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Sample records for metastatic castration-resistant prostate

  1. Bone targeted therapies in metastatic castration-resistant prostate cancer.

    PubMed

    Rajpar, Shanna; Fizazi, Karim

    2013-01-01

    Prostate cancer is the most common male cancer. About 90% of metastatic patients will develop bone metastases. Bone disease is responsible of pain, deterioration of quality of life and serious bone complications. Proliferation of prostate cancer cells in the bone marrow induces osteoclast activation and osteolysis. Targeting the bone microenvironment reduces morbidity. Relevant preclinical and clinical studies of bone-targeted therapies in castration-resistant prostate cancer were identified in PubMed and clinical trial databases. Different drugs are available or in development that target bone resorption (bisphosphonates, RANK ligand inhibitors), bone formation (endothelin 1 inhibitors), cancer cell migration (SRC-family kinase inhibitors, vascular endothelial growth factor-MET inhibitors), and survival (radiopharmaceuticals). In phase III trials, zoledronic acid, denosumab, and radium-223 were shown to significantly delay skeletal-related events. Radium-223 was also shown to improve overall survival. Biomarkers of bone resorption (urinary N-telopeptide) and bone making (alkaline phosphatase) have an independent prognostic impact. Targeting the bone microenvironment is an important component of castration-resistant prostate cancer management to reduce bone complications and improve overall survival. Biomarkers of bone turnover have an independent prognostic impact.

  2. Radium-223 in metastatic castration resistant prostate cancer.

    PubMed

    Vuong, Winston; Sartor, Oliver; Pal, Sumanta K

    2014-01-01

    In 2004, docetaxel was approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). For the next several years, there was a lull in drug approvals. However, from 2010 onwards, 5 additional therapies have been approved on the basis of showing a survival benefit in phase III studies. These agents include sipuleucel-T, cabazitaxel, abiraterone, enzalutamide and (most recently) radium-223. Amongst radiopharmaceuticals currently used for advanced prostate cancer (e.g. samarium-153 and strontium-89), radium-223 possesses several unique properties. As an alpha-emitting compound, the agent produces a high-energy output over a short range, facilitating selective destruction of tissue within the bone in the region of osteoblastic lesions while sparing surrounding normal tissue. The current review will outline biological rationale for radium-223 and also provide an overview of preclinical and clinical development of the agent. Rational sequencing of radium-223 and combinations, in the increasingly complex landscape of mCRPC will be discussed, along with factors influencing clinical implementation.

  3. Sipuleucel-T: in metastatic castration-resistant prostate cancer.

    PubMed

    Plosker, Greg L

    2011-01-01

    Sipuleucel-T is an autologous active cellular immunotherapy used in the treatment of men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (CRPC). It is the first therapeutic cancer vaccine to receive US FDA approval. Approximately 3 days prior to each infusion of sipuleucel-T, patients undergo a leukapheresis procedure for collection of autologous peripheral blood mononuclear cells. Preparation of sipuleucel-T involves enrichment for antigen-presenting cells from the leukapheresis product and activation ex vivo with a recombinant fusion protein (PA2024). In the randomized, double-blind, placebo-controlled IMPACT study in patients with metastatic CRPC, sipuleucel-T was associated with a 22% relative reduction in the risk of death (hazard ratio 0.78; p = 0.03), which was the primary endpoint of the trial. After a median follow-up period of 34.1 months, median survival was 4.1 months longer with sipuleucel-T than placebo (25.8 vs 21.7 months). There was no significant between-group difference for the median time to objective disease progression (a secondary endpoint). Almost all patients treated with sipuleucel-T in clinical trials reported an adverse event, although these were mild or moderate in severity (grade 1 or 2) in most patients. The most common adverse events (e.g. infusion-related events, such as chills and fever) generally occurred within the first day after administration of sipuleucel-T and resolved within 2 days.

  4. Glyphosate Vedotin for Treatment of Bone Metastatic Castration-Resistant Prostate Cancer

    DTIC Science & Technology

    2015-07-01

    74:869–879, 2014. # 2014 Wiley Periodicals, Inc. KEY WORDS: prostate cancer; castration-resistant; interleukin-17; tumor immunology ; tumor...disease. Immunology 2010;129(3):311–321. 21. Toy D, Kugler D, Wolfson M, Vanden Bos T, Gurgel J, Derry J, Tocker J, Peschon J. Cutting edge: Interleukin 17...Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–723. 4. Harvey RD. Immunologic and clinical

  5. Therapy decisions for the symptomatic patient with metastatic castration-resistant prostate cancer

    PubMed Central

    Markowski, Mark C; Pienta, Kenneth J

    2015-01-01

    Metastatic prostate cancer continues to kill approximately 30,000 men per year. Since 2010, five new therapeutic agents have been Food and Drug Administration (FDA) approved to treat metastatic castration-resistant prostate cancer (mCRPC). With the increasing number of therapies available to clinicians, the most effective sequence in which to implement these treatments remains unknown. The presence or absence of symptoms (i.e., bony pain, visceral crisis) is a key parameter that informs the decision-making process regarding therapy. Treatment algorithms based on: 1) asymptomatic/minimal symptoms, 2) moderate symptoms or chemotherapy ineligible or 3) symptomatic disease need to be developed. PMID:25865849

  6. Radium 223: how can we optimize this new tool for metastatic castration-resistant prostate cancer?

    PubMed

    Dorff, Tanya Barauskas; Gross, Mitchell E

    2015-01-01

    Radium 223 is an alpha-emitting intravenous radiotherapy approved for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC). The approved indication covers men with pain from bony metastatic disease and no visceral involvement; however, questions remain as to optimal patient selection and timing of this treatment relative to other life-extending therapies for mCRPC. Limited data exist to guide clinicians on how to position radium 223 in the therapeutic sequence, however, some theoretical considerations and data derived from the ALSYMPCA trial populations pre- and postdocetaxel will be outlined. Subgroup analyses may provide some insight into patient selection.

  7. Role of Chemotherapy and Mechanisms of Resistance to Chemotherapy in Metastatic Castration-Resistant Prostate Cancer

    PubMed Central

    Lohiya, Vipin; Aragon-Ching, Jeanny B.; Sonpavde, Guru

    2016-01-01

    Chemotherapy using the taxanes, docetaxel and cabazitaxel, remains an important therapeutic option in metastatic castration-resistant prostate cancer (CRPC). However, despite the survival benefits afforded by these agents, the survival increments are modest and resistance occurs universally. Efforts to overcome resistance to docetaxel by combining with biologic agents have heretofore been unsuccessful. Indeed, resistance to these taxanes is also associated with cross-resistance to the antiandrogen drugs, abiraterone and enzalutamide. Here, we discuss the various mechanisms of resistance to chemotherapy in metastatic CRPC and the potential role of emerging regimens and agents in varying clinical phases of development. PMID:27773999

  8. Radium-223 and metastatic castration-resistant prostate cancer: All that glitters is not gold

    PubMed Central

    Aprile, Carlo; Persico, Marco G; Lodola, Lorenzo; Buroni, Federica E

    2016-01-01

    After being approved by the National Drug Agency in several countries, Radium-223 (Ra-223) is gaining wide acceptance in the treatment of bone metastatic castration resistant prostate cancer. The exact mechanism of action remain unclear: The established model of direct alpha-particle irradiation from the remodelling bone surface, where Ra-223 accumulates, surrounding the tumor foci can explain a lethal effect only on metastatic microdeposits, but not on higher tumor burden. According to the “pre-metastatic niche model”, it is likely that Ra-223 targets several non-tumoral cell types of the tumor microenvironment involved in the complex mechanism of cancer bone homing and colonization. A deeper insight into this hypothetical mechanism will lead to a more accurate dosimetric approach and to find optimal sequencing and/or combination with the other therapeutic options. PMID:27843540

  9. Optimal Sequencing of New Drugs in Metastatic Castration-Resistant Prostate Cancer: Dream or Reality?

    PubMed

    Caffo, Orazio; Lunardi, Andrea; Trentin, Chiara; Maines, Francesca; Veccia, Antonello; Galligioni, Enzo

    2016-01-01

    The availability of new drugs capable of improving the overall survival of patients with metastatic castration-resistant prostate cancer has led to the possibility of using them sequentially in the hope of obtaining a cumulative survival benefit. The new agents have already been administered as third-line treatments in patients who have previously received them as second line in everyday clinical practice, but the efficacy of this practice is not yet supported by clinical trial data, and evidence of possible cross-resistance has reinforced the debate concerning the best sequence to use in order to maximise the benefit. Furthermore, the situation is further complicated by the possibility of administering new hormonal agents to chemotherapy-naïve patients, and novel chemotherapeutic agents to hormone-sensitive patients. This article critically reviews the available data concerning the sequential use of new drugs, and discusses the real evidence concerning their optimal positioning in the therapeutic strategy of metastatic castration-resistant prostate cancer.

  10. Targeting Met and VEGFR Axis in Metastatic Castration-Resistant Prostate Cancer: 'Game Over'?

    PubMed

    Modena, Alessandra; Massari, Francesco; Ciccarese, Chiara; Brunelli, Matteo; Santoni, Matteo; Montironi, Rodolfo; Martignoni, Guido; Tortora, Giampaolo

    2016-08-01

    Despite recent advances that have been made in the therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC), effective management of bone metastases remains a key goal not yet reached. The receptor tyrosine kinase MET and the vascular endothelial growth factor receptor (VEGFR) seem to play an important role in prostate cancer progression and pathological bone turnover, representing potential targets for improving clinical outcomes in mCRPC. Studies evaluating agents that target one or both these pathways have demonstrated modest activity but no improvement in overall survival. Nevertheless, this therapeutic strategy seems to still be a promising and engaging area of prostate cancer research and the interest in better understanding the MET/VEGFR axis and the mechanism of action of these inhibitors is growing. This review describes the rationale for targeting MET and VEGFR pathway in mCRPC and provides the clinical data available to date and an update on ongoing trials.

  11. Predicting survival time for metastatic castration resistant prostate cancer: An iterative imputation approach

    PubMed Central

    Deng, Detian; Du, Yu; Ji, Zhicheng; Rao, Karthik; Wu, Zhenke; Zhu, Yuxin; Coley, R. Yates

    2016-01-01

    In this paper, we present our winning method for survival time prediction in the 2015 Prostate Cancer DREAM Challenge, a recent crowdsourced competition focused on risk and survival time predictions for patients with metastatic castration-resistant prostate cancer (mCRPC). We are interested in using a patient's covariates to predict his or her time until death after initiating standard therapy. We propose an iterative algorithm to multiply impute right-censored survival times and use ensemble learning methods to characterize the dependence of these imputed survival times on possibly many covariates. We show that by iterating over imputation and ensemble learning steps, we guide imputation with patient covariates and, subsequently, optimize the accuracy of survival time prediction. This method is generally applicable to time-to-event prediction problems in the presence of right-censoring. We demonstrate the proposed method's performance with training and validation results from the DREAM Challenge and compare its accuracy with existing methods. PMID:28299176

  12. New Biomarkers for Selecting the Best Therapy Regimens in Metastatic Castration-Resistant Prostate Cancer.

    PubMed

    Heidegger, Isabel; Heidenreich, Axel; Pfister, David

    2017-02-01

    Prostate cancer is the most common cancer in men. In recent years, several new targeted therapeutic agents for the treatment of metastatic castration resistant prostate cancer (mCRPC) have been developed. These include androgen receptor targeting agents, new taxanes, radium-223, and immunotherapies. In this short review, we provide a summary of clinical and preclinical biomarkers for each of these new treatment strategies, also including new markers currently presented in conference papers only. Moreover, we address the role of these biomarkers in clinical routine with the aim to select best-personalized treatment strategies for patients. Finally, we provide a decision tree for selecting the proper therapy for patients with mCRPC according to the discussed biomarkers.

  13. Sipuleucel-T: autologous cellular immunotherapy for men with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer.

    PubMed

    Sims, Robert B

    2011-01-01

    Sipuleucel T is an autologous cellular immunotherapy designed to stimulate an immune response in men diagnosed with asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. Sipuleucel T improves overall survival and provides an additional treatment option for this patient population.

  14. Radium-223: Insight and Perspectives in Bone-metastatic Castration-resistant Prostate Cancer.

    PubMed

    Buroni, Federica Eleonora; Persico, Marco Giovanni; Pasi, Francesca; Lodola, Lorenzo; Nano, Rosanna; Aprile, Carlo

    2016-11-01

    (223)Ra prolongs overall survival in symptomatic patients affected by multiple bone-metastatic castration-resistant prostatic cancer, without visceral or nodal involvement. However, many questions remain about its mechanisms of action, and its use in clinical practice is still unresolved. First of all, what is the main target of alpha-particle emission, that is, in what way does it influences the tumor microenvironment? When is the best timing in the course of the disease, extending its use to asymptomatic low-volume or even to the micrometastatic phase? What are suitable biomarkers to be employed as prognostic factors and response indicators? Which associations with other drugs and their sequence can offer the best results, and is their effect additive or synergistic? Ultimately, in the current climate of spending review, what is the optimal cost and benefit ratio regarding available treatments? In this review, we tried to answer these questions by analyzing the available scientific literature.

  15. Challenges in the sequencing of therapies for the management of metastatic castration-resistant prostate cancer.

    PubMed

    Parente, Phillip; Parnis, Francis; Gurney, Howard

    2014-09-01

    Prior to 2010, docetaxel was the standard option for chemotherapy in men with metastatic castration-resistant prostate cancer (mCRPC). Today, the picture is vastly different: several additional therapies have each demonstrated a survival benefit such that we now have chemotherapy (cabazitaxel), androgen suppressive agents (abiraterone acetate and enzalutamide), a cellular vaccine (sipuleucel-T) and radium-233 (for symptomatic bone metastases). With several other agents in the pipeline for late-stage disease, the future looks promising for mCRPC. As the available data are not able to inform as to the optimum sequencing of therapy, this remains a challenge. This paper draws on insights from published and ongoing clinical studies to provide a practical patient-focused approach to maximize the benefits of the current therapeutic armamentarium. Preliminary sequencing suggestions are made based on clinical trial criteria. But until more data become available, clinical gestalt, experience, cost and individual patient preferences will continue to drive choices.

  16. Survival prognosis and variable selection: A case study for metastatic castrate resistant prostate cancer patients

    PubMed Central

    Wengel Mogensen, Søren; H. Petersen, Anne; Buchardt, Ann-Sophie; Hansen, Niels Richard

    2016-01-01

    Survival prognosis is challenging, and accurate prediction of individual survival times is often very difficult. Better statistical methodology and more data can help improve the prognostic models, but it is important that methods and data usages are evaluated properly. The Prostate Cancer DREAM Challenge offered a framework for training and blinded validation of prognostic models using a large and rich dataset on patients diagnosed with metastatic castrate resistant prostate cancer. Using the Prostate Cancer DREAM Challenge data we investigated and compared an array of methods combining imputation techniques of missing values for prognostic variables with tree-based and lasso-based variable selection and model fitting methods. The benchmark metric used was integrated AUC (iAUC), and all methods were benchmarked using cross-validation on the training data as well as via the blinded validation. We found that survival forests without prior variable selection achieved the best overall performance (cv-iAUC = 0.70, validation-iACU = 0.78), while a generalized additive model was best among those methods that used explicit prior variable selection (cv-iAUC = 0.69, validation-iACU = 0.76). Our findings largely concurred with previous results in terms of the choice of important prognostic variables, though we did not find the level of prostate specific antigen to have prognostic value given the other variables included in the data. PMID:28105311

  17. Contemporary agents in the management of metastatic castration-resistant prostate cancer

    PubMed Central

    Kapoor, Anil; Wu, Christopher; Shayegan, Bobby; Rybak, Adrian P.

    2016-01-01

    Docetaxel-based chemotherapy has been the standard of care for metastatic castration-resistant prostate cancer (mCRPC) since 2004. Over the past few years, there has been a significant paradigm shift in the treatment landscape of this disease. A deeper understanding of prostate cancer biology, along with the development of novel agents has created hope towards treating chemotherapy-naïve and resistant disease. Following the implementation of docetaxel as the first-line therapy for mCRPC, five novel therapies have demonstrated survival benefit in mCRPC. Cabazitaxel, abiraterone acetate, and enzalutamide are three agents recently approved for the treatment of mCRPC, having shown overall survival benefit in patients previously treated with docetaxel, while both abiraterone acetate and enzalutamide have also shown promise in the pre-docetaxel setting. Sipuleucel-T has shown overall survival benefit in asymptomatic mCRPC, while radium-223 provides survival benefit to patients with mCRPC who are symptomatic from their skeletal metastases in both docetaxel-naïve patients and post-docetaxel patients. Denosumab, an anti-RANKL antibody, has been approved for the prevention of skeletal-related events in patients with prostate cancer bone metastases. This review examines the phase 3 trials supporting the use of theses novel agents in the treatment of mCRPC. While these agents provide incremental increases in patient survival, further study to determine the best choice, combination, and/or sequencing of administration is still necessary. PMID:28096932

  18. Whole Transcriptome Sequencing Reveals Extensive Unspliced mRNA in Metastatic Castration-Resistant Prostate Cancer

    PubMed Central

    Sowalsky, Adam G.; Xia, Zheng; Wang, Liguo; Zhao, Hao; Chen, Shaoyong; Bubley, Glenn J.; Balk, Steven P.; Li, Wei

    2014-01-01

    Men with metastatic prostate cancer (PCa) who are treated with androgen deprivation therapies (ADT) usually relapse within 2–3 years with disease that is termed castration-resistant prostate cancer (CRPC). To identify the mechanism that drives these advanced tumors, paired-end RNA-sequencing (RNA-seq) was performed on a panel of CRPC bone marrow biopsy specimens. From this genome-wide approach, mutations were found in a series of genes with PCa relevance including: AR, NCOR1, KDM3A, KDM4A, CHD1, SETD5, SETD7, INPP4B, RASGRP3, RASA1, TP53BP1 and CDH1, and a novel SND1:BRAF gene fusion. Amongst the most highly-expressed transcripts were ten non-coding RNAs (ncRNAs), including MALAT1 and PABPC1, which are involved in RNA processing. Notably, a high percentage of sequence reads mapped to introns, which were determined to be the result of incomplete splicing at canonical splice junctions. Using quantitative PCR (qPCR) a series of genes (AR, KLK2, KLK3, STEAP2, CPSF6, and CDK19) were confirmed to have a greater proportion of unspliced RNA in CRPC specimens than in normal prostate epithelium, untreated primary PCa, and cultured PCa cells. This inefficient coupling of transcription and mRNA splicing suggests an overall increase in transcription or defect in splicing. PMID:25189356

  19. Cabazitaxel: A novel taxane for metastatic castration-resistant prostate cancer-current implications and future prospects

    PubMed Central

    Abidi, Afroz

    2013-01-01

    Recent advances in the management of prostate cancer have shown considerable development with time and many novel therapeutic agents have been approved over the past years. For patients with metastatic castration-resistant prostate cancer (mCRPC), initially docetaxel was the standard chemotherapy but once they became refractory to docetaxel, no treatment improved survival. This scenario changed in June 2010 when the US Food and Drug Administration (FDA) approved Cabazitaxel as a new therapeutic option for patients with mCRPC resistant to docetaxel. Cabazitaxel, being a novel tubulin-binding taxane with poor affinity for P-glycoprotein, decreases the chances of resistance. It has shown antitumor activity in preclinical, phase I, II and III clinical studies in docetaxel-resistant tumors. This article summarises the background, pharmacodynamic, kinetics and clinical development of cabazitaxel for the treatment of castration-resistant prostate cancer. Future development and rational use of this drug in other tumors is under therapeutic investigation. PMID:24250198

  20. Bone Scan Index: A Quantitative Treatment Response Biomarker for Castration-Resistant Metastatic Prostate Cancer

    PubMed Central

    Dennis, Elizabeth R.; Jia, Xiaoyu; Mezheritskiy, Irina S.; Stephenson, Ryan D.; Schoder, Heiko; Fox, Josef J.; Heller, Glenn; Scher, Howard I.; Larson, Steven M.; Morris, Michael J.

    2012-01-01

    Purpose There is currently no imaging biomarker for metastatic prostate cancer. The bone scan index (BSI) is a promising candidate, being a reproducible, quantitative expression of tumor burden seen on bone scintigraphy. Prior studies have shown the prognostic value of a baseline BSI. This study tested whether treatment-related changes in BSI are prognostic for survival and compared BSI to prostate-specific antigen (PSA) as an outcome measure. Patients and Methods We retrospectively examined serial bone scans from patients with castration-resistant metastatic prostate cancer (CRMPC) enrolled in four clinical trials. We calculated BSI at baseline and at 3 and 6 months on treatment and performed univariate and bivariate analyses of PSA, BSI, and survival. Results Eighty-eight patients were scanned, 81 of whom have died. In the univariate analysis, the log percent change in BSI from baseline to 3 and 6 months on treatment prognosticated for survival (hazard ratio [HR], 2.44; P = .0089 and HR, 2.54; P < .001, respectively). A doubling in BSI resulted in a 1.9-fold increase in risk of death. Log percent change in PSA at 6 months on treatment was also associated with survival (HR, 1.298; P = .013). In the bivariate analysis, change in BSI while adjusting for PSA was prognostic at 3 and 6 months on treatment (HR, 2.368; P = .012 and HR, 2.226; P = .002, respectively), but while adjusting for BSI, PSA was not prognostic. Conclusion These data furnish early evidence that on-treatment changes in BSI are a response indicator and support further exploration of bone scintigraphy as an imaging biomarker in CRMPC. PMID:22231045

  1. Abiraterone in the treatment of metastatic castration-resistant prostate cancer.

    PubMed

    Mostaghel, Elahe A

    2014-01-01

    Androgen deprivation therapy remains the single most effective treatment for the initial therapy of advanced prostate cancer, but is uniformly marked by progression to castration-resistant prostate cancer (CRPC). Residual tumor androgens and androgen axis activation are now recognized to play a prominent role in mediating CRPC progression. Despite suppression of circulating testosterone to castrate levels, castration does not eliminate androgens from the prostate tumor microenvironment and residual androgen levels are well within the range capable of activating the androgen receptor (AR) and AR-mediated gene expression. Accordingly, therapeutic strategies that more effectively target production of intratumoral androgens are necessary. The introduction of abiraterone, a potent suppressor of cytochrome P450 17 α-hydroxysteroid dehydrogenase-mediated androgen production, has heralded a new era in the hormonal treatment of men with metastatic CRPC. Herein, the androgen and AR-mediated mechanisms that contribute to CRPC progression and establish cytochrome P450 17 α-hydroxysteroid dehydrogenase as a critical therapeutic target are briefly reviewed. The mechanism of action and pharmacokinetics of abiraterone are reviewed and its recently described activity against AR and 3-β-hydroxysteroid dehydrogenase is discussed. The Phase I and II data initially demonstrating the efficacy of abiraterone and Phase III data supporting its approval for patients with metastatic CRPC are reviewed. The safety and tolerability of abiraterone, including the incidence and management of side effects and potential drug interactions, are discussed. The current place of abiraterone in CRPC therapy is reviewed and early evidence regarding cross-resistance of abiraterone with taxane therapy, mechanisms of resistance to abiraterone, and observations of an abiraterone withdrawal response are presented. Future directions in the use of abiraterone, including optimal dosing strategies, the role of

  2. Metastatic castration-resistant prostate cancer in very elderly patients: challenges and solutions

    PubMed Central

    Caffo, Orazio; Maines, Francesca; Rizzo, Mimma; Kinspergher, Stefania; Veccia, Antonello

    2017-01-01

    The treatment of elderly patients with cancer is usually viewed by clinicians as a challenge, because of the age-related decline in normal organ function and the frequent concomitant administration of multiple drugs for comorbid conditions. Clinicians therefore tend not to prescribe antineoplastic agents (mainly in the case of chemotherapy) to elderly patients, with the fear of excess toxicity leading to an unfavorable cost:benefit ratio. The cutoff age defining a cancer patient as elderly is usually 70 years, but over the last 10 years clinicians have paid more attention to functional status, as evaluated by means of a comprehensive geriatric assessment and comorbidity burden, rather than chronological age. In the case of metastatic castration-resistant prostate cancer (mCRPC), depending on their age at the time of diagnosis of PC, many (if not most) of the patients are more than 70 years old, and a fair number are very elderly patients aged ≥80 years. The availability of various agents capable of significantly prolonging survival has dramatically changed the therapeutic landscape of mCRPC patients, but very elderly patients are usually underrepresented in pivotal trials. This narrative review considers the available data concerning elderly and very elderly mCRPC patients enrolled in pivotal trials and the information provided by reports of everyday clinical practice, in order to explore the challenges related to the clinical management of this special population. PMID:28053513

  3. Resistance to Novel Antiandrogen Therapies in Metastatic Castration-Resistant Prostate Cancer

    PubMed Central

    Boudadi, Karim; Antonarakis, Emmanuel S.

    2016-01-01

    Despite the introduction of novel therapies that maximally decrease androgen-receptor (AR) signaling activity, metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease. Even though abiraterone and enzalutamide represent breakthroughs in the treatment of mCRPC and have demonstrated significant survival benefits, a significant proportion of patients have primary resistance to these agents and virtually all patients develop secondary resistance. While the mechanisms of resistance to these agents are not fully understood, many hypotheses of AR-dependent and AR-independent mechanisms are emerging, including upregulation of AR and cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17), induction of AR splice variants, AR point mutations, upregulation of glucocorticoid receptor, activation of alternative oncogenic signaling pathways, neuroendocrine transformation, and immune evasion via programmed death-ligand 1 upregulation. The aim of this review is to summarize the most clinically relevant mechanisms of resistance to novel androgen-directed agents, focusing on escape from enzalutamide and abiraterone. PMID:27013902

  4. Enzalutamide: targeting the androgen signalling pathway in metastatic castration-resistant prostate cancer.

    PubMed

    Schalken, Jack; Fitzpatrick, John M

    2016-02-01

    Significant progress has been made in the understanding of the underlying cancer biology of castration-resistant prostate cancer (CRPC) with the androgen receptor (AR) signalling pathway remaining implicated throughout the prostate cancer disease continuum. Reactivation of the AR signalling pathway is considered to be a key driver of CRPC progression and, as such, the AR is a logical target for therapy in CRPC. The objective of this review was to understand the importance of AR signalling in the treatment of patients with metastatic CRPC (mCRPC) and to discuss the clinical benefits associated with inhibition of the AR signalling pathway. A search was conducted to identify articles relating to the role of AR signalling in CRPC and therapies that inhibit the AR signalling pathway. Current understanding of prostate cancer has identified the AR signalling pathway as a logical target for the treatment of CRPC. Available therapies that inhibit the AR signalling pathway include AR blockers, androgen biosynthesis inhibitors, and AR signalling inhibitors. Enzalutamide, the first approved AR signalling inhibitor, has a novel mode of action targeting AR signalling at three key stages. The direct mode of action of enzalutamide has been shown to translate into clinical responses in patients with mCRPC. In conclusion, the targeting of the AR signalling pathway in patients with mCRPC results in numerous clinical benefits. As the number of treatment options increase, more trials evaluating the sequencing and combination of treatments are required. This review highlights the continued importance of targeting a key driver in the progression of CRPC, AR signalling, and the clinical benefits associated with inhibition of the AR signalling pathway in the treatment of patients with CRPC.

  5. Synergistic Simvastatin and Metformin Combination Chemotherapy for Osseous Metastatic Castration-Resistant Prostate Cancer

    PubMed Central

    Babcook, Melissa A.; Shukla, Sanjeev; Fu, Pingfu; Vazquez, Edwin J.; Puchowicz, Michelle A.; Molter, Joseph P.; Oak, Christine Z.; MacLennan, Gregory T.; Flask, Chris A.; Lindner, Daniel J.; Parker, Yvonne; Daneshgari, Firouz; Gupta, Sanjay

    2014-01-01

    Docetaxel (DTX) chemotherapy remains a standard-of-care for metastatic castration-resistant prostate cancer (CRPC). DTX modestly increases survival, yet results in frequent occurrence of side-effects and resistant disease. An alternate chemotherapy with greater efficacy and minimal side-effects is needed. Acquisition of metabolic aberrations promoting increased survival and metastasis in CRPC cells include constitutive activation of Akt, loss of adenosine monophosphate-activated protein kinase (AMPK) activity due to Ser-485/491 phosphorylation, and over-expression of 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMG-CoAR). We report that combination of simvastatin (SIM) and metformin (MET), within pharmacological dose range (500nM to 4µM SIM and 250µM to 2mM MET), significantly and synergistically reduces C4-2B3/B4 CRPC cell viability and metastatic properties with minimal adverse effects on normal prostate epithelial cells. Combination of SIM and MET decreased Akt Ser-473 and Thr-308 phosphorylation and AMPKα Ser-485/491 phosphorylation, increased Thr-172 phosphorylation and AMPKα activity as assessed by increased Ser-79 and Ser-872 phosphorylation of acetyl-CoA carboxylase and HMG-CoAR, respectively; decreased HMG-CoAR activity, and reduced total cellular cholesterol and its synthesis in both cell lines. Studies of C4-2B4 orthotopic NCr-nu/nu mice further demonstrated that combination of SIM and MET (3.5–7.0µg/g body weight SIM and 175–350µg/g body weight MET) daily by oral gavage over 9-week period significantly inhibited primary ventral prostate tumor formation, cachexia, bone metastasis, and biochemical failure more effectively than 24µg/g body weight DTX intraperitoneally-injected every three weeks, 7.0µg/g/day SIM, or 350µg/g/day MET treatment alone, with significantly less toxicity and mortality than DTX, establishing combination SIM and MET as a promising chemotherapeutic alternative for metastatic CRPC. PMID:25122066

  6. Patient experience in the treatment of metastatic castration-resistant prostate cancer: state of the science

    PubMed Central

    Nussbaum, N; George, D J; Abernethy, A P; Dolan, C M; Oestreicher, N; Flanders, S; Dorff, T B

    2016-01-01

    Background: Contemporary therapies for metastatic castration-resistant prostate cancer (mCRPC) have shown survival improvements, which do not account for patient experience and health-related quality of life (HRQoL). Methods: This literature review included a search of MEDLINE for randomized clinical trials enrolling ⩾50 patients with mCRPC and reporting on patient-reported outcomes (PROs) since 2010. Results: Nineteen of 25 publications describing seven treatment regimens (10 clinical trials and nine associated secondary analyses) met the inclusion criteria and were critically appraised. The most commonly used measures were the Functional Assessment of Cancer Therapy-Prostate (n=5 trials) and Brief Pain Inventory Short Form (n=4 trials) questionnaires. The published data indicated that HRQoL and pain status augmented the clinical efficacy data by providing a better understanding of treatment impact in mCRPC. Abiraterone acetate and prednisone, enzalutamide, radium-223 dichloride and sipuleucel-T offered varying levels of HRQoL benefit and/or pain mitigation versus their respective comparators, whereas three treatments (mitoxantrone, estramustine phosphate and docetaxel, and cabazitaxel) had no meaningful impact on HRQoL or pain. The main limitation of the data were that the PROs utilized were not developed for use in mCRPC patients and hence may not have comprehensively captured symptoms important to this population. Conclusions: Recently published randomized clinical trials of new agents for mCRPC have captured elements of the patient experience while on treatment. Further research is required to standardize methods for measuring, quantifying and reporting on HRQoL and pain in patients with mCRPC in the clinical practice setting. PMID:26832363

  7. Sipuleucel-T for the Treatment of Patients With Metastatic Castrate-resistant Prostate Cancer: Considerations for Clinical Practice.

    PubMed

    Pieczonka, Christopher M; Telonis, Dimitrios; Mouraviev, Vladimir; Albala, David

    2015-01-01

    Sipuleucel-T treatment is associated with a significant and consistent survival benefit in patients with metastatic castrate-resistant prostate cancer. Most adverse events are infusion related, manageable, and of short duration. Early screening and diagnosis of metastatic disease is important, as the greatest survival benefit may occur in patients with a lower disease burden. The short duration of sipuleucel-T treatment facilitates the use of subsequent therapies. Sipuleucel-T is now being used in the clinic for patients with a lower disease burden. We present our own experience with the use of sipuleucel-T in the setting of a large urology practice.

  8. Use of prednisone with abiraterone acetate in metastatic castration-resistant prostate cancer.

    PubMed

    Auchus, Richard J; Yu, Margaret K; Nguyen, Suzanne; Mundle, Suneel D

    2014-12-01

    Abiraterone acetate, a prodrug of the CYP17A1 inhibitor abiraterone that blocks androgen biosynthesis, is approved for treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) in combination with prednisone or prednisolone 5 mg twice daily. This review evaluates the basis for the effects of prednisone on mineralocorticoid-related adverse events that arise because of CYP17A1 inhibition with abiraterone. Coadministration with the recommended dose of glucocorticoid compensates for abiraterone-induced reductions in serum cortisol and blocks the compensatory increase in adrenocorticotropic hormone seen with abiraterone. Consequently, 5 mg prednisone twice daily serves as a glucocorticoid replacement therapy when coadministered with abiraterone acetate, analogous to use of glucocorticoid replacement therapy for certain endocrine disorders. We searched PubMed to identify safety concerns regarding glucocorticoid use, placing a focus on longitudinal studies in autoimmune and inflammatory diseases and cancer. In general, glucocorticoid-related adverse events, including bone loss, immunosuppression, hyperglycemia, mood and cognitive alterations, and myopathy, appear dose related and tend to occur at doses and/or treatment durations greater than the low dose of glucocorticoid approved in combination with abiraterone acetate for the treatment of mCRPC. Although glucocorticoids are often used to manage tumor-related symptoms or to prevent treatment-related toxicity, available evidence suggests that prednisone and dexamethasone might also offer modest therapeutic benefit in mCRPC. Given recent improvements in survival achieved for mCRPC with novel agents in combination with prednisone, the risks of these recommended glucocorticoid doses must be balanced with the benefits shown for these regimens.

  9. Radium-223 chloride: a new treatment option for metastatic castration-resistant prostate carcinoma.

    PubMed

    Pinto, Alvaro; Cruz, Patricia

    2012-12-01

    In the last few years, the treatment of castration-resistant prostate carcinoma (CRPC) has changed completely. The approval of docetaxel and subsequent investigation in this field have led to development of new agents that have demonstrated an improvement in overall survival in the post-docetaxel setting, such as cabazitaxel and abiraterone. Radium-223 chloride is a radioisotope that has recently shown efficacy after docetaxel and in patients unfit for docetaxel, with improvements in overall survival and the time to the first skeletal-related event, compared with placebo, without increasing toxicity. These findings have made this agent a new option for treatment of these patients in the near future.

  10. Sipuleucel-T in patients with metastatic castration-resistant prostate cancer: an insight for oncologists.

    PubMed

    Garcia, Jorge A

    2011-03-01

    Sipuleucel-T represents a novel immunotherapeutic compound designed to stimulate an immune response against castration-resistant prostate cancer (CRPC). Sipuleucel-T is an autologous active cellular immunotherapy product, which includes autologous dendritic cells pulsed ex vivo with PAP2024, a recombinant fusion protein made of prostatic acid phosphatase and granulocyte-macrophage colony-stimulating factor. Despite the lack of prostate-specific antigen and objective response, a recent phase III randomized trial demonstrated a significant improvement in overall survival in asymptomatic and minimally symptomatic CRPC patients. This review summarizes the clinical development of Sipuleucel-T in CRPC that led to the regulatory approval of this compound in the USA.

  11. Radium-223 dichloride for metastatic castration-resistant prostate cancer: the urologist's perspective.

    PubMed

    Shore, Neal D

    2015-04-01

    Radium-223 dichloride (radium-223) is an important therapeutic option for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases, and no visceral disease. The unique mechanism of action of this first-in-class alpha-emitting radiopharmaceutical underlies its favorable safety profile and low incidence of myelosuppression. In the pivotal phase 3 ALpharadin in SYMptomatic Prostate CAncer Patients study, radium-223 reduced the risk of death by 30% and prolonged time to first symptomatic skeletal event by 5.8 months. This article summarizes current guidelines and clinical studies that led to the approval of radium-223 as an overall survival therapy, and discusses the urologist's perspective on using radium-223 in clinical practice.

  12. Therapy decisions for the symptomatic patient with metastatic castration-resistant prostate cancer.

    PubMed

    Markowski, Mark C; Pienta, Kenneth J

    2015-01-01

    Metastatic prostate cancer continues to kill approximately 30,000 men per year. Since 2010, five new therapeutic agents have been Food and Drug Administration (FDA) approved to treat metastatic castration‑resistant prostate cancer (mCRPC). With the increasing number of therapies available to clinicians, the most effective sequence in which to implement these treatments remains unknown. The presence or absence of symptoms (i.e., bony pain, visceral crisis) is a key parameter that informs the decision‑making process regarding therapy. Treatment algorithms based on: 1) asymptomatic/minimal symptoms, 2) moderate symptoms or chemotherapy ineligible or 3) symptomatic disease need to be developed.

  13. SU-D-303-01: Spatial Distribution of Bone Metastases In Metastatic Castrate-Resistant Prostate Cancer

    SciTech Connect

    Perk, T; Bradshaw, T; Harmon, S; Perlman, S; Liu, G; Jeraj, R

    2015-06-15

    Purpose: Identification of metastatic bone lesions is critical in prostate cancer, where treatments may be more effective in patients with fewer lesions. This study aims characterize the distribution and spread of bone lesions and create a probability map of metastatic spread in bone. Methods: Fifty-five metastatic castrate-resistant prostate cancer patients received up to 3 whole-body [F-18]NaF PET/CT scans. Lesions were identified by physician on PET/CT and contoured using a threshold of SUV>15. An atlas-based segmentation method was used to create CT regions, which determined skeletal location of lesions. Patients were divided into 3 groups with low (N<40), medium (40100) numbers of lesions. A combination of articulated and deformable registrations was used to register the skeletal segments and lesions of each patient to a single skeleton. All the lesion data was then combined to make a probability map. Results: A total of 4038 metastatic lesions (mean 74, range 2–304) were identified. Skeletal regions with highest occurrence of lesions included ribs, thoracic spine, and pelvis with 21%, 19%, and 15% of the total number lesions and 8%, 18%, and 31 % of the total lesion volume, respectively. Interestingly, patients with fewer lesions were found to have a lower proportion of lesions in the ribs (9% in low vs. 27% in high number of lesions). Additionally, the probability map showed specific areas in the spine and pelvis where over 75% of patients had metastases, and other areas in the skeleton with a less than 2% of metastases. Conclusion: We identified skeletal regions with higher incidence of metastases and specific sub-regions in the skeleton that had high or low probability of occurrence of metastases. Additionally, we found that metastatic lesions in the ribs and skull occur more commonly in advanced disease. These results may have future applications in computer-aided diagnosis. Funding from the Prostate Cancer Foundation.

