresses a drug-loaded hydrogel, thus activating the release mechanism. External magnetic fields are exploited to propel the robot towards the target region, while intermagnetic forces are exploited to trigger drug release. After designing and fabricating the robot, the system has been tested in vitro with an anticancer drug (doxorubicin) embedded in the carrier. The efficiency of the drug release mechanism has been demonstrated by both quantifying the amount of drug released and by assessing the efficacy of this therapeutic procedure on human bladder cancer cells.

Novel EGFR-specific immunotoxins based on panitumumab and cetuximab show in vitro and ex vivo activity against different tumor entities.

PubMed

Niesen, Judith; Stein, Christoph; Brehm, Hannes; Hehmann-Titt, Grit; Fendel, Rolf; Melmer, Georg; Fischer, Rainer; Barth, Stefan

2015-12-01

The epidermal growth factor receptor (EGFR) is overexpressed in many solid tumors. EGFR-specific monoclonal antibodies (mAbs), such as cetuximab and panitumumab, have been approved for the treatment of colorectal and head and neck cancer. To increase tissue penetration, we constructed single-chain fragment variable (scFv) antibodies derived from these mAbs and evaluated their potential for targeted cancer therapy. The resulting scFv-based EGFR-specific immunotoxins (ITs) combine target specificity of the full-size mAb with the cell-killing activity of a toxic effector domain, a truncated version of Pseudomonas exotoxin A (ETA'). The ITs and corresponding imaging probes were tested in vitro against four solid tumor entities (rhabdomyosarcoma, breast, prostate and pancreatic cancer). Specific binding and internalization of the ITs scFv2112-ETA' (from cetuximab) and scFv1711-ETA' (from panitumumab) were demonstrated by flow cytometry and for the scFv-SNAP-tag imaging probes by live cell imaging. Cytotoxic potential of the ITs was analyzed in cell viability and apoptosis assays. Binding of the ITs was proofed ex vivo on rhabdomyosarcoma, prostate and breast cancer formalin-fixed paraffin-embedded biopsies. Both novel ITs showed significant pro-apoptotic and anti-proliferative effects toward the target cells, achieving IC50 values of 4 pM (high EGFR expression) to 460 pM (moderate EGFR expression). Additionally, rapid internalization and specific in vitro and ex vivo binding on patient tissue were confirmed. These data demonstrate the potent therapeutic activity of two novel EGFR-specific ETA'-based ITs. Both molecules are promising candidates for further development toward clinical use in the treatment of various solid tumors to supplement the existing therapeutic regimes.

Target-mediated drug disposition model for drugs with two binding sites that bind to a target with one binding site.

PubMed

Gibiansky, Leonid; Gibiansky, Ekaterina

2017-10-01

The paper extended the TMDD model to drugs with two identical binding sites (2-1 TMDD). The quasi-steady-state (2-1 QSS), quasi-equilibrium (2-1 QE), irreversible binding (2-1 IB), and Michaelis-Menten (2-1 MM) approximations of the model were derived. Using simulations, the 2-1 QSS approximation was compared with the full 2-1 TMDD model. As expected and similarly to the standard TMDD for monoclonal antibodies (mAb), 2-1 QSS predictions were nearly identical to 2-1 TMDD predictions, except for times of fast changes following initiation of dosing, when equilibrium has not yet been reached. To illustrate properties of new equations and approximations, several variations of population PK data for mAbs with soluble (slow elimination of the complex) or membrane-bound (fast elimination of the complex) targets were simulated from a full 2-1 TMDD model and fitted to 2-1 TMDD models, to its approximations, and to the standard (1-1) QSS model. For a mAb with a soluble target, it was demonstrated that the 2-1 QSS model provided nearly identical description of the observed (simulated) free drug and total target concentrations, although there was some minor bias in predictions of unobserved free target concentrations. The standard QSS approximation also provided a good description of the observed data, but was not able to distinguish between free drug concentrations (with no target attached and both binding site free) and partially bound drug concentrations (with one of the binding sites occupied by the target). For a mAb with a membrane-bound target, the 2-1 MM approximation adequately described the data. The 2-1 QSS approximation converged 10 times faster than the full 2-1 TMDD, and its run time was comparable with the standard QSS model.

Membrane Transporters: Structure, Function and Targets for Drug Design

NASA Astrophysics Data System (ADS)

Ravna, Aina W.; Sager, Georg; Dahl, Svein G.; Sylte, Ingebrigt

Current therapeutic drugs act on four main types of molecular targets: enzymes, receptors, ion channels and transporters, among which a major part (60-70%) are membrane proteins. This review discusses the molecular structures and potential impact of membrane transporter proteins on new drug discovery. The three-dimensional (3D) molecular structure of a protein contains information about the active site and possible ligand binding, and about evolutionary relationships within the protein family. Transporters have a recognition site for a particular substrate, which may be used as a target for drugs inhibiting the transporter or acting as a false substrate. Three groups of transporters have particular interest as drug targets: the major facilitator superfamily, which includes almost 4000 different proteins transporting sugars, polyols, drugs, neurotransmitters, metabolites, amino acids, peptides, organic and inorganic anions and many other substrates; the ATP-binding cassette superfamily, which plays an important role in multidrug resistance in cancer chemotherapy; and the neurotransmitter:sodium symporter family, which includes the molecular targets for some of the most widely used psychotropic drugs. Recent technical advances have increased the number of known 3D structures of membrane transporters, and demonstrated that they form a divergent group of proteins with large conformational flexibility which facilitates transport of the substrate.

Systems biology-embedded target validation: improving efficacy in drug discovery.

PubMed

Vandamme, Drieke; Minke, Benedikt A; Fitzmaurice, William; Kholodenko, Boris N; Kolch, Walter

2014-01-01

The pharmaceutical industry is faced with a range of challenges with the ever-escalating costs of drug development and a drying out of drug pipelines. By harnessing advances in -omics technologies and moving away from the standard, reductionist model of drug discovery, there is significant potential to reduce costs and improve efficacy. Embedding systems biology approaches in drug discovery, which seek to investigate underlying molecular mechanisms of potential drug targets in a network context, will reduce attrition rates by earlier target validation and the introduction of novel targets into the currently stagnant market. Systems biology approaches also have the potential to assist in the design of multidrug treatments and repositioning of existing drugs, while stratifying patients to give a greater personalization of medical treatment. © 2013 Wiley Periodicals, Inc.

Cetuximab for recurrent and/or metastatic squamous cell carcinoma of the head and neck: a NICE single technology appraisal.

PubMed

Bagust, Adrian; Greenhalgh, Janette; Boland, Angela; Fleeman, Nigel; McLeod, Claire; Dickson, Rumona; Dundar, Yenal; Proudlove, Christine; Shaw, Richard

2010-01-01

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of cetuximab (Merck Serono) to submit evidence for the clinical and cost effectiveness of cetuximab in combination with platinum-based chemotherapy (CTX) for the treatment of patients with recurrent and/or metastatic squamous cell cancer of the head and neck (SCCHN) according to the Institute's Single Technology Appraisal (STA) process. The Liverpool Reviews and Implementation Group at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG). This article summarizes the ERG's review of the evidence submitted by the manufacturer. A summary of the Appraisal Committee (AC) decision is provided. The ERG reviewed the clinical evidence in accordance with the decision problem defined by NICE. The analysis of the submitted model assessed the appropriateness of the manufacturer's approach to modelling the decision problem, the reliability of model implementation and the extent of conformity to published standards and prevailing norms of practice within the health economics modelling community. Particular attention was paid to issues likely to impact substantially on the base-case cost-effectiveness results. Clinical-effectiveness evidence was derived from a single randomized controlled trial (RCT). Results presented for clinical outcomes were strongly supportive of benefits resulting from the use of cetuximab. Cetuximab + platinum-based CTX with 5 fluorouracil (5-FU) extended median overall survival (OS) from 7.4 months in the CTX group to 10.1 months in the cetuximab + CTX group. Median progression-free survival rose from 3.3 months to 5.6 months, best overall response to therapy increased from 19.5% to 35.6%, disease control rate rose from 60% to 81.1% and median time to treatment failure was 4.8 months compared with 3.0 months. Exploratory subgroup analyses indicated significant OS benefits in 11 of 16 pre-planned analyses. The ERG identified a number

Drug Target Validation Methods in Malaria - Protein Interference Assay (PIA) as a Tool for Highly Specific Drug Target Validation.

PubMed

Meissner, Kamila A; Lunev, Sergey; Wang, Yuan-Ze; Linzke, Marleen; de Assis Batista, Fernando; Wrenger, Carsten; Groves, Matthew R

2017-01-01

The validation of drug targets in malaria and other human diseases remains a highly difficult and laborious process. In the vast majority of cases, highly specific small molecule tools to inhibit a proteins function in vivo are simply not available. Additionally, the use of genetic tools in the analysis of malarial pathways is challenging. These issues result in difficulties in specifically modulating a hypothetical drug target's function in vivo. The current "toolbox" of various methods and techniques to identify a protein's function in vivo remains very limited and there is a pressing need for expansion. New approaches are urgently required to support target validation in the drug discovery process. Oligomerisation is the natural assembly of multiple copies of a single protein into one object and this self-assembly is present in more than half of all protein structures. Thus, oligomerisation plays a central role in the generation of functional biomolecules. A key feature of oligomerisation is that the oligomeric interfaces between the individual parts of the final assembly are highly specific. However, these interfaces have not yet been systematically explored or exploited to dissect biochemical pathways in vivo. This mini review will describe the current state of the antimalarial toolset as well as the potentially druggable malarial pathways. A specific focus is drawn to the initial efforts to exploit oligomerisation surfaces in drug target validation. As alternative to the conventional methods, Protein Interference Assay (PIA) can be used for specific distortion of the target protein function and pathway assessment in vivo. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer.

PubMed

Misale, Sandra; Yaeger, Rona; Hobor, Sebastijan; Scala, Elisa; Janakiraman, Manickam; Liska, David; Valtorta, Emanuele; Schiavo, Roberta; Buscarino, Michela; Siravegna, Giulia; Bencardino, Katia; Cercek, Andrea; Chen, Chin-Tung; Veronese, Silvio; Zanon, Carlo; Sartore-Bianchi, Andrea; Gambacorta, Marcello; Gallicchio, Margherita; Vakiani, Efsevia; Boscaro, Valentina; Medico, Enzo; Weiser, Martin; Siena, Salvatore; Di Nicolantonio, Federica; Solit, David; Bardelli, Alberto

2012-06-28

A main limitation of therapies that selectively target kinase signalling pathways is the emergence of secondary drug resistance. Cetuximab, a monoclonal antibody that binds the extracellular domain of epidermal growth factor receptor (EGFR), is effective in a subset of KRAS wild-type metastatic colorectal cancers. After an initial response, secondary resistance invariably ensues, thereby limiting the clinical benefit of this drug. The molecular bases of secondary resistance to cetuximab in colorectal cancer are poorly understood. Here we show that molecular alterations (in most instances point mutations) of KRAS are causally associated with the onset of acquired resistance to anti-EGFR treatment in colorectal cancers. Expression of mutant KRAS under the control of its endogenous gene promoter was sufficient to confer cetuximab resistance, but resistant cells remained sensitive to combinatorial inhibition of EGFR and mitogen-activated protein-kinase kinase (MEK). Analysis of metastases from patients who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% (6 out of 10) of the cases. KRAS mutant alleles were detectable in the blood of cetuximab-treated patients as early as 10 months before radiographic documentation of disease progression. In summary, the results identify KRAS mutations as frequent drivers of acquired resistance to cetuximab in colorectal cancers, indicate that the emergence of KRAS mutant clones can be detected non-invasively months before radiographic progression and suggest early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance.

Pericyte-targeting drug delivery and tissue engineering.

PubMed

Kang, Eunah; Shin, Jong Wook

2016-01-01

Pericytes are contractile mural cells that wrap around the endothelial cells of capillaries and venules. Depending on the triggers by cellular signals, pericytes have specific functionality in tumor microenvironments, properties of potent stem cells, and plasticity in cellular pathology. These features of pericytes can be activated for the promotion or reduction of angiogenesis. Frontier studies have exploited pericyte-targeting drug delivery, using pericyte-specific peptides, small molecules, and DNA in tumor therapy. Moreover, the communication between pericytes and endothelial cells has been applied to the induction of vessel neoformation in tissue engineering. Pericytes may prove to be a novel target for tumor therapy and tissue engineering. The present paper specifically reviews pericyte-specific drug delivery and tissue engineering, allowing insight into the emerging research targeting pericytes.

Targeting efflux pumps to overcome antifungal drug resistance

PubMed Central

Holmes, Ann R; Cardno, Tony S; Strouse, J Jacob; Ivnitski-Steele, Irena; Keniya, Mikhail V; Lackovic, Kurt; Monk, Brian C; Sklar, Larry A; Cannon, Richard D

2016-01-01

Resistance to antifungal drugs is an increasingly significant clinical problem. The most common antifungal resistance encountered is efflux pump-mediated resistance of Candida species to azole drugs. One approach to overcome this resistance is to inhibit the pumps and chemosensitize resistant strains to azole drugs. Drug discovery targeting fungal efflux pumps could thus result in the development of azole-enhancing combination therapy. Heterologous expression of fungal efflux pumps in Saccharomyces cerevisiae provides a versatile system for screening for pump inhibitors. Fungal efflux pumps transport a range of xenobiotics including fluorescent compounds. This enables the use of fluorescence-based detection, as well as growth inhibition assays, in screens to discover compounds targeting efflux-mediated antifungal drug resistance. A variety of medium- and high-throughput screens have been used to identify a number of chemical entities that inhibit fungal efflux pumps. PMID:27463566