  14. Two-step feature selection for predicting survival time of patients with metastatic castrate resistant prostate cancer

    PubMed Central

    Shiga, Motoki

    2016-01-01

    Metastatic castrate resistant prostate cancer (mCRPC) is the major cause of death in prostate cancer patients. Even though some options for treatment of mCRPC have been developed, the most effective therapies remain unclear. Thus finding key patient clinical variables related with mCRPC is an important issue for understanding the disease progression mechanism of mCRPC and clinical decision making for these patients. The Prostate Cancer DREAM Challenge is a crowd-based competition to tackle this essential challenge using new large clinical datasets. This paper proposes an effective procedure for predicting global risks and survival times of these patients, aimed at sub-challenge 1a and 1b of the Prostate Cancer DREAM challenge. The procedure implements a two-step feature selection procedure, which first implements sparse feature selection for numerical clinical variables and statistical hypothesis testing of differences between survival curves caused by categorical clinical variables, and then implements a forward feature selection to narrow the list of informative features. Using Cox’s proportional hazards model with these selected features, this method predicted global risk and survival time of patients using a linear model whose input is a median time computed from the hazard model. The challenge results demonstrated that the proposed procedure outperforms the state of the art model by correctly selecting more informative features on both the global risk prediction and the survival time prediction. PMID:27990267

  15. Sustained complete response to CTLA-4 blockade in a patient with metastatic, castration-resistant prostate cancer.

    PubMed

    Graff, Julie N; Puri, Sachin; Bifulco, Carlo B; Fox, Bernard A; Beer, Tomasz M

    2014-05-01

    We present the case of a man with metastatic, castration-resistant prostate cancer, who had a complete prostate-specific antigen (PSA) response after 2½ doses of ipilimumab. His treatment course was complicated by diarrhea and autoimmune hepatitis, both of which resolved within 4 months. Sera and biopsy specimens were accessed, and sera from pretreatment and day 113 were analyzed. Augmented antibody responses were detected against 11 potential tumor antigens, with responses ranging from 5- to 20-fold in day 113 sera compared with baseline. Genes that were targets of a strong antibody response (arbitrarily set at 10-fold or greater increase) were analyzed by real-time PCR for expression in the tumor biopsy cDNA. Of the top 5 genes, only 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) could be identified in the amplified tumor biopsy cDNA. Using an antibody to HIBCH, immunohistochemical analysis documented strong expression of the protein. Together, these data suggest that an augmented antibody response to HIBCH, an antigen that was expressed by the patient's prostate cancer, could have contributed to the clinical response. After 16 months of PSA stability, he discontinued his androgen-suppression therapy. With the return of his testosterone, his PSA increased slightly, likely originating from his intact prostate. He has been disease free for the past 6 years without any additional therapy.

  16. Impact of enzalutamide on patient-related outcomes in metastatic castration-resistant prostate cancer: current perspectives

    PubMed Central

    Luo, Jia; Graff, Julie N

    2016-01-01

    Prostate cancer claims the lives of more than 25,000 men in the United States yearly, most from metastatic disease. In the past decade, several new medications have been approved for the treatment of metastatic prostate cancer including the antiandrogen enzalutamide. In addition, there has been mounting interest in evaluating health-related quality of life (QoL) in patients with cancer including new more detailed recommendations released by the Prostate Cancer Working Group 3 on how to evaluate patient-related outcomes in clinical trials. A total of four randomized double-blind placebo-controlled trials have evaluated patients with metastatic castration-resistant prostate cancer (mCRPC) randomized to receive enzalutamide vs control or bicalutamide. Each study used validated health-related QoL and pain surveys to evaluate patient-related outcomes. The studies suggest that patients with mCRPC, including those aged 75 years and older, have favorable overall QoL scores taking enzalutamide compared to standard of care. There was short-term improved pain control in patients taking enzalutamide compared to those in the placebo group. Some commonly reported adverse effects included fatigue, back pain, and hot flashes. These studies were limited in their patient attrition in filling out surveys as well as difficulty in comparing them to each other. Future studies examining patients with mCRPC taking enzalutamide will have to rigorously standardize ways patient-reported outcomes are collected and evaluate patients in a more diversified real-world population. PMID:27942507

  17. Radium-223 Therapy for Patients with Metastatic Castrate-Resistant Prostate Cancer: An Update on Literature with Case Presentation

    PubMed Central

    Appleman, Leonard J.; Mountz, James M.

    2016-01-01

    Background and Purpose. Radium-223 dichloride (Xofigo®, Bayer HealthCare Pharmaceuticals Inc.) is the first α-particle emitter therapeutic agent approved by the FDA, with benefits in overall survival and delay in symptomatic skeletal event for patients with metastatic castrate-resistant prostate cancer (CRPC). Recent post hoc analyses of the phase III ALSYMPCA trial support the previously established safety profile as well as therapeutic effect and clinical outcome of Radium-223. Currently, Radium-223 is approved as a single agent therapy for metastatic CRPC. Clinical trials are currently investigating Radium-223 in additional clinical settings such as earlier asymptomatic disease and in combination with other agents including hormonal therapeutic agents and immunotherapeutic as well as chemotherapeutic agents. Trials are also ongoing in patients with other primary cancers such as breast cancer, thyroid cancer, and renal cancer metastatic to bone. In this article, the physics and radiobiology, as well as a literature update on the use of Radium-223, are provided along with case presentations, aiming at a better appreciation of research data as well as the assimilation of research data into clinical practice. PMID:27774318

  18. Managing Metastatic Castration-Resistant Prostate Cancer in the Pre-chemotherapy Setting: A Changing Approach in the Era of New Targeted Agents.

    PubMed

    Zafeiriou, Zafeiris; Jayaram, Anuradha; Sharp, Adam; de Bono, Johann S

    2016-03-01

    In recent years, the therapeutic options for treating men with metastatic castration-resistant prostate cancer have increased substantially. The hormonal treatments abiraterone acetate and enzalutamide, the chemotherapeutics docetaxel and cabazitaxel, the radiopharmaceutical alpharadin and the immunotherapeutic Sipuleucel-T have entered the field. Additionally, corticosteroids, which are used extensively, have documented activity but no documented survival benefit. Physicians treating patients with metastatic prostate cancer immediately after castration resistance develops currently have at least four different options to choose from for the first treatment. These therapeutic choices and their several possible ways of sequential use have not yet been compared to each other head-to-head and may never be. Therefore, there is an unmet need to inform their use with prospective clinical data. Additionally, the new indications of docetaxel for hormone naïve prostate cancer is changing the landscape of prostate cancer treatment and questions the traditional classifications 'pre-chemotherapy' and 'post-chemotherapy'. In this work we attempt to address these challenges in the treatment of metastatic castration-resistant prostate cancer with the focus mainly on the non-cytotoxic agents. We try to integrate available clinical and preclinical information to suggest optimal ways of treatment.

  19. Development of sipuleucel-T: autologous cellular immunotherapy for the treatment of metastatic castrate resistant prostate cancer.

    PubMed

    Sims, Robert B

    2012-06-19

    Sipuleucel-T, the first autologous cellular immunotherapy approved by the United States Food and Drug Administration, is designed to stimulate an immune response to prostate cancer. Sipuleucel-T is manufactured by culturing a patient's peripheral blood mononuclear cells, including autologous antigen presenting cells (APCs), with a recombinant protein comprising a tumor-associated antigen (prostatic acid phosphatase [PAP]) and granulocyte colony-macrophage stimulating factor (GM-CSF). A full course of treatment comprises 3 infusions of sipuleucel-T, given at approximately 2-week intervals. The pattern of APC activation is consistent with priming by the first infusion, and boosting by the second and third infusions. Preclinical and clinical studies have demonstrated evidence of a robust antigen-specific immune response that includes a progressive and persistent increase in antigen-specific cellular and humoral immune responses. Treatment with sipuleucel-T has demonstrated a survival benefit in Phase 3 studies of subjects with metastatic castrate resistant (hormone refractory) prostate cancer (mCRPC). Adverse events with sipuleucel-T were generally mild to moderate and resolved within 2 days. Serious adverse events, autoimmune events, and cerebrovascular events occurred at a similar rate to control subjects. As the first autologous cellular immunotherapy to demonstrate an improvement in overall survival in asymptomatic or minimally symptomatic mCRPC patients, sipuleucel-T represents a new treatment paradigm in oncology.

  20. Pharmacotherapeutic Management of Metastatic, Castration-Resistant Prostate Cancer in the Elderly: Focus on Non-Chemotherapy Agents

    PubMed Central

    Beer, Tomasz M.

    2015-01-01

    In the past 4 years, five new agents have been approved for metastatic, castration-resistant prostate cancer. Four of them are non-chemotherapeutic and generally well tolerated. However, each has toxicities that can negatively impact patients, particularly the elderly. This review covers the epidemiology of prostate cancer in elderly men. It discusses the efficacy data for sipuleucel-T, abiraterone in chemotherapy-naïve patients, enzalutamide in chemotherapy-naïve patients and radium-223 and presents any additional studies done for those over 75 years of age. Disease burden, such as the presence or absence of visceral disease, and comorbid conditions weigh into the selection of therapy and are discussed here. Drug–drug interactions between these agents and other drugs commonly used in the elderly population are also considered. The emerging therapies tasquinimod and ipilimumab are reviewed. With the arrival of so many agents for prostate cancer, selection of the most appropriate agent can be perplexing, particularly because these agents were tested against placebo, not one another. Furthermore, the study population differs significantly from those seen in clinical practice. This review addresses these issues. PMID:25387443

  1. A urologic oncology roundtable discussion: issues to consider in choosing treatment for metastatic castration-resistant prostate cancer.

    PubMed

    Taplin, Mary-Ellen; Berry, William R; Casey, Alison M; Aslo, Angel

    2013-01-01

    A recent Elsevier survey of 100 urologists and 100 medical oncologists who treat patients with castration-resistant prostate cancer (CRPC) identified a knowledge gap in their understanding of the recently approved therapies and what information they wanted to know concerning how and when to properly prescribe these treatments. The survey also revealed that approximately 30% of urologists had yet to prescribe one of the newly approved therapies. In response to these findings, a panel of topic experts in the fields of oncology, nursing, and specialty pharmacy convened for a roundtable discussion and to develop a companion summary article to provide a knowledge-based perspective for physicians treating patients with metastatic CRPC (http://prostatecancer.urologiconcology.org/). These participating oncology experts discussed how CRPC is defined, how the newly approved agents should be sequenced in the management of a typical patient with CRPC, and the clinical considerations regarding the role of specialty pharmacy providers and nurse practitioners as patient advocates when selecting these therapies for treating metastatic CRPC.

  2. Development of AR-V7 as a putative treatment selection marker for metastatic castration-resistant prostate cancer.

    PubMed

    Luo, Jun

    2016-01-01

    Prostate cancer cells demonstrate a remarkable "addiction" to androgen receptor (AR) signaling in all stages of disease progression. As such, suppression of AR signaling remains the therapeutic goal in systemic treatment of prostate cancer. A number of molecular alterations arise in patients treated with AR-directed therapies. These molecular alterations may indicate the emergence of treatment resistance and may be targeted for the development of novel agents for prostate cancer. The presence of functional androgen receptor splice variants may represent a potential explanation for resistance to abiraterone and enzalutamide, newer AR-directed agents developed to treat metastatic castration-resistant prostate cancer (mCRPC). In the last 8 years, many androgen receptor splice variants have been identified and characterized. Among these, androgen receptor splice variant-7 (AR-V7) has been investigated extensively. In AR-V7, the entire COOH-terminal ligand-binding domain of the canonical AR is truncated and replaced with a variant-specific peptide of 16 amino acids. Functionally, AR-V7 is capable of mediating constitutive nuclear localization and androgen receptor signaling in the absence of androgens, or in the presence of enzalutamide. In this review, we will focus on clinical translational studies involving detection/measurement of AR-V7. Methods have been developed to detect AR-V7 in clinical mCRPC specimens. AR-V7 can be reliably measured in both tissue and circulating tumor cells derived from mCRPC patients, making it possible to conduct both cross-sectional and longitudinal clinical correlative studies. Current evidence derived from studies focusing on detection of AR-V7 in mCRPC support its potential clinical utility as a treatment selection marker.

  3. A Phase II Trial of Abiraterone Combined with Dutasteride for Men with Metastatic Castration-Resistant Prostate Cancer.

    PubMed

    McKay, Rana R; Werner, Lillian; Mostaghel, Elahe A; Lis, Rosina; Voznesensky, Olga; Zhang, Zhenwei; Marck, Brett T; Matsumoto, Alvin M; Domachevsky, Liran; Zukotynski, Katherine A; Bhasin, Manoj; Bubley, Glenn J; Montgomery, Bruce; Kantoff, Philip W; Balk, Steven P; Taplin, Mary-Ellen

    2017-02-15

    Purpose: Despite the efficacy of abiraterone, a CYP17A1 inhibitor, in metastatic castration-resistant prostate cancer (CRPC), nearly all patients develop resistance. The purpose of this phase II study was to evaluate mechanisms of resistance to more complete androgen synthesis inhibition with abiraterone and dutasteride.Experimental Design: Eligible patients with metastatic CRPC underwent a baseline metastasis biopsy. Patients received abiraterone and prednisone for two 4-week cycles. After this time, high-dose dutasteride (3.5 mg daily) was added. Patients continued therapy until study withdrawal or radiographic progression. Repeat metastasis biopsy was obtained at progression. The primary endpoint was to assess mechanisms of resistance. Serum hormone and abiraterone levels were assessed. Tissue was assessed for androgen receptor (AR) and AR splice variant-7 (ARV7) expression.Results: Forty patients were enrolled. Sixty percent (n = 24) achieved a ≥50% reduction in prostate-specific antigen (PSA). The median time to radiographic progression was 11 months. Nearly all baseline (n = 29 of 31) and posttreatment (n = 16 of 16) tumors tested for AR nuclear expression were positive. Of those tested, ARV7 expression was present in 48% (n = 10 of 21) of baseline and 42% (n = 5 of 12) of treatment discontinuation specimens. Compared with patients with higher serum abiraterone levels at treatment discontinuation, patients with lower levels had higher circulating androgens.Conclusions: Despite increased androgen synthesis inhibition, we demonstrate that tumor AR axis remains important in disease progression. We highlight that abiraterone metabolism and pharmacokinetics may play a role in resistance. The noncomparative design limits conclusions on the efficacy of dual therapy with abiraterone and dutasteride, but the results support development of further multifaceted approaches toward AR inhibition. Clin Cancer Res; 23(4); 935-45. ©2016 AACR.

  4. Radium-223 dichloride: illustrating the benefits of a multidisciplinary approach for patients with metastatic castration-resistant prostate cancer

    PubMed Central

    Renzulli, Joseph F; Collins, Jennifer; Mega, Anthony

    2015-01-01

    Improving options for patients with metastatic castration-resistant prostate cancer (mCRPC) provide latitude in designing treatment plans that meet patients’ medical needs and personal goals. The field’s rapid evolution opens avenues for contributions by multiple medical specialties and requires considering more options to ensure that each patient receives the most appropriate care. A multidisciplinary clinic (MDC) focusing on patients with cancers of the genitourinary tract demonstrates an efficient and cost-effective means of integrating the diverse professional knowledge and skills needed to develop an optimal patient treatment plan. As a guide to establishing an MDC for patients with mCRPC, this article describes the operation of the Genitourinary MDC at The Miriam Hospital in Providence, RI – specifically, the successful incorporation of radium-223 dichloride (radium-223) into the treatment algorithm for men with mCRPC and symptomatic bone metastases. Radium-223 is a new treatment that, unlike earlier radionuclide therapies, has shown a survival advantage in a large randomized phase 3 trial (ALSYMPCA). The overall survival benefit was comparable to that of newer immuno-and hormonal therapies in similar populations. Radium-223 treatment also delayed onset of symptomatic skeletal events. Both benefits were independent of prior docetaxel therapy or concurrent bisphosphonate use. In our clinic, radium-223 is used primarily to extend patient survival. Patient selection, patient management, and treatment sequencing are discussed here in the context of a multidisciplinary environment. PMID:26089679

  5. External validation of a prognostic model predicting overall survival in metastatic castrate-resistant prostate cancer patients treated with abiraterone.

    PubMed

    Ravi, Praful; Mateo, Joaquin; Lorente, David; Zafeiriou, Zafeiris; Altavilla, Amelia; Ferraldeschi, Roberta; Sideris, Spyridon; Grist, Emily; Smith, Alan; Wong, Sophia; Bianchini, Diletta; Attard, Gerhardt; de Bono, Johann S

    2014-07-01

    A prognostic model was derived from the population of the COU-AA-301 phase 3 trial for metastatic castrate-resistant prostate cancer patients treated with abiraterone after docetaxel, and it stratifies patients into three risk groups based on clinical parameters. We validated this model in an independent cohort of patients treated with abiraterone after docetaxel outside a clinical trial (group A; n=94) and explored its utility in patients treated with abiraterone in the prechemotherapy setting (group B; n=64). For group A, median overall survival (mOS) was significantly different across the three prognostic groups (good: n=39, mOS: 21.8 mo; intermediate: n=44, mOS: 10.6 mo; poor: n=7, mOS: 6.8 mo; p<0.001; area under the curve [AUC]: 0.71). Analysis of group B confirmed the ability of the model to prognosticate for survival in the prechemotherapy setting: (good: n=44, mOS: 45.6 mo; intermediate or poor: n=20, mOS: 34.5 mo; p=0.042; AUC: 0.61). These results serve to validate the prognostic model in an independent population treated with abiraterone after docetaxel and support clinical implementation of the score. Calibration of the model was poorer in patients receiving abiraterone prechemotherapy. Prospective evaluation of this model in clinical trials is needed.

  6. Cost-effectiveness analysis of abiraterone and sipuleucel-T in asymptomatic metastatic castration-resistant prostate cancer.

    PubMed

    Gong, Cynthia L; Hay, Joel W

    2014-10-01

    Of patients diagnosed with prostate cancer, 0% to 20% experience disease progression to metastatic castration-resistant prostate cancer (mCRPC). Recently, 4 novel therapies have been introduced for the treatment of mCRPC; of these, abiraterone and sipuleucel-T have been studied in the asymptomatic, pre-docetaxel population. Both have shown clinical benefits compared with placebo. This study evaluated the cost-effectiveness of abiraterone acetate and sipuleucel-T compared with prednisone in asymptomatic, pre-docetaxel mCRPC from a US societal perspective. A Markov model was constructed to simulate stable disease, progressed disease, and death. Survival and event rates were derived from published clinical trial data. Costs were derived from the literature and government reimbursement schedules. Outcomes were measured as average cost-effectiveness ratios (ACERs), incremental cost-effectiveness ratios (ICERs), and net monetary benefits (NMBs). One-way and probabilistic sensitivity analyses were conducted to test the robustness of the model. The base-case ACER was $114K/quality-adjusted life-years (QALY) for abiraterone, $85K/QALY for sipuleucel-T, and $31K/QALY for prednisone. The base-case ICER was $389K/QALY for abiraterone and $547K/QALY for sipuleucel-T. Prednisone dominates both abiraterone and sipuleucel-T in terms of NMB at willingness-to-pay (WTP) thresholds of $400K or less. One-way sensitivity analyses revealed that the model was most sensitive to overall survival and utility inputs. Probabilistic sensitivity analyses showed abiraterone to be cost-effective 50% or more of the time at a WTP of greater than $400K, whereas sipuleucel-T was cost-effective 50% or more of the time at a WTP of greater than $270K. Neither abiraterone nor sipuleucel-T was found to be cost-effective compared with prednisone in the treatment of asymptomatic, pre-docetaxel mCRPC.

  7. Indirect comparison between abiraterone acetate and enzalutamide for the treatment of metastatic castration-resistant prostate cancer: a systematic review.

    PubMed

    Zhang, Wei; Wu, Teng-Yun; Chen, Qi; Shi, Xiao-Lei; Xiao, Guang-An; Zhao, Lin; Xu, Chuan-Liang; Zhou, Tie; Sun, Ying-Hao

    2017-01-01

    This study was designed to evaluate the efficacy, tolerability, and sequential administration of abiraterone acetate (AA) and enzalutamide (Enz) for metastatic castration-resistant prostate cancer (mCRPC). A literature search was performed with PubMed, Embase, and Web of Science databases to identify relevant studies. Reviewed literature included published phase III trials of AA or Enz in mCRPC and studies regarding their sequential administration. Given the difference in control arms in AA (active comparator) and Enz (true placebo) randomized phase III studies, indirect comparisons between AA and Enz in mCRPC showed no statistically significant difference in overall survival in prechemotherapy and postchemotherapy settings (HR: 0.90, 95% CI, 0.73-1.11; HR: 0.85, 95% CI, 0.68-1.07). Compared with AA, Enz may better outperform control arms in treating mCRPC both before and after chemotherapy regarding secondary endpoints based on indirect comparisons: time to prostate-specific antigen (PSA) progression (HR: 0.34, 95% CI, 0.28-0.42; HR: 0.40, 95% CI, 0.30-0.53), radiographic progression-free survival (HR: 0.37, 95% CI, 0.28-0.48; HR: 0.61, 95% CI, 0.50-0.74), and PSA response rate (OR: 18.29, 95% CI, 11.20-29.88; OR: 10.69, 95% CI, 3.92-29.20). With regard to the effectiveness of Enz following AA or AA following Enz, recent retrospective case series reported overall survival and secondary endpoints for patients with mCRPC progression after chemotherapy. However, confirmatory head-to-head trials are necessary to determine the optimal sequencing of these agents.

  8. Food effects on abiraterone pharmacokinetics in healthy subjects and patients with metastatic castration-resistant prostate cancer.

    PubMed

    Chi, Kim N; Spratlin, Jennifer; Kollmannsberger, Christian; North, Scott; Pankras, Catherine; Gonzalez, Martha; Bernard, Apexa; Stieltjes, Hans; Peng, Lixian; Jiao, James; Acharya, Milin; Kheoh, Thian; Griffin, Thomas W; Yu, Margaret K; Chien, Caly; Tran, Nam Phuong

    2015-12-01

    Food effect on abiraterone pharmacokinetics and safety on abiraterone acetate coadministration with low-fat or high-fat meals was examined in healthy subjects and metastatic castration-resistant prostate cancer (mCRPC) patients. Healthy subjects (n = 36) were randomized to abiraterone acetate (single dose, 1000 mg) + low-fat meal, + high-fat meal, and fasted state. mCRPC patients received repeated doses (abiraterone acetate 1000 mg + 5 mg prednisone twice daily; days 1-7) in a modified fasting state followed by abiraterone acetate plus prednisone within 0.5 hours post-low-fat (n = 6) or high-fat meal (n = 18; days 8-14). In healthy subjects, geometric mean (GM) abiraterone area under plasma concentration-time curve (AUC) increased ∼5- and ∼10-fold, respectively, with low-fat and high-fat meals versus fasted state (GM [coefficient of variation], 1942 [48] and 4077 [37] ng · h/mL vs 421 [67] ng · h/mL, respectively). In mCRPC patients, abiraterone AUC was ∼2-fold higher with a high-fat meal and similar with a low-fat meal versus modified fasting state (GM [coefficient of variation]: 1992 [34] vs 973 [58] ng · h/mL and 1264 [65] vs 1185 [90] ng · h/mL, respectively). Adverse events (all grade ≤ 3) were similar, with high-fat/low-fat meals or fasted/modified fasting state. Short-term dosing with food did not alter abiraterone acetate safety.

  9. The Influence of Prednisone on the Efficacy of Docetaxel in Men with Metastatic Castration-Resistant Prostate Cancer

    PubMed Central

    Teply, Benjamin A.; Luber, Brandon; Denmeade, Samuel R.; Antonarakis, Emmanuel S.

    2015-01-01

    BACKGROUND Prednisone and other corticosteroids can provide palliation and tumor responses in patients with prostate cancer. The combination of docetaxel and prednisone was the first treatment shown to prolong survival in men with metastatic castration-resistant prostate cancer (mCRPC). Since the approval of docetaxel in 2004, additional treatments are available, including abiraterone, which is also administered with prednisone. Therefore, patients are increasingly likely to have prednisone therapy several times throughout their disease course, and the contribution of prednisone to the efficacy of docetaxel is unknown. METHODS We conducted a retrospective study of patients with mCPRC treated with docetaxel at our institution between 2004–2014. Patients were divided into 2 cohorts based upon whether prednisone was co-administered with docetaxel. Cohorts were further stratified based upon prior prednisone (with abiraterone) or hydrocortisone (with ketoconazole) use. The primary endpoint was clinical/radiographic progression-free survival (PFS). The secondary endpoints were >50% PSA response rate and PSA progression-free survival (PSA-PFS). A multivariable cox regression model was constructed to determine if prednisone use was independently predictive of PFS. RESULTS We identified 200 consecutive patients for inclusion in the study: 131 men received docetaxel with prednisone and 69 received docetaxel alone. The docetaxel-prednisone cohort had superior PFS compared to the docetaxel-alone cohort (median PFS: 7.8 vs 6.2 months, HR 0.68 [95% CI 0.48–0.97], p=0.03). Prednisone was associated with a reduced risk of progression on docetaxel in the propensity score-weighted multivariable Cox model (p=0.002). Among abiraterone- or ketoconazole-pretreated patients, no difference in PFS was observed between prednisone-containing and non-prednisone containing cohorts (median PFS: 7.1 vs 6.3 months, HR 0.96 [95% CI 0.59–1.57], p=0.87). CONCLUSIONS The incorporation of

  10. Radium 223 dichloride: a multidisciplinary approach to metastatic castration-resistant prostate cancer.

    PubMed

    Borsò, Elisa; Boni, Giuseppe; Galli, Luca; Ricci, Sergio; Farnesi, Azzurra; Mazzarri, Sara; Cianci, Claudia; Mariani, Giuliano; Falcone, Alfredo

    2015-01-01

    The role of nuclear medicine physicians in the multidisciplinary team for the management of patients with prostate cancer has been restricted because of a lack of available tools. The only drugs approved to relieve pain related to bone metastases were β-emitting radiopharmaceuticals. These drugs did not prove to prolong survival when used as single agent and resulted associated with important adverse events. This situation has changed with the introduction of radium 223 because of evidence of improved survival in patients, the good safety profile and the opportunity to avoid clonal selection of tumor cells. Cooperation among physicians involved in cancer management will lead to improvements in the treatment of bone metastases due to prostate cancer and is thought to extend to other tumor types.

  11. New drugs in the treatment of elderly patients with metastatic castration-resistance prostate cancer.

    PubMed

    Genestreti, Giovenzio; Di Battista, Monica; Cavallo, Giovanna; Brandes, Alba A

    2016-08-03

    Treatment of prostate cancer is continually evolving and new therapies have become available. However, the management of elderly patients is challenging due to their age and comorbidities. Androgen deprivation therapy remains the mainstay treatment of hormonal-sensitive disease. Nevertheless, when disease becomes resistant to castration, docetaxel-based chemotherapy represents the standard rescue therapy irrespective of patient age. Recently, chemotherapeutic agents such as cabazitaxel and hormonal therapies such as abiraterone acetate and enzalutamide have been shown to improve survival in patients with progression of disease before or following docetaxel. This review focuses on the safety and efficacy results of these new drugs in elderly patients.

  12. Role of free testosterone levels in patients with metastatic castration-resistant prostate cancer receiving second-line therapy

    PubMed Central

    von Klot, Christoph A.; Kuczyk, Markus A.; Boeker, Alena; Reuter, Christoph; Imkamp, Florian; Herrmann, Thomas R.W.; Tezval, Hossein; Kramer, Mario W.; Perner, Sven; Merseburger, Axel S.

    2017-01-01

    A range of new treatment options has recently become available for patients with advanced metastatic castration-resistant prostate cancer (mCRPC). Androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone is continued when performing chemotherapy or androgen deprivation with new second-generation therapeutic agents such as enzalutamide or abiraterone acetate. Despite the fact that free testosterone (FT) is the biologically active form, it is common practice that androgen suppression is monitored via total testosterone levels only. The aim of the present study was to evaluate the role of FT as a prognostic biomarker for cancer-specific survival (CSS) and its feasibility as an ADT monitoring biomarker in patients with mCRPC for the first time. The requirement for continued ADT in mCRPC patients is discussed within the basis of the current literature. A total of 34 patients with continuous measurements of FT levels and mCRPC status underwent therapy with docetaxel, abiraterone acetate, enzalutamide, cabozantinib, carboplatin or cabazitaxel. Data were obtained from the Departments of Urology and Urological Oncology, Hannover Medical School (Hannover, Germany) between March 2009 and April 2014. A cutoff point of 0.5 pg/ml was used to discriminate between patients according to FT levels. Statistical evaluation of CSS was performed by applying Kaplan Meier survival estimates, multivariate Cox regression analyses and log-rank tests. The median age of all 34 patients was 72 years (range, 51–86 years). The mean follow-up interval was 16.1 months (range, 0.7–55.6 months). Despite the fact that all patients were undergoing androgen deprivation, the mean serum FT levels for each patient varied; the mean FT concentration in the cohort was 0.328 pg/ml, ranging from 0.01–9.1 pg/ml. A notable difference with regard to CSS was observed for patients with regard to serum FT concentration; CSS was significantly longer for patients with a serum FT level below

  13. Survival Outcomes of Concurrent Treatment with Docetaxel and Androgen Deprivation Therapy in Metastatic Castration-Resistant Prostate Cancer

    PubMed Central

    Jang, Ho Seong; Koo, Kyo Chul; Cho, Kang Su

    2016-01-01

    Purpose Docetaxel-based chemotherapy (DTX) improves overall survival (OS) of men with metastatic castration-resistant prostate cancer (mCRPC). Considering the potential existence of androgen receptors that remain active at this stage, we aimed to assess the impact of the combined use of androgen deprivation therapy (ADT) with DTX for mCRPC. Materials and Methods We performed a single-institutional retrospective analysis of patients with mCRPC who received either DTX alone (DTX group, n=21) or concurrent DTX and ADT (DTX+ADT group, n=26) between August 2006 and February 2014. All patients received DTX doses of 75 mg/m2 every three weeks for at least three cycles. In the DTX+ADT group, all patients used luteinizing hormone releasing hormone agonist continuously as a concurrent ADT. Results The median follow-up period was 24.0 months (interquartile range 12.0–37.0) for the entire cohort. The median radiographic progression-free survival (rPFS) was 9.0 months and 6.0 months in the DTX+ADT and DTX groups, respectively (log-rank p=0.036). On multivariable Cox regression analysis, concurrent administration of ADT was the only significant predictor of rPFS [hazard ratio (HR)=0.525, 95% confidence intervals (CI) 0.284–0.970, p=0.040]. The median OS was 42.0 and 38.0 months in the DTX+ADT and DTX groups, respectively (log-rank p=0.796). On multivariable analysis, hemoglobin level at the time of DTX initiation was associated with OS (HR=0.532, 95% CI 0.381–0.744, p<0.001). Conclusion In chemotherapy-naive patients with mCRPC, the combined use of ADT with DTX improved rPFS. Our result suggests that the concurrent administration of ADT and DTX is superior to DTX alone. PMID:27401636

  14. Repurposing Itraconazole as a Treatment for Advanced Prostate Cancer: A Noncomparative Randomized Phase II Trial in Men With Metastatic Castration-Resistant Prostate Cancer

    PubMed Central

    Heath, Elisabeth I.; Smith, David C.; Rathkopf, Dana; Blackford, Amanda L.; Danila, Daniel C.; King, Serina; Frost, Anja; Ajiboye, A. Seun; Zhao, Ming; Mendonca, Janet; Kachhap, Sushant K.; Rudek, Michelle A.; Carducci, Michael A.

    2013-01-01

    Background. The antifungal drug itraconazole inhibits angiogenesis and Hedgehog signaling and delays tumor growth in murine prostate cancer xenograft models. We conducted a noncomparative, randomized, phase II study evaluating the antitumor efficacy of two doses of oral itraconazole in men with metastatic prostate cancer. Patients and Methods. We randomly assigned 46 men with chemotherapy-naïve metastatic castration-resistant prostate cancer (CRPC) to receive low-dose (200 mg/day) or high-dose (600 mg/day) itraconazole until disease progression or unacceptable toxicity. The primary endpoint was the prostate-specific antigen (PSA) progression-free survival (PPFS) rate at 24 weeks; a 45% success rate in either arm was prespecified as constituting clinical significance. Secondary endpoints included the progression-free survival (PFS) rate and PSA response rate (Prostate Cancer Working Group criteria). Exploratory outcomes included circulating tumor cell (CTC) enumeration, serum androgen measurements, as well as pharmacokinetic and pharmacodynamic analyses. Results. The high-dose arm enrolled to completion (n = 29), but the low-dose arm closed early (n = 17) because of a prespecified futility rule. The PPFS rates at 24 weeks were 11.8% in the low-dose arm and 48.0% in the high-dose arm. The median PFS times were 11.9 weeks and 35.9 weeks, respectively. PSA response rates were 0% and 14.3%, respectively. In addition, itraconazole had favorable effects on CTC counts, and it suppressed Hedgehog signaling in skin biopsy samples. Itraconazole did not reduce serum testosterone or dehydroepiandrostenedione sulfate levels. Common toxicities included fatigue, nausea, anorexia, rash, and a syndrome of hypokalemia, hypertension, and edema. Conclusion. High-dose itraconazole (600 mg/day) has modest antitumor activity in men with metastatic CRPC that is not mediated by testosterone suppression. PMID:23340005

  15. Nonmetastatic Castration-Resistant Prostate Cancer

    PubMed Central

    Hong, Jun Hyuk

    2014-01-01

    After the introduction of prostate cancer screening with the prostate-specific antigen (PSA) test, we have witnessed a dramatic stage migration. As a result, an increasing number of patients are diagnosed at earlier stages and receive local treatments including surgery or radiation. When these local treatments fail by the definition of increasing PSA levels, patients are usually treated with androgen-deprivation therapy. A fraction of these patients will finally reach a state of castration-resistant prostate cancer (CRPC) even without radiological evidence of metastasis, which is referred to as nonmetastatic CRPC (NM-CRPC). Most men with advanced or metastatic prostate cancer initially respond to various types of androgen ablation, but a considerable portion of them eventually progress to NM-CRPC. Among patients with NM-CPRC, about one-third will develop bone metastasis within 2 years. In these patients, PSA kinetics is the most powerful indicator of progression and is usually used to trigger further imaging studies and enrollment in clinical trials. Although CRPC remains largely driven by the androgen receptor, the benefit of second-line hormonal manipulations, including first-generation antiandrogens, adrenal synthesis inhibitors, and steroids, has not been investigated in men with NM-CRPC. To date, denosumab is the only agent that has been shown to delay the onset of bone metastasis. However, overall survival did not differ. In treating NM-CRPC patients, physicians should recognize the heterogeneity of the disease and acknowledge that the recently approved second-line treatments have been studied only in advanced stages of the disease. PMID:24648868

  16. Targeting Androgen Receptor Aberrations in Castration-Resistant Prostate Cancer.

    PubMed

    Sharp, Adam; Welti, Jonathan; Blagg, Julian; de Bono, Johann S

    2016-09-01

    Androgen receptor (AR) splice variants (SV) have been implicated in the development of metastatic castration-resistant prostate cancer and resistance to AR targeting therapies, including abiraterone and enzalutamide. Agents targeting AR-SV are urgently needed to test this hypothesis and further improve the outcome of patients suffering from this lethal disease. Clin Cancer Res; 22(17); 4280-2. ©2016 AACRSee related article by Yang et al., p. 4466.

  17. PLZF, a Tumor Suppressor Genetically Lost in Metastatic Castration Resistant Prostate Cancer, is a Mediator of Resistance to Androgen Deprivation Therapy

    PubMed Central

    Hsieh, Chen-Lin; Botta, Ginevra; Gao, Shuai; Li, Tiantian; Van Allen, Eliezer M.; Treacy, Daniel J.; Cai, Changmeng; He, Housheng Hansen; Sweeney, Christopher J.; Brown, Myles; Balk, Steven P.; Nelson, Peter S.

    2015-01-01

    Whole exome sequencing of metastatic castration-resistant prostate cancer (mCRPC) reveal that 5~7% of tumors harbor promyelocytic zinc finger protein (PLZF) homozygous deletions. PLZF is a canonical androgen-regulated putative tumor suppressor gene whose expression is inhibited by androgen deprivation therapy (ADT). Here, we demonstrate that knockdown of PLZF expression promotes a CRPC and enzalutamide resistant phenotype in prostate cancer cells. Reintroduction of PLZF expression is sufficient to reverse androgen-independent growth mediated by PLZF depletion. PLZF loss enhances CRPC tumor growth in a xenograft model. Bioinformatic analysis of the PLZF cistrome shows that PLZF negatively regulates multiple pathways including the MAPK pathway. Accordingly, our data support an oncogenic program activated by ADT and this acquired mechanism together with the finding of genetic loss in CRPC implicate PLZF inactivation as a mechanism promoting ADT resistance and the CRPC phenotype. PMID:25808865

  18. Randomized, Double-Blind, Phase III Trial of Ipilimumab Versus Placebo in Asymptomatic or Minimally Symptomatic Patients With Metastatic Chemotherapy-Naive Castration-Resistant Prostate Cancer.

    PubMed

    Beer, Tomasz M; Kwon, Eugene D; Drake, Charles G; Fizazi, Karim; Logothetis, Christopher; Gravis, Gwenaelle; Ganju, Vinod; Polikoff, Jonathan; Saad, Fred; Humanski, Piotr; Piulats, Josep M; Gonzalez Mella, Pablo; Ng, Siobhan S; Jaeger, Dirk; Parnis, Francis X; Franke, Fabio A; Puente, Javier; Carvajal, Roman; Sengeløv, Lisa; McHenry, M Brent; Varma, Arvind; van den Eertwegh, Alfonsus J; Gerritsen, Winald

    2017-01-01

    Purpose Ipilimumab increases antitumor T-cell responses by binding to cytotoxic T-lymphocyte antigen 4. We evaluated treatment with ipilimumab in asymptomatic or minimally symptomatic patients with chemotherapy-naive metastatic castration-resistant prostate cancer without visceral metastases. Patients and Methods In this multicenter, double-blind, phase III trial, patients were randomly assigned (2:1) to ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Ipilimumab 10 mg/kg or placebo maintenance therapy was administered to nonprogressing patients every 3 months. The primary end point was overall survival (OS). Results Four hundred patients were randomly assigned to ipilimumab and 202 to placebo; 399 were treated with ipilimumab and 199 with placebo. Median OS was 28.7 months (95% CI, 24.5 to 32.5 months) in the ipilimumab arm versus 29.7 months (95% CI, 26.1 to 34.2 months) in the placebo arm (hazard ratio, 1.11; 95.87% CI, 0.88 to 1.39; P = .3667). Median progression-free survival was 5.6 months in the ipilimumab arm versus 3.8 with placebo arm (hazard ratio, 0.67; 95.87% CI, 0.55 to 0.81). Exploratory analyses showed a higher prostate-specific antigen response rate with ipilimumab (23%) than with placebo (8%). Diarrhea (15%) was the only grade 3 to 4 treatment-related adverse event (AE) reported in ≥ 10% of ipilimumab-treated patients. Nine (2%) deaths occurred in the ipilimumab arm due to treatment-related AEs; no deaths occurred in the placebo arm. Immune-related grade 3 to 4 AEs occurred in 31% and 2% of patients, respectively. Conclusion Ipilimumab did not improve OS in patients with metastatic castration-resistant prostate cancer. The observed increases in progression-free survival and prostate-specific antigen response rates suggest antitumor activity in a patient subset.

  19. Predictors of Response to Radioligand Therapy of Metastatic Castrate-Resistant Prostate Cancer with 177Lu-PSMA-617.

    PubMed

    Ferdinandus, Justin; Eppard, Elisabeth; Gaertner, Florian C; Kürpig, Stefan; Fimmers, Rolf; Yordanova, Anna; Hauser, Stefan; Feldmann, Georg; Essler, Markus; Ahmadzadehfar, Hojjat

    2017-02-01

    Radioligand therapy (RLT) with (177)Lu-PSMA-617 (PSMA is prostate-specific membrane antigen) is a novel targeted therapy for metastatic prostate cancer. In this study, we evaluated the effect of different pretherapeutic parameters on the therapeutic response measured by prostate-specific antigen (PSA) 2 mo after RLT.

  20. Addressing the expected survival benefit for clinical trial design in metastatic castration-resistant prostate cancer: Sensitivity analysis of randomized trials.

    PubMed

    Massari, Francesco; Modena, Alessandra; Ciccarese, Chiara; Pilotto, Sara; Maines, Francesca; Bracarda, Sergio; Sperduti, Isabella; Giannarelli, Diana; Carlini, Paolo; Santini, Daniele; Tortora, Giampaolo; Porta, Camillo; Bria, Emilio

    2016-02-01

    We performed a sensitivity analysis, cumulating all randomized clinical trials (RCTs) in which patients with metastatic castration-resistant prostate cancer (mCRPC) received systemic therapy, to evaluate if the comparison of RCTs may drive to biased survival estimations. An overall survival (OS) significant difference according to therapeutic strategy was more likely be determined in RCTs evaluating hormonal drugs versus those studies testing immunotherapy, chemotherapy or other strategies. With regard to control arm, an OS significant effect was found for placebo-controlled trials versus studies comparing experimental treatment with active therapies. Finally, regarding to docetaxel (DOC) timing, the OS benefit was more likely to be proved in Post-DOC setting in comparison with DOC and Pre-DOC. These data suggest that clinical trial design should take into account new benchmarks such as the type of treatment strategy, the choice of the comparator and the phase of the disease in relation to the administration of standard chemotherapy.

  1. Circulating AR copy number and outcome to enzalutamide in docetaxel-treated metastatic castration-resistant prostate cancer.

    PubMed

    Salvi, Samanta; Casadio, Valentina; Conteduca, Vincenza; Lolli, Cristian; Gurioli, Giorgia; Martignano, Filippo; Schepisi, Giuseppe; Testoni, Sara; Scarpi, Emanuela; Amadori, Dino; Calistri, Daniele; Attard, Gerhardt; De Giorgi, Ugo

    2016-06-21

    In the present study, we aimed to evaluate the association of circulating AR copy number (CN) and outcome in a cohort of patients with advanced castration-resistant prostate cancer (CRPC) treated with enzalutamide after docetaxel. Fifty-nine CRPC patients were evaluated. AR CN was analyzed with real-time and digital PCR in the serum collected at starting of treatment. Progressive disease was defined on the basis of Prostate Cancer Working Group 2 criteria. AR CN gain was found in 21 of 59 (36%) patients. Median baseline PSA, alkaline phosphatase and lactate dehydrogenase levels were higher in the AR CN gained group (p = 0.007, p = 0.003, p = 0.0009, respectively). Median PFS of patients with AR CN gain was 2.4 (95%CI: 1.9-3.2) vs. 4.0 months (95%CI: 3.0-6.5) of those with no gain (p = 0.0004). Median OS of patients with AR CN gain was 6.1 (95%CI: 3.4-8.6) vs. 14.1 months (95%CI: 8.2-20.5) of those with no gain (p = 0.0003). At multivariate analysis, PSA decline ≥ 50% and AR CN showed a significant association with PFS (p = 0.008 and p = 0.002, respectively) and OS (p = 0.009 and p = 0.001, respectively). These findings indicate that the detection of circulating AR CN gain is a promising non-invasive biomarker for outcome prediction to enzalutamide treatment in CRPC patients.

  2. Hormonal therapy and chemotherapy in hormone-naive and castration resistant prostate cancer

    PubMed Central

    Sternberg, Cora N.

    2015-01-01

    The management of advanced castration resistant prostate cancer (CRPC) has been rapidly changing and is still evolving. In the last years, there has been an increasing knowledge of prostate cancer biology. New therapeutic agents and approaches have been evaluated demonstrating benefits in survival and quality of life in patients with metastatic prostate cancer. PMID:26816835

  3. Effects of androgen deprivation therapy and bisphosphonate treatment on bone in patients with metastatic castration-resistant prostate cancer: results from the University of Washington Rapid Autopsy Series.

    PubMed

    Morrissey, Colm; Roudier, Martine P; Dowell, Alex; True, Lawrence D; Ketchanji, Melanie; Welty, Christopher; Corey, Eva; Lange, Paul H; Higano, Celestia S; Vessella, Robert L

    2013-02-01

    Qualitative and quantitative bone features were determined in nondecalcified and decalcified bone from 20 predetermined bone sites in each of 44 patients who died with castration-resistant prostate cancer (CRPC), some of which received bisphosphonate treatment (BP) in addition to androgen-deprivation therapy (ADT). Thirty-nine of the 44 patients (89%) had evidence of bone metastases. By histomorphometric analysis, these bone metastases were associated with a range of bone responses from osteoblastic to osteolytic with a wide spectrum of bone responses often seen within an individual patient. Overall, the average bone volume/tissue volume (BV/TV) was 25.7%, confirming the characteristic association of an osteoblastic response to prostate cancer bone metastasis when compared with the normal age-matched weighted mean BV/TV of 14.7%. The observed new bone formation was essentially woven bone, and this was a localized event. In comparing BV/TV at metastatic sites between patients who had received BP treatment and those who had not, there was a significant difference (28.6% versus 19.3%, respectively). At bone sites that were not invaded by tumor, the average BV/TV was 10.1%, indicating significant bone loss owing to ADT that was not improved (11%) in those patients who had received BPs. Surprisingly, there was no significant difference in the number of osteoclasts present at the metastatic sites between patients treated or not treated with BPs, but in bone sites where the patient had been treated with BPs, giant osteoclasts were observed. Overall, 873 paraffin-embedded specimens and 661 methylmethacrylate-embedded specimens were analyzed. Our results indicate that in CRPC patients, ADT induces serious bone loss even in patients treated with BP. Furthermore, in this cohort of patients, BP treatment increased BV and did not decrease the number of osteoclasts in prostate cancer bone metastases compared with bone metastases from patients who did not receive BP.

  4. A HPLC-fluorescence method for the quantification of abiraterone in plasma from patients with metastatic castration-resistant prostate cancer.

    PubMed

    Belleville, Tiphaine; Noé, Gaëlle; Huillard, Olivier; Thomas-Schoemann, Audrey; Vidal, Michel; Goldwasser, François; Alexandre, Jerome; Blanchet, Benoit

    2015-05-01

    Abiraterone acetate is an oral prodrug of abiraterone, a selective inhibitor of CYP17, used for patients with metastatic castration-resistant prostate cancer (mCRPC). To date, a single liquid chromatographic-tandem mass spectroscopy method has been reported to assay abiraterone concentration in plasma from mCRPC patients. The aim of this study was to develop a simple and sensitive high performance liquid chromatographic (HPLC) method with fluorescence detection for quantification of abiraterone in plasma from mCRPC patients. After protein precipitation with acetonitrile and a liquid-liquid extraction with diethyl ether, abiraterone, and hydroxy-itraconazole (internal standard) were separated on a C8 Xterra(®) MS column using a mobile phase of acetonitrile and glycine buffer 88.4 mM (pH 9.0) (60:40, v/v). Samples were eluted isocratically at a flow rate of 0.9 ml/min throughout an 11-min run. Fluorescence wavelengths' excitation and emission were 255 and 373 nm, respectively. The calibration was linear in the range 1.75-50 ng/ml. Inter- and intraday imprecision were less than 3.5 and 7%, respectively. This method is simple, sensitive, and selective. This analytical method was successfully applied to determine the steady-state plasma exposure to abiraterone in mCRPC patients. This method can be used in routine clinical practice to monitor plasma abiraterone concentrations in mCRPC patients.

  5. The hallmarks of castration-resistant prostate cancers.

    PubMed

    Katsogiannou, Maria; Ziouziou, Hajer; Karaki, Sara; Andrieu, Claudia; Henry de Villeneuve, Marie; Rocchi, Palma

    2015-07-01

    Prostate cancer has become a real public health issue in industrialized countries, mainly due to patients' relapse by castration-refractory disease after androgen ablation. Castration-resistant prostate cancer is an incurable and highly aggressive terminal stage of prostate cancer, seriously jeopardizing the patient's quality of life and lifespan. The management of castration-resistant prostate cancer is complex and has opened new fields of research during the last decade leading to an improved understanding of the biology of the disease and the development of new therapies. Most advanced tumors resistant to therapy still maintain the androgen receptor-pathway, which plays a central role for survival and growth of most castration-resistant prostate cancers. Many mechanisms induce the emergence of the castration resistant phenotype through this pathway. However some non-related AR pathways like neuroendocrine cells or overexpression of anti-apoptotic proteins like Hsp27 are described to be involved in CRPC progression. More recently, loss of expression of tumor suppressor gene, post-transcriptional modification using miRNA, epigenetic alterations, alternatif splicing and gene fusion became also hallmarks of castration-resistant prostate cancer. This review presents an up-to-date overview of the androgen receptor-related mechanisms as well as the latest evidence of the non-AR-related mechanisms underlying castration-resistant prostate cancer progression.

  6. Contributions of epithelial-mesenchymal transition and cancer stem cells to the development of castration resistance of prostate cancer

    PubMed Central

    2014-01-01

    An important clinical challenge in prostate cancer therapy is the inevitable transition from androgen-sensitive to castration-resistant and metastatic prostate cancer. Albeit the androgen receptor (AR) signaling axis has been targeted, the biological mechanism underlying the lethal event of androgen independence remains unclear. New emerging evidences indicate that epithelial-to-mesenchymal transition (EMT) and cancer stem cells (CSCs) play crucial roles during the development of castration-resistance and metastasis of prostate cancer. Notably, EMT may be a dynamic process. Castration can induce EMT that may enhance the stemness of CSCs, which in turn results in castration-resistance and metastasis. Reverse of EMT may attenuate the stemness of CSCs and inhibit castration-resistance and metastasis. These prospective approaches suggest that therapies target EMT and CSCs may cast a new light on the treatment of castration-resistant prostate cancer (CRPC) in the future. Here we review recent progress of EMT and CSCs in CRPC. PMID:24618337

  7. A Transient Increase in Eosinophils is Associated with Prolonged Survival in Men with Metastatic Castration-Resistant Prostate Cancer Who Receive Sipuleucel-T

    PubMed Central

    McNeel, Douglas G.; Gardner, Thomas A.; Higano, Celestia S.; Kantoff, Philip W.; Small, Eric J.; Wener, Mark H.; Sims, Robert B.; DeVries, Todd; Sheikh, Nadeem A.; Dreicer, Robert

    2014-01-01

    Sipuleucel-T is an autologous cellular immunotherapy used to treat asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Traditional short-term indicators of clinical response commonly used with chemotherapy have not correlated with survival in patients treated with sipuleucel-T. This retrospective study aimed to evaluate laboratory parameters as possible early biomarkers associated with clinical benefit following sipuleucel-T treatment. Patients treated with sipuleucel-T from 3 randomized, controlled, phase III clinical trials in mCRPC were considered: IMPACT (NCT00065442, n = 512), D9901 (NCT00005947, n = 127), and D9902A (NCT01133704, n = 98). Patients from these trials were included in this study if their samples were analyzed by the central laboratory, and if data were available from baseline and ≥1 post-treatment time point (n = 377). We found that sipuleucel-T treatment was associated with a transient increase in serum eosinophil count at week 6 that resolved by week 14 in 28% of patients (105/377). This eosinophil increase correlated with induced immune response, longer prostate cancer-specific survival (HR = 0.713; 95% confidence interval [CI], 0.525–0.970; P = 0.031) and trend in overall survival (HR = 0.753; 95% CI, 0.563–1.008; P = 0.057). Median serum globulin protein levels also increased transiently, which was associated with antigen-specific antibody responses; however, this did not correlate with longer survival. We conclude that transient increases in eosinophils at week 6 may be a useful, objective, short-term indicator of global immune activation and survival benefit with sipuleucel-T in patients with mCRPC. This observation warrants prospective evaluation in future clinical trials. PMID:25189164

  8. Phase I/II trial of cabazitaxel plus abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel and abiraterone

    PubMed Central

    Mateo, J.; Loriot, Y.; Pezaro, C.; Albiges, L.; Mehra, N.; Varga, A.; Bianchini, D.; Ryan, C. J.; Petrylak, D. P.; Attard, G.; Shen, L.; Fizazi, K.; de Bono, J.

    2017-01-01

    Abstract Background Abiraterone and cabazitaxel improve survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We conducted an open-label phase I/II trial of cabazitaxel plus abiraterone to assess the antitumor activity and tolerability in patients with progressive mCRPC after docetaxel (phase I), and after docetaxel and abiraterone (phase II) (NCT01511536). Patients and methods The primary objectives were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel plus abiraterone (phase I), and the prostate-specific antigen (PSA) response defined as a ≥ 50% decrease confirmed ≥3 weeks later with this combination (phase II). Results Ten patients were enrolled in the phase I component; nine were evaluable. No DLTs were identified. The MTD was established as the approved doses for both drugs (cabazitaxel 25 mg/m2 every 3 weeks and abiraterone 1000 mg once daily). Daily abiraterone treatment did not impact on cabazitaxel clearance. Twenty-seven patients received cabazitaxel plus abiraterone plus prednisone (5 mg twice daily) in phase II. The median number of cycles administered (cabazitaxel) was seven (range: 1–28). Grade 3–4 treatment-emergent adverse events included asthenia (in 5 patients; 14%), neutropenia (in 5 patients; 14%) and diarrhea (in 3 patients; 8%). Nine patients (24%) required dose reductions of cabazitaxel. Of 26 evaluable patients, 12 achieved a PSA response [46%; 95% confidence interval (CI): 26.6–66.6%]. Median PSA-progression-free survival was 6.9 months (95% CI: 4.1–10.3 months). Of 14 patients with measurable disease at baseline, 3 (21%) achieved a partial response per response evaluation criteria in solid tumors. Conclusions The combination of cabazitaxel and abiraterone has a manageable safety profile and shows antitumor activity in patients previously treated with docetaxel and abiraterone. PMID:28039155

  9. Treatment evolution for metastatic castration-resistant prostate cancer with recent introduction of novel agents: retrospective analysis of real-world data.

    PubMed

    Flaig, Thomas W; Potluri, Ravi C; Ng, Yvette; Todd, Mary B; Mehra, Maneesha

    2016-02-01

    Despite increasing drug treatment options for metastatic castration-resistant prostate cancer (mCRPC) patients, real-world treatment data are lacking. We conducted retrospective analyses of commercial claims and electronic medical record (EMR) databases to understand how treatment patterns for mCRPC have changed in a US-based real-world population. Truven Health Analytics MarketScan(®) (2000-2013) and EMR (2004-2013) databases were used to identify patients with an index prostate cancer diagnosis (ICD-9 codes 185X or 233.4X) and prescription claims for an mCRPC drug (mitoxantrone, estramustine, docetaxel, sipuleucel-T, cabazitaxel, abiraterone acetate, enzalutamide, or radium-223). Regimen analyses for first line of therapy (LOT1), second line of therapy, and beyond were performed among cohorts based on year of first mCRPC drug usage. mCRPC drug usage and treatment duration were compared across cohorts and age groups within each cohort. The commercial claims cohort yielded 3437 evaluable patients. Most men (91%) commencing mCRPC treatment had docetaxel as LOT1 in 2010; this number had declined to 15% in 2013. In 2013, 67% and 9% of patients used abiraterone acetate and enzalutamide, respectively, as LOT1. Among both commercial claims and EMR cohorts, treatment pattern changes were most pronounced in men aged >80 years, and median treatment duration for some mCRPC drugs was shorter than expected based on available clinical trial information. These results demonstrate a shift in mCRPC treatments during the past 5 years, with greater use of newer noncytotoxic treatments than docetaxel. These real-world data aid in understanding the changing role of chemotherapy in the management of mCRPC.

  10. A transient increase in eosinophils is associated with prolonged survival in men with metastatic castration-resistant prostate cancer who receive sipuleucel-T.

    PubMed

    McNeel, Douglas G; Gardner, Thomas A; Higano, Celestia S; Kantoff, Philip W; Small, Eric J; Wener, Mark H; Sims, Robert B; DeVries, Todd; Sheikh, Nadeem A; Dreicer, Robert

    2014-10-01

    Sipuleucel-T is an autologous cellular immunotherapy used to treat asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Traditional short-term indicators of clinical response commonly used with chemotherapy have not correlated with survival in patients treated with sipuleucel-T. This retrospective study aimed to evaluate laboratory parameters as possible early biomarkers associated with clinical benefit following sipuleucel-T treatment. Patients treated with sipuleucel-T from three randomized, controlled, phase III clinical trials in mCRPC were considered: IMPACT (NCT00065442; n = 512), D9901 (NCT00005947; n = 127), and D9902A (NCT01133704; n = 98). Patients from these trials were included in this study if their samples were analyzed by the central laboratory and if data were available from baseline and ≥ 1 posttreatment time point (n = 377). We found that sipuleucel-T treatment was associated with a transient increase in serum eosinophil count at week 6 that resolved by week 14 in 28% of patients (105 of 377). This eosinophil increase correlated with induced immune response, longer prostate cancer-specific survival [HR, 0.713; 95% confidence interval (CI), 0.525-0.970; P = 0.031], and a trend in overall survival (HR, 0.753; 95% CI, 0.563-1.008; P = 0.057). Median serum globulin protein levels also increased transiently, which was associated with antigen-specific antibody responses; however, this finding did not correlate with longer survival. We conclude that transient increases in eosinophils at week 6 may be a useful, objective, short-term indicator of global immune activation and survival benefit with sipuleucel-T in patients with mCRPC. This observation warrants prospective evaluation in future clinical trials.

  11. Samarium-153-EDTMP (Quadramet®) with or without vaccine in metastatic castration-resistant prostate cancer: A randomized Phase 2 trial

    PubMed Central

    Heery, Christopher R.; Madan, Ravi A.; Stein, Mark N.; Stadler, Walter M.; Di Paola, Robert S.; Rauckhorst, Myrna; Steinberg, Seth M.; Marté, Jennifer L.; Chen, Clara C.; Grenga, Italia; Donahue, Renee N.; Jochems, Caroline; Dahut, William L.; Schlom, Jeffrey; Gulley, James L.

    2016-01-01

    PSA-TRICOM is a therapeutic vaccine in late stage clinical testing in metastatic castration-resistant prostate cancer (mCRPC). Samarium-153-ethylene diamine tetramethylene phosphonate (Sm-153-EDTMP; Quadramet®), a radiopharmaceutical, binds osteoblastic bone lesions and emits beta particles causing local tumor cell destruction. Preclinically, Sm-153-EDTMP alters tumor cell phenotype facilitating immune-mediated killing. This phase 2 multi-center trial randomized patients to Sm-153-EDTMP alone or with PSA-TRICOM vaccine. Eligibility required mCRPC, bone metastases, prior docetaxel and no visceral disease. The primary endpoint was the proportion of patients without radiographic disease progression at 4 months. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and immune responses. Forty-four patients enrolled. Eighteen and 21 patients were evaluable for the primary endpoint in Sm-153-EDTMP alone and combination arms, respectively. There was no statistical difference in the primary endpoint, with two of 18 (11.1%) and five of 21 (23.8%) in Sm-153-EDTMP alone and combination arms, respectively, having stable disease at approximately the 4-month evaluation time point (P = 0.27). Median PFS was 1.7 vs. 3.7 months in the Sm-153-EDTMP alone and combination arms (P = 0.041, HR = 0.51, P = 0.046). No patient in the Sm-153-EDTMP alone arm achieved prostate-specific antigen (PSA) decline > 30% compared with four patients (of 21) in the combination arm, including three with PSA decline > 50%. Toxicities were similar between arms and related to number of Sm-153-EDTMP doses administered. These results provide the rationale for clinical evaluation of new radiopharmaceuticals, such as Ra-223, in combination with PSA-TRICOM. PMID:27486817

  12. Common Genetic Variation in CYP17A1 and Response to Abiraterone Acetate in Patients with Metastatic Castration-Resistant Prostate Cancer

    PubMed Central

    Binder, Moritz; Zhang, Ben Y.; Hillman, David W.; Kohli, Rhea; Kohli, Tanvi; Lee, Adam; Kohli, Manish

    2016-01-01

    Treatment with abiraterone acetate and prednisone (AA/P) prolongs survival in metastatic castration-resistant prostate cancer (mCRPC) patients. We evaluated the genetic variation in CYP17A1 as predictive of response to AA/P. A prospective collection of germline DNA prior to AA/P initiation and follow-up of a mCRPC cohort was performed. Five common single-nucleotide polymorphisms (SNPs) in CYP17A1 identified using a haplotype-based tagging algorithm were genotyped. Clinical outcomes included biochemical response and time to biochemical progression on AA/P. Logistic regression was used to assess the association between tag SNPs and biochemical response. Proportional hazards regression was used to assess the association between tag SNPs and time to biochemical progression. Odds or hazard ratio per minor allele were estimated and p-values below 0.05 were considered statistically significant. Germline DNA was successfully genotyped for four tag SNPs in 87 patients. The median age was 73 years (54–90); the median prostate-specific antigen was 66 ng/dL (0.1–99.9). A single SNP, rs2486758, was associated with lower odds of experiencing a biochemical response (Odds ratio 0.22, 95% confidence interval 0.07–0.63, p = 0.005) and a shorter time to biochemical progression (Hazard ratio 2.23, 95% confidence interval 1.39–3.56, p < 0.001). This tag SNP located in the promoter region of CYP17A1 will need further validation as a predictive biomarker for AA/P therapy. PMID:27409606

  13. The effectiveness of the TAX 327 nomogram in predicting overall survival in Chinese patients with metastatic castration-resistant prostate cancer.

    PubMed

    Bian, Xiao-Jie; Zhu, Yao; Shen, Yi-Jun; Wang, Jin-You; Ma, Chun-Guang; Zhang, Hai-Liang; Dai, Bo; Zhang, Shi-Lin; Yao, Xu-Dong; Ye, Ding-Wei

    2013-09-01

    Based on the results of TAX 327, a nomogram was developed to predict the overall survival of metastatic castration-resistant prostate cancer (mCRPC) after first-line chemotherapy. The nomogram, however, has not been validated in an independent dataset, especially in a series out of clinical trials. Thus, the objective of the current study was to validate the TAX 327 nomogram in a community setting in China. A total of 146 patients with mCRPC who received first-line chemotherapy (docetaxel or mitoxantrone) were identified. Because clinical trials are limited in mainland China, those patients did not receive investigational treatment after the failure of first-line chemotherapy. The predicted overall survival rate was calculated from the TAX 327 nomogram. The validity of the model was assessed with discrimination, calibration and decision curve analysis. The median survival of the cohort was 21 months (docetaxel) and 19 months (mitoxantrone) at last follow-up. The predictive c-index of the TAX 327 nomogram was 0.66 (95% CI: 0.54-0.70). The calibration plot demonstrated that the 2-year survival rate was underestimated by the nomogram. Decision curve analysis showed a net benefit of the nomogram at a threshold probability greater than 30%. In conclusion, the present validation study did not confirm the predictive value of the TAX 327 nomogram in a contemporary community series of men in China, and further studies with a large sample size to develop or validate nomograms for predicting survival and selecting therapies in advanced prostate cancer are necessary.

  14. Skeletal-related events significantly impact health-related quality of life in metastatic castration-resistant prostate cancer: data from PREVAIL and AFFIRM trials

    PubMed Central

    Saad, F; Ivanescu, C; Phung, D; Loriot, Y; Abhyankar, S; Beer, T M; Tombal, B; Holmstrom, S

    2017-01-01

    Background: We investigated the impact of skeletal-related events (SREs) on health-related quality of life (HRQoL) in patients with metastatic castration-resistant prostate cancer (mCRPC) in phase III trials of enzalutamide versus placebo. Methods: Patients with mCRPC experiencing at least one SRE during AFFIRM and PREVAIL were assessed for trajectory-adjusted mean change in HRQoL by first SRE using Functional Assessment of Cancer Therapy-Prostate (FACT-P; AFFIRM, three domains, and PREVAIL, nine domains) and EQ-5D (PREVAIL) instruments. Results: First SREs caused HRQoL deterioration in both trials. Spinal cord compression had the largest impact, with clinically meaningful reductions in seven of nine FACT-P domains in PREVAIL and all three in AFFIRM (mean (95% confidence interval (CI)) change in FACT-P total score –16.95 (–26.47, –7.44) and –9.69 (–16.10, –3.27), respectively). In PREVAIL, first SREs caused clinically meaningful declines in EQ-5D utility index, irrespective of category; spinal cord compression had the largest impact (mean (95% CI) change –0.24 (–0.39, –0.08)). In AFFIRM, FACT-P and FACT-General total scores showed clinically meaningful declines after radiation/surgery to bone. Conclusions: SREs were associated with clinically meaningful functional declines in the daily lives of patients with mCRPC. Spinal cord compression had the largest impact on HRQoL. PMID:28045115

  15. Sipuleucel-T (Provenge) autologous vaccine approved for treatment of men with asymptomatic or minimally symptomatic castrate-resistant metastatic prostate cancer.

    PubMed

    Gardner, Thomas A; Elzey, Bennett D; Hahn, Noah M

    2012-04-01

    Sipuleucel-T (Provenge) (Sip-T) is first -in class as a therapeutic autologous vaccine approved for the treatment of men with asymptomatic or minimally symptomatic castrate-resistant metastatic prostate cancer. This product is the culmination of decades of basic immunological and prostate cancer investigations and 13 y of clinical trial investigations. Sip-T represents a paradigm shift in cancer therapeutics and represents the first approved autologous therapeutic cancer vaccine, which has demonstrated a survival benefit. The potential benefit of this product is the excellent risk to benefit ratio, which will allow for the combination of this approach with other more toxic therapies. The favorable risk to benefit will also afford the opportunity for trials investigating this product earlier in the disease state and in combination with local therapies. The ability to target more localized or lower volume disease will maximize the therapeutic benefit over a longer period of time. The novelty of the platform of this approach could be used to treat any cancer with a tumor-specific cell surface target. The main product of Sip-T is the re-infusion of a patient's antigen presenting cells from leukapheresis after ex-vivo exposure to a chimeric protein of human GM-CSF and PAP. In metastatic CRPC patients three infusions of these activated cells over a month lead to statistically significant 4.1 mo increase in median survival and a 22.5% reduction in risk of death. The main side effect from this re-infusion of activated immune cells is a "flu-like" syndrome that includes chills, fatigue, fevers, back pain, nausea, joints aches and headaches in decreasing order of frequency. Immune monitoring during the clinical trials also demonstrated a specific cellular and antibody immune response, suggesting the proposed mechanism of adoptive immunotherapy to PAP was behind this survival benefit. This product also serves as a proof of principle for targeted immunotherapy for others

  16. Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study.

    PubMed

    Beer, Tomasz M; Armstrong, Andrew J; Rathkopf, Dana; Loriot, Yohann; Sternberg, Cora N; Higano, Celestia S; Iversen, Peter; Evans, Christopher P; Kim, Choung-Soo; Kimura, Go; Miller, Kurt; Saad, Fred; Bjartell, Anders S; Borre, Michael; Mulders, Peter; Tammela, Teuvo L; Parli, Teresa; Sari, Suha; van Os, Steve; Theeuwes, Ad; Tombal, Bertrand

    2017-02-01

    Enzalutamide significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) among men with chemotherapy-naïve metastatic castration-resistant prostate cancer at the prespecified interim analysis of PREVAIL, a phase 3, double-blind, randomized study. We evaluated the longer-term efficacy and safety of enzalutamide up to the prespecified number of deaths in the final analysis, which included an additional 20 mo of follow-up for investigator-assessed rPFS, 9 mo of follow-up for OS, and 4 mo of follow-up for safety. Enzalutamide reduced the risk of radiographic progression or death by 68% (hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.28-0.37; p<0.0001) and the risk of death by 23% (HR 0.77, 95% CI 0.67-0.88; p=0.0002). Median investigator-assessed rPFS was 20.0 mo (95% CI 18.9-22.1) in the enzalutamide arm and 5.4 mo (95% CI 4.1-5.6) in the placebo arm. Median OS was 35.3 mo (95% CI 32.2-not yet reached) in the enzalutamide arm and 31.3 mo (95% CI 28.8-34.2) in the placebo arm. At the time of the OS analysis, 167 patients in the placebo arm had crossed over to receive enzalutamide. The most common adverse events in the enzalutamide arm were fatigue, back pain, constipation, and arthralgia. This final analysis of PREVAIL provides more complete assessment of the clinical benefit of enzalutamide. PREVAIL is registered on ClinicalTrials.gov as NCT01212991.

  17. Impact of abiraterone acetate with and without prior docetaxel chemotherapy on the survival of patients with metastatic castration-resistant prostate cancer: a population-based study

    PubMed Central

    Rocha, Joice; Aprikian, Armen G.; Vanhuyse, Marie; Cury, Fabio L.; Hu, Jason; Prévost, Noémie; Dragomir, Alice

    2017-01-01

    Background: Abiraterone acetate was introduced in Quebec in 2012 for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in patients who had received chemotherapy with docetaxel. This study describes abiraterone use in the early postapproval period and its clinical effectiveness in Quebec, for both patients who had received docetaxel chemotherapy and those who could not receive docetaxel therapy owing to medical reasons. Methods: A retrospective cohort study was conducted using Quebec public health care administrative databases. Our cohort consisted of patients with mCRPC who received abiraterone between January 2012 and June 2013. Treatment groups were defined as patients who received abiraterone following docetaxel chemotherapy and those who received abiraterone without having had chemotherapy, under the "exception patient" measure. Study outcomes included overall survival, duration of abiraterone therapy and number of hospital days. Cox proportional hazard regression was used to estimate the effectiveness of abiraterone adjusted for several covariates. Results: Our cohort consisted of 303 patients with mCRPC treated with abiraterone (99 after chemotherapy and 204 as exception patients). The median age at initiation of abiraterone therapy was 75.0 for the postchemotherapy group and 80.0 for the exception patient group. The corresponding median survival values were 12 and 14 months (log-rank test p = 0.8). Risk of death was similar in the 2 groups (adjusted hazard ratio 0.89 [95% confidence interval 0.57-1.38]). Interpretation: The effectiveness of abiraterone in older patients who were ineligible for chemotherapy was similar to that of patients with prior docetaxel exposure. Overall, the real-world survival benefits of abiraterone were similar to those in the COU-AA-301 trial.

  18. The Role of the Neutrophil to Lymphocyte Ratio for Survival Outcomes in Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Abiraterone

    PubMed Central

    Boegemann, Martin; Schlack, Katrin; Thomes, Stefan; Steinestel, Julie; Rahbar, Kambiz; Semjonow, Axel; Schrader, Andres Jan; Aringer, Martin; Krabbe, Laura-Maria

    2017-01-01

    The purpose of this study was to examine the prognostic capability of baseline neutrophil-to-lymphocyte-ratio (NLR) and NLR-change under Abiraterone in metastatic castration-resistant prostate cancer patients. The impact of baseline NLR and change after eight weeks of treatment on progression-free survival (PFS) and overall survival (OS) was analyzed using Kaplan-Meier-estimates and Cox-regression. 79 men with baseline NLR <5 and 17 with NLR >5 were analyzed. In baseline analysis of PFS NLR >5 was associated with non-significantly shorter median PFS (five versus 10 months) (HR: 1.6 (95%CI:0.9–2.8); p = 0.11). After multivariate adjustment (MVA), ECOG > 0–1, baseline LDH>upper limit of normal (UNL) and presence of visceral metastases were independent prognosticators. For OS, NLR >5 was associated with shorter survival (seven versus 19 months) (HR: 2.3 (95%CI:1.3–4.0); p < 0.01). In MVA, ECOG > 0–1 and baseline LDH > UNL remained independent prognosticators. After 8 weeks of Abiraterone NLR-change to <5 prognosticated worse PFS (five versus 12 months) (HR: 4.1 (95%CI:1.1–15.8); p = 0.04). MVA showed a trend towards worse PFS for NLR-change to <5 (p = 0.11). NLR-change to <5 led to non-significant shorter median OS (seven versus 16 months) (HR: 2.3 (95%CI:0.7–7.1); p = 0.15). MVA showed non-significant difference for OS. We concluded baseline NLR <5 is associated with improved survival. In contrast, in patients with baseline NLR >5, NLR-change to <5 after eight weeks of Abiraterone was associated with worse survival and should be interpreted carefully. PMID:28208664

  19. Radiographic Progression-Free Survival As a Response Biomarker in Metastatic Castration-Resistant Prostate Cancer: COU-AA-302 Results

    PubMed Central

    Morris, Michael J.; Molina, Arturo; Small, Eric J.; de Bono, Johann S.; Logothetis, Christopher J.; Fizazi, Karim; de Souza, Paul; Kantoff, Philip W.; Higano, Celestia S.; Li, Jinhui; Kheoh, Thian; Larson, Steven M.; Matheny, Shannon L.; Naini, Vahid; Burzykowski, Tomasz; Griffin, Thomas W.; Scher, Howard I.; Ryan, Charles J.

    2015-01-01

    Purpose Progression-free survival (PFS) in metastatic castration-resistant prostate cancer (mCRPC) trials has been inconsistently defined and poorly associated with overall survival (OS). A reproducible quantitative definition of radiographic PFS (rPFS) was tested for association with a coprimary end point of OS in a randomized trial of abiraterone in patients with mCRPC. Patients and Methods rPFS was defined as ≥ two new lesions on an 8-week bone scan plus two additional lesions on a confirmatory scan, ≥ two new confirmed lesions on any scan ≥ 12 weeks after random assignment, and/or progression in nodes or viscera on cross-sectional imaging, or death. rPFS was assessed by independent review at 15% of deaths and by investigator review at 15% and 40% of deaths. rPFS and OS association was evaluated by Spearman's correlation. Results A total of 1,088 patients were randomly assigned to abiraterone plus prednisone or prednisone alone. At first interim analysis, the hazard ratio (HR) by independent review was 0.43 (95% CI, 0.35 to 0.52; P < .001; abiraterone plus prednisone: median rPFS, not estimable; prednisone: median rPFS, 8.3 months). Similar HRs were obtained by investigator review at the first two interim analyses (HR, 0.49; 95% CI, 0.41 to 0.60; P < .001 and HR, 0.53; 95% CI, 0.45 to 0.62; P < .001, respectively), validating the imaging data assay used. Spearman's correlation coefficient between rPFS and OS was 0.72. Conclusion rPFS was highly consistent and highly associated with OS, providing initial prospective evidence on further developing rPFS as an intermediate end point in mCRPC trials. PMID:25624432

  20. Systemic Therapy in Men With Metastatic Castration-Resistant Prostate Cancer: American Society of Clinical Oncology and Cancer Care Ontario Clinical Practice Guideline

    PubMed Central

    Basch, Ethan; Loblaw, D. Andrew; Oliver, Thomas K.; Carducci, Michael; Chen, Ronald C.; Frame, James N.; Garrels, Kristina; Hotte, Sebastien; Kattan, Michael W.; Raghavan, Derek; Saad, Fred; Taplin, Mary-Ellen; Walker-Dilks, Cindy; Williams, James; Winquist, Eric; Bennett, Charles L.; Wootton, Ted; Rumble, R. Bryan; Dusetzina, Stacie B.; Virgo, Katherine S.

    2014-01-01

    Purpose To provide treatment recommendations for men with metastatic castration-resistant prostate cancer (CRPC). Methods The American Society of Clinical Oncology and Cancer Care Ontario convened an expert panel to develop evidence-based recommendations informed by a systematic review of the literature. Results When added to androgen deprivation, therapies demonstrating improved survival, improved quality of life (QOL), and favorable benefit-harm balance include abiraterone acetate/prednisone, enzalutamide, and radium-223 (223Ra; for men with predominantly bone metastases). Improved survival and QOL with moderate toxicity risk are associated with docetaxel/prednisone. For asymptomatic/minimally symptomatic men, improved survival with unclear QOL impact and low toxicity are associated with sipuleucel-T. For men who previously received docetaxel, improved survival, unclear QOL impact, and moderate to high toxicity risk are associated with cabazitaxel/prednisone. Modest QOL benefit (without survival benefit) and high toxicity risk are associated with mitoxantrone/prednisone after docetaxel. No benefit and excess toxicity are observed with bevacizumab, estramustine, and sunitinib. Recommendations Continue androgen deprivation (pharmaceutical or surgical) indefinitely. Abiraterone acetate/prednisone, enzalutamide, or 223Ra should be offered; docetaxel/prednisone should also be offered, accompanied by discussion of toxicity risk. Sipuleucel-T may be offered to asymptomatic/minimally symptomatic men. For men who have experienced progression with docetaxel, cabazitaxel may be offered, accompanied by discussion of toxicity risk. Mitoxantrone may be offered, accompanied by discussion of limited clinical benefit and toxicity risk. Ketoconazole or antiandrogens (eg, bicalutamide, flutamide, nilutamide) may be offered, accompanied by discussion of limited known clinical benefit. Bevacizumab, estramustine, and sunitinib should not be offered. There is insufficient evidence to

  1. The Added Value of Circulating Tumor Cell Enumeration to Standard Markers in Assessing Prognosis in a Metastatic Castration-Resistant Prostate Cancer Population.