Prostate Cancer Relevant Antigens and Enzymes for Targeted Drug Delivery

PubMed Central

Barve, Ashutosh; Jin, Wei; Cheng, Kun

2014-01-01

Chemotherapy is one of the most widely used approaches in combating advanced prostate cancer, but its therapeutic efficacy is usually insufficient due to lack of specificity and associated toxicity. Lack of targeted delivery to prostate cancer cells is also the primary obstacles in achieving feasible therapeutic effect of other promising agents including peptide, protein, and nucleic acid. Consequently, there remains a critical need for strategies to increase the selectivity of anti-prostate cancer agents. This review will focus on various prostate cancer-specific antigens and enzymes that could be exploited for prostate cancer targeted drug delivery. Among various targeting strategies, active targeting is the most advanced approach to specifically deliver drugs to their designated cancer cells. In this approach, drug carriers are modified with targeting ligands that can specifically bind to prostate cancer-specific antigens. Moreover, there are several specific enzymes in the tumor microenvironment of prostate cancer that can be exploited for stimulus-responsive drug delivery systems. These systems can specifically release the active drug in the tumor microenvironment of prostate cancer, leading to enhanced tumor penetration efficiency. PMID:24878184

Nanobiotechnology-based drug delivery in brain targeting.

PubMed

Dinda, Subas C; Pattnaik, Gurudutta

2013-01-01

Blood brain barrier (BBB) found to act as rate limiting factor in drug delivery to brain in combating the central nervous system (CNS) disorders. Such limiting physiological factors include the reticuloendothelial system and protein opsonization, which present across BBB, play major role in reducing the passage of drug. Several approaches employed to improve the drug delivery across the BBB. Nanoparticles (NP) are the solid colloidal particle ranges from 1 to 1000 nm in size utilized as career for drug delivery. At present NPs are found to play a significant advantage over the other methods of available drug delivery systems to deliver the drug across the BBB. Nanoparticles may be because of its size and functionalization characteristics able to penetrate and facilitate the drug delivery through the barrier. There are number of mechanisms and strategies found to be involved in this process, which are based on the type of nanomaterials used and its combination with therapeutic agents, such materials include liposomes, polymeric nanoparticles and non-viral vectors of nano-sizes for CNS gene therapy, etc. Nanotechnology is expected to reduce the need for invasive procedures for delivery of therapeutics to the CNS. Some devices such as implanted catheters and reservoirs however will still be needed to overcome the problems in effective drug delivery to the CNS. Nanomaterials are found to improve the safety and efficacy level of drug delivery devices in brain targeting. Nanoegineered devices are found to be delivering the drugs at cellular levels through nono-fluidic channels. Different drug delivery systems such as liposomes, microspheres, nanoparticles, nonogels and nonobiocapsules have been used to improve the bioavailability of the drug in the brain, but microchips and biodegradable polymeric nanoparticulate careers are found to be more effective therapeutically in treating brain tumor. The physiological approaches also utilized to improve the transcytosis capacity

Affinity Maturation of a Cyclic Peptide Handle for Therapeutic Antibodies Using Deep Mutational Scanning*

PubMed Central

van Rosmalen, Martijn; Janssen, Brian M. G.; Hendrikse, Natalie M.; van der Linden, Ardjan J.; Pieters, Pascal A.; Wanders, Dave; de Greef, Tom F. A.; Merkx, Maarten

2017-01-01

Meditopes are cyclic peptides that bind in a specific pocket in the antigen-binding fragment of a therapeutic antibody such as cetuximab. Provided their moderate affinity can be enhanced, meditope peptides could be used as specific non-covalent and paratope-independent handles in targeted drug delivery, molecular imaging, and therapeutic drug monitoring. Here we show that the affinity of a recently reported meditope for cetuximab can be substantially enhanced using a combination of yeast display and deep mutational scanning. Deep sequencing was used to construct a fitness landscape of this protein-peptide interaction, and four mutations were identified that together improved the affinity for cetuximab 10-fold to 15 nm. Importantly, the increased affinity translated into enhanced cetuximab-mediated recruitment to EGF receptor-overexpressing cancer cells. Although in silico Rosetta simulations correctly identified positions that were tolerant to mutation, modeling did not accurately predict the affinity-enhancing mutations. The experimental approach reported here should be generally applicable and could be used to develop meditope peptides with low nanomolar affinity for other therapeutic antibodies. PMID:27974464

Cetuximab Plus Chemoradiotherapy for HIV-Associated Anal Carcinoma: A Phase II AIDS Malignancy Consortium Trial

PubMed Central

Lee, Jeannette Y.; Palefsky, Joel; Henry, David H.; Wachsman, William; Rajdev, Lakshmi; Aboulafia, David; Ratner, Lee; Fitzgerald, Thomas J.; Kachnic, Lisa; Mitsuyasu, Ronald

2017-01-01

Purpose Squamous cell carcinoma of the anal canal (SCCAC) is characterized by high locoregional failure (LRF) rates after definitive chemoradiation (CRT), associated with anogenital human papilloma virus, and often appears in HIV infection. Because cetuximab enhances the effect of radiation therapy in human papilloma virus–associated oropharyngeal SCC, we hypothesized that adding cetuximab to CRT would reduce LRF in SCCAC. Methods Forty-five patients with stage I to III SCCAC and HIV infection received CRT: 45 to 54 Gy radiation therapy to the primary tumor and regional lymph nodes plus eight once-weekly doses of concurrent cetuximab and two cycles of cisplatin and fluorouracil. The study was designed to detect at least a 50% reduction in 3-year LRF rate (one-sided α, 0.10; power, 90%), assuming a 35% LRF rate from historical data. Results The 3-year LRF rate was 42% (95% CI, 28% to 56%; one-sided P = .9) by binomial proportional estimate using the prespecified end point (LRF or alive without LRF and followed < 3 years), and 20% (95% CI, 10% to 37%) by Kaplan-Meier estimate in post hoc analysis using definitions and methods consistent with historical data. Three-year rates by Kaplan-Meier estimate were 72% (95% CI, 56% to 84%) for progression-free survival and 79% (95% CI, 63% to 89%) for overall survival. Grade 4 toxicity occurred in 26%, and 4% had treatment-associated deaths. Conclusion HIV-associated SCCAC is potentially curable with definitive CRT. Although addition of cetuximab may result in less LRF, the 20% recurrence and 26% grade 4 toxicity rates indicate the continued need for more-effective and less-toxic therapies. PMID:27937092

Afatinib and Cetuximab in Four Patients With EGFR Exon 20 Insertion-Positive Advanced NSCLC.