    PubMed

    Heller, Glenn; Fizazi, Karim; McCormack, Robert; Molina, Arturo; MacLean, David; Webb, Iain J; Saad, Fred; de Bono, Johann S; Scher, Howard I

    2016-09-27

    Purpose: Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease for which better prognostic models for survival are needed. We examined the added value of circulating tumor cell (CTC) enumeration relative to common prognostic laboratory measures from patients with CRPC.Methods: Utility of CTC enumeration as a baseline and postbaseline prognostic biomarker was examined using data from two prospective randomized registration-directed trials (COU-AA-301 and ELM-PC4) within statistical models used to estimate risk for survival. Discrimination and calibration were used to measure model predictive accuracy and the added value for CTC enumeration in the context of a Cox model containing albumin, lactate dehydrogenase (LDH), PSA, hemoglobin, and alkaline phosphatase (ALK). Discrimination quantifies how accurately a risk model predicts short-term versus long-term survivors. Calibration measures the closeness of actual survival time to the predicted survival time.Results: Adding CTC enumeration to a model containing albumin, LDH, PSA, hemoglobin, and ALK ("ALPHA") improved its discriminatory power. The weighted c-index for ALPHA without CTCs was 0.72 (SE, 0.02) versus 0.75 (SE, 0.02) for ALPHA + CTCs. The increase in discrimination was restricted to the lower-risk cohort. In terms of calibration, adding CTCs produced a more accurate model-based prediction of patient survival. The absolute prediction error for ALPHA was 3.95 months (SE, 0.28) versus 3.75 months (SE, 0.22) for ALPHA + CTCs.Conclusion: Addition of CTC enumeration to standard measures provides more accurate assessment of patient risk in terms of baseline and postbaseline prognosis in the mCRPC population. Clin Cancer Res; 1-7. ©2016 AACR.

  2. A randomized phase II clinical trial of personalized peptide vaccination with metronomic low-dose cyclophosphamide in patients with metastatic castration-resistant prostate cancer.

    PubMed

    Noguchi, Masanori; Moriya, Fukuko; Koga, Noriko; Matsueda, Satoko; Sasada, Tetsuro; Yamada, Akira; Kakuma, Tatsuyuki; Itoh, Kyogo

    2016-02-01

    This study investigated the effect of metronomic cyclophosphamide (CPA) in combination with personalized peptide vaccination (PPV) on regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC), and whether it could improve the antitumor effect of PPV. Seventy patients with metastatic castration-resistant prostate cancer were randomly assigned (1:1) to receive PPV plus oral low-dose CPA (50 mg/day), or PPV alone. PPV treatment used a maximum of four peptides chosen from 31 pooled peptides according to human leukocyte antigen types and antigen-specific humoral immune responses before PPV, for 8 subcutaneous weekly injections. Peptide-specific cytotoxic T lymphocyte (CTL) and immunoglobulin G responses were measured before and after PPV. The incidence of grade 3 or 4 hematologic adverse events was higher in the PPV plus CPA arm than in the PPV alone arm. Decrease in Treg and increase in MDSC were more pronounced in PPV plus CPA treatment than in PPV alone (p = 0.036 and p = 0.048, respectively). There was no correlation between the changes in Treg or MDSC and CTL response. There was no difference in positive immune responses between the two arms, although overall survival in patients with positive immune responses was longer than in those with negative immune responses (p = 0.001). Significant differences in neither progression-free survival nor overall survival were observed between the two arms. Low-dose CPA showed no change in the antitumor effect of PPV, possibly due to the simultaneous decrease in Treg and increase in MDSC, in patients under PPV.

  3. First-line non-cytotoxic therapy in chemotherapy-naive patients with metastatic castration-resistant prostate cancer: a systematic review of 10 randomised clinical trials.

    PubMed

    Poorthuis, Michiel H F; Vernooij, Robin W M; van Moorselaar, R Jeroen A; de Reijke, Theo M

    2017-01-06

    The aim of this study is to systematically evaluate all available treatment options in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC). We systematically searched PubMed, EMBASE, and the Cochrane libraries up to 1 March 2016 for peer-reviewed publications on randomised clinical trials (RCTs). RCTs were included if progression-free survival (PFS), overall survival (OS), quality of life (QoL), or adverse events (AEs) were quantitatively evaluated. We assessed the risk of bias with the Cochrane Collaboration's tool and graded the evidence with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group's approach. We included 25 articles, reporting on 10 unique RCTs describing seven different comparisons. In one RCT, a prolonged OS and PFS (high quality) were found with abiraterone and prednisone compared to placebo plus prednisone. In one RCT, a prolonged OS and PFS (high quality) were found with enzalutamide compared to placebo. In two RCTs, a prolonged OS (high and moderate quality) was found with (223) radium compared to placebo, but its effect on PFS is unknown. In three RCTs, a prolonged OS (moderate quality) was found with sipuleucel-T compared to placebo, but no prolonged PFS (low quality). In one RCT a prolonged PFS (high quality) was found with orteronel compared to placebo, but no prolonged OS (moderate quality). In one RCT, a prolonged OS (moderate quality) was found with bicalutamide compared to placebo, but its effect on PFS is unknown. In one RCT, a prolonged PFS (high quality) was found with enzalutamide compared to bicalutamide, but its effect on OS is unknown. The best evidence was found for abiraterone and enzalutamide for effective prolongation of OS and PFS to treat chemotherapy-naive patients with mCRPC. However, taking both QoL and AEs into consideration, other treatment modalities could be considered for individual patients.

  4. CAST: A retrospective analysis of cabazitaxel and abiraterone acetate sequential treatment in patients with metastatic castrate-resistant prostate cancer previously treated with docetaxel.

    PubMed

    Wissing, Michel D; Coenen, Jules L L M; van den Berg, Pieter; Westgeest, Hans M; van den Eertwegh, Alfons J M; van Oort, Inge M; Bos, Monique M; Bergman, André M; Hamberg, Paul; Ten Tije, Albert J; Los, Maartje; Lolkema, Martijn P J K; de Wit, Ronald; Gelderblom, Hans

    2015-03-15

    Cabazitaxel and abiraterone have both received approval for treating metastatic castrate-resistant prostate cancer (mCRPC) patients after first-line docetaxel therapy. In the cabazitaxel and abiraterone sequential treatment (CAST) study, the clinical outcome of docetaxel-treated mCRPC patients treated sequentially with both cabazitaxel and abiraterone was studied. Data were collected retrospectively from mCRPC patients at 12 hospitals across the Netherlands who initiated cabazitaxel and/or abiraterone before December 2012. Primary outcome measure was overall survival (OS); secondary measures were progression-free survival (PFS), biochemical PFS, and best clinical and PSA response. Hospital admission data during treatment were collected, as well as toxicities resulting in treatment discontinuation or patient death. Sixty-three and 69 patients received Cab→Abi (cabazitaxel prior to abiraterone) and Abi→Cab before July 10th, 2013, respectively. Median OS was 19.1 months and 17.0 months in Cab→Abi and Abi→Cab treated patients, respectively (p = 0.369). Median PFS and biochemical PFS were significantly longer in Cab→Abi treated patients: 8.1 versus 6.5 (p = 0.050) and 9.5 versus 7.7 months (p = 0.024), respectively. Although partial responses to cabazitaxel occurred in both groups, Abi→Cab treated patients had a significantly decreased antitumor response from cabazitaxel than Cab→Abi treated patients (median PFS 5.0 versus 2.6 months, p < 0.001). Minor differences in toxicities were observed based on therapy sequence; generally, toxicity from cabazitaxel could be severe, while abiraterone toxicity was milder. This retrospective analysis indicates that primary progression on cabazitaxel or abiraterone did not preclude a response to the other agent in mCRPC patients. However, tumor response of both agents, particularly cabazitaxel, was lower when administered as higher-line therapy in the selected study population.

  5. Phase I clinical trial of sipuleucel-T combined with escalating doses of ipilimumab in progressive metastatic castrate-resistant prostate cancer

    PubMed Central

    Scholz, Mark; Yep, Sabrina; Chancey, Micah; Kelly, Colleen; Chau, Ken; Turner, Jeffrey; Lam, Richard; Drake, Charles G

    2017-01-01

    Background Sipuleucel-T (SIP-T), which functions by stimulating cancer-specific dendritic cells, prolongs survival in men with prostate cancer. Ipilimumab (IPI) achieved a borderline survival advantage in a large randomized trial. SIP-T and IPI are potentially synergistic. Patients and Methods Nine men with progressive metastatic castrate-resistant prostate cancer (mCRPC) were treated prospectively with SIP-T followed immediately by IPI with one of the following doses of IPI: 1 mg/kg at 1 week after SIP-T; 1 mg/kg at 1 and 4 weeks after SIP-T; or 1 mg/kg at 1, 4, and 7 weeks after SIP-T. Three patients were evaluated at each level. Cancer-specific immunoglobulins directed at granulocyte-macrophage-colony-stimulating factor/prostatic acid phosphatase (PAP) fusion protein (PA2024) and PAP were measured prior to SIP-T, after SIP-T, 1 week after IPI, every other month for 5 months, then every 3 months for an additional 12 months. Results Adverse events of SIP-T were consistent with previous reports. IPI only caused a transient grade 1 rash in one patient. Median age, Gleason score, and number of previous hormonal interventions were 77 years, 8, and 3, respectively. Eight men had bone metastases and one had lymph node metastasis. Statistically significant increases in serum immunoglobulin G (IgG) and IgG-IgM specific for PA2024 and PAP occurred after SIP-T. An additional statistically significant increase in the aforementioned immunoglobulins – above the levels achieved by SIP-T – occurred after IPI. Median clinical follow-up was 36 months (range: 26–40). Three patients died from progressive disease after 9, 18, and 20 months. Out of the remaining six patients, five of them needed further treatment that included abiraterone acetate, enzalutamide, radium-223 dichloride, and spot radiation. One patient had an undetectable PSA, who did not receive any other treatment except spot radiation. Median PSA at last follow-up for the surviving patients was 3.8 (range: 0.6

  6. CpG-STAT3siRNA for Castration-Resistant Prostate Cancer Therapy

    DTIC Science & Technology

    2013-10-01

    simultaneously target both castration-resistant prostate cancer cells and tumor-associated immune cells, such as myeloid-derived suppressor cells ( MDSCs ...generate potent antitumor immunity, with minimal adverse effects . Body The main goals of this study are: optimization of the CpG(A)-siRNA strategy...for targeting survival signaling in metastatic prostate cancer cells and for breaking immunosuppressive effects of the prostate cancer

  7. A Phase I/II Study of the Investigational Drug Alisertib in Combination With Abiraterone and Prednisone for Patients With Metastatic Castration-Resistant Prostate Cancer Progressing on Abiraterone

    PubMed Central

    Patel, Sheel A.; Sama, Ashwin R.; Hoffman-Censits, Jean H.; Kennedy, Brooke; Kilpatrick, Deborah; Ye, Zhong; Yang, Hushan; Mu, Zhaomei; Leiby, Benjamin; Lewis, Nancy; Cristofanilli, Massimo; Kelly, William Kevin

    2016-01-01

    Lessons Learned Patients with metastatic castration-resistant prostate cancer did not tolerate the combination of alisertib with abiraterone and prednisone. There was no clear signal indicating that adding alisertib might be beneficial for those patients progressing on abiraterone. Background. We hypothesized that Aurora A kinase (AK) contributes to castrate resistance in prostate cancer (PCa) and that inhibiting AK with alisertib can resensitize PCa cells to androgen receptor (AR) inhibitor abiraterone. Methods. This was a phase I/II trial to determine the safety and efficacy of alisertib when given in combination with abiraterone plus prednisone (AP). Metastatic castration-resistant prostate cancer (mCRPC) patients were treated with dose escalation (alisertib at 30, 40, and 50 mg orally b.i.d., days 1–7 every 21 days) per standard 3+3 design. Results. Nine of 43 planned subjects were enrolled. The maximum tolerated dose (MTD) was not reached, and the dose-limiting toxicities (DLTs) included neutropenic fever (1 of 9), neutropenia (1 of 9), fatigue with memory impairment (1 of 9), and diarrhea/mucositis (1 of 9). No prostate-specific antigen (PSA) decrease or circulating tumor cell (CTC) changes were observed during the study. Pharmacodynamically, adding alisertib did not affect total testosterone or dehydroepiandrosterone (DHEA) levels. There was some change in neuroendocrine markers after therapy. Mean duration on study was 2.5 months. The trial was terminated early. Conclusion. A tolerable dose of alisertib in combination with AP in mCRPC was not established in this study. There was no clear signal indicating that alisertib might be beneficial for patients with mCRPC progressing on abiraterone. PMID:28178640

  8. Efficacy of Cabazitaxel Treatment in Metastatic Castration Resistant Prostate Cancer in Second and Later Lines. An Experience from Two German Centers

    PubMed Central

    Zschäbitz, Stefanie; Vallet, Sonia; Hadaschik, Boris; Debatin, Daniel; Fuxius, Stefan; Karcher, Andreas; Pahernik, Sascha; Spath, Cathleen; Duensing, Stefan; Jäger, Dirk; Hohenfellner, Markus; Grüllich, Carsten

    2017-01-01

    Purpose: Several new treatment options for patients with metastatic castration resistant prostate cancer (mCRPC) have been approved within the last years - among them cabazitaxel (CAB), abiraterone acetate, enzalutamide, and radium-223. The aim of this study was to assess factors predictive for efficacy of CAB. Methods: We analyzed all patients with mCRPC treated with CAB at our institutions between 2011 and 2016. Data were retrieved retrospectively from the electronical patient chart. Results: 69 patients received CAB (26.1% 2nd line, 36.2% 3rd line, 37.3% >3rd line). Median overall survival (OS) on CAB was 10.0 months (95%CI 7.1-12.9). Median progression free survival (PFS) on CAB was 3.9 months (95%CI 3.0-4.8). There were no differences in OS and PFS regarding treatment line of CAB (2nd vs. higher; 2nd/3rd vs. higher). Duration of remission on 1st line treatment (> 6 months vs.

  9. Assessment of a prognostic model, PSA metrics and toxicities in metastatic castrate resistant prostate cancer using data from Project Data Sphere (PDS)

    PubMed Central

    Hamilton, Robert J.; Abdallah, Kald; Pintilie, Melania; Joshua, Anthony M.

    2017-01-01

    Background Prognostic models in metastatic castrate resistant prostate cancer (mCRPC) may have clinical utility. Using data from PDS, we aimed to 1) validate a contemporary prognostic model (Templeton et al., 2014) 2) evaluate prognostic impact of concomitant medications and PSA decrease 3) evaluate factors associated with docetaxel toxicity. Methods We accessed data on 2,449 mCRPC patients in PDS. The existing model was validated with a continuous risk score, time-dependent receiver operating characteristic (ROC) curves, and corresponding time-dependent Area under the Curve (tAUC). The prognostic effects of concomitant medications and PSA response were assessed by Cox proportional hazards models. One year tAUC was calculated for multivariable prognostic model optimized to our data. Conditional logistic regression models were used to assess associations with grade 3/4 adverse events (G3/4 AE) at baseline and after cycle 1 of treatment. Results Despite limitations of the PDS data set, the existing model was validated; one year AUC, was 0.68 (95% CI 95% CI, .66 to .71) to 0.78 (95%CI, .74 to .81) depending on the subset of datasets used. A new model was constructed with an AUC of .74 (.72 to .77). Concomitant medications low molecular weight heparin and warfarin were associated with poorer survival, Metformin and Cox2 inhibitors were associated with better outcome. PSA response was associated with survival, the effect of which was greatest early in follow-up. Age was associated with baseline risk of G3/4 AE. The odds of experiencing G3/4 AE later on in treatment were significantly greater for subjects who experienced a G3/4 AE in their first cycle (OR 3.53, 95% CI 2.53–4.91, p < .0001). Conclusion Despite heterogeneous data collection protocols, PDS provides access to large datasets for novel outcomes analysis. In this paper, we demonstrate its utility for validating existing models and novel model generation including the utility of concomitant medications in

  10. Chemotherapy options in castration-resistant prostate cancer

    PubMed Central

    Teply, Benjamin A.; Hauke, Ralph J.

    2016-01-01

    Introduction: The treatment landscape for patients with metastatic castration-resistant prostate cancer (CRPC) is evolving, with recent approvals of immune therapy, novel hormonal therapy, and bone-targeted therapy. Chemotherapy remains an essential component of the armamentarium. Herein, we review current chemotherapy options for patients with CRPC and discuss future challenges. Methods: We reviewed literature for chemotherapy agents in prostate cancer, with special attention to the evidence for efficacy of the currently approved agents. We also reviewed emerging data on biomarkers of response to chemotherapy for CRPC. Results: Taxanes, especially docetaxel and cabazitaxel, have first- and second-line indications for CRPC, respectively, with both providing a survival benefit. Multiple attempts to improve on the single agent efficacy of docetaxel with combination therapy have not generally been successful although platinum combinations are used for resistant phenotypes. Reductions in prostate-specific antigen by ≥30% and reductions in circulating tumor cells (CTCs) to ≤ 5 are associated with improved survival on chemotherapy. Chemotherapy may continue to be effective therapy for patients with biomarkers that are associated with resistance to androgen-directed therapies (androgen receptor splice variant 7 positivity in CTCs or high CTC heterogeneity). Conclusions: Chemotherapy remains an essential component of CRPC therapy, and biomarkers are being identified to define clinical scenarios where chemotherapy may be the optimal therapy choice. PMID:27843207

  11. Visceral disease in castration-resistant prostate cancer.

    PubMed

    Pezaro, Carmel J; Omlin, Aurelius; Lorente, David; Nava Rodrigues, Daniel; Ferraldeschi, Roberta; Bianchini, Diletta; Mukherji, Deborah; Riisnaes, Ruth; Altavilla, Amelia; Crespo, Mateus; Tunariu, Nina; de Bono, Johann S; Attard, Gerhardt

    2014-02-01

    Metastatic involvement of the viscera in men with advanced castration-resistant prostate cancer (CRPC) has been poorly characterised to date. In 359 CRPC patients treated between June 2003 and December 2011, the frequency of radiologically detected visceral metastases before death was 32%. Of the 92 patients with computed tomography performed within 3 mo of death, 49% had visceral metastases. Visceral metastases most commonly involved the liver (20%) and lung (13%). Median survival from diagnosis of visceral disease was 7.1 mo (95% confidence interval, 5.9-8.3). Survival was affected by the degree of bone involvement at detection of visceral disease, varying from 6.1 mo in men with more than six bone metastases to 18.2 mo in men with no bone metastases (p=0.001). Heterogeneity was noted in clinical phenotypes and prostate-specific antigen trends at development of visceral metastases. Visceral metastases are now more commonly detected in men with CRPC, likely due to the introduction of novel survival-prolonging treatments.

  12. Radiation Dosimetry for (177)Lu-PSMA I&T in Metastatic Castration-Resistant Prostate Cancer: Absorbed Dose in Normal Organs and Tumor Lesions.

    PubMed

    Okamoto, Shozo; Thieme, Anne; Allmann, Jakob; D'Alessandria, Calogero; Maurer, Tobias; Retz, Margitta; Tauber, Robert; Heck, Matthias M; Wester, Hans-Juergen; Tamaki, Nagara; Fendler, Wolfgang P; Herrmann, Ken; Pfob, Christian H; Scheidhauer, Klemens; Schwaiger, Markus; Ziegler, Sibylle; Eiber, Matthias

    2017-03-01

    Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy is increasingly used in metastatic castration-resistant prostate cancer. We aimed to estimate the absorbed doses for normal organs and tumor lesions using (177)Lu-PSMA I&T (I&T is imaging and therapy) in patients undergoing up to 4 cycles of radioligand therapy. Results were compared with pretherapeutic Glu-NH-CO-NH-Lys-(Ahx)-[(68)Ga(HBEDCC)] ((68)Ga-PSMA-HBED-CC) PET. Methods: A total of 34 cycles in 18 patients were analyzed retrospectively. In 15 patients the first, in 9 the second, in 5 the third, and in 5 the fourth cycle was analyzed, respectively. Whole-body scintigraphy was performed at least between 30-120 min, 24 h, and 6-8 d after administration. Regions of interest covering the whole body, organs, and up to 4 tumor lesions were drawn. Organ and tumor masses were derived from pretherapeutic (68)Ga-PSMA-HBED-CC PET/CT. Absorbed doses for individual cycles were calculated using OLINDA/EXM. SUVs from pretherapeutic PET were compared with absorbed doses and with change of SUV. Results: The mean whole-body effective dose for all cycles was 0.06 ± 0.03 Sv/GBq. The mean absorbed organ doses were 0.72 ± 0.21 Gy/GBq for the kidneys; 0.12 ± 0.06 Gy/GBq for the liver; and 0.55 ± 0.14 Gy/GBq for the parotid, 0.64 ± 0.40 Gy/GBq for the submandibular, and 3.8 ± 1.4 Gy/GBq for the lacrimal glands. Absorbed organ doses were relatively constant among the 4 different cycles. Tumor lesions received a mean absorbed dose per cycle of 3.2 ± 2.6 Gy/GBq (range, 0.22-12 Gy/GBq). Doses to tumor lesions gradually decreased, with 3.5 ± 2.9 Gy/GBq for the first, 3.3 ± 2.5 Gy/GBq for the second, 2.7 ± 2.3 Gy/GBq for the third, and 2.4 ± 2.2 Gy/GBq for the fourth cycle. SUVs of pretherapeutic PET moderately correlated with absorbed dose (r = 0.44, P < 0.001 for SUVmax; r = 0.43, P < 0.001 for SUVmean) and moderately correlated with the change of SUV (r = 0.478, P < 0.001 for SUVmax, and r = 0.50, P < 0

  13. Combination of circulating tumor cell enumeration and tumor marker detection in predicting prognosis and treatment effect in metastatic castration-resistant prostate cancer.

    PubMed

    Chang, Kun; Kong, Yun-Yi; Dai, Bo; Ye, Ding-Wei; Qu, Yuan-Yuan; Wang, Yue; Jia, Zhong-Wei; Li, Gao-Xiang

    2015-12-08

    Although circulating tumor cell (CTC) enumeration in peripheral blood has already been validated as a reliable biomarker in predicting prognosis in metastatic castration-resistant prostate cancer (mCRPC), patients with favorable CTC counts (CTC < 5/7.5 ml) still experience various survival times. Assays that can reduce patients' risks are urgently needed. In this study, we set up a real-time quantitative polymerase chain reaction (RT-qPCR) method to detect epithelial-mesenchymal transition (EMT) and stem cell gene expression status in peripheral blood to validate whether they could complement CTC enumeration. From January 2013 to June 2014 we collected peripheral blood from 70 mCRPC patients and enumerated CTC in these blood samples using CellSearch system. At the same time, stem cell-related genes (ABCG2, PROM1 and PSCA) and EMT-related genes (TWIST1 and vimentin) were detected in these peripheral blood samples using an RT-qPCR assay. Patient overall survival (OS) and treatment methods were recorded in the follow-up. For patients who received first-line chemotherapy, docetaxel plus prednisone, PSA progression-free survival (PSA-PFS) and PSA response rate were recorded. At the time of analysis, 35 patients had died of prostate cancer with a median follow-up of 16.0 months. Unfavorable CTC enumerations (CTC ≥5/7.5 ml) were predictive of shorter OS (p = 0.01). Also, positive stem cell gene expression indicated poor prognosis in mCRPC patients (p = 0.01). However, EMT gene expression status failed to show any prognostic value in OS (p = 0.78). A multivariate analysis indicated that serum albumin (p = 0.04), ECOG performance status (p < 0.01), CTC enumeration (p = 0.02) and stem cell gene expression status (p = 0.01) were independent prognostic factors for OS. For the 40 patients categorized into the favorable CTC enumeration group, positive stem cell gene expression also suggested poor prognosis (p < 0.01). A combined prognostic model consisting of stem cell gene

  14. [Strategy in advanced castration-resistant prostate cancer].

    PubMed

    Gross-Goupil, Marine; Roca, Sophie; Pasticier, Gilles; Ravaud, Alain

    2012-07-01

    If androgen deprivation, chemical with LH-RH analogs or surgical with bilateral orchiectomy, still remains the stone edge of treatment of prostate cancer, in the metastatic setting, this hormonosensitivity, most of the time long, finally move on in hormonal-failure. If rare changes in the therapeutic strategy have been achieved in this setting since 2004 and the arrival of docetaxel, it is the global perception of the disease that has been modified and the definition of one specific entity: the castrate-resistant prostate cancer. This new definition and the changes of design and end-points of clinical trials testing new agents with strong recruitment during the past years have conducted to a real revolution in the management of castrate-refractory prostate cancer. The place of secondary hormonal manipulations, such as withdrawal of the anti-androgen, oestrogen or ketoconazole, still exists for a selected group of patients. In case of aggressive disease and symptoms, chemotherapy should be selected, docetaxel, in a three weeks schedule, and may be combined with Estracyt. It is time to consider the revolution of the post-chemotherapy setting with the arrival of two new drugs ; a cytotoxic one, the cabazitaxel and hormonal for the second one, the abiraterone acetate. The place of the immunotherapy with the sipuleucel-T may be more difficult to precise, especially in Europe, even if it has been finally indicated in the United States in the metastatic setting. Concerning bone metastasis, zoledronic acid was during a long time the only bone-targeted agent, effective in reducing the incidence of skeletal related events, and was recently exceeded by the denosumab, an anti-RANK ligand. Finally, let us hope that other changes will be achieved in the near future, with the cabazitaxel-docetaxel confrontation in the first-line setting, and the introduction of the abiraterone acetate before chemotherapy with docetaxel, already tested in ongoing trials.

  15. Abiraterone Acetate and Castration Resistant Ductal Adenocarcinoma of the Prostate

    PubMed Central

    Linden-Castro, Edgar; Pelayo-Nieto, Marcela; Alias-Melgar, Alejandro; Espinosa-Perezgrovas, Daniel; Ramirez-Galindo, Ivan; Catalan-Quinto, Gabriel

    2014-01-01

    Ductal adenocarcinoma of the prostate is a rare histological variant that only represents <1% of prostate tumors. This histological variant has several important clinical implications with respect to their evolution, clinical prognosis, and treatment. We report the case of a 64-year-old patient with ductal adenocarcinoma of the prostate, which progresses to castration-resistant prostate cancer, that was treated with abiraterone acetate with good clinical response, to our knowledge, the first case of ductal adenocarcinoma of the prostate in treatment with abiraterone acetate. PMID:24891969

  16. Abiraterone Acetate for the Treatment of Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer: An Evidence Review Group Perspective of an NICE Single Technology Appraisal.

    PubMed

    Ramaekers, Bram L T; Riemsma, Rob; Tomini, Florian; van Asselt, Thea; Deshpande, Sohan; Duffy, Steven; Armstrong, Nigel; Severens, Johan L; Kleijnen, Jos; Joore, Manuela A

    2017-02-01

    The National Institute for Health and Care Excellence (NICE) invited Janssen, the company manufacturing abiraterone acetate (AA; tradename Zytiga(®)), to submit evidence for the clinical and cost effectiveness of AA in combination with prednisone/prednisolone (AAP) compared with watchful waiting (i.e. best supportive care [BSC]) for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC). Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Maastricht University Medical Center, was commissioned as the Evidence Review Group (ERG). This paper presents a summary of the company submission (CS), the ERG report, subsequent addenda, and the development of the NICE guidance for the use of this drug in England and Wales by the Appraisal Committee (AC). The ERG produced a critical review of the clinical and cost effectiveness of AAP based on the CS. An important question in this appraisal was, according to the ERG, whether AAP followed by docetaxel is more effective than BSC followed by docetaxel. In the COU-AA-302 trial, 239 of 546 (43.8 %) AAP patients and 304 of 542 (56.1 %) BSC patients received docetaxel as subsequent therapy, following AA or placebo. The results for this specific group of patients were not presented in the CS; therefore, the ERG asked the company to provide these data in the clarification letter; however, these data were presented as commercial-in-confidence and cannot therefore be reported here. The ERG's critical assessment of the company's economic evaluation highlighted a number of concerns, including (a) not using the intention-to-treat (ITT) population; (b) inconsistencies in estimating prediction equations; (c) not fully incorporating the impact of adverse events; (d) incorrectly incorporating the new patient access scheme (PAS); and (e) the assumption that AA non-compliance leads to recoverable drug costs. Although some of these issues were adjusted in the ERG base case, the ERG could not estimate

  17. Statin derivatives as therapeutic agents for castration-resistant prostate cancer.

    PubMed

    Ingersoll, Matthew A; Miller, Dannah R; Martinez, October; Wakefield, C Brent; Hsieh, Kuan-Chan; Simha, M Vijaya; Kao, Chai-Lin; Chen, Hui-Ting; Batra, Surinder K; Lin, Ming-Fong

    2016-12-01

    Despite recent advances in modern medicine, castration-resistant prostate cancer remains an incurable disease. Subpopulations of prostate cancer cells develop castration-resistance by obtaining the complete steroidogenic ability to synthesize androgens from cholesterol. Statin derivatives, such as simvastatin, inhibit cholesterol biosynthesis and may reduce prostate cancer incidence as well as progression to advanced, metastatic phenotype. In this study, we demonstrate novel simvastatin-related molecules SVA, AM1, and AM2 suppress the tumorigenicity of prostate cancer cell lines including androgen receptor-positive LNCaP C-81 and VCaP as well as androgen receptor-negative PC-3 and DU145. This is achieved through inhibition of cell proliferation, colony formation, and migration as well as induction of S-phase cell-cycle arrest and apoptosis. While the compounds effectively block androgen receptor signaling, their mechanism of inhibition also includes suppression of the AKT pathway, in part, through disruption of the plasma membrane. SVA also possess an added effect on cell growth inhibition when combined with docetaxel. In summary, of the compounds studied, SVA is the most potent inhibitor of prostate cancer cell tumorigenicity, demonstrating its potential as a promising therapeutic agent for castration-resistant prostate cancer.

  18. Phase II study of Cilengitide (EMD 121974, NSC 707544) in patients with non-metastatic castration resistant prostate cancer, NCI-6735. A study by the DOD/PCF Prostate Cancer Clinical Trials Consortium

    PubMed Central

    Alva, Ajjai; Slovin, Susan; Daignault, Stephanie; Carducci, Michael; DiPaola, Robert; Pienta, Ken; Agus, David; Cooney, Kathleen; Chen, Alice; Smith, David C.; Hussain, Maha

    2011-01-01

    Background Integrins mediate invasion and angiogenesis in prostate cancer bone metastases. We conducted a phase II study of Cilengitide, a selective antagonist of αvβ3 and αvβ5 integrins, in non-metastatic castration resistant prostate cancer with rising PSA. Methods Patients were observed for 4 weeks with PSA monitoring, and then treated with 2,000 mg IV of cilengitide twice weekly until toxicity/progression. PSA, circulating tumor cells (CTCs) and circulating endothelial cells (CECs) were monitored each cycle with imaging performed every 3 cycles. Primary end point was PSA decline by ≥ 50%. Secondary endpoints were safety, PSA slope, time to progression (TTP), overall survival (OS), CTCs, CECs and gene expression. Results 16 pts were enrolled; 13 were eligible with median age 65.5 years, baseline PSA 8.4 ng/mL and median Gleason sum 7. Median of 3 cycles was administered. Treatment was well tolerated with 2 grade 3 toxicities and no grade 4 toxicities. There were no PSA responses; 11 patients progressed by PSA after 3 cycles. Median TTP was 1.8 months and median OS has not been reached. Median pre- and on-treatment PSA slopes were 1.1 and 1.8 ng/mL/month. Baseline CTCs were detected in 1/9 patients. CTC increased (0 to 1; 2 pts), remained at 0 (2 pts) or decreased (23 to 0; 1 patient) at progression. Baseline median CEC was 26 (0–61) and at progression, 47 (15–148). Low cell counts precluded gene expression studies. Conclusions Cilengitide was well tolerated but had no detectable clinical activity. CTCs are of questionable utility in non-metastatic prostate cancer. PMID:21049281

  19. Everolimus Combined With Gefitinib in Patients with Metastatic Castration-Resistant Prostate Cancer: Phase I/II Results and Signaling Pathway Implications

    PubMed Central

    Rathkopf, Dana E.; Larson, Steven M.; Anand, Aseem; Morris, Michael J.; Slovin, Susan F.; Shaffer, David R.; Heller, Glenn; Carver, Brett; Rosen, Neal; Scher, Howard I.

    2015-01-01

    Background The effects of mammalian target of rapamycin (mTOR) inhibition are limited by feedback reactivation of receptor tyrosine kinase signaling in PTEN-null tumors, thus we tested the combination of mTOR inhibition (everolimus) and EGFR inhibition (gefitinib) in castration-resistant prostate cancer (CRPC). Methods In phase I, 12 patients (10 CRPC, 2 glioblastoma) received daily gefitinib (250 mg) with weekly everolimus (30, 50, or 70 mg). In phase II, 27 CRPC patients received gefitinib with everolimus 70 mg. Results Phase I revealed no pharmacokinetic interactions and no dose-limiting toxicities. In phase II, 18 of 27 (67%) patients discontinued treatment before the 12-week evaluation due to progression as evidenced by prostate-specific antigen (PSA) levels (n=6) or imaging (n=5), or grade ≥2 toxicity (n=7). Thirteen of the total 37 (35%) CRPC patients exhibited a rapidly rising PSA after starting treatment which declined upon discontinuation. Fluorodeoxyglucose positron emission tomography at 24 to 72 hours after starting treatment showed a decrease in standardized uptake value consistent with mTOR inhibition in 27 of 33 (82%) evaluable patients; there was a corresponding rise in PSA in 20 of these 27 patients (74%). Conclusions The combination of gefitinib and everolimus did not result in significant antitumor activity. The induction of PSA in tumors treated with mTOR inhibitors was consistent with preclinical data that PI3K pathway signaling feedback inhibits the androgen receptor (AR). This clinical evidence of relief of feedback inhibition promoting enhanced AR activity supports future studies combining PI3K pathway inhibitors and second-generation AR inhibitors in CRPC. PMID:26178426

  20. Novel Therapeutic Targets to Inhibit Tumor Microenvironment Induced Castration-resistant Prostate Cancer

    DTIC Science & Technology

    2015-10-01

    AWARD NUMBER: W81XWH-13-1-0163 TITLE: Novel Therapeutic Targets to Inhibit Tumor Microenvironment Induced Castration-resistant Prostate Cancer ...Castration-resistant Prostate Cancer 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Feng Yang, Ph.D. 5d. PROJECT NUMBER 5e. TASK...Annual Progress Report W81XWH-13-1-0163 Novel Therapeutic Targets to Inhibit Tumor Microenvironment Induced Castration-resistant Prostate Cancer

  1. Crosstalk between epithelial-mesenchymal transition and castration resistance mediated by Twist1/AR signaling in prostate cancer.

    PubMed

    Shiota, Masaki; Itsumi, Momoe; Takeuchi, Ario; Imada, Kenjiro; Yokomizo, Akira; Kuruma, Hidetoshi; Inokuchi, Junichi; Tatsugami, Katsunori; Uchiumi, Takeshi; Oda, Yoshinao; Naito, Seiji

    2015-12-01

    Although invasive and metastatic progression via the epithelial-mesenchymal transition (EMT) and acquisition of resistance to castration are both critical steps in prostate cancer, the molecular mechanism of this interaction remains unclear. In this study, we aimed to elucidate the interaction of signaling between castration resistance and EMT, and to apply this information to the development of a novel therapeutic concept using transforming growth factor-β (TGF-β) inhibitor SB525334 combined with androgen-deprivation therapy against prostate cancer using an in vivo model. This study revealed that an EMT inducer (TGF-β) induced full-length androgen receptor (AR) and AR variant expression. In addition, a highly invasive clone showed augmented full-length AR and AR variant expression as well as acquisition of castration resistance. Conversely, full-length AR and AR as well as Twist1 and mesenchymal molecules variant expression were up-regulated in castration-resistant LNCaP xenograft. Finally, TGF-β inhibitor suppressed Twist1 and AR expression as well as prostate cancer growth combined with castration. Taken together, these results demonstrate that Twist1/AR signaling was augmented in castration resistant as well as mesenchymal-phenotype prostate cancer, indicating the molecular mechanism of mutual and functional crosstalk between EMT and castration resistance, which may play a crucial role in prostate carcinogenesis and progression.

  2. Castration-resistant prostate cancer: potential targets and therapies.

    PubMed

    Parray, Aijaz; Siddique, Hifzur R; Nanda, Sanjeev; Konety, Badrinath R; Saleem, Mohammad

    2012-01-01

    The treatment landscape for patients with castration-resistant prostate cancer (CRPC) is undergoing significant changes with the advent of new therapies and multidisciplinary efforts by scientists and clinicians. As activation of multiple molecular pathways in the neoplastic prostate makes it impossible for single-target drugs to be completely effective in treating CRPC, this has led to combination therapy strategy, where several molecules involved in tumor growth and disease progression are targeted by a therapeutic regimen. In the present review, we provide an update on the molecular pathways that play an important role in the pathogenesis of CRPC and discuss the current wave of new treatments to combat this lethal disease.