PubMed

van Veggel, Bianca; de Langen, Adrianus J; Hashemi, Sayed M S; Monkhorst, Kim; Heideman, Daniëlle A M; Thunnissen, Erik; Smit, Egbert F

2018-04-24

EGFR exon 20 insertions comprise 4% to 9% of EGFR mutated NSCLC. Despite being an oncogenic driver, they are associated with primary resistance to EGFR tyrosine kinase inhibitors (TKIs). We hypothesized that dual EGFR blockade with afatinib, an irreversible EGFR TKI, and cetuximab, a monoclonal antibody against EGFR, could induce tumor responses. Four patients with EGFR exon 20 insertion-positive NSCLC were treated with afatinib 40 mg once daily and cetuximab 250 mg/m 2 to 500 mg/m 2 every 2 weeks. All patients had stage IV adenocarcinoma of the lung harboring an EGFR exon 20 insertion mutation. Previous lines of treatment consisted of platinum doublet chemotherapy (n = 4) and EGFR TKI (n = 2). Three of four patients showed a partial response according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Median progression-free survival was 5.4 months (95% confidence interval: 0.0 - 14.2 months; range 2.7 months - 17.6 months). Toxicity was manageable with appropriate skin management and dose reduction being required in two patients. Dual EGFR blockade with afatinib and cetuximab may induce tumor responses in patients with EGFR exon 20 insertion-positive NSCLC. Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Phase II clinical study of valproic acid plus cisplatin and cetuximab in recurrent and/or metastatic squamous cell carcinoma of Head and Neck-V-CHANCE trial.

PubMed

Caponigro, Francesco; Di Gennaro, Elena; Ionna, Franco; Longo, Francesco; Aversa, Corrado; Pavone, Ettore; Maglione, Maria Grazia; Di Marzo, Massimiliano; Muto, Paolo; Cavalcanti, Ernesta; Petrillo, Antonella; Sandomenico, Fabio; Maiolino, Piera; D'Aniello, Roberta; Botti, Gerardo; De Cecio, Rossella; Losito, Nunzia Simona; Scala, Stefania; Trotta, Annamaria; Zotti, Andrea Ilaria; Bruzzese, Francesca; Daponte, Antonio; Calogero, Ester; Montano, Massimo; Pontone, Monica; De Feo, Gianfranco; Perri, Francesco; Budillon, Alfredo

2016-11-25

Recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) has a poor prognosis and the combination of cisplatin and cetuximab, with or without 5-fluorouracil, is the gold standard treatment in this stage. Thus, the concomitant use of novel compounds represents a critical strategy to improve treatment results. Histone deacetylase inhibitors (HDACi) enhance the activity of several anticancer drugs including cisplatin and anti-Epidermal Growth Factor Receptor (anti-EGFR) compounds. Preclinical studies in models have shown that vorinostat is able to down regulate Epidermal Growth Factor Receptor (EGFR) expression and to revert epithelial to mesenchimal transition (EMT). Due to its histone deacetylase (HDAC) inhibiting activity and its safe use as a chronic therapy for epileptic disorders, valproic acid (VPA) has been considered a good candidate for anticancer therapy. A reasonable option may be to employ the combination of cisplatin, cetuximab and VPA in recurrent/metastatic SCCHN taking advantage of the possible positive interaction between histone deacetylase inhibitors, cisplatin and/or anti-EGFR. V-CHANCE is a phase 2 clinical trial evaluating, in patients with recurrent/metastatic squamous cell carcinoma of the head and neck never treated with first-line chemotherapy, the concomitant standard administration of cisplatin (on day 1, every 3 weeks) and cetuximab (on day 1, weekly), in combination with oral VPA given daily from day -14 with a titration strategy in each patient (target serum level of 50-100 μg/ml). Primary end point is the objective response rate measured according to Response Evaluation Criteria in Solid Tumors (RECIST). Sample size, calculated according to Simon 2 stage minimax design will include 21 patients in the first stage with upper limit for rejection being 8 responses, and 39 patients in the second stage, with upper limit for rejection being 18 responses. Secondary endpoints are time to progression, duration of response

Assessment of the cardiac safety between cetuximab and panitumumab as single therapy in Chinese chemotherapy-refractory mCRC.

PubMed

Tang, Xue-Miao; Chen, Hao; Li, Qing; Song, Yiling; Zhang, Shuping; Xu, Xiao-Shuan; Xu, Yiwei; Chen, Shulin

2018-01-01

The cardiac safety of cetuximab and panitumumab, particularly as single agents, has not been investigated extensively. This trial was designed to specifically evaluate the cardiac safety of cetuximab and panitumumab as single therapy in Chinese chemotherapy-refractory metastatic colorectal cancer (mCRC) patients. Sixty-one patients received cetuximab at an initial dose of 400 mg/m 2 intravenously over 120 minutes on day 1 (week 1), followed by a maintenance dose of 250 mg/m 2 intravenously over 60 minutes on day 1 of each 7-day cycle. Forty-three patients received panitumumab at a dose of 6 mg/kg intravenously every 14 days. Routine laboratory tests and electrocardiogram (ECG) were performed at baseline, during therapy and after the treatment (4th and 10th months). The incidence of elevation of troponin I ultra (TNI Ultra), abnormal ECGs, cardiac events and noncardiac adverse events (AEs) were recorded and analyzed. The incidence of elevation of TNI Ultra between the two groups had no significance ( p =0.681), and TNI Ultra+ was observed more frequently in patients with metastases to more than three organs and they received fourth or above lines of chemotherapy. The most frequent abnormal ECG manifestations were nonspecific ST changes and QTc prolongation in the two groups. At 10 months after treatment, most of the abnormal ECG manifestations were reversed. The most common cardiac AEs of cetuximab and panitumumab included palpitations, dyspnea, chest pain and arrhythmias requiring treatment. Most of the events were mild and transient. The incidence of cardiac AEs had no significant difference between the two groups. Rash was still the most common noncardiac AE in both groups. Cetuximab and panitumumab showed favorable cardiac safety as single agents for Chinese chemotherapy-refractory mCRC patients. But monitoring for cardiac AEs is still necessary throughout the entire treatment process.

Targeting cysteine proteases in trypanosomatid disease drug discovery.

PubMed

Ferreira, Leonardo G; Andricopulo, Adriano D

2017-12-01

Chagas disease and human African trypanosomiasis are endemic conditions in Latin America and Africa, respectively, for which no effective and safe therapy is available. Efforts in drug discovery have focused on several enzymes from these protozoans, among which cysteine proteases have been validated as molecular targets for pharmacological intervention. These enzymes are expressed during the entire life cycle of trypanosomatid parasites and are essential to many biological processes, including infectivity to the human host. As a result of advances in the knowledge of the structural aspects of cysteine proteases and their role in disease physiopathology, inhibition of these enzymes by small molecules has been demonstrated to be a worthwhile approach to trypanosomatid drug research. This review provides an update on drug discovery strategies targeting the cysteine peptidases cruzain from Trypanosoma cruzi and rhodesain and cathepsin B from Trypanosoma brucei. Given that current chemotherapy for Chagas disease and human African trypanosomiasis has several drawbacks, cysteine proteases will continue to be actively pursued as valuable molecular targets in trypanosomatid disease drug discovery efforts. Copyright © 2017. Published by Elsevier Inc.