  3. First Line Androgen Deprivation Therapy Duration Is Associated with the Efficacy of Abiraterone Acetate Treated Metastatic Castration-Resistant Prostate Cancer after Docetaxel

    PubMed Central

    Li, Jian-Ri; Wang, Shian-Shiang; Yang, Cheng-Kuang; Chen, Chuan-Su; Ho, Hao-Chung; Chiu, Kun-Yuan; Hung, Chi-Feng; Cheng, Chen-Li; Yang, Chi-Rei; Chen, Cheng-Che; Wang, Shu-Chi; Lin, Chia-Yen; Ou, Yen-Chuan

    2017-01-01

    Introduction: We performed a chart review study in our castration-resistant prostate cancer (CRPC) patients who received Abiraterone acetate (AA) treatment after docetaxel and identified clinical markers which can predict treatment outcome. Materials and Methods: From 2012 to 2016, 64 patients who received docetaxel after CRPC followed by AA treatment were included. Clinical parameters were recorded and analysis was performed to identify associations between pre-treatment variables and treatment outcome. Results: Thirty three patients (51.6%) achieved a decrease in PSA of 50%. The median PSA progression-free survival and overall survival in the total cohort of 64 patients were 6.6 and 24 months, respectively. Adverse events (AEs) in all grades developed in 35.9% (23/64) patients and mostly were grade 1 or 2. The most common AEs were gastric upset, hypokalemia and elevated liver function tests. Of the eight variables analyzed, first line androgen deprivation therapy (ADT) duration showed positive association to progression free survival (HR 0.98, 95% CI [0.96–0.99], p = 0.012) and overall survival (HR 0.97, 95% CI [0.94–0.99], p = 0.019). Pre-AA PSA and PSA progression ratio showed negative association only to progression free survival (HR 1.0, 95% CI [1.000–1.002], p = 0.025, HR 1.01, 95% CI [1.00–1.01], p < 0.001, respectively). Conclusion: First line ADT duration was positively associated with AA treatment efficacy in progression free survival and overall survival. It can be used as a pre-treatment predictor. PMID:28243202

  4. Olaparib With or Without Cediranib in Treating Patients With Metastatic Hormone-Resistant Prostate Cancer

    ClinicalTrials.gov

    2017-04-04

    Castration-Resistant Prostate Carcinoma; Hormone-Resistant Prostate Cancer; Metastatic Prostate Carcinoma; Prostate Adenocarcinoma With Focal Neuroendocrine Differentiation; Prostate Carcinoma Metastatic in the Bone; Prostate Small Cell Carcinoma; Stage IV Prostate Adenocarcinoma

  5. Clinical Outcomes from Androgen Signaling-directed Therapy after Treatment with Abiraterone Acetate and Prednisone in Patients with Metastatic Castration-resistant Prostate Cancer: Post Hoc Analysis of COU-AA-302.

    PubMed

    Smith, Matthew R; Saad, Fred; Rathkopf, Dana E; Mulders, Peter F A; de Bono, Johann S; Small, Eric J; Shore, Neal D; Fizazi, Karim; Kheoh, Thian; Li, Jinhui; De Porre, Peter; Todd, Mary B; Yu, Margaret K; Ryan, Charles J

    2017-03-14

    In the COU-AA-302 trial, abiraterone acetate plus prednisone significantly increased overall survival for patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). Limited information exists regarding response to subsequent androgen signaling-directed therapies following abiraterone acetate plus prednisone in patients with mCRPC. We investigated clinical outcomes associated with subsequent abiraterone acetate plus prednisone (55 patients) and enzalutamide (33 patients) in a post hoc analysis of COU-AA-302. Prostate-specific antigen (PSA) response was assessed. Median time to PSA progression was estimated using the Kaplan-Meier method. The PSA response rate (≥50% PSA decline, unconfirmed) was 44% and 67%, respectively. The median time to PSA progression was 3.9 mo (range 2.6-not estimable) for subsequent abiraterone acetate plus prednisone and 2.8 mo (range 1.8-not estimable) for subsequent enzalutamide. The majority of patients (68%) received intervening chemotherapy before subsequent abiraterone acetate plus prednisone or enzalutamide. While acknowledging the limitations of post hoc analyses and high censoring (>75%) in both treatment groups, these results suggest that subsequent therapy with abiraterone acetate plus prednisone or enzalutamide for patients who progressed on abiraterone acetate is associated with limited clinical benefit.

  6. [Peptide vaccination for castration-resistant prostate cancer].

    PubMed

    Koga, Noriko; Noguchi, Masanori

    2014-12-01

    Since both tumor cells and host immune cell repertoires are diverse and heterogeneous, immune responses against tumor associated antigens shall be substantially different among individual patients with prostate cancer. Subsequently, selection of suitable peptide vaccines for individual patients based on the pre-existing host immunity before vaccination could induce potent anti-tumor responses capable of providing clinical benefit for prostate cancer patients. We have developed a novel immunotherapeutic approach of personalized peptide vaccination (PPV) in which a maximum of four human leukocyte antigen (HLA)-class IA-matched peptides were selected for vaccination among pooled peptides based on both HLA-class IA type and the pre-existing host immunity before vaccination. We discuss our recent results of clinical studies of peptide vaccination for castration-resistant prostate cancer and the future direction of therapeutic cancer vaccines.

  7. Castration-resistant prostate cancer: latest evidence and therapeutic implications

    PubMed Central

    Suzman, Daniel L.

    2014-01-01

    Medical oncologists who treat men with castration-resistant prostate cancer (CRPC) have seen an abundance of new agents approved by the United States Food and Drug Administration in the last decade for a disease that was previously difficult to treat after becoming resistant to androgen-deprivation therapy. Advances in understanding of the mechanisms of castration-resistance and prostate cancer progression have highlighted several pathways and targets that appear promising to better treat CRPC. As the majority of CRPC appears to continue to rely on the androgen receptor for growth and progression, several of these agents directly or indirectly target the androgen receptor. A novel microtubule-targeted agent, cabazitaxel, has demonstrated an overall survival benefit following progression on docetaxel. Other agents target tumor immunogenicity and immune checkpoint pathways to attempt to harness the host immune system. The recently approved radiopharmaceutical, radium-223 dichloride, has demonstrated impressive results in patients with extensive bony metastases with minimal toxicity. Lastly, further understanding of the pathways underlying CRPC progression has led to late-phase clinical trials with the novel agents: custirsen, tasquinimod and cabozantinib. This article reviews the approved therapies for CRPC, the agents currently in late-phase clinical trials, and notable early-phase trials of novel therapies and their combinations, with particular attention to trials incorporating novel biomarkers and intermediate endpoints to better identify those men who may or may not benefit from specific therapies. PMID:25057303

  8. Therapeutic response and side effects of repeated radioligand therapy with 177Lu-PSMA-DKFZ-617 of castrate-resistant metastatic prostate cancer.

    PubMed

    Ahmadzadehfar, Hojjat; Eppard, Elisabeth; Kürpig, Stefan; Fimmers, Rolf; Yordanova, Anna; Schlenkhoff, Carl Diedrich; Gärtner, Florian; Rogenhofer, Sebastian; Essler, Markus

    2016-03-15

    Prostate-specific membrane antigen (PSMA) is highly expressed on prostate epithelial cells and strongly up-regulated in prostate cancer (PC), making it an optimal target for the treatment of metastasized PC. Radioligand therapy (RLT) with 177Lu-PSMA-DKFZ-617 (Lu-PSMA) is a targeted therapy for metastatic PC. In this study, we retrospectively analyzed the side effects and the response rate of 24 hormone and/or chemorefractory PC patients with a mean age of 75.2 years (range: 64-82) with distant metastases and progressive disease according to the PSA level, who were treated with Lu-PSMA. Median PSA was 522 ng/ml (range: 17-2360). Forty-six cycles of Lu-PSMA were performed. Of the 24 patients, 22 received two cycles. Eight weeks after the first cycle of Lu-PSMA therapy 79.1% experienced a decline in PSA level. Eight weeks after the second cycle of Lu-PSMA therapy 68.2% experienced a decline in PSA relative to the baseline value. Apart from two cases of grade 3 anemia, there was no relevant hemato- or nephrotoxicity (grade 3 or 4). These results confirmed that Lu-PSMA is a safe treatment option for metastatic PC patients and has a low toxicity profile. A positive response to therapy in terms of decline in PSA occurs in about 70% of patients.

  9. Therapeutic response and side effects of repeated radioligand therapy with 177Lu-PSMA-DKFZ-617 of castrate-resistant metastatic prostate cancer

    PubMed Central

    Ahmadzadehfar, Hojjat; Eppard, Elisabeth; Kürpig, Stefan; Fimmers, Rolf; Yordanova, Anna; Schlenkhoff, Carl Diedrich; Gärtner, Florian; Rogenhofer, Sebastian; Essler, Markus

    2016-01-01

    Prostate-specific membrane antigen (PSMA) is highly expressed on prostate epithelial cells and strongly up-regulated in prostate cancer (PC), making it an optimal target for the treatment of metastasized PC. Radioligand therapy (RLT) with 177Lu-PSMA-DKFZ-617 (Lu-PSMA) is a targeted therapy for metastatic PC. In this study, we retrospectively analyzed the side effects and the response rate of 24 hormone and/or chemorefractory PC patients with a mean age of 75.2 years (range: 64–82) with distant metastases and progressive disease according to the PSA level, who were treated with Lu-PSMA. Median PSA was 522 ng/ml (range: 17–2360). Forty-six cycles of Lu-PSMA were performed. Of the 24 patients, 22 received two cycles. Eight weeks after the first cycle of Lu-PSMA therapy 79.1% experienced a decline in PSA level. Eight weeks after the second cycle of Lu-PSMA therapy 68.2% experienced a decline in PSA relative to the baseline value. Apart from two cases of grade 3 anemia, there was no relevant hemato- or nephrotoxicity (grade 3 or 4). These results confirmed that Lu-PSMA is a safe treatment option for metastatic PC patients and has a low toxicity profile. A positive response to therapy in terms of decline in PSA occurs in about 70% of patients. PMID:26871285

  10. Novel Imidazopyridine Derivatives Possess Anti-Tumor Effect on Human Castration-Resistant Prostate Cancer Cells.

    PubMed

    Ingersoll, Matthew A; Lyons, Anastesia S; Muniyan, Sakthivel; D'Cunha, Napoleon; Robinson, Tashika; Hoelting, Kyle; Dwyer, Jennifer G; Bu, Xiu R; Batra, Surinder K; Lin, Ming-Fong

    2015-01-01

    Prostate cancer (PCa) is the second leading cause of cancer-related death afflicting United States males. Most treatments to-date for metastatic PCa include androgen-deprivation therapy and second-generation anti-androgens such as abiraterone acetate and enzalutamide. However, a majority of patients eventually develop resistance to these therapies and relapse into the lethal, castration-resistant form of PCa to which no adequate treatment option remains. Hence, there is an immediate need to develop effective therapeutic agents toward this patient population. Imidazopyridines have recently been shown to possess Akt kinase inhibitory activity; thus in this study, we investigated the inhibitory effect of novel imidazopyridine derivatives HIMP, M-MeI, OMP, and EtOP on different human castration-resistant PCa cells. Among these compounds, HIMP and M-MeI were found to possess selective dose- and time-dependent growth inhibition: they reduced castration-resistant PCa cell proliferation and spared benign prostate epithelial cells. Using LNCaP C-81 cells as the model system, these compounds also reduced colony formation as well as cell adhesion and migration, and M-MeI was the most potent in all studies. Further investigation revealed that while HIMP primarily inhibits PCa cell growth via suppression of PI3K/Akt signaling pathway, M-MeI can inhibit both PI3K/Akt and androgen receptor pathways and arrest cell growth in the G2 phase. Thus, our results indicate the novel compound M-MeI to be a promising candidate for castration-resistant PCa therapy, and future studies investigating the mechanism of imidazopyridine inhibition may aid to the development of effective anti-PCa agents.

  11. Novel Imidazopyridine Derivatives Possess Anti-Tumor Effect on Human Castration-Resistant Prostate Cancer Cells

    PubMed Central

    Muniyan, Sakthivel; D’Cunha, Napoleon; Robinson, Tashika; Hoelting, Kyle; Dwyer, Jennifer G.; Bu, Xiu R.; Batra, Surinder K.; Lin, Ming-Fong

    2015-01-01

    Prostate cancer (PCa) is the second leading cause of cancer-related death afflicting United States males. Most treatments to-date for metastatic PCa include androgen-deprivation therapy and second-generation anti-androgens such as abiraterone acetate and enzalutamide. However, a majority of patients eventually develop resistance to these therapies and relapse into the lethal, castration-resistant form of PCa to which no adequate treatment option remains. Hence, there is an immediate need to develop effective therapeutic agents toward this patient population. Imidazopyridines have recently been shown to possess Akt kinase inhibitory activity; thus in this study, we investigated the inhibitory effect of novel imidazopyridine derivatives HIMP, M-MeI, OMP, and EtOP on different human castration-resistant PCa cells. Among these compounds, HIMP and M-MeI were found to possess selective dose- and time-dependent growth inhibition: they reduced castration-resistant PCa cell proliferation and spared benign prostate epithelial cells. Using LNCaP C-81 cells as the model system, these compounds also reduced colony formation as well as cell adhesion and migration, and M-MeI was the most potent in all studies. Further investigation revealed that while HIMP primarily inhibits PCa cell growth via suppression of PI3K/Akt signaling pathway, M-MeI can inhibit both PI3K/Akt and androgen receptor pathways and arrest cell growth in the G2 phase. Thus, our results indicate the novel compound M-MeI to be a promising candidate for castration-resistant PCa therapy, and future studies investigating the mechanism of imidazopyridine inhibition may aid to the development of effective anti-PCa agents. PMID:26121643

  12. Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer

    PubMed Central

    Stoyanova, Tanya; Riedinger, Mireille; Lin, Shu; Faltermeier, Claire M.; Smith, Bryan A.; Zhang, Kelvin X.; Going, Catherine C.; Goldstein, Andrew S.; Lee, John K.; Drake, Justin M.; Rice, Meghan A.; Hsu, En-Chi; Nowroozizadeh, Behdokht; Castor, Brandon; Orellana, Sandra Y.; Blum, Steven M.; Cheng, Donghui; Pienta, Kenneth J.; Reiter, Robert E.; Pitteri, Sharon J.; Huang, Jiaoti; Witte, Owen N.

    2016-01-01

    Metastatic castration-resistant prostate cancer (CRPC) is the primary cause of prostate cancer-specific mortality. Defining new mechanisms that can predict recurrence and drive lethal CRPC is critical. Here, we demonstrate that localized high-risk prostate cancer and metastatic CRPC, but not benign prostate tissues or low/intermediate-risk prostate cancer, express high levels of nuclear Notch homolog 1, translocation-associated (Notch1) receptor intracellular domain. Chronic activation of Notch1 synergizes with multiple oncogenic pathways altered in early disease to promote the development of prostate adenocarcinoma. These tumors display features of epithelial-to-mesenchymal transition, a cellular state associated with increased tumor aggressiveness. Consistent with its activation in clinical CRPC, tumors driven by Notch1 intracellular domain in combination with multiple pathways altered in prostate cancer are metastatic and resistant to androgen deprivation. Our study provides functional evidence that the Notch1 signaling axis synergizes with alternative pathways in promoting metastatic CRPC and may represent a new therapeutic target for advanced prostate cancer. PMID:27694579

  13. Castration-resistant prostate cancer: potential targets and therapies

    PubMed Central

    Parray, Aijaz; Siddique, Hifzur R; Nanda, Sanjeev; Konety, Badrinath R; Saleem, Mohammad

    2012-01-01

    The treatment landscape for patients with castration-resistant prostate cancer (CRPC) is undergoing significant changes with the advent of new therapies and multidisciplinary efforts by scientists and clinicians. As activation of multiple molecular pathways in the neoplastic prostate makes it impossible for single-target drugs to be completely effective in treating CRPC, this has led to combination therapy strategy, where several molecules involved in tumor growth and disease progression are targeted by a therapeutic regimen. In the present review, we provide an update on the molecular pathways that play an important role in the pathogenesis of CRPC and discuss the current wave of new treatments to combat this lethal disease. PMID:22956858

  14. Investigating BRCA Mutations: A Breakthrough in Precision Medicine of Castration-Resistant Prostate Cancer.

    PubMed

    Modena, Alessandra; Iacovelli, Roberto; Scarpa, Aldo; Brunelli, Matteo; Ciccarese, Chiara; Fantinel, Emanuela; Bimbatti, Davide; Massari, Francesco; Martignoni, Guido; Tortora, Giampaolo

    2016-10-01

    Despite the development of novel effective therapeutic strategies, metastatic castration-resistant prostate cancer (mCRPC) remains a disease with a lethal course and a high biological and molecular heterogeneity. To date, germline mutations in the BRCA gene represent one of the main risk factors for developing prostate cancer, with a strong association with aggressive phenotype and poor clinical outcomes. A better understanding of the genomic landscape of prostate cancer has strengthened the idea that "synthetic lethality" of this disease might be useful in cancer-drug discovery, focusing on agents such as platinum compounds and poly (adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi). In this review, we summarize the main data available on BRCA mutations and discuss the clinical implications of these genomic aberrations in the management of prostate cancer, stressing the need to identify prognostic and predictive biomarkers and to deeply understand the mechanisms of treatment resistance, in order to maximize personalized medicine protocols and therefore clinical benefit.

  15. Immunotherapy in castration-resistant prostate cancer: integrating sipuleucel-T into our current treatment paradigm.

    PubMed

    Garcia, Jorge A; Dreicer, Robert

    2011-03-01

    The availability of several novel antibodies, coupled with viral, DNA, and dendritic-cell vaccines, has renewed interest in immunotherapeutic approaches to the treatment of advanced prostate cancer. Although promising, none of these approaches have led to major clinical activity, and in the case of cell-based immunotherapy with GVAX, new concerns about safety arose when this therapy was used in the castration-resistant setting. A more attractive yet toxic approach has also utilized a check-point blockade with CTLA-4 antibodies. Although initial clinical efficacy has been observed, toxicity appears to be the major limitation of its use in prostate cancer. Sipuleucel-T (Provenge) is an autologous active cellular immunotherapy product that includes autologous dendritic cells pulsed ex vivo with PAP2024, a recombinant fusion protein made of prostatic acid phosphataase (PAP) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Despite the lack of objective anti-tumor activity seen with sipuleucel-T, a recently reported phase III trial demonstrated a significant improvement in the overall survival of men with asymptomatic, minimally symptomatic metastatic castration-resistant prostate cancer (CRPC). This agent is the first FDA-approved novel immunotherapeutic compound for the treatment of a solid malignancy. A better understanding of how clinicians should incorporate this novel agent into the current management of CRPC is needed.

  16. Radium Ra 223 dichloride in castration-resistant prostate cancer.

    PubMed

    Joung, J Y; Ha, Y S; Kim, I Y

    2013-08-01

    Radium Ra 223 dichloride (Xofigo®, formerly Alpharadin) is one of the representative α-particle-emitting isotopes that delivers radiation with a higher biological effect to a more localized area. Preclinical studies in mouse, rat and canine models have demonstrated that radium Ra 223 dichloride has a definite skeletal affinity and antitumor effect with a relatively low toxicity on bone marrow. More recently, in a large randomized phase III trial (ALSYMPCA), patients with bone metastasis and castration-resistant prostate cancer (CRPC) received six cycles of 50 kBq/kg of radium Ra 223 dichloride in 4-week intervals. In these men, radium Ra 223 dichloride improved the median overall survival by 3.6 months when compared to the placebo group. Collectively, these results suggest that radium Ra 223 dichloride is a promising candidate for managing bone metastases in patients with CRPC.

  17. Osteoblasts promote castration-resistant prostate cancer by altering intratumoral steroidogenesis.

    PubMed

    Hagberg Thulin, Malin; Nilsson, Maria E; Thulin, Pontus; Céraline, Jocelyn; Ohlsson, Claes; Damber, Jan-Erik; Welén, Karin

    2016-02-15

    The skeleton is the preferred site for prostate cancer (PC) metastasis leading to incurable castration-resistant disease. The increased expression of genes encoding steroidogenic enzymes found in bone metastatic tissue from patients suggests that up-regulated steroidogenesis might contribute to tumor growth at the metastatic site. Because of the overall sclerotic phenotype, we hypothesize that osteoblasts regulate the intratumoral steroidogenesis of castration resistant prostate cancer (CRPC) in bone. We here show that osteoblasts alter the steroidogenic transcription program in CRPC cells, closely mimicking the gene expression pattern described in CRPC. Osteoblast-stimulated LNCaP-19 cells displayed an increased expression of genes encoding for steroidogenic enzymes (CYP11A1, HSD3B1, and AKR1C3), estrogen signaling-related genes (CYP19A1, and ESR2), and genes for DHT-inactivating enzymes (UGT2B7, UGT2B15, and UGT2B17). The observed osteoblast-induced effect was exclusive to osteogenic CRPC cells (LNCaP-19) in contrast to osteolytic PC-3 and androgen-dependent LNCaP cells. The altered steroid enzymatic pattern was specific for the intratibial tumors and verified by immunohistochemistry in tissue specimens from LNCaP-19 xenograft tumors. Additionally, the overall steroidogenic effect was reflected by corresponding levels of progesterone and testosterone in serum from castrated mice with intratibial xenografts. A bi-directional interplay was demonstrated since both proliferation and Esr2 expression of osteoblasts were induced by CRPC cells in steroid-depleted conditions. Together, our results demonstrate that osteoblasts are important mediators of the intratumoral steroidogenesis of CRPC and for castration-resistant growth in bone. Targeting osteoblasts may therefore be important in the development of new therapeutic approaches.

  18. Investigating Genomic Mechanisms of Treatment Resistance in Castration Resistant Prostate Cancer

    DTIC Science & Technology

    2015-05-01

    Prostate Cancer PRINCIPAL INVESTIGATOR: Terence W. Friedlander, MD CONTRACTING ORGANIZATION: University of California, San Francisco San...5a. CONTRACT NUMBER W81XWH-12-1-0160 Castration Resistant Prostate Cancer 5b. GRANT NUMBER PC110126 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S...mechanisms of resistance to androgen biosynthesis inhibitors in men with castration resistant prostate cancer , and to investigate clinical methods of

  19. Health Economics and Radium-223 (Xofigo®) in the Treatment of Metastatic Castration-Resistant Prostate Cancer (mCRPC): A Case History and a Systematic Review of the Literature

    PubMed Central

    Norum, Jan; Traasdahl, Erik R.; Totth, Arpad; Nieder, Carsten; Olsen, Jan Abel

    2016-01-01

    Objectives: Prostate cancer (PC) is the most common cancer in Western countries. Recent advances in the treatment of metastatic castration resistant prostate cancer (mCRPC) have caused significant pressure on health care budgets. We aimed to exemplify this dilemma presenting an example, radium-223 (Xofigo®), and review the literature. Methods: A 74-year-old man diagnosed with mCRPC was referred to our department in October 2014 for radium-223 therapy. We faced the following dilemma: is radium-223 standard therapy? Is it cost-effective? Medline was searched employing the following search criteria: “radium-223”, “alpharadin”, “Xofigo” and “prostate”. Exclusion and inclusion criteria were applied. Guidelines and cost-effectiveness analyses were focused. We also searched the websites of ASCO, ESMO and ISPOR. The web was searched, using Yahoo and Google search engines, for Health Technology Assessments (HTAs). Results: 181 publications were identified in the Medline database. Only four studies included the word “cost”, three “economics” and none “budget” in heading or abstract. None of the publications were thorough of cost analysis (cost-effectiveness, cost-utility, cost-minimizing or cost-of-illness analysis). Six HTAs and eight national guidelines were identified. The cost per quality adjusted life years was indicated €80.000-94,000. HTAs concluded reimbursement being not recommendable or no ultimate statement could be made. One pointed towards a limited use with caution. Conclusion: Guidelines were based on data from randomized clinical trials (RCTs). Health economics was not considered when guidelines were made. Most HTAs concluded this therapy not cost-effective or there was insufficient data for final conclusions. Licensing and reimbursement processes should be run simultaneously. PMID:26573043

  20. A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate Resistant Prostate Cancer

    DTIC Science & Technology

    2015-12-01

    SUPPLEMENTARY NOTES 14. ABSTRACT This is a Clinical Exploration Award funding a clinical trial for patients with metastatic, castration resistant prostate... clinical trial within this award is a phase I/II clinical trial of the GR antagonist mifepristone in combination with the FDA-approved AR antagonist...enzalutamide. The first objective is, within the context of a phase I clinical trial, to establish safe and pharmacologically active doses of the two

  1. Novel non-AR therapeutic targets in castrate resistant prostate cancer

    PubMed Central

    Toren, Paul J.

    2013-01-01

    Castrate resistant prostate cancer (CRPC) remains a disease with significant morbidity and mortality. The recent approval of abiraterone and enzalutamide highlight the improvements which can be made targeting the androgen receptor (AR) axis. Nonetheless, resistance inevitably develops and there is continued interest in targeting alternate pathways which cause disease resistance and progression. Here, we review non-AR targets in CRPC, with an emphasis on novel agents now in development. This includes therapeutics which target the tumour microenvironment, the bone metastatic environment, microtubules, cellular energetics, angiogenesis, the stress response, survival proteins, intracellular signal transduction, DNA damage repair and dendritic cells. Understanding the hallmarks of prostate cancer resistance in CRPC has led to the identification and development of these new targets. We review the molecular rationale, as well at the clinical experience for each of these different classes of agents which are in clinical development. PMID:26816739

  2. Novel therapeutic approaches for the treatment of castration-resistant prostate cancer.

    PubMed

    Heidegger, Isabel; Massoner, Petra; Eder, Iris E; Pircher, Andreas; Pichler, Renate; Aigner, Friedrich; Bektic, Jasmin; Horninger, Wolfgang; Klocker, Helmut

    2013-11-01

    Prostate cancer is a leading cause of cancer death in men in developed countries. Once the tumor has achieved a castration-refractory metastatic stage, treatment options are limited with the average survival of patients ranging from two to three years only. Recently, new drugs for treatment of castration-resistant prostate cancer (CRPC) have been approved, and others are in an advanced stage of clinical testing. In this review we provide an overview of the new therapeutic agents that arrived in the clinical praxis or are tested in clinical studies and their mode of action including hormone synthesis inhibitors, new androgen receptor blockers, bone targeting and antiangiogenic agents, endothelin receptor antagonists, growth factor inhibitors, novel radiotherapeutics and taxanes, and immunotherapeutic approaches. Results and limitations from clinical studies as well as future needs for improvement of CRPC treatments are critically discussed.

  3. The Effect of Prior Androgen Synthesis Inhibition on Outcomes of Subsequent Therapy with Docetaxel in Patients with Metastatic Castrate Resistant Prostate Cancer: Results from a Retrospective Analysis of a Randomized Phase 3 Clinical Trial (CALGB 90401) (Alliance)

    PubMed Central

    Aggarwal, Rahul; Halabi, Susan; Kelly, William Kevin; George, Daniel; Mahoney, John F.; Millard, Frederick; Stadler, Walter M.; Morris, Michael J.; Kantoff, Philip; Monk, J. Paul; Carducci, Michael; Small, Eric J.

    2013-01-01

    Background Preliminary data suggests a potential decreased benefit of docetaxel in metastatic castration-resistant prostate cancer (mCRPC) patients previously treated with abiraterone acetate, a novel androgen synthesis inhibitor (ASI). CALGB 90401 (Alliance), a phase 3 trial of mCRPC patients treated with docetaxel-based chemotherapy, offered the opportunity to evaluate effect of prior ketoconazole, an earlier generation ASI, on clinical outcomes following docetaxel. Methods CALGB 90401 randomized 1050 men with chemotherapy-naïve, mCRPC to treatment with docetaxel and prednisone with either bevacizumab or placebo. 1005 men (96%) had data available regarding prior ketoconazole therapy. The effect of prior ketoconazole on overall survival (OS), progression-free survival (PFS), PSA decline, and objective response rate (ORR) observed was assessed using proportional hazards and Poisson regression method adjusted for validated prognostic factors and treatment arm. Results Baseline characteristics between patients with (N=277) and without (N=728) prior ketoconazole therapy were similar. There were no statistically significant differences between patients with and without prior ketoconazole therapy with respect to OS (median OS 21.1 vs. 22.3 months, stratified log-rank p-value=0.635); PFS (median PFS 8.1 vs. 8.6 months, stratified log-rank p-value=0.342); ≥50% PSA decline (61% vs. 66%, relative risk=1.09, adjusted p-value=0.129); or ORR (39% vs. 43%, relative risk=1.11, adjusted p-value=0.366). Conclusions As measured by OS, PFS, PSA and ORR, there is no evidence that prior treatment with ketoconazole impacts clinical outcomes in mCRPC patients treated with subsequent docetaxel-based therapy. Prospective studies are needed to assess for potential cross-resistance with novel ASIs and to define the optimal sequence of therapy in mCRPC. PMID:23913744

  4. Phase I/II clinical trial of dendritic-cell based immunotherapy (DCVAC/PCa) combined with chemotherapy in patients with metastatic, castration-resistant prostate cancer

    PubMed Central

    Becht, Etienne; Rozkova, Daniela; Bilkova, Pavla; Sochorova, Klara; Hromadkova, Hana; Kayserova, Jana; Vavrova, Katerina; Lastovicka, Jan; Vrabcova, Petra; Kubackova, Katerina; Gasova, Zdenka; Jarolim, Ladislav; Babjuk, Marek; Spisek, Radek; Bartunkova, Jirina; Fucikova, Jitka

    2015-01-01

    Purpose We conducted an open-label, single-arm Phase I/II clinical trial in metastatic CRPC (mCRPC) patients eligible for docetaxel combined with treatment with autologous mature dendritic cells (DCs) pulsed with killed LNCaP prostate cancer cells (DCVAC/PCa). The primary and secondary endpoints were safety and immune responses, respectively. Overall survival (OS), followed as a part of the safety evaluation, was compared to the predicted OS according to the Halabi and MSKCC nomograms. Experimental design Twenty-five patients with progressive mCRPC were enrolled. Treatment comprised of initial 7 days administration of metronomic cyclophosphamide 50 mg p.o. DCVAC/PCa treatment consisted of a median twelve doses of 1 × 107 dendritic cells per dose injected s.c. (Aldara creme was applied at the site of injection) during a one-year period. The initial 2 doses of DCVAC/PCa were administered at a 2-week interval, followed by the administration of docetaxel (75 mg/m2) and prednisone (5 mg twice daily) given every 3 weeks until toxicity or intolerance was observed. The DCVAC/PCa was then injected every 6 weeks up to the maximum number of doses manufactured from one leukapheresis. Results No serious DCVAC/PCa-related adverse events have been reported. The median OS was 19 months, whereas the predicted median OS was 11.8 months with the Halabi nomogram and 13 months with the MSKCC nomogram. Kaplan-Meier analyses showed that patients had a lower risk of death compared with both MSKCC (Hazard Ratio 0.26, 95% CI: 0.13–0.51) and Halabi (Hazard Ratio 0.33, 95% CI: 0.17–0.63) predictions. We observed a significant decrease in Tregs in the peripheral blood. The long-term administration of DCVAC/PCa led to the induction and maintenance of PSA specific T cells. We did not identify any immunological parameter that significantly correlated with better OS. Conclusions In patients with mCRPC, the combined chemoimmunotherapy with DCVAC/PCa and docetaxel was safe and resulted in

  5. Abiraterone Improves Survival in Metastatic Prostate Cancer

    Cancer.gov

    A multinational phase III trial found that the drug abiraterone acetate prolonged the median survival of patients with metastatic castration-resistant prostate cancer by 4 months compared with patients who received a placebo.

  6. 68Ga-PSMA-11 PET Represents the Tumoricidal Effect of 223Ra in a Patient With Castrate-Resistant Metastatic Prostate Cancer.

    PubMed

    Ahmadzadehfar, Hojjat; Schlenkhoff, Carl Diedrich; Rogenhofer, Sebastian; Yordanova, Anna; Essler, Markus

    2016-09-01

    A 64-year-old man with prostate cancer and an increasing prostate-specific antigen (PSA) level under therapy with abiraterone acetate underwent a therapy with Ra. Before the first therapy and 4 weeks after the last cycle, the patient underwent Ga-PSMA PET, which showed a clear response of bone metastases.

  7. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial

    PubMed Central

    Kwon, Eugene D; Drake, Charles G; Scher, Howard I; Fizazi, Karim; Bossi, Alberto; van den Eertwegh, Alfons J M; Krainer, Michael; Houede, Nadine; Santos, Ricardo; Mahammedi, Hakim; Ng, Siobhan; Maio, Michele; Franke, Fabio A; Sundar, Santhanam; Agarwal, Neeraj; Bergman, Andries M; Ciuleanu, Tudor E; Korbenfeld, Ernesto; Sengeløv, Lisa; Hansen, Steinbjorn; Logothetis, Christopher; Beer, Tomasz M; McHenry, M Brent; Gagnier, Paul; Liu, David; Gerritsen, Winald R

    2015-01-01

    Summary Background Ipilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel chemotherapy. Methods We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one fraction) followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly assigned to either treatment group via a minimisation algorithm, and stratified by Eastern Cooperative Oncology Group performance status, alkaline phosphatase concentration, haemoglobin concentration, and investigator site. Patients and investigators were masked to treatment allocation. The primary endpoint was overall survival, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00861614. Findings From May 26, 2009, to Feb 15, 2012, 799 patients were randomly assigned (399 to ipilimumab and 400 to placebo), all of whom were included in the intention-to-treat analysis. Median overall survival was 11·2 months (95% CI 9·5–12·7) with ipilimumab and 10·0 months (8·3–11·0) with placebo (hazard ratio [HR] 0·85, 0·72–1·00; p=0·053). However, the assessment of the proportional hazards assumption showed that it was violated (p=0·0031). A piecewise hazard model showed that the HR changed over time: the HR for 0–5 months was 1·46 (95% CI 1·10–1·95), for 5–12 months was 0·65 (0·50–0·85), and

  8. Metastasis Initiating Cells in Primary Prostate Cancer Tissues From Transurethral Resection of the Prostate (TURP) Predicts Castration-Resistant Progression and Survival of Prostate Cancer Patients

    PubMed Central

    Li, Qinlong; Li, Quanlin; Nuccio, Jill; Liu, Chunyan; Duan, Peng; Wang, Ruoxiang; Jones, Lawrence W.; Chung, Leland W. K.; Zhau, Haiyen E.

    2016-01-01

    BACKGROUND We previouslyreported that the activation of RANK and c-Met signaling components in both experimental mouse models and human prostate cancer (PC) specimens predicts bone metastatic potential and PC patient survival. This study addresses whether a population of metastasis-initiating cells (MICs) known to express a stronger RANKL, phosphorylated c-Met (p-c-Met), and neuropilin-1 (NRP1) signaling network than bystander or dormant cells (BDCs) can be detected in PC tissues from patients subjected to transurethral resection of the prostate (TURP) for urinary obstruction prior to the diagnosis of PC with or without prior hormonal manipulation, and whether the relative abundance of MICs over BDCs could predict castration-resistant progression and PC patient survival. METHODS We employed a multiplexed quantum-dot labeling (mQDL) protocol to detect and quantify MICs and BDCs at the single cell level in TURP tissues obtained from 44 PC patients with documented overall survival and castration resistance status. RESULTS PC tissues with a higher number of MICs and an activated RANK signaling network, including increased expression of RANKL, p-c-Met, and NRP1 compared to BDCs, were found to correlate with the development of castration resistance and overall survival. CONCLUSIONS The assessment of PC cells with MIC and BDC phenotypes in primary PC tissues from hormone-naïve patients can predict the progression to castration resistance and the overall survival of PC patients. PMID:25990623

  9. A Novel Role for Raloxifene Nanomicelles in Management of Castrate Resistant Prostate Cancer

    PubMed Central

    Rosengren, Rhonda J.; Greish, Khaled

    2014-01-01

    Of patients with castrate resistant prostate cancer (CRPC), less than 25–33% survive more than five years. Recent studies have implicated estrogen, acting either alone or synergistically with androgens in the development of castrate resistant prostate cancer. Several in vitro and in vivo studies, as well as a limited number of clinical trials, have highlighted the potential of selective estrogen receptor modulators, such as raloxifene (Ral) for the treatment of castrate resistant prostate cancer. However, the poor oral bioavailability and metabolism of selective estrogen receptor modulators limit their efficiency in clinical application. To overcome these limitations, we have used styrene co-maleic acid (SMA) micelle to encapsulate raloxifene. Compared to free drug, SMA-Ral micelles had 132 and 140% higher cytotoxicity against PC3 and DU 145 prostate cell lines, respectively. SMA-Ral effectively inhibits cell cycle progression, increases apoptosis, and alters the integrity of tumor spheroid models. In addition, the micellar system induced changes in expression and localization of estrogen receptors, epidermal growth factor receptor (EGFR), and downstream effectors associated with cell proliferation and survival. Finally, SMA-Ral treatment decreased migration and invasion of castrate resistant prostate cancer cell lines. In conclusion, SMA-Ral micelles can potentially benefit new strategies for clinical management of castrate resistant prostate cancer. PMID:24689036

  10. Sox2 Is an Androgen Receptor-Repressed Gene That Promotes Castration-Resistant Prostate Cancer

    PubMed Central

    Kregel, Steven; Kiriluk, Kyle J.; Rosen, Alex M.; Cai, Yi; Reyes, Edwin E.; Otto, Kristen B.; Tom, Westin; Paner, Gladell P.; Szmulewitz, Russell Z.; Vander Griend, Donald J.

    2013-01-01

    Despite advances in detection and therapy, castration-resistant prostate cancer continues to be a major clinical problem. The aberrant activity of stem cell pathways, and their regulation by the Androgen Receptor (AR), has the potential to provide insight into novel mechanisms and pathways to prevent and treat advanced, castrate-resistant prostate cancers. To this end, we investigated the role of the embryonic stem cell regulator Sox2 [SRY (sex determining region Y)-box 2] in normal and malignant prostate epithelial cells. In the normal prostate, Sox2 is expressed in a portion of basal epithelial cells. Prostate tumors were either Sox2-positive or Sox2-negative, with the percentage of Sox2-positive tumors increasing with Gleason Score and metastases. In the castration-resistant prostate cancer cell line CWR-R1, endogenous expression of Sox2 was repressed by AR signaling, and AR chromatin-IP shows that AR binds the enhancer element within the Sox2 promoter. Likewise, in normal prostate epithelial cells and human embryonic stem cells, increased AR signaling also decreases Sox2 expression. Resistance to the anti-androgen MDV3100 results in a marked increase in Sox2 expression within three prostate cancer cell lines, and in the castration-sensitive LAPC-4 prostate cancer cell line ectopic expression of Sox2 was sufficient to promote castration-resistant tumor formation. Loss of Sox2 expression in the castration-resistant CWR-R1 prostate cancer cell line inhibited cell growth. Up-regulation of Sox2 was not associated with increased CD133 expression but was associated with increased FGF5 (Fibroblast Growth Factor 5) expression. These data propose a model of elevated Sox2 expression due to loss of AR-mediated repression during castration, and consequent castration-resistance via mechanisms not involving induction of canonical embryonic stem cell pathways. PMID:23326489

  11. Development of a New Class of Drugs to Inhibit All Forms of Androgen Receptor in Castration-Resistant Prostate Cancers

    DTIC Science & Technology

    2015-10-01

    AWARD NUMBERS: W81XWH-14-1-0519 TITLE: Development of a New Class of Drugs to Inhibit All Forms of Androgen Receptor in Castration-Resistant...of Drugs to Inhibit All Forms of Androgen Receptor in Castration-Resistant Prostate Cancers 5b. GRANT NUMBER W81XWH-14- 1-0519 5c. PROGRAM...castration. However, despite a growing armamentarium of drugs targeting the androgen/AR signaling axis, progression of castration-resistant prostate

  12. Current treatments and novel therapeutic targets for castration resistant prostate cancer with bone metastasis

    PubMed Central

    Wei, Juncheng; Wang, Zhilin; Makarov, Danil; Li, Xin

    2013-01-01

    Prostate cancer is a leading cause of cancer death in men in developed countries. While early stage disease can often be cured, many patients eventually develop castration resistant prostate cancer (CRPC). The majority of CRPC patients have bone metastases, which cause significant morbidity and mortality. Although there is no cure for prostate cancer metastatic to bone, several bone-targeted agents have been approved to prevent skeletal-related events (SREs). Among them, bisphosphonates were the first class of drugs investigated for prevention of SREs. Denosumab is a recently approved agent that binds to the receptor activator of nuclear factor-κB ligand (RANKL) as a humanized monoclonal antibody. Both agents target prostate cancer skeletal metastasis through the inhibition of bone resorption. Alpharadin is the first radiopharmaceutical agent that has significant overall survival benefit. It has benefits in pain palliation and SREs as well. Another newly approved drug is Abiraterone acetate, which decreases circulating levels of testosterone by targeting an enzyme expressed in the testis and the adrenal, as well as in prostate cancer tissues. This review outlines the clinical and preclinical data supporting the use of these and new agents in development for CRPC with bone metastasis. PMID:25374898

  13. Castration Resistance in Prostate Cancer Is Mediated by the Kinase NEK6. | Office of Cancer Genomics

    Cancer.gov

    In prostate cancer, the development of castration resistance is pivotal in progression to aggressive disease. However, understanding of the pathways involved remains incomplete. In this study, we performed a high-throughput genetic screen to identify kinases that enable tumor formation by androgen-dependent prostate epithelial (LHSR-AR) cells under androgen-deprived conditions.

  14. Estrogen related receptor alpha in castration-resistant prostate cancer cells promotes tumor progression in bone

    PubMed Central

    Delliaux, Carine; Gervais, Manon; Kan, Casina; Benetollo, Claire; Pantano, Francesco; Vargas, Geoffrey; Bouazza, Lamia; Croset, Martine; Bala, Yohann; Leroy, Xavier; Rosol, Thomas J; Rieusset, Jennifer; Bellahcène, Akeila; Castronovo, Vincent; Aubin, Jane E; Clézardin, Philippe; Duterque-Coquillaud, Martine; Bonnelye, Edith

    2016-01-01

    Bone metastases are one of the main complications of prostate cancer and they are incurable. We investigated whether and how estrogen receptor-related receptor alpha (ERRα) is involved in bone tumor progression associated with advanced prostate cancer. By meta-analysis, we first found that ERRα expression is correlated with castration-resistant prostate cancer (CRPC), the hallmark of progressive disease. We then analyzed tumor cell progression and the associated signaling pathways in gain-of-function/loss-of-function CRPC models in vivo and in vitro. Increased levels of ERRα in tumor cells led to rapid tumor progression, with both bone destruction and formation, and direct impacts on osteoclasts and osteoblasts. VEGF-A, WNT5A and TGFβ1 were upregulated by ERRα in tumor cells and all of these factors also significantly and positively correlated with ERRα expression in CRPC patient specimens. Finally, high levels of ERRα in tumor cells stimulated the pro-metastatic factor periostin expression in the stroma, suggesting that ERRα regulates the tumor stromal cell microenvironment to enhance tumor progression. Taken together, our data demonstrate that ERRα is a regulator of CRPC cell progression in bone. Therefore, inhibiting ERRα may constitute a new therapeutic strategy for prostate cancer skeletal-related events. PMID:27776343

  15. The role of MicroRNA in castration resistant prostate cancer

    PubMed Central

    de Vere White, Ralph; Evans, Christopher P.

    2015-01-01

    Introduction Castration resistant prostate cancer (CRPC) has a historically low median survival rate but recent advances and discoveries in micro RNAs (miRNAs) have opened the potential for new prognostication modalities to enhance therapeutic success. As new chemotherapies and immunotherapies are developed there is an increasing need for precision and stratification of CRPC to allow for optimization and personalization of therapy. Methods A systematic literature review was conducted via electronic database resulting in the selection of forty-two articles based on title, abstract, study format, and content by a consensus of all participating authors. The majority of selected articles were published between 2002 and 2013. In this review, we will discuss the robustness of miRNAs as a biomarker platform, miRNAs associated with prostate cancer, and recent discoveries of miRNA associations with CRPC. Results The associations discovered have been of interest due to the ability to differentiate between CRPC and localized prostate cancer. With evaluation of multiple miRNAs, it is possible to provide a profile in regards to tumor characteristics. Furthermore, actions of miRNAs on CRPC tumor cells have the ability to suppress metastatic phenotypes. Conclusion miRNAs may have a growing role in CRPC prognostication and potentially transform into a therapeutic potential. PMID:24935732

  16. Antiproliferative activity of novel imidazopyridine derivatives on castration-resistant human prostate cancer cells

    PubMed Central

    Muniyan, Sakthivel; Chou, Yu-Wei; Ingersoll, Matthew A.; Devine, Alexus; Morris, Marisha; Odero-Marah, Valerie A.; Khan, Shafiq A.; Chaney, William G.; Bu, Xiu R.; Lin, Ming-Fong

    2014-01-01

    Metastatic prostate cancer (mPCa) relapses after a short period of androgen deprivation therapy and becomes the castration-resistant prostate cancer (CR PCa); to which the treatment is limited. Hence, it is imperative to identify novel therapeutic agents towards this patient population. In the present study, antiproliferative activities of novel imidazopyridines were compared. Among three derivatives, PHE, AMD and AMN, examined, AMD showed the highest inhibitory activity on LNCaP C-81 cell proliferation, following dose- and time-dependent manner. Additionally, AMD exhibited significant antiproliferative effect against a panel of PCa cells, but not normal prostate epithelial cells. Further, when compared to AMD, its derivative DME showed higher inhibitory activities on PCa cell proliferation, clonogenic potential and in vitro tumorigenicity. The inhibitory activity was apparently in part due to the induction of apoptosis. Mechanistic studies indicate that AMD and DME treatments inhibited both AR and PI3K/Akt signaling. The results suggest that better understanding of inhibitory mechanisms of AMD and DME could help design novel therapeutic agents for improving the treatment of CR PCa. PMID:25050738

  17. Targeting the androgen receptor in the management of castration-resistant prostate cancer: rationale, progress, and future directions

    PubMed Central

    Leibowitz–Amit, R.; Joshua, A.M.

    2012-01-01

    Since the year 2000, tremendous progress has been made in the understanding of castration-resistant prostate cancer (crpc), a disease state now recognized to retain androgen receptor (ar)—dependency in most cases. That understanding led to the rational design of novel therapeutic agents targeting hormonal pathways in metastatic crpc. Two new drugs—the CYP17 inhibitor abiraterone acetate and the potent ar antagonist enzalutamide—were recently shown to prolong overall survival after chemotherapy treatment in patients with metastatic disease, with the former agent also demonstrating impressive activity in the pre-chemotherapy setting. Other new drugs targeting the ar—as well as drugs targeting heat shock proteins that protect cytoplasmic ar from degradation—are currently undergoing clinical development. This review briefly describes the molecular mechanisms underlying castration resistance and hormonal dependence in prostate tumours and summarizes the current ongoing and completed clinical trials that are targeting hormonal pathways in metastatic crpc. Potential mechanisms of resistance to these novel hormonal agents are reviewed. Finally, future research directions, including questions about drug sequencing and combination, are discussed. PMID:23355790

  18. Biomarkers for Taxane Sensitivity and Hormonal Resistance in Patients with Castration Resistant Prostate Cancer

    DTIC Science & Technology

    2016-04-01

    Prostate Cancer PRINCIPAL INVESTIGATOR: R. Bruce Montgomery, MD CONTRACTING ORGANIZATION: University of Washington Seattle, WA REPORT DATE: April 2016...Resistant Prostate Cancer 5b. GRANT NUMBER W81XWH-14-1-0017 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER Robert Bruce Montgomery, Stephen...variant, circulating tumor cells, castration resistant prostate cancer 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF

  19. Dual-Targeting of AR and Akt Pathways by Berberine in Castration-Resistant Prostate Cancer

    DTIC Science & Technology

    2013-08-01

    Berberine in Castration-Resistant Prostate Cancer PRINCIPAL INVESTIGATOR: Haitao Zhang CONTRACTING ORGANIZATION: Tulane University...Resistant Prostate Cancer 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER Haitao Zhang 5e. TASK NUMBER...had no adverse effects on normal organs. Since Pten loss or inactivation is common in prostate cancer , these results provide support for the use

  20. Serum biomarkers of bone metabolism in castration resistant prostate cancer patients with skeletal metastases

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background. Prior studies suggest that elevated markers of bone turnover are prognostic for poor survival in castration resistant prostate cancer (CRPC). The predictive role of these markers relative to bone-targeted therapy is unknown. We prospectively evaluated the prognostic and predictive value ...

  1. Stilbenes inhibit androgen receptor expression in 22Rv1 castrate-resistant prostate cancer cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Androgen receptor (AR) signaling plays an important role in the development and progression of prostate cancer (PCa). Importantly, AR continues to be expressed in advanced stages of castrate-resistant PCa (CRPC), where it can have ligand- independent activity. Identification of naturally occurring s...

  2. Excellent Response to 177Lu-PSMA-617 Radioligand Therapy in a Patient With Advanced Metastatic Castration Resistant Prostate Cancer Evaluated by 68Ga-PSMA PET/CT.

    PubMed

    Roll, Wolfgang; Bode, Axel; Weckesser, Matthias; Bögemann, Martin; Rahbar, Kambiz

    2017-02-01

    Recently radiolabeled ligands targeting prostate specific membrane antigen (PSMA) have been introduced for diagnostics and treatment of prostate cancer. Labeled with Lutetium, PSMA radioligand therapy (RLT) is one of the most promising new treatments of metastatic castration refractory prostate cancer. We present images of Ga-PSMA PET/CT and parameters of response of a 75-year-old heavily pretreated metastatic castration refractory prostate cancer patient with extended bone metastases, showing an extraordinary biochemical response in PSA-levels concordant to SUV decline in bone metastases. Furthermore, this case shows that CT is of no use in assessing response in bone metastases of prostate cancer.

  3. Therapeutic Targeting of BET Bromodomain Proteins in Castration-Resistant Prostate Cancer

    PubMed Central

    Asangani, Irfan A.; Dommeti, Vijaya L.; Wang, Xiaoju; Malik, Rohit; Cieslik, Marcin; Yang, Rendong; Escara-Wilke, June; Wilder-Romans, Kari; Dhanireddy, Sudheer; Engelke, Carl; Iyer, Mathew K.; Jing, Xiaojun; Wu, Yi-Mi; Cao, Xuhong; Qin, Zhaohui S.; Wang, Shaomeng; Feng, Felix Y.; Chinnaiyan, Arul M.

    2014-01-01

    Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. The development and progression to CRPC following androgen ablation therapy is predominantly driven by unregulated androgen receptor (AR) signaling1-3. Despite the success of recently approved therapies targeting AR signaling such as abiraterone4-6 and second generation anti-androgens MDV3100 (enzalutamide)7,8, durable responses are limited, presumably due to acquired resistance. Recently JQ1 and I-BET, two selective small molecule inhibitors that target the amino-terminal bromodomains of BRD4, have been shown to exhibit anti-proliferative effects in a range of malignancies9-12. Here we show that AR signaling-competent CRPC cell lines are preferentially sensitive to BET bromodomain inhibition. BRD4 physically interacts with the N-terminal domain of AR and can be disrupted by JQ111,13. Like the direct AR antagonist, MDV3100, JQ1 disrupted AR recruitment to target gene loci. In contrast to MDV3100, JQ1 functions downstream of AR, and more potently abrogated BRD4 localization to AR target loci and AR-mediated gene transcription including induction of TMPRSS2-ERG and its oncogenic activity. In vivo, BET bromodomain inhibition was more efficacious than direct AR antagonism in CRPC xenograft models. Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in advanced prostate cancer. PMID:24759320

  4. Radium-223 for the treatment of castration-resistant prostate cancer

    PubMed Central

    El-Amm, Joelle; Aragon-Ching, Jeanny B

    2015-01-01

    The vast majority of patients with metastatic castration-resistant prostate cancer (mCRPC) develop bone metastases. Bone metastases are a source of significant morbidity and affect quality of life in these patients. Several bone-targeting agents are approved for the treatment of bone metastases in prostate cancer, including bisphosphonates, denosumab, and radiopharmaceuticals. Radium-223 is a novel first-in-class alpha-emitting radiopharmaceutical that has been approved for treatment of patients with mCRPC with bone metastases. Radium-223 delivers cytotoxic radiation to the sites of bone metastases and offers the advantage of minimal myelosuppression. The landmark Phase III ALSYMPCA trial demonstrated that, in addition to providing bone-related palliation, radium-223 can also prolong overall survival in patients with mCRPC with bone metastases in the absence of visceral metastases and in the absence of lymphadenopathy greater than 3 cm. Ongoing trials will further elucidate its use in sequence or combination with other available therapies for mCRPC. PMID:26056474

  5. Abiraterone in the management of castration-resistant prostate cancer prior to chemotherapy.

    PubMed

    Gartrell, Benjamin A; Saad, Fred

    2015-08-01

    The treatment armamentarium for metastatic castration-resistant prostate cancer (mCRPC) has increased significantly over the past several years. Approved drugs associated with improved survival include androgen pathway-targeted agents (abiraterone acetate and enzalutamide), chemotherapeutics (docetaxel and cabazitaxel), an autologous vaccine (sipuleucel-T) and a radiopharmaceutical (radium-223). Abiraterone acetate, a prodrug of abiraterone, inhibits the CYP17A enzyme, a critical enzyme in androgen biosynthesis. Abiraterone has regulatory approval in mCRPC in both chemotherapy-naïve patients and in the post-docetaxel setting based on results from two randomized phase III studies. In the COU-AA-302 trial, abiraterone demonstrated significant improvement in the coprimary endpoints of radiographic progression-free survival and overall survival, as well as in a number of secondary endpoints including time until initiation of chemotherapy, time until opiate use for cancer-related pain, prostate-specific antigen progression-free survival and decline in performance status. Abiraterone is well-tolerated, although adverse events associated with this agent include abnormalities in liver function testing and mineralocorticoid-associated adverse events. This review evaluates the use of abiraterone in mCRPC prior to the use of chemotherapy.

  6. A profile of enzalutamide for the treatment of advanced castration resistant prostate cancer

    PubMed Central

    Greasley, Rosa; Khabazhaitajer, Mohammad; Rosario, Derek J

    2015-01-01

    Recent advances in understanding the mechanisms underlying the development and progression of castration resistant prostate cancer from androgen-sensitive prostate cancer have provided new avenues exploring efficacious therapies in a disease which is the second leading cause of cancer deaths among men in the western world. In the evolution of second generation anti-androgens, enzalutamide, a novel androgen-receptor signaling inhibitor, has emerged targeting multiple steps within the androgenic stimulation pathway. This review discusses what is currently known of the mechanisms surrounding castration resistant prostate cancer development and the current human clinical trials to determine whether enzalutamide presents a new hope for men with advanced prostate cancer. The issues of therapy resistance, withdrawal effects and cross-resistance are briefly touched upon. PMID:26109877

  7. MiR-146-SIAH2-AR Signaling in Castration-Resistant Prostate Cancer

    DTIC Science & Technology

    2015-09-01

    clinical response and PCa patients invariably relapse with more aggressive Castration-Resistant Prostate Cancer (CRPC). The mechanism of CRPC development...blocks AR-signaling often fails after significant initial clinical response and PCa patients invariably relapse with more aggressive form of PCa...phenotype, which may result in more 5 aggressive prostate cancers. In summary, our in vitro data suggest that miR-146a-SIAH2-AR signaling may play a

  8. Acquired resistance to the second-generation androgen receptor antagonist enzalutamide in castration-resistant prostate cancer

    PubMed Central

    Kregel, Steven; Chen, James L.; Tom, Westin; Krishnan, Venkatesh; Kach, Jacob; Brechka, Hannah; Fessenden, Tim B.; Isikbay, Masis; Paner, Gladell P.

    2016-01-01

    Enzalutamide (MDV3100) is a second generation Androgen Receptor (AR) antagonist with proven efficacy in the treatment of castration resistant prostate cancer (CRPC). The majority of treated patients, however, develop resistance and disease progression and there is a critical need to identify novel targetable pathways mediating resistance. The purpose of this study was to develop and extensively characterize a series of enzalutamide-resistant prostate cancer cell lines. Four genetically distinct AR-positive and AR-pathway dependent prostate cancer cell lines (CWR-R1, LAPC-4, LNCaP, VCaP) were made resistant to enzalutamide by long-term culture (> 6 months) in enzalutamide. Extensive characterization of these lines documented divergent in vitro growth characteristics and AR pathway modulation. Enzalutamide-resistant LNCaP and CWR-R1 cells, but not LAPC-4 and VCAP cells, demonstrated increased castration-resistant and metastatic growth in vivo. Global gene expression analyses between short-term enzalutamide treated vs. enzalutamide-resistant cells identified both AR pathway and non-AR pathway associated changes that were restored upon acquisition of enzalutamide resistance. Further analyses revealed very few common gene expression changes between the four resistant cell lines. Thus, while AR-mediated pathways contribute in part to enzalutamide resistance, an unbiased approach across several cell lines demonstrates a greater contribution toward resistance via pleiotropic, non-AR mediated mechanisms. PMID:27036029

  9. A combination of sorafenib and nilotinib reduces the growth of castrate-resistant prostate cancer

    PubMed Central

    Archibald, Monica; Pritchard, Tara; Nehoff, Hayley; Rosengren, Rhonda J; Greish, Khaled; Taurin, Sebastien

    2016-01-01

    Castrate-resistant prostate cancer (CRPC) remains incurable due to the lack of effective therapies. Several tyrosine kinases have been implicated in the development and growth of CRPC, as such targeting these kinases may offer an alternative therapeutic strategy. We established the combination of two tyrosine kinase inhibitors (TKIs), sorafenib and nilotinib, as the most cytotoxic. In addtion, to improve their bioavailability and reduce their metabolism, we encapsulated sorafenib and nilotinib into styrene-co-maleic acid micelles. The micelles’ charge, size, and release rate were characterized. We assessed the effect of the combination on the cytotoxicity, cell cycle, apoptosis, protein expression, tumor spheroid integrity, migration, and invasion. The micelles exhibited a mean diameter of 100 nm, a neutral charge, and appeared highly stable. The micellar TKIs promoted greater cytotoxicity, decreased cell proliferation, and increased apoptosis relative to the free TKIs. In addition, the combination reduced the expression and activity of several tyrosine kinases and reduced tumor spheroid integrity and metastatic potential of CRPC cell lines more efficiently than the single treatments. The combination increased the therapeutic potential and demonstrated the relevance of a targeted combination therapy for the treatment of CRPC. In addition, the efficacy of the encapsulated drugs provides the basis for an in vivo preclinical testing. PMID:26811677

  10. Sortilin Regulates Progranulin Action in Castration-Resistant Prostate Cancer Cells

    PubMed Central

    Tanimoto, Ryuta; Morcavallo, Alaide; Terracciano, Mario; Xu, Shi-Qiong; Stefanello, Manuela; Buraschi, Simone; Lu, Kuojung G.; Bagley, Demetrius H.; Gomella, Leonard G.; Scotlandi, Katia; Belfiore, Antonino; Iozzo, Renato V.

    2015-01-01

    The growth factor progranulin is as an important regulator of transformation in several cellular systems. We have previously demonstrated that progranulin acts as an autocrine growth factor and stimulates motility, proliferation, and anchorage-independent growth of castration-resistant prostate cancer cells, supporting the hypothesis that progranulin may play a critical role in prostate cancer progression. However, the mechanisms regulating progranulin action in castration-resistant prostate cancer cells have not been characterized. Sortilin, a single-pass type I transmembrane protein of the vacuolar protein sorting 10 family, binds progranulin in neurons and negatively regulates progranulin signaling by mediating progranulin targeting for lysosomal degradation. However, whether sortilin is expressed in prostate cancer cells and plays any role in regulating progranulin action has not been established. Here, we show that sortilin is expressed at very low levels in castration-resistant PC3 and DU145 cells. Significantly, enhancing sortilin expression in PC3 and DU145 cells severely diminishes progranulin levels and inhibits motility, invasion, proliferation, and anchorage-independent growth. In addition, sortilin overexpression negatively modulates Akt (protein kinase B, PKB) stability. These results are recapitulated by depleting endogenous progranulin in PC3 and DU145 cells. On the contrary, targeting sortilin by short hairpin RNA approaches enhances progranulin levels and promotes motility, invasion, and anchorage-independent growth. We dissected the mechanisms of sortilin action and demonstrated that sortilin promotes progranulin endocytosis through a clathrin-dependent pathway, sorting into early endosomes and subsequent lysosomal degradation. Collectively, these results point out a critical role for sortilin in regulating progranulin action in castration-resistant prostate cancer cells, suggesting that sortilin loss may contribute to prostate cancer progression

  11. Targeting Taxanes to Castration-Resistant Prostate Cancer Cells by Nanobubbles and Extracorporeal Shock Waves

    PubMed Central

    Argenziano, Monica; Cavalli, Roberta; Sassi, Francesca; D’Amelio, Patrizia; Battaglia, Antonino; Gontero, Paolo; Bosco, Ornella; Peluso, Rossella; Fortunati, Nicoletta; Frairia, Roberto; Catalano, Maria Graziella

    2016-01-01

    To target taxanes to castration-resistant prostate cancer cells, glycol-chitosan nanobubbles loaded with paclitaxel and docetaxel were constructed. The loaded nanobubbles were then combined with Extracorporeal Shock Waves, acoustic waves widely used in urology and orthopedics, with no side effects. Nanobubbles, with an average diameter of 353.3 ± 15.5 nm, entered two different castration-resistant prostate cancer cells (PC3 and DU145) as demonstrated by flow cytometry and immunofluorescence. The shock waves applied increased the amount of intracellular nanobubbles. Loading nanobubbles with paclitaxel and docetaxel and combining them with shock waves generated the highest cytotoxic effects, resulting in a paclitaxel GI50 reduction of about 55% and in a docetaxel GI50 reduction of about 45% respectively. Combined treatment also affected cell migration. Paclitaxel-loaded nanobubbles and shock waves reduced cell migration by more than 85% with respect to paclitaxel alone; whereas docetaxel-loaded nanobubbles and shock waves reduced cell migration by more than 82% with respect to docetaxel alone. The present data suggest that nanobubbles can act as a stable taxane reservoir in castration-resistant prostate cancer cells and shock waves can further increase drug release from nanobubbles leading to higher cytotoxic and anti-migration effect. PMID:28002459

  12. Crosstalk between RON and androgen receptor signaling in the development of castration resistant prostate cancer

    PubMed Central

    Batth, Izhar; Yun, Huiyoung; Hussain, Suleman; Meng, Peng; Osumulski, Powel; Huang, Tim Hui-Ming; Bedolla, Roble; Profit, Amanda; Reddick, Robert; Kumar, Addanki

    2016-01-01

    Castrate-resistant prostate cancer (CRPC) is the fatal form of prostate cancer. Although reactivation of androgen receptor (AR) occurs following androgen deprivation, the precise mechanism involved is unclear. Here we show that the receptor tyrosine kinase, RON alters mechanical properties of cells to influence epithelial to mesenchymal transition and functions as a transcription factor to differentially regulate AR signaling. RON inhibits AR activation and subset of AR-regulated transcripts in androgen responsive LNCaP cells. However in C4-2B, a castrate-resistant sub-line of LNCaP and AR-negative androgen independent DU145 cells, RON activates subset of AR-regulated transcripts. Expression of AR in PC-3 cells leads to activation of RON under androgen deprivation but not under androgen proficient conditions implicating a role for RON in androgen independence. Consistently, RON expression is significantly elevated in castrate resistant prostate tumors. Taken together our results suggest that RON activation could aid in promoting androgen independence and that inhibition of RON in combination with AR antagonist(s) merits serious consideration as a therapeutic option during hormone deprivation therapy. PMID:26872377

  13. Targeting Taxanes to Castration-Resistant Prostate Cancer Cells by Nanobubbles and Extracorporeal Shock Waves.

    PubMed

    Marano, Francesca; Rinella, Letizia; Argenziano, Monica; Cavalli, Roberta; Sassi, Francesca; D'Amelio, Patrizia; Battaglia, Antonino; Gontero, Paolo; Bosco, Ornella; Peluso, Rossella; Fortunati, Nicoletta; Frairia, Roberto; Catalano, Maria Graziella

    2016-01-01

    To target taxanes to castration-resistant prostate cancer cells, glycol-chitosan nanobubbles loaded with paclitaxel and docetaxel were constructed. The loaded nanobubbles were then combined with Extracorporeal Shock Waves, acoustic waves widely used in urology and orthopedics, with no side effects. Nanobubbles, with an average diameter of 353.3 ± 15.5 nm, entered two different castration-resistant prostate cancer cells (PC3 and DU145) as demonstrated by flow cytometry and immunofluorescence. The shock waves applied increased the amount of intracellular nanobubbles. Loading nanobubbles with paclitaxel and docetaxel and combining them with shock waves generated the highest cytotoxic effects, resulting in a paclitaxel GI50 reduction of about 55% and in a docetaxel GI50 reduction of about 45% respectively. Combined treatment also affected cell migration. Paclitaxel-loaded nanobubbles and shock waves reduced cell migration by more than 85% with respect to paclitaxel alone; whereas docetaxel-loaded nanobubbles and shock waves reduced cell migration by more than 82% with respect to docetaxel alone. The present data suggest that nanobubbles can act as a stable taxane reservoir in castration-resistant prostate cancer cells and shock waves can further increase drug release from nanobubbles leading to higher cytotoxic and anti-migration effect.

  14. Targeting DNA Repair: The Role of PARP Inhibition in the Treatment of Castration-Resistant Prostate Cancer.

    PubMed

    Castro, Elena; Mateo, Joaquin; Olmos, David; de Bono, Johann S

    Several genomic studies have identified DNA repair gene defects in prostate cancer in the last 5 years. The mechanisms by which these DNA repair defects promote carcinogenesis and tumor progression in the prostate have not been fully elucidated, but their presence in at least 20-25% of metastatic castration-resistant prostate cancers (CRPCs) provides an opportunity for a therapeutic strategy that turns a tumor strength into its weakness and may lead to arguably the first molecularly stratified treatment for this disease.Poly(ADP-ribose) polymerase (PARP) inhibitors have been developed as an anticancer synthetic lethal therapeutic strategy for tumors with impaired homologous recombination DNA repair, based on a synthetic lethal effect. Poly(ADP-ribose) polymerase inhibitors have shown to induce significant tumor responses in cancer patients carrying germline BRCA1/2 mutations. Recent evidence from a phase II clinical trial supports further testing of PARP inhibitors for the treatment of metastatic CRPC with either germline or somatic defects in BRCA2, ATM, PALB2, and other DNA repair genes.We review the current evidence of how this strategy is relevant for the treatment of advanced prostate cancers, the available data from trials with PARP inhibitors in metastatic CRPC, and the ongoing studies analyzing combinations of these drugs with other therapies.

  15. Proteomic Profiling of Androgen-independent Prostate Cancer Cell Lines Reveals a Role for Protein S during the Development of High Grade and Castration-resistant Prostate Cancer

    PubMed Central

    Saraon, Punit; Musrap, Natasha; Cretu, Daniela; Karagiannis, George S.; Batruch, Ihor; Smith, Chris; Drabovich, Andrei P.; Trudel, Dominique; van der Kwast, Theodorus; Morrissey, Colm; Jarvi, Keith A.; Diamandis, Eleftherios P.

    2012-01-01

    Androgen deprivation constitutes the principal therapy for advanced and metastatic prostate cancers. However, this therapeutic intervention usually results in the transition to a more aggressive androgen-independent prostate cancer. The elucidation of molecular alterations during the progression to androgen independence is an integral step toward discovering more effective targeted therapies. With respect to identifying crucial mediators of this transition, we compared the proteomes of androgen-independent (PC3, DU145, PPC1, LNCaP-SF, and 22Rv1) and androgen-dependent (LNCaP and VCaP) and/or normal prostate epithelial (RWPE) cell lines using mass spectrometry. We identified more than 100 proteins that were differentially secreted in the androgen-independent cell lines. Of these, Protein S (PROS1) was elevated in the secretomes of all of the androgen-independent prostate cancer cell lines, with no detectable secretion in normal and androgen-dependent cell lines. Using quantitative PCR, we observed significantly higher (p < 0.05) tissue expression levels of PROS1 in prostate cancer samples, further indicating its importance in prostate cancer progression. Similarly, immunohistochemistry analysis revealed elevation of PROS1 in high grade prostate cancer (Gleason grade ≥8), and further elevation in castration-resistant metastatic prostate cancer lesions. We also observed its significant (p < 0.05) elevation in high grade prostate cancer seminal plasma samples. Taken together, these results show that PROS1 is elevated in high grade and castration-resistant prostate cancer and could serve as a potential biomarker of aggressive disease. PMID:22908226

  16. Non-Coding RNAs in Castration-Resistant Prostate Cancer: Regulation of Androgen Receptor Signaling and Cancer Metabolism.

    PubMed

    Shih, Jing-Wen; Wang, Ling-Yu; Hung, Chiu-Lien; Kung, Hsing-Jien; Hsieh, Chia-Ling

    2015-12-04

    Hormone-refractory prostate cancer frequently relapses from therapy and inevitably progresses to a bone-metastatic status with no cure. Understanding of the molecular mechanisms conferring resistance to androgen deprivation therapy has the potential to lead to the discovery of novel therapeutic targets for type of prostate cancer with poor prognosis. Progression to castration-resistant prostate cancer (CRPC) is characterized by aberrant androgen receptor (AR) expression and persistent AR signaling activity. Alterations in metabolic activity regulated by oncogenic pathways, such as c-Myc, were found to promote prostate cancer growth during the development of CRPC. Non-coding RNAs represent a diverse family of regulatory transcripts that drive tumorigenesis of prostate cancer and various other cancers by their hyperactivity or diminished function. A number of studies have examined differentially expressed non-coding RNAs in each stage of prostate cancer. Herein, we highlight the emerging impacts of microRNAs and long non-coding RNAs linked to reactivation of the AR signaling axis and reprogramming of the cellular metabolism in prostate cancer. The translational implications of non-coding RNA research for developing new biomarkers and therapeutic strategies for CRPC are also discussed.

  17. Non-Coding RNAs in Castration-Resistant Prostate Cancer: Regulation of Androgen Receptor Signaling and Cancer Metabolism

    PubMed Central

    Shih, Jing-Wen; Wang, Ling-Yu; Hung, Chiu-Lien; Kung, Hsing-Jien; Hsieh, Chia-Ling

    2015-01-01

    Hormone-refractory prostate cancer frequently relapses from therapy and inevitably progresses to a bone-metastatic status with no cure. Understanding of the molecular mechanisms conferring resistance to androgen deprivation therapy has the potential to lead to the discovery of novel therapeutic targets for type of prostate cancer with poor prognosis. Progression to castration-resistant prostate cancer (CRPC) is characterized by aberrant androgen receptor (AR) expression and persistent AR signaling activity. Alterations in metabolic activity regulated by oncogenic pathways, such as c-Myc, were found to promote prostate cancer growth during the development of CRPC. Non-coding RNAs represent a diverse family of regulatory transcripts that drive tumorigenesis of prostate cancer and various other cancers by their hyperactivity or diminished function. A number of studies have examined differentially expressed non-coding RNAs in each stage of prostate cancer. Herein, we highlight the emerging impacts of microRNAs and long non-coding RNAs linked to reactivation of the AR signaling axis and reprogramming of the cellular metabolism in prostate cancer. The translational implications of non-coding RNA research for developing new biomarkers and therapeutic strategies for CRPC are also discussed. PMID:26690121

  18. Niclosamide inhibits androgen receptor variants expression and overcomes enzalutamide resistance in castration resistant prostate cancer

    PubMed Central

    Zhu, Yezi; Nadiminty, Nagalakshmi; Schwartz, Chad T.; Evans, Christopher P.; Gao, Allen C.

    2014-01-01

    Purpose Enzalutamide, a second-generation antiandrogen, was recently approved for the treatment of castration-resistant prostate cancer (CRPC) in patients who no longer respond to docetaxel. Despite these advances that provide temporary respite, resistance to enzalutamide occurs frequently. AR splice variants such as AR-V7 have recently been shown to drive castration resistant growth and resistance to enzalutamide. This study was designed to identify inhibitors of AR variants and test its ability to overcome resistance to enzalutamide. Experimental Design The drug screening was conducted using luciferase activity assay to determine the activity of AR-V7 after treatment with the compounds in the Prestwick Chemical Library, which contains about 1120 FDA-approved drugs. The effects of the identified inhibitors on AR-V7 activity and enzalutamide sensitivity were characterized in CRPC and enzalutamide-resistant prostate cancer cells in vitro and in vivo. Results Niclosamide, an FDA-approved anti-helminthic drug, was identified as a potent AR-V7 inhibitor in prostate cancer cells. Niclosamide significantly downregulated AR-V7 protein expression by protein degradation through a proteasome dependent pathway. Niclosamide also inhibited AR-V7 transcription activity and reduced the recruitment of AR-V7 to the PSA promoter. Niclosamide inhibited prostate cancer cell growth in vitro and tumor growth in vivo. Furthermore, the combination of niclosamide and enzalutamide resulted in significantly inhibition of enzalutamide-resistant tumor growth, suggesting that Niclosamide enhances enzalutamide therapy and overcomes enzalutamide resistance in castration resistant prostate cancer cells. Conclusions Niclosamide was identified as a novel inhibitor of AR variants. Our findings offer preclinical validation of niclosamide as a promising inhibitor of androgen receptor variants to treat, either alone or in combination with current antiandrogen therapies, advanced prostate cancer patients

  19. PP2A inhibition as a novel therapeutic target in castration-resistant prostate cancer.

    PubMed

    González-Alonso, Paula; Cristóbal, Ion; Manso, Rebeca; Madoz-Gúrpide, Juan; García-Foncillas, Jesús; Rojo, Federico

    2015-08-01

    Protein phosphatase 2A (PP2A) is a well-known tumor suppressor frequently inhibited in human cancer. Alterations affecting PP2A subunits together with the deregulation of endogenous PP2A inhibitors such as CIP2A and SET have been described as contributing mechanisms to inactivate PP2A in prostate cancer. Moreover, recent findings highlight that functional inactivation of PP2A could represent a key event in the acquisition of castration-resistant phenotype and a novel molecular target with high impact at both clinical and therapeutic levels in prostate cancer.

  20. Andrographolide Targets Androgen Receptor Pathway in Castration-Resistant Prostate Cancer

    PubMed Central

    Liu, Chengfei; Nadiminty, Nagalakshmi; Tummala, Ramakumar; Chun, Jae Yeon; Lou, Wei; Zhu, Yezi; Sun, Meng; Evans, Christopher P.; Zhou, Qinghua; Gao, Allen C.

    2011-01-01

    Androgen receptor (AR) signaling not only plays a pivotal role in the development of androgen-dependent prostate cancer but is also important in the growth and survival of castration-resistant prostate cancer (CRPC). The first line of treatment of androgen-dependent prostate cancer is the use of androgen deprivation therapy. However, most patients will eventually relapse due to development of CRPC. Thus, development of a strategy to target AR for treatment of CRPC is urgently needed. The authors have previously identified andrographolide as an inhibitor of interleukin-6, which can suppress tumor growth of prostate cancer cells by screening compounds from the Prestwick Natural compound library. In this study, they identified that andrographolide can inhibit AR expression and prostate cancer cell growth and induce apoptosis. Andrographolide is able to down-regulate AR expression at both mRNA and protein levels, prevents its nuclear translocation, and inhibits transactivation of its target genes. Andrographolide prevents the binding of Hsp90 to AR, resulting in proteasome-mediated AR degradation. Furthermore, andrographolide inhibits castration-resistant C4-2 cell growth by reducing AR expression and activity. Thus, andrographolide can be developed as a potential therapeutic agent for prostate cancer by inhibition of androgen receptor signaling. PMID:21779488

  1. The Rationale for Optimal Combination Therapy With Sipuleucel-T for Patients With Castration-resistant Prostate Cancer.

    PubMed

    Mouraviev, Vladimir; Mariados, Neil; Albala, David; Concepcion, Raoul S; Shore, Neal D; Sims, Robert B; Emberton, Mark; Pieczonka, Christopher M

    2014-01-01

    Immunotherapy encourages the recipient's own immune response to destroy cancer cells, and current evidence suggests that immunotherapies may be most beneficial in early metastatic castration-resistant prostate cancer (mCRPC). Sipuleucel-T is the first therapeutic cancer vaccine to be approved by both the US Food and Drug Administration and European Medicines Agency for the treatment of asymptomatic or minimally symptomatic mCRPC. Combining immunotherapy with other treatments may have potent anticancer effects; cytoreductive therapies can release tumor antigens and promote a proinflammatory environment that could augment immunotherapies. However, some cytoreductive agents or coadministered drugs may be immunosuppressive. Understanding these interactions between different mCRPC treatment modalities may offer further potential to improve patient outcomes.