Genome-Scale Screening of Drug-Target Associations Relevant to Ki Using a Chemogenomics Approach

PubMed Central

Cao, Dong-Sheng; Liang, Yi-Zeng; Deng, Zhe; Hu, Qian-Nan; He, Min; Xu, Qing-Song; Zhou, Guang-Hua; Zhang, Liu-Xia; Deng, Zi-xin; Liu, Shao

2013-01-01

The identification of interactions between drugs and target proteins plays a key role in genomic drug discovery. In the present study, the quantitative binding affinities of drug-target pairs are differentiated as a measurement to define whether a drug interacts with a protein or not, and then a chemogenomics framework using an unbiased set of general integrated features and random forest (RF) is employed to construct a predictive model which can accurately classify drug-target pairs. The predictability of the model is further investigated and validated by several independent validation sets. The built model is used to predict drug-target associations, some of which were confirmed by comparing experimental data from public biological resources. A drug-target interaction network with high confidence drug-target pairs was also reconstructed. This network provides further insight for the action of drugs and targets. Finally, a web-based server called PreDPI-Ki was developed to predict drug-target interactions for drug discovery. In addition to providing a high-confidence list of drug-target associations for subsequent experimental investigation guidance, these results also contribute to the understanding of drug-target interactions. We can also see that quantitative information of drug-target associations could greatly promote the development of more accurate models. The PreDPI-Ki server is freely available via: http://sdd.whu.edu.cn/dpiki. PMID:23577055

[A Case of Chemotherapy with FOLFOXIRI plus Cetuximab for Liver Metastasis of Sigmoid ColonCan cer].

PubMed

Saito, Akina; Konishi, Ken; Fukunaga, Mutsumi; Takiguchi, Nobuo; Nakai, Shigeto; Honda, Shoko; Yukimoto, Ryohei; Okamoto, Aoi; Takeoka, Tomohira; Matsuno, Hiroshi; Okada, Kazuyuki; Ota, Hideo; Yokoyama, Shigekazu; Konishi, Muneharu; Kobayashi, Kenji

2018-03-01

We report a case of chemotherapy with FOLFOXIRI plus cetuximab for liver metastasis of sigmoid colon cancer. The patient was a 40's man who was diagnosed with sigmoid colon cancer with liver metastasis. Colonoscopy revealed a type 2 tumor with stenosis in the sigmoid colon. He underwent sigmoidectomy under laparotomy, and after the operation, received 7 courses of chemotherapy with FOLFOXIRI plus cetuximab. The liver tumor was sufficiently reduced, and laparotomy and liver right lobectomy were performed. Histopathology revealed a modified, Grade 2 tumor regression. He has been followed for 1 year 4months after the operation.

The application of antitumor drug-targeting models on liver cancer.

PubMed

Yan, Yan; Chen, Ningbo; Wang, Yunbing; Wang, Ke

2016-06-01

Hepatocarcinoma animal models, such as the induced tumor model, transplanted tumor model, gene animal model, are significant experimental tools for the evaluation of targeting drug delivery system as well as the pre-clinical studies of liver cancer. The application of antitumor drug-targeting models not only furnishes similar biological characteristics to human liver cancer but also offers guarantee of pharmacokinetic indicators of the liver-targeting preparations. In this article, we have reviewed some kinds of antitumor drug-targeting models of hepatoma and speculated that the research on this field would be capable of attaining a deeper level and expecting a superior achievement in the future.

Targeting of drugs and nanoparticles to tumors

PubMed Central

Bhatia, Sangeeta N.; Sailor, Michael J.

2010-01-01

The various types of cells that comprise the tumor mass all carry molecular markers that are not expressed or are expressed at much lower levels in normal cells. These differentially expressed molecules can be used as docking sites to concentrate drug conjugates and nanoparticles at tumors. Specific markers in tumor vessels are particularly well suited for targeting because molecules at the surface of blood vessels are readily accessible to circulating compounds. The increased concentration of a drug in the site of disease made possible by targeted delivery can be used to increase efficacy, reduce side effects, or achieve some of both. We review the recent advances in this delivery approach with a focus on the use of molecular markers of tumor vasculature as the primary target and nanoparticles as the delivery vehicle. PMID:20231381

LHRH-Targeted Drug Delivery Systems for Cancer Therapy.

PubMed

Li, Xiaoning; Taratula, Oleh; Taratula, Olena; Schumann, Canan; Minko, Tamara

2017-01-01

Targeted delivery of therapeutic and diagnostic agents to cancer sites has significant potential to improve the therapeutic outcome of treatment while minimizing severe side effects. It is widely accepted that decoration of the drug delivery systems with targeting ligands that bind specifically to the receptors on the cancer cells is a promising strategy that may substantially enhance accumulation of anticancer agents in the tumors. Due to the transformed cellular nature, cancer cells exhibit a variety of overexpressed cell surface receptors for peptides, hormones, and essential nutrients, providing a significant number of target candidates for selective drug delivery. Among others, luteinizing hormonereleasing hormone (LHRH) receptors are overexpressed in the majority of cancers, while their expression in healthy tissues, apart from pituitary cells, is limited. The recent studies indicate that LHRH peptides can be employed to efficiently guide anticancer and imaging agents directly to cancerous cells, thereby increasing the amount of these substances in tumor tissue and preventing normal cells from unnecessary exposure. This manuscript provides an overview of the targeted drug delivery platforms that take advantage of the LHRH receptors overexpression by cancer cells.

The Impact of Cetuximab Plus AKT- or mTOR- Inhibitor in a Patient-Derived Colon Cancer Cell Model with Wild-Type RAS and PIK3CA Mutation.

PubMed

Kim, Ju Sun; Kim, Jung Eun; Kim, Kyung; Lee, Jeeyun; Park, Joon Oh; Lim, Ho Yeong; Park, Young Suk; Kang, Won Ki; Kim, Seung Tae

2017-01-01

Background: Anti-EGFR therapies have been recommended for advanced colorectal cancer (CRC) with wild-type RAS and PIK3CA mutation. However, PIK3CA mutations are a poor prognostic marker and a negative predictor of response to anti-EGFR therapies in RAS wild-type CRC. Therefore, new and advanced treatment strategies are needed for personalized medical treatment of patients with wild-type RAS and PIK3CA mutation. Methods: Patient-derived tumor cells were collected from the ascites of a refractory colon cancer patient with wild-type RAS and PIK3CA mutation. We performed a cell viability assay for cetuximab, AZD5363 (AKT inhibitor), and everolimus (mTOR inhibitor) using PDCs. We also evaluated combinations of cetuximab plus AZD5363 or everolimus in a cell viability assay. Results: Based on cellular proliferation by MTT assay, tumor cells were significantly inhibited by 1uM cetuximab (control vs. cetuximab, mean growth = 100.0% vs 58.07%, p = 0.0103), 1uM AZD5363 (control vs. AZD5363, mean growth = 100.0% vs 58.22%, p = 0.0123), and 1uM everolimus (control vs. everolimus, mean growth = 100.0% vs 52.17%, p = 0.0011). Tumor cell growth was more profoundly reduced by combinations of cetuximab plus AZD5363 (control vs. cetuximab plus AZD5363, mean growth = 100.0% vs 25.00%, p < 0.0001) or everolimus (control vs. cetuximab+everolimus, mean growth = 100.0% vs 28.24%, p < 0.0001). Conclusions: Taken together, these results indicate that RAS wild-type and PIK3CA mutant PDCs originating from CRC are considerably inhibited by treatment with cetuximab plus AZD5363 or everolimus, with downregulation of the AKT and ERK pathways. These combinations may be considered as new options for advanced CRC patients with wild-type RAS and PIK3CA mutation in the context of clinical trials.