  2. Targeting the androgenic pathway in elderly patients with castration-resistant prostate cancer

    PubMed Central

    Roviello, Giandomenico; Cappelletti, Maria Rosa; Zanotti, Laura; Gobbi, Angela; Senti, Chiara; Bottini, Alberto; Ravelli, Andrea; Bonetta, Alberto; Paganini, Giovanni; Generali, Daniele

    2016-01-01

    Abstract Background: The novel hormonal drugs have recently entered in the armamentarium of therapies for treatment of metastatic castration-resistant prostate cancer (CRPC). First reports are available for their use in elderly men with CRPC. Method: A meta-analysis of randomized controlled trials (RCTs) has been performed. PubMed, the Cochrane Library, and American Society of Clinical Oncology (ASCO) University Meeting were searched for data on the use of new hormonal treatment in elderly patients with CRPC. Results: Nine studies for a total of 3512 elderly patients were available for meta-analysis. Six studies reported outcomes of patients aged >75 years old while 2 studies reported on patients aged >70 years old. The pooled analysis of the androgen synthesis inhibitors revealed significantly increased overall survival (OS) due to antiandrogen agents compared with placebo or placebo and prednisone (hazard ratio (HR) for death: HR = 0.74, 95% CI: 0.67–0.82; P < 0.00001). Moreover, the new antiandrogenic therapy significantly improved the progression-free survival (HR = 0.45, 95% CI: 0.31–0.65; P < 0.0001). The incidence of any grade ≥3 adverse effect was only moderately higher during with the antiandrogenic therapy as compared to the control arms (response rate = 1.03, 95% CI: 0.88–1.20; P = 0.72). Conclusion: This study confirmed that agents targeting the androgen axis (i.e., enzalutamide, abiraterone) significantly prolonged OS in elderly men with CRPC. PMID:27787354

  3. Targeting Oct1 genomic function inhibits androgen receptor signaling and castration-resistant prostate cancer growth.

    PubMed

    Obinata, D; Takayama, K; Fujiwara, K; Suzuki, T; Tsutsumi, S; Fukuda, N; Nagase, H; Fujimura, T; Urano, T; Homma, Y; Aburatani, H; Takahashi, S; Inoue, S

    2016-12-08

    Androgen receptor (AR) functions as a ligand-dependent transcription factor to regulate its downstream signaling for prostate cancer progression. AR complex formation by multiple transcription factors is important for enhancer activity and transcriptional regulation. However, the significance of such collaborative transcription factors has not been fully understood. In this study, we show that Oct1, an AR collaborative factor, coordinates genome-wide AR signaling for prostate cancer growth. Using global analysis by chromatin immunoprecipitation sequencing (ChIP-seq), we found that Oct1 is recruited to AR-binding enhancer/promoter regions and facilitates androgen signaling. Moreover, a major target of AR/Oct1 complex, acyl-CoA synthetase 3 (ACSL3), contributes to tumor growth in nude mice, and its high expression is associated with poor prognosis in prostate cancer patients. Next, we examined the therapeutic effects of pyrrole-imidazole polyamides that target the Oct1-binding sequence identified in the center of the ACSL3 AR-binding site. We observed that treatment with Oct1 polyamide severely blocked the Oct1 binding at the ACSL3 enhancer responsible for its transcriptional activity and ACSL3 induction. In addition, Oct1 polyamides suppressed castration-resistant tumor growth and specifically repressed global Oct1 chromatin association and androgen signaling in prostate cancer cells, with few nonspecific effects on basal promoter activity. Thus, targeting Oct1 binding could be a novel therapeutic strategy for AR-activated castration-resistant prostate cancer.

  4. Using a Novel Transgenic Mouse Model to Study c-Myc Oncogenic Pathway in Castration Resistance and Chemoresistance of Prostate Cancer

    DTIC Science & Technology

    2015-10-01

    Oncogenic Pathway in Castration Resistance and Chemoresistance of Prostate Cancer 3 Annual Progress Report W81XWH-13-1-0162 Using a Novel...Transgenic Mouse Model to Study c-Myc Oncogenic Pathway in Castration Resistance and Chemoresistance of Prostate Cancer Feng Yang, Ph.D. Department of...AWARD NUMBER: W81XWH-13-1-0162 TITLE: Using a Novel Transgenic Mouse Model to Study c-Myc Oncogenic Pathway in Castration Resistance and

  5. Wnt signaling in castration-resistant prostate cancer: implications for therapy

    PubMed Central

    Yokoyama, Noriko N; Shao, Shujuan; Hoang, Bang H; Mercola, Dan; Zi, Xiaolin

    2014-01-01

    Increasing evidence has indicated that Wnt signaling plays complex roles in castration resistant prostate cancer (CRPC). Although not all data were consistent, β-catenin nuclear localization and its co-localization with androgen receptor (AR) were more frequently observed in CRPC compared to hormone naïve prostate cancer. This direct interaction between AR and β-catenin seemed to elicit a specific expression of a set of target genes in low androgen conditions in CRPC. Paracrine Wnt signaling also was shown to aid resistance to chemotherapy and androgen deprivation therapy. Results from the next generation sequencing studies (i.e. RNA-seq and whole exosome sequcing) of CRPC specimens have identified the Wnt pathway as one of the top signaling pathways with significant genomic alterations in CRPC, whereas, Wnt pathway alterations were virtually absent in hormone naïve primary prostate cancer. Furthermore, Wnt signaling has been suggested to play an important role in cancer stem cell functions in prostate cancer recurrence and resistance to androgen deprivation therapy. Therefore, in this review we have summarized existing knowledge regarding potential roles of Wnt signaling in CRPC and underline Wnt signaling as a potential therapeutic target for CRPC. Further understanding of Wnt signaling in castration resistance may eventually contribute new insights into possible treatment options for this incurable disease. PMID:25143959

  6. Activation of GRP/GRP-R signaling contributes to castration-resistant prostate cancer progression

    PubMed Central

    Qiao, Jingbo; Grabowska, Magdalena M.; Forestier, Ingrid S.; Mirosevich, Janni; Case, Thomas C.; Chung, Dai H.; Cates, Justin M.M.; Matusik, Robert J.; Manning, H. Charles; Jin, Renjie

    2016-01-01

    Numerous studies indicate that androgen receptor splice variants (ARVs) play a critical role in the development of castration-resistant prostate cancer (CRPC), including the resistance to the new generation of inhibitors of androgen receptor (AR) action. Previously, we demonstrated that activation of NF-κB signaling increases ARVs expression in prostate cancer (PC) cells, thereby promoting progression to CRPC. However, it is unclear how NF-κB signaling is activated in CRPC. In this study, we report that long-term treatment with anti-androgens increases a neuroendocrine (NE) hormone — gastrin-releasing peptide (GRP) and its receptor (GRP-R) expression in PC cells. In addition, activation of GRP/GRP-R signaling increases ARVs expression through activating NF-κB signaling. This results in an androgen-dependent tumor progressing to a castrate resistant tumor. The knock-down of AR-V7 restores sensitivity to antiandrogens of PC cells over-expressing the GRP/GRP-R signaling pathway. These findings strongly indicate that the axis of Androgen-Deprivation Therapy (ADT) induces GRP/GRP-R activity, activation NF-κB and increased levels of AR-V7 expression resulting in progression to CRPC. Both prostate adenocarcinoma and small cell NE prostate cancer express GRP-R. Since the GRP-R is clinically targetable by analogue-based approach, this provides a novel therapeutic approach to treat advanced CRPC. PMID:27542219

  7. GRP78-targeted nanotherapy against castrate-resistant prostate cancer cells expressing membrane GRP78.

    PubMed

    Delie, Florence; Petignat, Patrick; Cohen, Marie

    2013-12-01

    Glucose-regulated protein 78, GRP78, is a chaperone protein mainly located in the endoplasmic reticulum (ER) of normal cells. In stress conditions, GRP78 is overexpressed and in different cancer cell types, it is expressed at the cell surface, whereas it stays intracellular in non-cancerous cells. Therefore, it appears as a strategic target to recognize malignant cells. Prostate cancer is one of the most diagnosed cancers in men. The development of castrate resistant tumors and the resistance to chemotherapy frequently occur. The carboxy-terminal ER retention domain is defined by the KDEL amino acid sequence. We developed anti-KDEL functionalized polymeric nanoparticles (NPs) loaded with paclitaxel (Tx) to specifically target prostate cancer cells expressing GRP78. The sensitivity to Tx in different formulations was compared in three prostate cell lines: PNT1B, a normal cell line, PC3, a cancer cell line faintly expressing GRP78 at its surface, and DU145, a cancer cell line expressing GRP78 at its cell surface. Our results show that the targeted formulation significantly increases Tx sensitivity of cell line expressing GRP78 at its surface compared to other treatments suggesting the added value of GRP78 targeted therapy for castrate resistant tumor which expresses GRP78 at its cell surface.

  8. PRKAR2B plays an oncogenic role in the castration-resistant prostate cancer

    PubMed Central

    Sha, Jianjun; Xue, Wei; Dong, Baijun; Pan, Jiahua; WU, Xiaorong; Li, Dong; Liu, Dongming; Huang, Yiran

    2017-01-01

    Castration-resistant prostate cancer (CRPC) is an advanced form of prostate cancer. Despite some progresses have been made, the mechanism of CRPC development is still largely unknown, including the genes involved in its development have not been well defined. Here, we identifiedPRKAR2B to be a gene over-expressingin castration-resistant prostate cancer by analyzing the different online databases. Followed functional validation experiments showed that PRKAR2B promoted CRPC cell proliferation and invasion, and inhibited CRPC cell apoptosis. Whole genome transcriptome and GO enrichment analyses of the knock-down of PRKAR2B in CRPC cells showed that PRKAR2B mainly accelerated cell cycle biological process and modulated multiple cell cycle genes, such as CCNB1, MCM2, PLK1 and AURKB. Our study firstly identified PRKAR2B as a novel oncogenic gene involved in CRPC development and suggested it is a promising target for the future investigation and the treatment of CRPC. PMID:28008150

  9. Bmi1 marks distinct castration-resistant luminal progenitor cells competent for prostate regeneration and tumour initiation

    PubMed Central

    Yoo, Young A.; Roh, Meejeon; Naseem, Anum F.; Lysy, Barbara; Desouki, Mohamed M.; Unno, Kenji; Abdulkadir, Sarki A.

    2016-01-01

    Identification of defined cell populations with stem/progenitor properties is key for understanding prostate development and tumorigenesis. Here we show that the polycomb repressor protein Bmi1 marks a population of castration-resistant luminal epithelial cells enriched in the mouse proximal prostate. We employ lineage tracing to show that these castration-resistant Bmi1-expressing cells (or CARBs) are capable of tissue regeneration and self-renewal. Notably, CARBs are distinct from the previously described luminal castration-resistant Nkx3.1-expressing cells (CARNs). CARBs can serve as a prostate cancer cell-of-origin upon Pten deletion, yielding luminal prostate tumours. Clonal analysis using the R26R-confetti allele indicates preferential tumour initiation from CARBs localized to the proximal prostate. These studies identify Bmi1 as a marker for a distinct population of castration-resistant luminal epithelial cells enriched in the proximal prostate that can serve as a cell of origin for prostate cancer. PMID:27703144

  10. Targeting cancer stem cell in castration resistant prostate cancer

    PubMed Central

    Yun, Eun-Jin; Zhou, Jiancheng; Lin, Chun-Jung; Hernandez, Elizabeth; Fazli, Ladan; Gleave, Martin; Hsieh, Jer-Tsong

    2015-01-01

    Purpose Clinical evidence suggests an increased CSC in tumor mass may contribute to the failure of conventional therapies since CSCs seem to be more resistant than differentiated tumor cells. Thus, unveiling the mechanism regulating CSCs and candidate target molecules will provide new strategy to cure the patients. Experimental design The stem-like cell properties were determined by a prostasphere assay, and dye exclusion assay. To find critical stem cell marker and reveal regulation mechanism, basic biochemical and molecular biological methods such as qRT-PCR, Western blot, reporter gene assay and chromatin immunoprecipitation assay were employed. In addition, to determine the effect of combination therapy targeting both CSCs and its progeny, in vitro MTT assay and in vivo xenograft model was used. Results We demonstrate immortalized normal human prostate epithelial cells, appeared non-tumorigenic in vivo, become tumorigenic and acquire stem cell phenotype after knocking down a tumor suppressor gene. Also, those stem-like cells increase chemoresistance to conventional anti-cancer reagent. Mechanistically, we unveil that Wnt signaling is a key pathway regulating well-known stem cell marker CD44 by directly interacting to the promoter. Thus, by targeting CSCs using Wnt inhibitors synergistically enhances the efficacy of conventional drugs. Furthermore, the in vivo mice model bearing xenografts showed a robust inhibition of tumor growth after combination therapy. Conclusions Overall, this study provides strong evidence of CSC in CRPC. This new combination therapy strategy targeting CSC could significantly enhance therapeutic efficacy of current chemotherapy regimen only targeting non-CSC cells. PMID:26490309

  11. The European medicines agency review of abiraterone for the treatment of metastatic castration-resistant prostate cancer in adult men after docetaxel chemotherapy and in chemotherapy-naive disease: summary of the scientific assessment of the committee for medicinal products for human use.

    PubMed

    Gravanis, Iordanis; Lopez, Arantxa Sancho; Hemmings, Robert James; Jiménez, Jorge Camarero; Garcia-Carbonero, Rocio; Gallego, Isabel García; Giménez, Elena Valencia; O'Connor, Daniel; Giuliani, Rosa; Salmonson, Tomas; Pignatti, Francesco

    2013-01-01

    On September 5, 2011, abiraterone was approved in the European Union in combination with prednisone or prednisolone for the treatment of metastatic castration-resistant prostate cancer (CRPC) in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen. On December 18, 2012, the therapeutic indication was extended to include the use of abiraterone in combination with prednisone or prednisolone for the treatment of metastatic CRPC in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated. Abiraterone is a selective, irreversible inhibitor of cytochrome P450 17α, an enzyme that is key in the production of androgens. Inhibition of androgen biosynthesis deprives prostate cancer cells from important signals for growth, even in cases of resistance to castration. At the time of European Union approval and in a phase III trial in CRPC patients who had failed at least one docetaxel-based chemotherapy regimen, median overall survival for patients treated with abiraterone was 14.8 months versus 10.9 months for those receiving placebo (hazard ratio, 0.65; 95% confidence interval 0.54-0.77; p < .0001). In a subsequent phase III trial in a similar but chemotherapy-naïve patient population, median radiographic progression-free survival was 16.5 months for patients in the abiraterone treatment arm versus 8.3 months for patients in the placebo arm (hazard ratio, 0.53; 95% confidence interval, 0.45-0.62; p < .0001). Abiraterone was most commonly associated with adverse reactions resulting from increased or excessive mineralocorticoid activity. These were generally manageable with basic medical interventions. The most common side effects (affecting more than 10% of patients) were urinary tract infection, hypokalemia, hypertension, and peripheral edema.

  12. The European Medicines Agency Review of Abiraterone for the Treatment of Metastatic Castration-Resistant Prostate Cancer in Adult Men After Docetaxel Chemotherapy and in Chemotherapy-Naïve Disease: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use

    PubMed Central

    Lopez, Arantxa Sancho; Hemmings, Robert James; Jiménez, Jorge Camarero; Garcia-Carbonero, Rocio; Gallego, Isabel García; Giménez, Elena Valencia; O'Connor, Daniel; Giuliani, Rosa; Salmonson, Tomas; Pignatti, Francesco

    2013-01-01

    On September 5, 2011, abiraterone was approved in the European Union in combination with prednisone or prednisolone for the treatment of metastatic castration-resistant prostate cancer (CRPC) in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen. On December 18, 2012, the therapeutic indication was extended to include the use of abiraterone in combination with prednisone or prednisolone for the treatment of metastatic CRPC in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated. Abiraterone is a selective, irreversible inhibitor of cytochrome P450 17α, an enzyme that is key in the production of androgens. Inhibition of androgen biosynthesis deprives prostate cancer cells from important signals for growth, even in cases of resistance to castration. At the time of European Union approval and in a phase III trial in CRPC patients who had failed at least one docetaxel-based chemotherapy regimen, median overall survival for patients treated with abiraterone was 14.8 months versus 10.9 months for those receiving placebo (hazard ratio, 0.65; 95% confidence interval 0.54–0.77; p < .0001). In a subsequent phase III trial in a similar but chemotherapy-naïve patient population, median radiographic progression-free survival was 16.5 months for patients in the abiraterone treatment arm versus 8.3 months for patients in the placebo arm (hazard ratio, 0.53; 95% confidence interval, 0.45–0.62; p < .0001). Abiraterone was most commonly associated with adverse reactions resulting from increased or excessive mineralocorticoid activity. These were generally manageable with basic medical interventions. The most common side effects (affecting more than 10% of patients) were urinary tract infection, hypokalemia, hypertension, and peripheral edema. PMID:23966222

  13. Therapeutic opportunities for castration-resistant prostate cancer patients with bone metastases.

    PubMed

    Zustovich, Fable; Fabiani, Francesca

    2014-08-01

    Patients with castration-resistant prostate cancer are burdened not only with an unavoidable risk of mortality but also by severe mobility issues. This disease has a high tendency to induce bone metastases with concomitant general suffering, impaired mobility, and reduced self-sufficiency. The treatment of bone pain consists of opioids, nonsteroidal anti-inflammatory drugs, radiopharmaceuticals, and radiotherapy. To date, abiraterone, enzalutamide, zoledronate and denosumab are the only drugs able to delay skeletal events, and docetaxel is the only chemotherapeutic agent able to prolong survival after castration progression. Recently, 5 new drugs have proven to be efficacious in prolonging survival. Sipuleucel-T, cabazitaxel, abiraterone, enzalutamide, and radium-223 have broadened the therapeutic choices, thus changing the clinical paradigm. This review analyzes the data supporting the use of all presently available therapeutic approaches for the management of pain, skeletal events, and survival in castration-resistant prostate cancer patients with bone metastases. Data based on phase 3 trials could identify new approaches depending on patient, disease, and therapy characteristics.

  14. Determining the frequency of pathogenic germline variants from exome sequencing in patients with castrate-resistant prostate cancer

    PubMed Central

    Hart, Steven N; Ellingson, Marissa S; Schahl, Kim; Vedell, Peter T; Carlson, Rachel E; Sinnwell, Jason P; Barman, Poulami; Sicotte, Hugues; Eckel-Passow, Jeanette E; Wang, Liguo; Kalari, Krishna R; Qin, Rui; Kruisselbrink, Teresa M; Jimenez, Rafael E; Bryce, Alan H; Tan, Winston; Weinshilboum, Richard; Wang, Liewei; Kohli, Manish

    2016-01-01

    Objectives To determine the frequency of pathogenic inherited mutations in 157 select genes from patients with metastatic castrate-resistant prostate cancer (mCRPC). Design Observational. Setting Multisite US-based cohort. Participants Seventy-one adult male patients with histological confirmation of prostate cancer, and had progressive disease while on androgen deprivation therapy. Results Twelve patients (17.4%) showed evidence of carrying pathogenic or likely pathogenic germline variants in the ATM, ATR, BRCA2, FANCL, MSR1, MUTYH, RB1, TSHR and WRN genes. All but one patient opted in to receive clinically actionable results at the time of study initiation. We also found that pathogenic germline BRCA2 variants appear to be enriched in mCRPC compared to familial prostate cancers. Conclusions Pathogenic variants in cancer-susceptibility genes are frequently observed in patients with mCRPC. A substantial proportion of patients with mCRPC or their family members would derive clinical utility from mutation screening. Trial registration number NCT01953640; Results. PMID:27084275

  15. [Treatment sequence using newly developed agents for men with castration resistant prostate cancer].

    PubMed

    Fujimoto, Naohiro

    2014-12-01

    Abiraterone acetate(AA), enzalutamide (EZL) and cabazitaxel (CBZ) are becoming available in Japan. Clinical trials demonstrated the benefit of these agents in men with castration resistant prostate cancer (CRPC). However, data on sequence therapy using these agents are very limited. Based on the mechanisms of agents and clinical data, AA and EZL may be indicated in early stage and CBZ may be indicated in late stage of CRPC. Prostate cancer is significantly heterogeneous between individuals and useful biomarkers for deciding the best treatment are unavailable yet. Therefore, it is hard to establish a standard sequence of the treatments. Until clinical trials demonstrate the best treatment sequence, individualized therapy is required for each patient based on patient and disease characteristics.

  16. Management of bone metastases in patients with castration-resistant prostate cancer.

    PubMed

    Cathomas, Richard; Bajory, Zoltan; Bouzid, Mounira; El Ghoneimy, Ahmed; Gillessen, Silke; Goncalves, Frederico; Kacso, Gabriel; Kramer, Gero; Milecki, Piotr; Pacik, Dalibor; Tantawy, Wahid; Lesniewski-Kmak, Krzystof

    2014-01-01

    Bone metastases are a very common problem in prostate cancer. They are associated with considerable morbidity, adversely affect quality of life and frequently lead to advanced bone events (so-called skeletal-related events, SREs); SREs include fractures, spinal cord compression and the requirement for bone surgery or bone radiation. The aim of this paper was to evaluate currently available treatment options in the prevention and management of SREs and bone metastases in men with castration-resistant prostate cancer and to outline the importance of interdisciplinary management strategies. It also discusses the diagnostic workup of osseous metastases and practical considerations for the utilization of bone-targeted therapies in accordance with current guidelines to provide a consensus for special and/or difficult clinical situations.

  17. New strategies for medical management of castration-resistant prostate cancer.

    PubMed

    Asmane, Irène; Céraline, Jocelyn; Duclos, Brigitte; Rob, Lynn; Litique, Valère; Barthélémy, Philippe; Bergerat, Jean-Pierre; Dufour, Patrick; Kurtz, Jean-Emmanuel

    2011-01-01

    Although advanced prostate cancer patients respond very well to front-line androgen deprivation, failure to hormonal therapy most often occurs after a median time of 18-24 months. The care of castration-resistant prostate cancer (CRPC) has significantly evolved over the past decade, with the onset of first-line therapy with docetaxel. Although numerous therapy schedules have been investigated alongside docetaxel, in either first-line or salvage therapy, results were dismal. However, CRPC chemotherapy is currently evolving, with, on the one hand, new agents targeting androgen metabolism and, on the other hand, significant progress in chemotherapy drugs, particularly for second-line therapy. The aim of the present review is to describe the current treatments for CRPC chemotherapy alongside their challengers that might shortly become new standards. In this article, we discuss the most recent data from clinical trials to provide the reader with a comprehensive, state-of-the-art overview of CRPC chemotherapy and hormonal therapy.

  18. Targeting the adaptive molecular landscape of castration-resistant prostate cancer

    PubMed Central

    Wyatt, Alexander W; Gleave, Martin E

    2015-01-01

    Castration and androgen receptor (AR) pathway inhibitors induce profound and sustained responses in advanced prostate cancer. However, the inevitable recurrence is associated with reactivation of the AR and progression to a more aggressive phenotype termed castration-resistant prostate cancer (CRPC). AR reactivation can occur directly through genomic modification of the AR gene, or indirectly via co-factor and co-chaperone deregulation. This mechanistic heterogeneity is further complicated by the stress-driven induction of a myriad of overlapping cellular survival pathways. In this review, we describe the heterogeneous and evolvable molecular landscape of CRPC and explore recent successes and failures of therapeutic strategies designed to target AR reactivation and adaptive survival pathways. We also discuss exciting areas of burgeoning anti-tumour research, and their potential to improve the survival and management of patients with CRPC. PMID:25896606

  19. Cholesterol biosynthesis inhibitor RO 48-8071 suppresses growth of hormone-dependent and castration-resistant prostate cancer cells

    PubMed Central

    Liang, Yayun; Mafuvadze, Benford; Aebi, Johannes D; Hyder, Salman M

    2016-01-01

    Standard treatment for primary prostate cancer includes systemic exposure to chemotherapeutic drugs that target androgen receptor or antihormone therapy (chemical castration); however, drug-resistant cancer cells generally emerge during treatment, limiting the continued use of systemic chemotherapy. Patients are then treated with more toxic standard therapies. Therefore, there is an urgent need for novel and more effective treatments for prostate cancer. The cholesterol biosynthetic pathway is an attractive therapeutic target for treating endocrine-dependent cancers because cholesterol is an essential structural and functional component of cell membranes as well as the metabolic precursor of endogenous steroid hormones. In this study, we have examined the effects of RO 48-8071 (4′-[6-(allylmethylamino)hexyloxy]-4-bromo-2′-fluorobenzophenone fumarate; Roche Pharmaceuticals internal reference: RO0488071) (RO), which is an inhibitor of 2, 3-oxidosqualene cyclase (a key enzyme in the cholesterol biosynthetic pathway), on prostate cancer cells. Exposure of both hormone-dependent and castration-resistant human prostate cancer cells to RO reduced prostate cancer cell viability and induced apoptosis in vitro. RO treatment reduced androgen receptor protein expression in hormone-dependent prostate cancer cells and increased estrogen receptor β (ERβ) protein expression in both hormone-dependent and castration-resistant prostate cancer cell lines. Combining RO with an ERβ agonist increased its ability to reduce castration-resistant prostate cancer cell viability. In addition, RO effectively suppressed the growth of aggressive castration-resistant human prostate cancer cell xenografts in vivo without any signs of toxicity to experimental animals. Importantly, RO did not reduce the viability of normal prostate cells in vitro. Our study is the first to demonstrate that the cholesterol biosynthesis inhibitor RO effectively suppresses growth of human prostate cancer cells

  20. Comparative analyses of chromosome alterations in soft-tissue metastases within and across patients with castration-resistant prostate cancer

    PubMed Central

    Holcomb, Ilona N.; Young, Janet M.; Coleman, Ilsa M.; Salari, Keyan; Grove, Douglas I.; Hsu, Li; True, Lawrence D.; Roudier, Martine P.; Morrissey, Colm M.; Higano, Celestia S.; Nelson, Peter S.; Vessella, Robert L.; Trask, Barbara J.

    2009-01-01

    Androgen deprivation is the mainstay of therapy for progressive prostate cancer. Despite initial and dramatic tumor inhibition, most men eventually fail therapy and die of metastatic castration-resistant (CR) disease. Here, we characterize the profound degree of genomic alteration found in CR tumors using array CGH, gene expression arrays, and FISH. By cluster analysis, we show that the similarity of the genomic profiles from primary and metastatic tumors is driven by the patient. Using data adjusted for this similarity, we identify numerous high-frequency alterations in the CR tumors, such as 8p loss and chromosome 7 and 8q gain. By integrating array CGH and expression array data, we reveal genes whose correlated values suggest they are relevant to prostate cancer biology. We find alterations that are significantly associated with the metastases of specific organ sites, and others with CR tumors versus the tumors of patients with localized prostate cancer not treated with androgen deprivation. Within the high-frequency sites of loss in CR metastases, we find an over-representation of genes involved in cellular lipid metabolism, including PTEN. Finally, using FISH we verify the presence of a gene fusion between TMPRSS2 and ERG suggested by chromosome-21 deletions detected by array CGH. We find the fusion in 54% of our CR tumors, and 81% of the fusion-positive tumors contain cells with multiple copies of the fusion. Our investigation lays the foundation for a better understanding of and possible therapeutic targets for CR disease, the poorly responsive and final stage of prostate cancer. PMID:19773449

  1. Phase III, Randomized, Double-Blind, Multicenter Trial Comparing Orteronel (TAK-700) Plus Prednisone With Placebo Plus Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer That Has Progressed During or After Docetaxel-Based Therapy: ELM-PC 5

    PubMed Central

    Fizazi, Karim; Jones, Robert; Oudard, Stephane; Efstathiou, Eleni; Saad, Fred; de Wit, Ronald; De Bono, Johann; Cruz, Felipe Melo; Fountzilas, George; Ulys, Albertas; Carcano, Flavio; Agarwal, Neeraj; Agus, David; Bellmunt, Joaquim; Petrylak, Daniel P.; Lee, Shih-Yuan; Webb, Iain J.; Tejura, Bindu; Borgstein, Niels; Dreicer, Robert

    2015-01-01

    Purpose Orteronel (TAK-700) is an investigational, nonsteroidal, reversible, selective 17,20-lyase inhibitor. This study examined orteronel in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel therapy. Patients and Methods In our study, 1,099 men were randomly assigned in a 2:1 schedule to receive orteronel 400 mg plus prednisone 5 mg twice daily or placebo plus prednisone 5 mg twice daily, stratified by region (Europe, North America [NA], and non-Europe/NA) and Brief Pain Inventory–Short Form worst pain score. Primary end point was overall survival (OS). Key secondary end points (radiographic progression-free survival [rPFS], ≥ 50% decrease of prostate-specific antigen [PSA50], and pain response at 12 weeks) were to undergo statistical testing only if the primary end point analysis was significant. Results The study was unblinded after crossing a prespecified OS futility boundary. The median OS was 17.0 months versus 15.2 months with orteronel-prednisone versus placebo-prednisone (hazard ratio [HR], 0.886; 95% CI, 0.739 to 1.062; P = .190). Improved rPFS was observed with orteronel-prednisone (median, 8.3 v 5.7 months; HR, 0.760; 95% CI, 0.653 to 0.885; P < .001). Orteronel-prednisone showed advantages over placebo-prednisone in PSA50 rate (25% v 10%, P < .001) and time to PSA progression (median, 5.5 v 2.9 months, P < .001) but not pain response rate (12% v 9%; P = .128). Adverse events (all grades) were generally more frequent with orteronel-prednisone, including nausea (42% v 26%), vomiting (36% v 17%), fatigue (29% v 23%), and increased amylase (14% v 2%). Conclusion Our study did not meet the primary end point of OS. Longer rPFS and a higher PSA50 rate with orteronel-prednisone indicate antitumor activity. PMID:25624429

  2. A Phase II Study of 2-Methoxyestradiol (2ME2) NanoCrystal® Dispersion (NCD) in Patients with Taxane-Refractory, Metastatic Castrate-Resistant Prostate Cancer (CRPC)

    PubMed Central

    Harrison, Michael R.; Hahn, Noah M.; Pili, Roberto; Oh, William K.; Hammers, Hans; Sweeney, Christopher; Kim, KyungMann; Perlman, Scott; Arnott, Jamie; Sidor, Carolyn; Wilding, George; Liu, Glenn

    2010-01-01

    Purpose 2ME2 (Panzem®) is a non-estrogenic derivative of estradiol with antiproliferative and antiangiogenic activity. Preclinical data support antitumor activity in prostate cancer. This trial evaluated the efficacy of 2ME2 NCD in patients with taxane-refractory, metastatic CRPC. Experimental Design Patients with metastatic CRPC who had progressed on only one prior taxane-based regimen were eligible. All patients received 2ME2 NCD at 1500 mg orally four times daily, repeated in 28 day cycles. The primary endpoint was progression free survival at month 6, with a secondary endpoint of PSA response. An exploratory endpoint was metabolic response on FDG-PET imaging. Results A total of 50 pts was planned. The study was terminated after 21 pts when a futility analysis showed the primary endpoint was unlikely to be reached. The median number of cycles on study was 2 (range <1 to 12). Adverse events (AE) of grade ≥3 related to the study drug occurred in 7 unique patients (33%): elevations in liver function tests, fatigue or weakness, gastrointestinal hemorrhage, and hyponatremia. Paired FDG-PET scans were obtained for 11 pts. No metabolic responses were observed. Conclusions 2ME2 NCD did not appear to have clinically significant activity in this study. 2ME2 NCD was well-tolerated and showed some evidence of biologic activity. Given the aggressive biology in this taxane-refractory population, the potential benefit from a cytostatic agent like 2ME2 might better be realized in the pre-chemotherapy (or rising PSA only) stage of CRPC. PMID:20499131

  3. Radium-223 dichloride: a review of its use in patients with castration-resistant prostate cancer with symptomatic bone metastases.

    PubMed

    Shirley, Matt; McCormack, Paul L

    2014-04-01

    Radium-223 dichloride (Xofigo®; formerly Alpharadin™) [hereafter referred to as radium-223] is a first-in-class alpha particle-emitting radiopharmaceutical that has recently been approved for the treatment of patients with castration-resistant prostate cancer (CRPC) with symptomatic bone metastases and no known visceral metastatic disease. Radium-223 is a calcium mimetic, which targets bone, delivering cytotoxic radiation to the sites of bone metastases. In the recently reported Alpharadin™ in Symptomatic Prostate Cancer (ALSYMPCA) phase III study, radium-223 was associated with significantly improved overall survival compared with placebo, making it the first bone-targeted CRPC therapy for which an overall survival benefit has been demonstrated. The ALSYMPCA study also demonstrated the beneficial effects of radium-223 on disease-related symptomatic skeletal events, pain and health-related quality of life. Radium-223 was generally well tolerated, being associated with low rates of myelosuppression and generally mild gastrointestinal adverse events. Thus, radium-223 is a valuable addition to the treatment options for this poor-prognosis population.

  4. ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer

    PubMed Central

    Wang, Junjian; Zou, June X.; Xue, Xiaoqian; Cai, Demin; Zhang, Yan; Duan, Zhijian; Xiang, Qiuping; Yang, Joy C.; Louie, Maggie C.; Borowsky, Alexander D.; Gao, Allen C.; Evans, Christopher P.; Lam, Kit S.; Xu, Jianzhen; Kung, Hsing-Jien; Evans, Ronald M.; Xu, Yong; Chen, Hong-Wu

    2016-01-01

    The androgen receptor (AR) is overexpressed and hyperactivated in human castration-resistant prostate cancer (CRPC). However, the determinants of AR overexpression in CRPC are poorly defined. Here we show that retinoid acid receptor-related orphan receptor γ (ROR-γ) is overexpressed and amplified in metastatic CRPC tumors, and that ROR-γ drives AR expression in the tumors. ROR-γ recruits coactivators SRC-1 and -3 to an AR-RORE to stimulate AR gene transcription. ROR-γ antagonists suppress the expression of AR and its variant AR-V7 in prostate cancer (PCa) cell lines and tumors. ROR-γ antagonists also markedly diminish genome-wide AR binding, H3K27ac abundance and expression of the AR gene network. Lastly, ROR-γ antagonists suppressed tumor growth in multiple AR-expressing but not AR-negative xenograft PCa models, and effectively sensitized CRPC tumors to enzalutamide, without overt toxicity in mice. Together, these results establish ROR-γ as a key player in CRPC by acting upstream of AR and a potential therapeutic target for advanced PCa. PMID:27019329

  5. NANOG reprograms prostate cancer cells to castration resistance via dynamically repressing and engaging the AR/FOXA1 signaling axis

    PubMed Central

    Jeter, Collene R; Liu, Bigang; Lu, Yue; Chao, Hsueh-Ping; Zhang, Dingxiao; Liu, Xin; Chen, Xin; Li, Qiuhui; Rycaj, Kiera; Calhoun-Davis, Tammy; Yan, Li; Hu, Qiang; Wang, Jianmin; Shen, Jianjun; Liu, Song; Tang, Dean G

    2016-01-01

    The pluripotency transcription factor NANOG has been implicated in tumor development, and NANOG-expressing cancer cells manifest stem cell properties that sustain tumor homeostasis, mediate therapy resistance and fuel tumor progression. However, how NANOG converges on somatic circuitry to trigger oncogenic reprogramming remains obscure. We previously reported that inducible NANOG expression propels the emergence of aggressive castration-resistant prostate cancer phenotypes. Here we first show that endogenous NANOG is required for the growth of castration-resistant prostate cancer xenografts. Genome-wide chromatin immunoprecipitation sequencing coupled with biochemical assays unexpectedly reveals that NANOG co-occupies a distinctive proportion of androgen receptor/Forkhead box A1 genomic loci and physically interacts with androgen receptor and Forkhead box A1. Integrative analysis of chromatin immunoprecipitation sequencing and time-resolved RNA sequencing demonstrates that NANOG dynamically alters androgen receptor/Forkhead box A1 signaling leading to both repression of androgen receptor-regulated pro-differentiation genes and induction of genes associated with cell cycle, stem cells, cell motility and castration resistance. Our studies reveal global molecular mechanisms whereby NANOG reprograms prostate cancer cells to a clinically relevant castration-resistant stem cell-like state driven by distinct NANOG-regulated gene clusters that correlate with patient survival. Thus, reprogramming factors such as NANOG may converge on and alter lineage-specific master transcription factors broadly in somatic cancers, thereby facilitating malignant disease progression and providing a novel route for therapeutic resistance. PMID:27867534

  6. Mechanisms of acquired resistance to androgen receptor targeting drugs in castration resistant prostate cancer

    PubMed Central

    Chism, David D.; De Silva, Dinuka; Whang, Young E.

    2014-01-01

    After initial response to androgen receptor targeting drugs abiraterone or enzalutamide, most patients develop progressive disease and therefore, castration resistant prostate cancer (CRPC) remains a terminal disease. Multiple mechanisms underlying acquired resistance have been postulated. Intratumoral androgen synthesis may resume after abiraterone treatment. A point mutation in the ligand binding domain of androgen receptor may confer resistance to enzalutamide. Emergence of androgen receptor splice variants lacking the ligand binding domain may mediate resistance to abiraterone and enzalutamide. Steroid receptors such as glucocorticoid receptor may substitute for androgen receptor. Drugs with novel mechanisms of action or combination therapy, along with biomarkers for patient selection, may be needed to improve the therapy of CRPC. PMID:24927631

  7. Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer

    PubMed Central

    Pollock, Julie A.; Wardell, Suzanne E.; Parent, Alexander A.; Stagg, David B.; Ellison, Stephanie J.; Alley, Holly M.; Chao, Christina A.; Lawrence, Scott A.; Stice, James P.; Spasojevic, Ivan; Baker, Jennifer G.; Kim, Sung Hoon; McDonnell, Donald P.; Katzenellenbogen, John A.; Norris, John D.