Epigenetic Drug Repositioning for Alzheimer's Disease Based on Epigenetic Targets in Human Interactome.

PubMed

Chatterjee, Paulami; Roy, Debjani; Rathi, Nitin

2018-01-01

Epigenetics has emerged as an important field in drug discovery. Alzheimer's disease (AD), the leading neurodegenerative disorder throughout the world, is shown to have an epigenetic basis. Currently, there are very few effective epigenetic drugs available for AD. In this work, for the first time we have proposed 14 AD repositioning epigenetic drugs and identified their targets from extensive human interactome. Interacting partners of the AD epigenetic proteins were identified from the extensive human interactome to construct Epigenetic Protein-Protein Interaction Network (EP-PPIN). Epigenetic Drug-Target Network (EP-DTN) was constructed with the drugs associated with the proteins of EP-PPIN. Regulation of non-coding RNAs associated with the target proteins of these drugs was also studied. AD related target proteins, epigenetic targets, enriched pathways, and functional categories of the proposed repositioning drugs were also studied. The proposed 14 AD epigenetic repositioning drugs have overlapping targets and miRs with known AD epigenetic targets and miRs. Furthermore, several shared functional categories and enriched pathways were obtained for these drugs with FDA approved epigenetic drugs and known AD drugs. The findings of our work might provide insight into future AD epigenetic-therapeutics.

Synergistic Effect of MiR-146a Mimic and Cetuximab on Hepatocellular Carcinoma Cells

PubMed Central

Huang, Suning; Rong, Minhua; Dang, Yiwu

2014-01-01

Previously, we found that the expression of microRNA-146a (miR-146a) was downregulated in hepatocellular carcinoma (HCC) formalin-fixed paraffin-embedded (FFPE) tissues compared to the adjacent noncancerous hepatic tissues. In the current study, we have explored the in vitro effect of miR-146a on the malignant phenotypes of HCC cells. MiR-146a mimic could suppress cell growth and increase cellular apoptosis in HCC cell lines HepG2, HepB3, and SNU449, as assessed by spectrophotometry, fluorimetry, and fluorescence microscopy, respectively. Furthermore, western blot showed that miR-146a mimic downregulated EGFR, ERK1/2, and stat5 signalings. These effects were less potent compared to that of a siRNA targeting EGFR, a known target gene of miR-146a. Moreover, miR-146a mimic could enhance the cell growth inhibition and apoptosis induction impact of various EGFR targeting agents. The most potent combination was miR-146a mimic with cetuximab, presenting a synergistic effect. In conclusion, miR-146a plays a vital role in the cell growth and apoptosis of HCC cells and inducing miR-146a level might be a critical targeted molecular therapy strategy for HCC. PMID:24895573

Synergistic effect of MiR-146a mimic and cetuximab on hepatocellular carcinoma cells.

PubMed

Huang, Suning; He, Rongquan; Rong, Minhua; Dang, Yiwu; Chen, Gang

2014-01-01

Previously, we found that the expression of microRNA-146a (miR-146a) was downregulated in hepatocellular carcinoma (HCC) formalin-fixed paraffin-embedded (FFPE) tissues compared to the adjacent noncancerous hepatic tissues. In the current study, we have explored the in vitro effect of miR-146a on the malignant phenotypes of HCC cells. MiR-146a mimic could suppress cell growth and increase cellular apoptosis in HCC cell lines HepG2, HepB3, and SNU449, as assessed by spectrophotometry, fluorimetry, and fluorescence microscopy, respectively. Furthermore, western blot showed that miR-146a mimic downregulated EGFR, ERK1/2, and stat5 signalings. These effects were less potent compared to that of a siRNA targeting EGFR, a known target gene of miR-146a. Moreover, miR-146a mimic could enhance the cell growth inhibition and apoptosis induction impact of various EGFR targeting agents. The most potent combination was miR-146a mimic with cetuximab, presenting a synergistic effect. In conclusion, miR-146a plays a vital role in the cell growth and apoptosis of HCC cells and inducing miR-146a level might be a critical targeted molecular therapy strategy for HCC.

Repurposing anticancer drugs for targeting necroptosis.

PubMed

Fulda, Simone

2018-04-25

Necroptosis represents a form of programmed cell death that can be engaged by various upstream signals, for example by ligation of death receptors, by viral sensors or by pattern recognition receptors. It depends on several key signaling proteins, including the kinases Receptor-Interacting Protein (RIP)1 and RIP3 and the pseudokinase mixed-lineage kinase domain-like protein (MLKL). Necroptosis has been implicated in a number of physiological and pathophysiological conditions and is disturbed in many human diseases. Thus, targeted interference with necroptosis signaling may offer new opportunities for the treatment of human diseases. Besides structure-based drug design, in recent years drug repositioning has emerged as a promising alternative to develop drug-like compounds. There is accumulating evidence showing that multi-targeting kinase inhibitors, for example Dabrafenib, Vemurafenib, Sorafenib, Pazopanib and Ponatinib, used for the treatment of cancer also display anti-necroptotic activity. This review summarizes recent evidence indicating that some anticancer kinase inhibitors also negatively affect necroptosis signaling. This implies that some cancer therapeutics may be repurposed for other pathologies, e.g. ischemic or inflammatory diseases.

Drug-repositioning opportunities for cancer therapy: novel molecular targets for known compounds.

PubMed

Würth, Roberto; Thellung, Stefano; Bajetto, Adriana; Mazzanti, Michele; Florio, Tullio; Barbieri, Federica

2016-01-01

Drug repositioning is gaining increasing attention in drug discovery because it represents a smart way to exploit new molecular targets of a known drug or target promiscuity among diverse diseases, for medical uses different from the one originally considered. In this review, we focus on known non-oncological drugs with new therapeutic applications in oncology, explaining the rationale behind this approach and providing practical evidence. Moving from incompleteness of the knowledge of drug-target interactions, particularly for older molecules, we highlight opportunities for repurposing compounds as cancer therapeutics, underling the biologically and clinically relevant affinities for new targets. Ideal candidates for repositioning can contribute to the therapeutically unmet need for more-efficient anticancer agents, including drugs that selectively target cancer stem cells. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Flavivirus Protease As a Target for Drug Discovery

PubMed Central

Brecher, Matthew; Zhang, Jing; Li, Hongmin

2014-01-01

Many flaviviruses are significant human pathogens causing considerable disease burdens, including encephalitis and hemorrhagic fever, in the regions in which they are endemic. A paucity of treatments for flaviviral infections has driven interest in drug development targeting proteins essential to flavivirus replication, such as the viral protease. During viral replication, the flavivirus genome is translated as a single polyprotein precursor, which must be cleaved into individual proteins by a complex of the viral protease, NS3, and its cofactor, NS2B. Because this cleavage is an obligate step of the viral life-cycle, the flavivirus protease is an attractive target for antiviral drug development. In this review, we will survey recent drug development studies targeting the NS3 active site, as well as studies targeting an NS2B/NS3 interaction site determined from flavivirus protease crystal structures. PMID:24242363

The flavivirus protease as a target for drug discovery.

PubMed

Brecher, Matthew; Zhang, Jing; Li, Hongmin

2013-12-01

Many flaviviruses are significant human pathogens causing considerable disease burdens, including encephalitis and hemorrhagic fever, in the regions in which they are endemic. A paucity of treatments for flaviviral infections has driven interest in drug development targeting proteins essential to flavivirus replication, such as the viral protease. During viral replication, the flavivirus genome is translated as a single polyprotein precursor, which must be cleaved into individual proteins by a complex of the viral protease, NS3, and its cofactor, NS2B. Because this cleavage is an obligate step of the viral life-cycle, the flavivirus protease is an attractive target for antiviral drug development. In this review, we will survey recent drug development studies targeting the NS3 active site, as well as studies targeting an NS2B/NS3 interaction site determined from flavivirus protease crystal structures.

Rationale for combination of therapeutic antibodies targeting tumor cells and immune checkpoint receptors: Harnessing innate and adaptive immunity through IgG1 isotype immune effector stimulation.

PubMed

Ferris, Robert L; Lenz, Heinz-Josef; Trotta, Anna Maria; García-Foncillas, Jesús; Schulten, Jeltje; Audhuy, François; Merlano, Marco; Milano, Gerard

2018-02-01

Immunoglobulin (Ig) G1 antibodies stimulate antibody-dependent cell-mediated cytotoxicity (ADCC). Cetuximab, an IgG1 isotype monoclonal antibody, is a standard-of-care treatment for locally advanced and recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) and metastatic colorectal cancer (CRC). Here we review evidence regarding the clinical relevance of cetuximab-mediated ADCC and other immune functions and provide a biological rationale concerning why this property positions cetuximab as an ideal partner for immune checkpoint inhibitors (ICIs) and other emerging immunotherapies. We performed a nonsystematic review of available preclinical and clinical data involving cetuximab-mediated immune activity and combination approaches of cetuximab with other immunotherapies, including ICIs, in SCCHN and CRC. Indeed, cetuximab mediates ADCC activity in the intratumoral space and primes adaptive and innate cellular immunity. However, counterregulatory mechanisms may lead to immunosuppressive feedback loops. Accordingly, there is a strong rationale for combining ICIs with cetuximab for the treatment of advanced tumors, as targeting CTLA-4, PD-1, and PD-L1 can ostensibly overcome these immunosuppressive counter-mechanisms in the tumor microenvironment. Moreover, combining ICIs (or other immunotherapies) with cetuximab is a promising strategy for boosting immune response and enhancing response rates and durability of response. Cetuximab immune activity-including, but not limited to, ADCC-provides a strong rationale for its combination with ICIs or other immunotherapies to synergistically and fully mobilize the adaptive and innate immunity against tumor cells. Ongoing prospective studies will evaluate the clinical effect of these combination regimens and their immune effect in CRC and SCCHN and in other indications. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Retrieval of Enterobacteriaceae drug targets using singular value decomposition.

PubMed

Silvério-Machado, Rita; Couto, Bráulio R G M; Dos Santos, Marcos A

2015-04-15

The identification of potential drug target proteins in bacteria is important in pharmaceutical research for the development of new antibiotics to combat bacterial agents that cause diseases. A new model that combines the singular value decomposition (SVD) technique with biological filters composed of a set of protein properties associated with bacterial drug targets and similarity to protein-coding essential genes of Escherichia coli (strain K12) has been created to predict potential antibiotic drug targets in the Enterobacteriaceae family. This model identified 99 potential drug target proteins in the studied family, which exhibit eight different functions and are protein-coding essential genes or similar to protein-coding essential genes of E.coli (strain K12), indicating that the disruption of the activities of these proteins is critical for cells. Proteins from bacteria with described drug resistance were found among the retrieved candidates. These candidates have no similarity to the human proteome, therefore exhibiting the advantage of causing no adverse effects or at least no known adverse effects on humans. rita_silverio@hotmail.com. Supplementary data are available at Bioinformatics online. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

The druggable genome and support for target identification and validation in drug development.

PubMed

Finan, Chris; Gaulton, Anna; Kruger, Felix A; Lumbers, R Thomas; Shah, Tina; Engmann, Jorgen; Galver, Luana; Kelley, Ryan; Karlsson, Anneli; Santos, Rita; Overington, John P; Hingorani, Aroon D; Casas, Juan P

2017-03-29

Target identification (determining the correct drug targets for a disease) and target validation (demonstrating an effect of target perturbation on disease biomarkers and disease end points) are important steps in drug development. Clinically relevant associations of variants in genes encoding drug targets model the effect of modifying the same targets pharmacologically. To delineate drug development (including repurposing) opportunities arising from this paradigm, we connected complex disease- and biomarker-associated loci from genome-wide association studies to an updated set of genes encoding druggable human proteins, to agents with bioactivity against these targets, and, where there were licensed drugs, to clinical indications. We used this set of genes to inform the design of a new genotyping array, which will enable association studies of druggable genes for drug target selection and validation in human disease. Copyright © 2017, American Association for the Advancement of Science.

Safety and Tumor-specificity of Cetuximab-IRDye800 for Surgical Navigation in Head and Neck Cancer

PubMed Central

Rosenthal, Eben L; Warram, Jason M; de Boer, Esther; Chung, Thomas K; Korb, Melissa L; Brandwein-Gensler, Margie; Strong, Theresa V; Schmalbach, Cecelia E; Morlandt, Anthony B; Agarwal, Garima; Hartman, Yolanda E; Carroll, William R; Richman, Joshua S; Clemons, Lisa K; Nabell, Lisle M; Zinn, Kurt R

2016-01-01

Purpose Positive margins dominate clinical outcomes after surgical resections in most solid cancer types including head and neck squamous cell carcinoma. Unfortunately, surgeons remove cancer in the same manner they have for a century with complete dependence on subjective tissue changes to identify cancer in the operating room. To effect change, we hypothesize that epidermal growth factor receptor (EGFR) can be targeted for safe and specific real-time localization of cancer. Experimental design A dose escalation study of cetuximab conjugated to IRDye800 was performed in patients (n=12) undergoing surgical resection of squamous cell carcinoma arising in the head and neck. Safety and pharmacokinetic data were obtained out to 30 days post-infusion. Multi-instrument fluorescence imaging was performed in the operating room and in surgical pathology. Results There were no grade 2 or higher adverse events attributable to cetuximab-IRDye800. Fluorescence imaging with an intraoperative, wide-field device successfully differentiated tumor from normal tissue during resection with an average tumor-to-background ratio of 5.2 in the highest dose range. Optical imaging identified opportunity for more precise identification of tumor during the surgical procedure and during the pathological analysis of tissues ex-vivo. Fluorescence levels positively correlated with EGFR levels. Conclusion We demonstrate for the first time that commercially available antibodies can be fluorescently labeled and safely administered to humans to identify cancer with sub-millimeter resolution, which has the potential to improve outcomes in clinical oncology. PMID:25904751

Polymeric micelles with stimuli-triggering systems for advanced cancer drug targeting.

PubMed

Nakayama, Masamichi; Akimoto, Jun; Okano, Teruo

2014-08-01

Since the 1990s, nanoscale drug carriers have played a pivotal role in cancer chemotherapy, acting through passive drug delivery mechanisms and subsequent pharmaceutical action at tumor tissues with reduction of adverse effects. Polymeric micelles, as supramolecular assemblies of amphiphilic polymers, have been considerably developed as promising drug carrier candidates, and a number of clinical studies of anticancer drug-loaded polymeric micelle carriers for cancer chemotherapy applications are now in progress. However, these systems still face several issues; at present, the simultaneous control of target-selective delivery and release of incorporated drugs remains difficult. To resolve these points, the introduction of stimuli-responsive mechanisms to drug carrier systems is believed to be a promising approach to provide better solutions for future tumor drug targeting strategies. As possible trigger signals, biological acidic pH, light, heating/cooling and ultrasound actively play significant roles in signal-triggering drug release and carrier interaction with target cells. This review article summarizes several molecular designs for stimuli-responsive polymeric micelles in response to variation of pH, light and temperature and discusses their potentials as next-generation tumor drug targeting systems.

A comparative study of disease genes and drug targets in the human protein interactome

PubMed Central

2015-01-01

Background Disease genes cause or contribute genetically to the development of the most complex diseases. Drugs are the major approaches to treat the complex disease through interacting with their targets. Thus, drug targets are critical for treatment efficacy. However, the interrelationship between the disease genes and drug targets is not clear. Results In this study, we comprehensively compared the network properties of disease genes and drug targets for five major disease categories (cancer, cardiovascular disease, immune system disease, metabolic disease, and nervous system disease). We first collected disease genes from genome-wide association studies (GWAS) for five disease categories and collected their corresponding drugs based on drugs' Anatomical Therapeutic Chemical (ATC) classification. Then, we obtained the drug targets for these five different disease categories. We found that, though the intersections between disease genes and drug targets were small, disease genes were significantly enriched in targets compared to their enrichment in human protein-coding genes. We further compared network properties of the proteins encoded by disease genes and drug targets in human protein-protein interaction networks (interactome). The results showed that the drug targets tended to have higher degree, higher betweenness, and lower clustering coefficient in cancer Furthermore, we observed a clear fraction increase of disease proteins or drug targets in the near neighborhood compared with the randomized genes. Conclusions The study presents the first comprehensive comparison of the disease genes and drug targets in the context of interactome. The results provide some foundational network characteristics for further designing computational strategies to predict novel drug targets and drug repurposing. PMID:25861037

A comparative study of disease genes and drug targets in the human protein interactome.

PubMed

Sun, Jingchun; Zhu, Kevin; Zheng, W; Xu, Hua

2015-01-01

Disease genes cause or contribute genetically to the development of the most complex diseases. Drugs are the major approaches to treat the complex disease through interacting with their targets. Thus, drug targets are critical for treatment efficacy. However, the interrelationship between the disease genes and drug targets is not clear. In this study, we comprehensively compared the network properties of disease genes and drug targets for five major disease categories (cancer, cardiovascular disease, immune system disease, metabolic disease, and nervous system disease). We first collected disease genes from genome-wide association studies (GWAS) for five disease categories and collected their corresponding drugs based on drugs' Anatomical Therapeutic Chemical (ATC) classification. Then, we obtained the drug targets for these five different disease categories. We found that, though the intersections between disease genes and drug targets were small, disease genes were significantly enriched in targets compared to their enrichment in human protein-coding genes. We further compared network properties of the proteins encoded by disease genes and drug targets in human protein-protein interaction networks (interactome). The results showed that the drug targets tended to have higher degree, higher betweenness, and lower clustering coefficient in cancer Furthermore, we observed a clear fraction increase of disease proteins or drug targets in the near neighborhood compared with the randomized genes. The study presents the first comprehensive comparison of the disease genes and drug targets in the context of interactome. The results provide some foundational network characteristics for further designing computational strategies to predict novel drug targets and drug repurposing.

Adverse drug reaction prediction using scores produced by large-scale drug-protein target docking on high-performance computing machines.

PubMed

LaBute, Montiago X; Zhang, Xiaohua; Lenderman, Jason; Bennion, Brian J; Wong, Sergio E; Lightstone, Felice C

2014-01-01

Late-stage or post-market identification of adverse drug reactions (ADRs) is a significant public health issue and a source of major economic liability for drug development. Thus, reliable in silico screening of drug candidates for possible ADRs would be advantageous. In this work, we introduce a computational approach that predicts ADRs by combining the results of molecular docking and leverages known ADR information from DrugBank and SIDER. We employed a recently parallelized version of AutoDock Vina (VinaLC) to dock 906 small molecule drugs to a virtual panel of 409 DrugBank protein targets. L1-regularized logistic regression models were trained on the resulting docking scores of a 560 compound subset from the initial 906 compounds to predict 85 side effects, grouped into 10 ADR phenotype groups. Only 21% (87 out of 409) of the drug-protein binding features involve known targets of the drug subset, providing a significant probe of off-target effects. As a control, associations of this drug subset with the 555 annotated targets of these compounds, as reported in DrugBank, were used as features to train a separate group of models. The Vina off-target models and the DrugBank on-target models yielded comparable median area-under-the-receiver-operating-characteristic-curves (AUCs) during 10-fold cross-validation (0.60-0.69 and 0.61-0.74, respectively). Evidence was found in the PubMed literature to support several putative ADR-protein associations identified by our analysis. Among them, several associations between neoplasm-related ADRs and known tumor suppressor and tumor invasiveness marker proteins were found. A dual role for interstitial collagenase in both neoplasms and aneurysm formation was also identified. These associations all involve off-target proteins and could not have been found using available drug/on-target interaction data. This study illustrates a path forward to comprehensive ADR virtual screening that can potentially scale with increasing number

Drug Target Mining and Analysis of the Chinese Tree Shrew for Pharmacological Testing

PubMed Central

Liu, Jie; Lee, Wen-hui; Zhang, Yun