    2016-01-01

    Clinical resistance to the second-generation antiandrogen enzalutamide in castration resistant prostate cancer (CRPC), despite persistent androgen receptor (AR) activity in tumors, highlights the unmet medical need for next generation antagonists. We have identified and characterized tetra-aryl cyclobutanes (CBs) as a new class of competitive AR antagonists that exhibit a unique mechanism of action. These CBs are structurally distinct from current antiandrogens (hydroxyflutamide, bicalutamide, and enzalutamide), and inhibit AR-mediated gene expression, cell proliferation, and tumor growth in several models of CRPC. Conformational profiling revealed that CBs stabilize an AR conformation resembling an unliganded receptor. Using a variety of techniques, it was determined that the AR:CB complex was not recruited to AR-regulated promoters and, like apo AR, remains sequestered in the cytoplasm bound to heat shock proteins. Thus, we have identified third generation AR antagonists whose unique mechanism of action suggests that they may have therapeutic potential in CRPC. PMID:27501397

  8. Resistance to abiraterone in castration-resistant prostate cancer: a review of the literature.

    PubMed

    Giacinti, Silvana; Bassanelli, Maria; Aschelter, Anna Maria; Milano, Annalisa; Roberto, Michela; Marchetti, Paolo

    2014-11-01

    Persistent androgen signaling is functionally significant in castration-resistant prostate cancer (CRPC) and it is actually considered a validated therapeutic target. Residual intra-tumoral androgens compensate for the effects of androgen ablation, activating the androgen receptor (AR), AR-mediated gene expression and driving CRPC. The intra-tumoral biosynthesis of androgens takes place in different ways and cytochrome P450 17A1 (CYP17A1) has a crucial role in this context. Abiraterone, a CYP17A1 inhibitor, has shown impressive results in pre- and post-chemotherapy settings, prolonging the survival of patients with CRPC. However, not all patients respond to the treatment and most responders develop resistance, with a widely variable duration of response. Although many hypotheses are emerging, the mechanisms of resistance to abiraterone treatment have not yet been elucidated. The aim of the present review is to describe the main data currently available on resistance to abiraterone.

  9. EPI-001, A Compound Active against Castration-Resistant Prostate Cancer, Targets Transactivation Unit 5 of the Androgen Receptor.

    PubMed

    De Mol, Eva; Fenwick, R Bryn; Phang, Christopher T W; Buzón, Victor; Szulc, Elzbieta; de la Fuente, Alex; Escobedo, Albert; García, Jesús; Bertoncini, Carlos W; Estébanez-Perpiñá, Eva; McEwan, Iain J; Riera, Antoni; Salvatella, Xavier

    2016-09-16

    Castration-resistant prostate cancer is the lethal condition suffered by prostate cancer patients that become refractory to androgen deprivation therapy. EPI-001 is a recently identified compound active against this condition that modulates the activity of the androgen receptor, a nuclear receptor that is essential for disease progression. The mechanism by which this compound exerts its inhibitory activity is however not yet fully understood. Here we show, by using high resolution solution nuclear magnetic resonance spectroscopy, that EPI-001 selectively interacts with a partially folded region of the transactivation domain of the androgen receptor, known as transactivation unit 5, that is key for the ability of prostate cells to proliferate in the absence of androgens, a distinctive feature of castration-resistant prostate cancer. Our results can contribute to the development of more potent and less toxic novel androgen receptor antagonists for treating this disease.

  10. EPI-001, a compound active against castration-resistant prostate cancer, targets transactivation unit 5 of the androgen receptor

    PubMed Central

    De Mol, Eva; Fenwick, R. Bryn; Phang, Christopher T. W.; Buzón, Victor; Szulc, Elzbieta; de la Fuente, Alex; Escobedo, Albert; García, Jesús; Bertoncini, Carlos W.; Estébanez-Perpiñá, Eva; McEwan, Iain J.; Riera, Antoni; Salvatella, Xavier

    2016-01-01

    Castration-resistant prostate cancer is the lethal condition suffered by prostate cancer patients that become refractory to androgen deprivation therapy. EPI-001 is a recently identified compound active against this condition that modulates the activity of the androgen receptor, a nuclear receptor that is essential for disease progression. The mechanism by which this compound exerts its inhibitory activity is however not yet fully understood. Here we show, by using high resolution solution nuclear magnetic resonance spectroscopy, that EPI-001 selectively interacts with a partially folded region of the transactivation domain of the androgen receptor, known as transactivation unit 5, that is key for the ability of prostate cells to proliferate in the absence of androgens, a distinctive feature of castration-resistant prostate cancer. Our results can contribute to the development of more potent and less toxic novel androgen receptor antagonists for treating this disease. PMID:27356095

  11. Inhibition of Hsp90 Augments Docetaxel Therapy in Castrate Resistant Prostate Cancer

    PubMed Central

    Ku, ShengYu; Lasorsa, Elena; Adelaiye, Remi; Ramakrishnan, Swathi; Ellis, Leigh; Pili, Roberto

    2014-01-01

    First line treatment of patients with castrate resistant prostate cancer (CRPC) primarily involves administration of docetaxel chemotherapy. Unfortunately, resistance to docetaxel therapy is an ultimate occurrence. Alterations in androgen receptor (AR) expression and signaling are associated mechanisms underlying resistance to docetaxel treatment in CRPC. Heat shock protein 90 (Hsp90) is a molecular chaperone, which regulates the activation, maturation and stability of critical signaling proteins involved in prostate cancer, including the AR. This knowledge and recent advances in compound design and development have highlighted Hsp90 as an attractive therapeutic target for the treatment of CRPC. We recently reported the development of a MYC-CaP castrate resistant (MYC-CaP/CR) transplant tumor model, which expresses amplified wild type AR. Within, we report that a second generation Hsp90 inhibitor, NVP-AUY922, inhibits cell growth and significantly induces cell death in MYC-CaP/CR and Pten-CaP/cE2 cell lines. NVP-AUY922 induced proteasome degradation of AR, though interestingly does not require loss of AR protein to inhibit AR transcriptional activity. Further, NVP-AUY922 increased docetaxel toxicity in MYC-CaP/CR and Pten-CaP/cE2 cell lines in vitro. Finally, NVP-AUY922/docetaxel combination therapy in mice bearing MYC-CaP/CR tumors resulted in greater anti-tumor activity compared to single treatment. This study demonstrates that NVP-AUY922 elicits potent activity towards AR signaling and augments chemotherapy response in a mouse model of CRPC, providing rationale for the continued clinical development of Hsp90 inhibitors in clinical trials for treatment of CRPC patients. PMID:25072314

  12. Targeting GPR30 with G-1: a new therapeutic target for castration-resistant prostate cancer

    PubMed Central

    Lam, Hung-Ming; Ouyang, Bin; Chen, Jing; Ying, Jun; Wang, Jiang; Wu, Chin-Lee; Li, Jia; Medvedovic, Mario; Vessella, Robert L.; Ho, Shuk-Mei

    2014-01-01

    Castration-resistant prostate cancer (CRPC) is an advanced-stage prostate cancer (PC) associated with high mortality. We reported that G-1, a selective agonist of G protein-coupled receptor 30 (GPR30), inhibited PC cell growth by inducing G2 cell cycle arrest and arrested PC-3 xenograft growth. However, therapeutic actions of G-1 and their relationships with androgen in vivo are unclear. Using the LNCaP xenograft to model PC growth during androgen-sensitive (AS) versus castration-resistant (CR) phase, we found that G-1 inhibited growth of CR but not AS tumors with no observable toxicity to the host. Substantial necrosis (~65%) accompanied by marked intratumoral infiltration of neutrophils was observed only in CR tumors. Global transcriptome profiling of human genes identified 99 differential expressed genes with “interplay between innate and adaptive immune response” as the top pathway. Quantitative-PCR confirmed upregulation of neutrophil-related chemokines and inflammation-mediated cytokines only in the G-1-treated CR tumors. Expression of murine neutrophil-related cytokines also was elevated in these tumors. GPR30 expression was significantly higher in CR than AS tumors. In cell-based experiments, androgen repressed GPR30 expression, a response reversible by anti-androgen or siRNA-induced androgen receptor silencing. Finally, in clinical specimens, 80% of CRPC metastases (n=123) express a high level of GPR30 whereas only 54% of the primary PCs (n=232) showed high GPR30 expression. Together, these results provide the first evidence that GPR30 is an androgen-repressed target and G-1 mediates the anti-tumor effect via neutrophil infiltration-associated necrosis in CRPC. Additional studies are warranted to firmly establish GPR30 as a therapeutic target in CRPC. PMID:25287069

  13. Identification and Targeting of Candidate Pre-Existing Lurker Cells that Give Rise to Castration-Resistant Prostate Cancer

    DTIC Science & Technology

    2015-10-01

    The selection theory predicts that pre-existing androgen-independent prostate cancer cells (termed lurker cells ) contribute to CRPC, as they are...AWARD NUMBER: W81XWH-13-1-0470 TITLE: Identification and Targeting of Candidate Pre-Existing Lurker Cells that Give Rise to Castration... Cells that Give Rise to 5a. CONTRACT NUMBER Castration-Resistant Prostate Cancer 5b. GRANT NUMBER W81XWH-13-1-0470 5c. PROGRAM ELEMENT NUMBER 6

  14. Interdisciplinary critique of sipuleucel-T as immunotherapy in castration-resistant prostate cancer.

    PubMed

    Huber, Marie L; Haynes, Laura; Parker, Chris; Iversen, Peter

    2012-02-22

    Sipuleucel-T was approved by the US Food and Drug Administration on April 29, 2010, as an immunotherapy for late-stage prostate cancer. To manufacture sipuleucel-T, mononuclear cells harvested from the patient are incubated with a recombinant prostatic acid phosphatase (PAP) antigen and reinfused. The manufacturer proposes that antigen-presenting cells exogenously activated by PAP induce endogenous T-cells to attack PAP-bearing prostate cancer cells. However, the lack of demonstrable tumor responses has prompted calls for scrutiny of the design of the trials in which sipuleucel-T demonstrated a 4-month survival benefit. Previously unpublished data from the sipuleucel-T trials show worse overall survival in older vs younger patients in the placebo groups, which have not been shown previously to be prognostic for survival in castration-resistant prostate cancer patients receiving chemotherapy. Because two-thirds of the cells harvested from placebo patients, but not from the sipuleucel-T arm, were frozen and not reinfused, a detrimental effect of this large repeated cell loss provides a potential alternative explanation for the survival "benefit." Patient safety depends on adequately addressing this alternative explanation for the trial results.

  15. Estradiol suppresses tissue androgens and prostate cancer growth in castration resistant prostate cancer

    PubMed Central

    2010-01-01

    Background Estrogens suppress tumor growth in prostate cancer which progresses despite anorchid serum androgen levels, termed castration resistant prostate cancers (CRPC), although the mechanisms are unclear. We hypothesize that estrogen inhibits CRPC in anorchid animals by suppressing tumoral androgens, an effect independent of the estrogen receptor. Methods The human CRPC xenograft LuCaP 35V was implanted into orchiectomized male SCID mice and established tumors were treated with placebo, 17β-estradiol or 17β-estradiol and estrogen receptor antagonist ICI 182,780. Effects of 17β-estradiol on tumor growth were evaluated and tissue testosterone (T) and dihydrotestosterone (DHT) evaluated by mass spectrometry. Results Treatment of LuCaP 35V with 17β-estradiol slowed tumor growth compared to controls (tumor volume at day 21: 785 ± 81 mm3 vs. 1195 ± 84 mm3, p = 0.002). Survival was also significantly improved in animals treated with 17β-estradiol (p = 0.03). The addition of the estrogen receptor antagonist ICI 182,780 did not significantly change survival or growth. 17β-estradiol in the presence and absence of ICI 182,780 suppressed tumor testosterone (T) and dihydrotestosterone (DHT) as assayed by mass spectrometry. Tissue androgens in placebo treated LuCaP 35V xenografts were; T = 0.71 ± 0.28 pg/mg and DHT = 1.73 ± 0.36 pg/mg. In 17β-estradiol treated LuCaP35V xenografts the tissue androgens were, T = 0.20 ± 0.10 pg/mg and DHT = 0.15 ± 0.15 pg/mg, (p < 0.001 vs. controls). Levels of T and DHT in control liver tissue were < 0.2 pg/mg. Conclusions CRPC in anorchid animals maintains tumoral androgen levels despite castration. 17β-estradiol significantly suppressed tumor T and DHT and inhibits growth of CRPC in an estrogen receptor independent manner. The ability to manipulate tumoral androgens will be critical in the development and testing of agents targeting CRPC through tissue steroidogenesis. PMID:20509933

  16. The cistrome and gene signature of androgen receptor splice variants in castration-resistant prostate cancer cells

    PubMed Central

    Lu, Ji; Lonergan, Peter E.; Nacusi, Lucas P.; Wang, Liguo; Schmidt, Lucy J.; Sun, Zhifu; Van der Steen, Travis; Boorjian, Stephen A.; Kosari, Farhad; Vasmatzis, George; Klee, George G.; Balk, Steven P.; Huang, Haojie; Wang, Chunxi; Tindall, Donald J.

    2015-01-01

    Purpose Spliced variant forms of androgen receptor (AR-Vs) have been identified recently in castration-resistant prostate cancer (CRPC) cell lines and clinical samples. We identified the cistrome and gene signature of AR-Vs in CRPC cell lines and determined the clinical significance of AR-Vs regulated genes. Materials and Methods The CRPC cell line 22Rv1, which expresses both full length androgen receptor (AR-FL) and AR-Vs endogenously, was used as the research model. We established 22Rv1-ARFL−/ARVs+ and 22Rv1- ARFL−/ARVs− through RNA interference. ChIP-seq and microarray techniques were used to identify cistrome and gene expression profiles of AR-Vs in the absence of androgen. Results AR-Vs binding sites were identified in 22Rv1-ARFL−/ARVs+. A set of genes was found to be regulated uniquely by AR-Vs, but not by full-length AR in the absence of androgen. Integrated analysis revealed that some genes are modulated by AR-Vs directly. Unsupervised clustering analysis showed that the AR-Vs gene signature can differentiate not only benign from malignant prostate tissue, but also localized prostate cancer from metastatic CRPC specimens. Some genes that were modulated uniquely by AR-Vs also correlated with histological grade and biochemical failure. Conclusions We conclude that AR-Vs can bind to DNA independently of full-length AR in the absence of androgen and modulate a unique set of genes that is not regulated by AR-FL. The AR-Vs gene signature correlates with disease progression, and distinguishes between primary cancer and CRPC specimens, as well as benign and malignant prostate specimens. PMID:25132238

  17. Castration resistant prostate cancer (CRPC): state of the art, perspectives and new challenges.

    PubMed

    Massari, Francesco; Maines, Francesca; Modena, Alessandra; Brunelli, Matteo; Bria, Emilio; Artibani, Walter; Martignoni, Guido; Tortora, Giampaolo

    2013-07-01

    The rapid approval of several novel agents has given prostate cancer patients and their treating physicians many new and effective therapeutic options. Four new medical therapies were recently approved on the basis of prolonged overall survival in castration-resistant prostate cancer (CRPC) patients: sipuleucel-T, cabazitaxel, abiraterone acetate and MDV3100. Additionally, there are several other promising prostate cancer agents in late-stage development, including PROSTVAC-VF, orteronel and radium-223 chloride, each with a novel mechanism of action. The treatment paradigm for these patients is rapidly evolving, with future study needed to define the optimal sequencing and potential combinations of these new agents. In this review, we discuss the recent progress in understanding the biology of this disease and examining the development of a variety of new agents with promising activity and a favorable toxicity profile, that have been investigated in the setting of hormonal, cytotoxic, immune and targeted therapy. In this new therapeutic setting of CRPC, clinicians will have an opportunity to balance benefits and harms of these new agents in an individual context.

  18. Raman spectroscopy, a potential tool in diagnosis and prognosis of castration-resistant prostate cancer

    NASA Astrophysics Data System (ADS)

    Wang, Lei; He, Dalin; Zeng, Jin; Guan, Zhenfeng; Dang, Qiang; Wang, Xinyang; Wang, Jun; Huang, Liqing; Cao, Peilong; Zhang, Guanjun; Hsieh, JerTong; Fan, Jinhai

    2013-08-01

    Purpose: We evaluated the feasibility of Raman spectroscopy (RS) in diagnosis and prognosis of castration-resistant prostate cancer (CRPC) in patients with prostate cancer (PC). Materials and methods: Raman spectra are detected from PC cell lines (LNCaP and C4-2) and tissues using a Labram HR 800 RS. Then, principal component analysis (PCA) and support vector machine (SVM) are applied for prediction. A leave-one-out cross-validation is used to train and test the SVM. Results: There are 50 qualified patients, including 33 with androgen-dependent prostate cancer (ADPC) and 17 with CRPC. The spectral changes at 1126, 1170, 1315 to 1338, and 1447 cm-1 between CRPC and ADPC are detected in both cells and tissues models, which are assigned to specific amino acids and DNA. PCA/SVM algorithm provided a sensitivity of 88.2% and a specificity of 87.9% for diagnosing CRPC tissues. Furthermore, 14 patients with ADPC progressed to CRPC within 12 months. These patients are separated into two groups depending on whether their cancers progressed to CRPC within 12 months. PCA/SVM could differentiate these two groups with a sensitivity of 85.7% and a specificity of 88.9%. Conclusions: RS has the potential in diagnosis and prognosis of CRPC in clinical practice.

  19. AKR1C3 as a target in castrate resistant prostate cancer.

    PubMed

    Adeniji, Adegoke O; Chen, Mo; Penning, Trevor M

    2013-09-01

    Aberrant androgen receptor (AR) activation is the major driver of castrate resistant prostate cancer (CRPC). CRPC is ultimately fatal and more therapeutic agents are needed to treat this disease. Compounds that target the androgen axis by inhibiting androgen biosynthesis and or AR signaling are potential candidates for use in CRPC treatment and are currently being pursued aggressively. Aldo-keto reductase 1C3 (AKR1C3) plays a pivotal role in androgen biosynthesis within the prostate. It catalyzes the 17-ketoreduction of weak androgen precursors to give testosterone and 5α-dihydrotestosterone. AKR1C3 expression and activity has been implicated in the development of CRPC, making it a rational target. Selective inhibition of AKR1C3 will be important, however, due to the presence of closely related isoforms, AKR1C1 and AKR1C2 that are also involved in androgen inactivation. We examine the evidence that supports the vital role of AKR1C3 in CRPC and recent developments in the discovery of potent and selective AKR1C3 inhibitors. This article is part of a Special Issue entitled 'CSR 2013'.

  20. Inhibition of the hexosamine biosynthetic pathway promotes castration-resistant prostate cancer

    PubMed Central

    Kaushik, Akash K.; Shojaie, Ali; Panzitt, Katrin; Sonavane, Rajni; Venghatakrishnan, Harene; Manikkam, Mohan; Zaslavsky, Alexander; Putluri, Vasanta; Vasu, Vihas T.; Zhang, Yiqing; Khan, Ayesha S.; Lloyd, Stacy; Szafran, Adam T.; Dasgupta, Subhamoy; Bader, David A.; Stossi, Fabio; Li, Hangwen; Samanta, Susmita; Cao, Xuhong; Tsouko, Efrosini; Huang, Shixia; Frigo, Daniel E.; Chan, Lawrence; Edwards, Dean P.; Kaipparettu, Benny A.; Mitsiades, Nicholas; Weigel, Nancy L.; Mancini, Michael; McGuire, Sean E.; Mehra, Rohit; Ittmann, Michael M.; Chinnaiyan, Arul M.; Putluri, Nagireddy; Palapattu, Ganesh S.; Michailidis, George; Sreekumar, Arun

    2016-01-01

    The precise molecular alterations driving castration-resistant prostate cancer (CRPC) are not clearly understood. Using a novel network-based integrative approach, here, we show distinct alterations in the hexosamine biosynthetic pathway (HBP) to be critical for CRPC. Expression of HBP enzyme glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) is found to be significantly decreased in CRPC compared with localized prostate cancer (PCa). Genetic loss-of-function of GNPNAT1 in CRPC-like cells increases proliferation and aggressiveness, in vitro and in vivo. This is mediated by either activation of the PI3K-AKT pathway in cells expressing full-length androgen receptor (AR) or by specific protein 1 (SP1)-regulated expression of carbohydrate response element-binding protein (ChREBP) in cells containing AR-V7 variant. Strikingly, addition of the HBP metabolite UDP-N-acetylglucosamine (UDP-GlcNAc) to CRPC-like cells significantly decreases cell proliferation, both in-vitro and in animal studies, while also demonstrates additive efficacy when combined with enzalutamide in-vitro. These observations demonstrate the therapeutic value of targeting HBP in CRPC. PMID:27194471

  1. PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer

    PubMed Central

    Raina, Kanak; Lu, Jing; Qian, Yimin; Altieri, Martha; Gordon, Deborah; Rossi, Ann Marie K.; Wang, Jing; Chen, Xin; Dong, Hanqing; Siu, Kam; Winkler, James D.; Crew, Andrew P.; Crews, Craig M.; Coleman, Kevin G.

    2016-01-01

    Prostate cancer has the second highest incidence among cancers in men worldwide and is the second leading cause of cancer deaths of men in the United States. Although androgen deprivation can initially lead to remission, the disease often progresses to castration-resistant prostate cancer (CRPC), which is still reliant on androgen receptor (AR) signaling and is associated with a poor prognosis. Some success against CRPC has been achieved by drugs that target AR signaling, but secondary resistance invariably emerges, and new therapies are urgently needed. Recently, inhibitors of bromodomain and extra-terminal (BET) family proteins have shown growth-inhibitory activity in preclinical models of CRPC. Here, we demonstrate that ARV-771, a small-molecule pan-BET degrader based on proteolysis-targeting chimera (PROTAC) technology, demonstrates dramatically improved efficacy in cellular models of CRPC as compared with BET inhibition. Unlike BET inhibitors, ARV-771 results in suppression of both AR signaling and AR levels and leads to tumor regression in a CRPC mouse xenograft model. This study is, to our knowledge, the first to demonstrate efficacy with a small-molecule BET degrader in a solid-tumor malignancy and potentially represents an important therapeutic advance in the treatment of CRPC. PMID:27274052

  2. Lyn tyrosine kinase regulates androgen receptor expression and activity in castrate-resistant prostate cancer

    PubMed Central

    Zardan, A; Nip, K M; Thaper, D; Toren, P; Vahid, S; Beraldi, E; Fazli, L; Lamoureux, F; Gust, K M; Cox, M E; Bishop, J L; Zoubeidi, A

    2014-01-01

    Castrate-resistant prostate cancer (CRPC) progression is a complex process by which prostate cells acquire the ability to survive and proliferate in the absence or under very low levels of androgens. Most CRPC tumors continue to express the androgen receptor (AR) as well as androgen-responsive genes owing to reactivation of AR. Protein tyrosine kinases have been implicated in supporting AR activation under castrate conditions. Here we report that Lyn tyrosine kinase expression is upregulated in CRPC human specimens compared with hormone naive or normal tissue. Lyn overexpression enhanced AR transcriptional activity both in vitro and in vivo and accelerated CRPC. Reciprocally, specific targeting of Lyn resulted in a decrease of AR transcriptional activity in vitro and in vivo and prolonged time to castration. Mechanistically, we found that targeting Lyn kinase induces AR dissociation from the molecular chaperone Hsp90, leading to its ubiquitination and proteasomal degradation. This work indicates a novel mechanism of regulation of AR stability and transcriptional activity by Lyn and justifies further investigation of the Lyn tyrosine kinase as a therapeutic target for the treatment of CRPC. PMID:25133482

  3. Mechanistic Support for Combined MET and AR Blockade in Castration-Resistant Prostate Cancer.

    PubMed

    Qiao, Yuanyuan; Feng, Felix Y; Wang, Yugang; Cao, Xuhong; Han, Sumin; Wilder-Romans, Kari; Navone, Nora M; Logothetis, Christopher; Taichman, Russell S; Keller, Evan T; Palapattu, Ganesh S; Alva, Ajjai S; Smith, David C; Tomlins, Scott A; Chinnaiyan, Arul M; Morgan, Todd M

    2016-01-01

    A recent phase III trial of the MET kinase inhibitor cabozantinib in men with castration-resistant prostate cancer (CRPC) failed to meet its primary survival end point; however, most men with CRPC have intact androgen receptor (AR) signaling. As previous work supports negative regulation of MET by AR signaling, we hypothesized that intact AR signaling may have limited the efficacy of cabozantinib in some of these patients. To assess the role of AR signaling on MET inhibition, we first performed an in silico analysis of human CRPC tissue samples stratified by AR signaling status ((+) or (-)), which identified MET expression as markedly increased in AR(-) samples. In vitro, AR signaling inhibition in AR(+) CRPC models increased MET expression and resulted in susceptibility to ligand (HGF) activation. Likewise, MET inhibition was only effective in blocking cancer phenotypes in cells with MET overexpression. Using multiple AR(+) CRPC in vitro and in vivo models, we showed that combined cabozantinib and enzalutamide (AR antagonist) treatment was more efficacious than either inhibitor alone. These data provide a compelling rationale to combine AR and MET inhibition in CRPC and may explain the negative results of the phase III cabozantinib study in CRPC. Similarly, the expression of MET in AR(-) disease, whether due to AR inhibition or loss of AR signaling, suggests potential utility for MET inhibition in select patients with AR therapy resistance and in AR(-) prostate cancer.

  4. Niclosamide enhances abiraterone treatment via inhibition of androgen receptor variants in castration resistant prostate cancer

    PubMed Central

    Liu, Chengfei; Armstrong, Cameron; Zhu, Yezi; Lou, Wei; Gao, Allen C.

    2016-01-01

    Considerable evidence from both clinical and experimental studies suggests that androgen receptor variants, particularly androgen receptor variant 7 (AR-V7), are critical in the induction of resistance to enzalutamide and abiraterone. In this study, we investigated the role of AR-V7 in the cross-resistance of enzalutamide and abiraterone and examined if inhibition of AR-V7 can improve abiraterone treatment response. We found that enzalutamide-resistant cells are cross-resistant to abiraterone, and that AR-V7 confers resistance to abiraterone. Knock down of AR-V7 by siRNA in abiraterone resistant CWR22Rv1 and C4-2B MDVR cells restored their sensitivity to abiraterone, indicating that AR-V7 is involved in abiraterone resistance. Abiraterone resistant prostate cancer cells generated by chronic treatment with abiraterone showed enhanced AR-V7 protein expression. Niclosamide, an FDA-approved antihelminthic drug that has been previously identified as a potent inhibitor of AR-V7, re-sensitizes resistant cells to abiraterone treatment in vitro and in vivo. In summary, this preclinical study suggests that overexpression of AR-V7 contributes to resistance to abiraterone, and supports the development of combination of abiraterone with niclosamide as a potential treatment for advanced castration resistant prostate cancer. PMID:27049719

  5. Hydrazinobenzoylcurcumin inhibits androgen receptor activity and growth of castration-resistant prostate cancer in mice

    PubMed Central

    Wu, Min; Kim, Sahn-Ho; Datta, Indrani; Levin, Albert; Dyson, Gregory; Li, Jing; Kaypee, Stephanie; Swamy, M. Mahadeva; Gupta, Nilesh; Kwon, Ho Jeong; Menon, Mani; Kundu, Tapas K.; Reddy, G. Prem-Veer

    2015-01-01

    There is a critical need for therapeutic agents that can target the amino-terminal domain (NTD) of androgen receptor (AR) for the treatment of castration-resistant prostate cancer (CRPC). Calmodulin (CaM) binds to the AR NTD and regulates AR activity. We discovered that Hydrazinobenzoylcurcumin (HBC), which binds exclusively to CaM, inhibited AR activity. HBC abrogated AR interaction with CaM, suppressed phosphorylation of AR Serine81, and blocked the binding of AR to androgen-response elements. RNA-Seq analysis identified 57 androgen-regulated genes whose expression was significantly (p ≤ 0.002) altered in HBC treated cells as compared to controls. Oncomine analysis revealed that genes repressed by HBC are those that are usually overexpressed in prostate cancer (PCa) and genes stimulated by HBC are those that are often down-regulated in PCa, suggesting a reversing effect of HBC on androgen-regulated gene expression associated with PCa. Ingenuity Pathway Analysis revealed a role of HBC affected genes in cellular functions associated with proliferation and survival. HBC was readily absorbed into the systemic circulation and inhibited the growth of xenografted CRPC tumors in nude mice. These observations demonstrate that HBC inhibits AR activity by targeting the AR NTD and suggest potential usefulness of HBC for effective treatment of CRPC. PMID:25704883

  6. Niclosamide enhances abiraterone treatment via inhibition of androgen receptor variants in castration resistant prostate cancer.

    PubMed

    Liu, Chengfei; Armstrong, Cameron; Zhu, Yezi; Lou, Wei; Gao, Allen C

    2016-05-31

    Considerable evidence from both clinical and experimental studies suggests that androgen receptor variants, particularly androgen receptor variant 7 (AR-V7), are critical in the induction of resistance to enzalutamide and abiraterone. In this study, we investigated the role of AR-V7 in the cross-resistance of enzalutamide and abiraterone and examined if inhibition of AR-V7 can improve abiraterone treatment response. We found that enzalutamide-resistant cells are cross-resistant to abiraterone, and that AR-V7 confers resistance to abiraterone. Knock down of AR-V7 by siRNA in abiraterone resistant CWR22Rv1 and C4-2B MDVR cells restored their sensitivity to abiraterone, indicating that AR-V7 is involved in abiraterone resistance. Abiraterone resistant prostate cancer cells generated by chronic treatment with abiraterone showed enhanced AR-V7 protein expression. Niclosamide, an FDA-approved antihelminthic drug that has been previously identified as a potent inhibitor of AR-V7, re-sensitizes resistant cells to abiraterone treatment in vitro and in vivo. In summary, this preclinical study suggests that overexpression of AR-V7 contributes to resistance to abiraterone, and supports the development of combination of abiraterone with niclosamide as a potential treatment for advanced castration resistant prostate cancer.

  7. Marine compound rhizochalinin shows high in vitro and in vivo efficacy in castration resistant prostate cancer

    PubMed Central

    Alsdorf, Winfried H.; Hauschild, Jessica; Lange, Tobias; Venz, Simone; Bauer, Christiane K.; Bähring, Robert; Amann, Kerstin; Mandanchi, Ramin; Schumacher, Udo; Schröder-Schwarz, Jennifer; Makarieva, Tatyana N.; Guzii, Alla G.; Tabakmakher, Kseniya M.; Fedorov, Sergey N.; Shubina, Larisa K.; Kasheverov, Igor E.; Ehmke, Heimo; Steuber, Thomas; Stonik, Valentin A.; Bokemeyer, Carsten; Honecker, Friedemann; von Amsberg, Gunhild

    2016-01-01

    Development of drug resistance is an inevitable phenomenon in castration-resistant prostate cancer (CRPC) cells requiring novel therapeutic approaches. In this study, efficacy and toxicity of Rhizochalinin (Rhiz) – a novel sphingolipid-like marine compound – was evaluated in prostate cancer models, resistant to currently approved standard therapies. In vitro activity and mechanism of action of Rhiz were examined in the human prostate cancer cell lines PC-3, DU145, LNCaP, 22Rv1, and VCaP. Rhiz significantly reduced cell viability at low micromolar concentrations showing most pronounced effects in enzalutamide and abiraterone resistant AR-V7 positive cells. Caspase-dependent apoptosis, inhibition of pro-survival autophagy, downregulation of AR-V7, PSA and IGF-1 expression as well as inhibition of voltage-gated potassium channels were identified as mechanisms of action. Remarkably, Rhiz re-sensitized AR-V7 positive cells to enzalutamide and increased efficacy of taxanes. In vivo activity and toxicity were evaluated in PC-3 and 22Rv1 NOD SCID mouse xenograft models using i.p. administration. Rhiz significantly reduced growth of PC-3 and 22Rv1 tumor xenografts by 27.0% (p = 0.0156) and 46.8% (p = 0.047) compared with controls with an increased fraction of tumor cells showing apoptosis secondary to Rhiz exposure. In line with the in vitro data, Rhiz was most active in AR-V7 positive xenografts in vivo. In animals, no severe side effects were observed. In conclusion, Rhiz is a promising novel marine-derived compound characterized by a unique combination of anticancer properties. Its further clinical development is of high impact for patients suffering from drug resistant prostate cancer especially those harboring AR-V7 mediated resistance to enzalutamide and abiraterone. PMID:27626485

  8. Low-dose docetaxel, estramustine and prednisolone combination chemotherapy for castration-resistant prostate cancer

    PubMed Central

    NAKANO, MAYURA; SHOJI, SUNAO; HIGURE, TARO; KAWAKAMI, MASAYOSHI; TOMONAGA, TETSURO; TERACHI, TOSHIRO; UCHIDA, TOYOAKI

    2016-01-01

    The objective of this study was to report our experience with weekly low-dose docetaxel (DOC) chemotherapy for patients with castration-resistant prostate cancer (CRPC). From 2007 to 2014, 39 consecutive patients received weekly low-dose DOC; the oncological effectiveness, side effects and tolerability were prospectively analyzed. The median patient age, serum prostate-specific antigen (PSA) level and Gleason score at diagnosis of prostate cancer were 71 years (range, 55–83 years), 187 ng/ml (range, 2.0–1711 ng/ml) and 8 (range, 5–10), respectively. The median number of cycles of DOC was 7 (range, 1–45 cycles). Of the 39 patients, the PSA level decreased by >50% in 13 (33%). In the multivariate analysis of prediction of patient overall survival, a decrease of the PSA level to <50% was a significant predictor (hazard ratio = 6.913; 95% confidence interval: 1.147–41.669; P=0.035). The median cancer-specific overall survival from the diagnosis of CRPC was 16.7 months (range, 2–54 months). Grade 3 toxicities were observed in 5 patients (13%); specifically, limb edema, nausea and hepatic disorders were detected in 2 (5%), 2 (5%) and 1 patient (3%), respectively. Treatment-related death (grade 5) occurred in 1 patient due to interstitial pneumonia after two courses of chemotherapy. The chemotherapy was completed in the majority of the patients (n=37, 94.8%) in the outpatient department, without interruption. These findings suggest that weekly low-dose DOC is feasible and safe for selected patients with CRPC, without treament with novel agents, such as abiraterone, enzalutamide and cabazitaxel. PMID:27284427

  9. The Steroid Receptor Coactivator-3 Is Required for the Development of Castration-resistant Prostate Cancer

    PubMed Central

    Tien, Jean Ching-Yi; Liu, Zhaoliang; Liao, Lan; Wang, Fen; Xu, Yixiang; Wu, Ye-Lin; Zhou, Niya; Ittmann, Michael; Xu, Jianming

    2013-01-01

    The transcriptional coactivator SRC-3 plays a key role to enhance prostate cancer (CaP) cell proliferation. Although SRC-3 is highly expressed in advanced CaP, its role in castration resistant CaP (CRPC) driven by PTEN mutation is unknown. We documented elevated SRC-3 in human CRPC and in PTEN-negative human CaP. Patients with high SRC-3 and undetectable PTEN exhibited decreased recurrence-free survival. To explore the causal relationship in these observations, we generated mice in which both Pten and SRC-3 were inactivated in prostate epithelial cells (Pten3CKO mice), comparing them to mice in which only Pten was inactivated in these cells (PtenCKO mice). SRC-3 deletion impaired cellular proliferation and reduced tumor size. Notably, while castration of PtenCKO control mice increased the aggressiveness of prostate tumors relative to non-castrated counterparts, deletion of SRC-3 in Pten3CKO mice reversed all these changes. In support of this finding, castrated Pten3CKO mice also exhibited decreased levels of phospho-Akt, S6 kinase (RPS6KB1) and phosphorylated S6 protein (RPS6), all of which mediate cell growth and proliferation. Moreover, these tumors appeared to be more differentiated as evidenced by higher levels of Fkbp5, an AR-responsive gene that inhibits Akt signaling. Lastly, these tumors also displayed lower levels of certain androgen-repressed genes such as cyclin E2 and MMP10. Together, our results show that SRC-3 drives CRPC formation and offer preclinical proof of concept for a transcriptional coactivator as a therapeutic target to abrogate CRPC progression. PMID:23650284

  10. Ailanthone targets p23 to overcome MDV3100 resistance in castration-resistant prostate cancer

    PubMed Central

    He, Yundong; Peng, Shihong; Wang, Jinhua; Chen, Huang; Cong, Xiaonan; Chen, Ang; Hu, Meichun; Qin, Min; Wu, Haigang; Gao, Shuman; Wang, Liguo; Wang, Xin; Yi, Zhengfang; Liu, Mingyao

    2016-01-01

    Androgen receptor (AR) antagonist MDV3100 is the first therapeutic approach in treating castration-resistant prostate cancer (CRPC), but tumours frequently become drug resistant via multiple mechanisms including AR amplification and mutation. Here we identify the small molecule Ailanthone (AIL) as a potent inhibitor of both full-length AR (AR-FL) and constitutively active truncated AR splice variants (AR-Vs). AIL binds to the co-chaperone protein p23 and prevents AR's interaction with HSP90, thus resulting in the disruption of the AR-chaperone complex followed by ubiquitin/proteasome-mediated degradation of AR as well as other p23 clients including AKT and Cdk4, and downregulates AR and its target genes in PCa cell lines and orthotopic animal tumours. In addition, AIL blocks tumour growth and metastasis of CRPC. Finally, AIL possesses favourable drug-like properties such as good bioavailability, high solubility, lack of CYP inhibition and low hepatotoxicity. In general, AIL is a potential candidate for the treatment of CRPC. PMID:27959342

  11. Aurora A regulates expression of AR-V7 in models of castrate resistant prostate cancer

    PubMed Central

    Jones, Dominic; Noble, Martin; Wedge, Steve R.; Robson, Craig N.; Gaughan, Luke

    2017-01-01

    Androgen receptor variants (AR-Vs) provide a mechanism of therapy evasion in castrate-resistant prostate cancer (CRPC), yet mechanisms of regulation remain largely unknown. Here we investigate the role of Aurora A kinase on AR-Vs in models of CRPC and show depletion of Aurora A reduces AR-V target gene expression. Importantly, knockdown of Aurora A reconfigures splicing of AR pre-mRNA to discriminately down-regulate synthesis of AR-V transcripts, including AR-V7, without effecting full-length AR mRNA; and as a consequence, AR-V-driven proliferation and survival of CRPC cells is markedly reduced. Critically, these effects are reproduced by Aurora A inhibition. We show that Aurora A levels increase in advanced disease and AURKA is an AR-V target gene demonstrating a positive feedback mechanism of androgenic signalling in CRPC. In all, our data suggests that Aurora A plays a pivotal role in regulation of AR-V7 expression and represents a new therapeutic target in CRPC. PMID:28205582

  12. Economic evaluation of sipuleucel-T immunotherapy in castration-resistant prostate cancer.

    PubMed

    Holko, Przemysław; Kawalec, Paweł

    2014-01-01

    The objective is to examine the cost-utility of sipuleucel-T immunotherapy in asymptomatic or minimally symptomatic castration-resistant prostate cancer patients. The addition of sipuleucel-T immunotherapy to standard treatment led to a gain of 0.37 quality-adjusted life-year (QALY) at an additional cost of US$104,536. The incremental cost-utility ratio was US$283,000 per QALY saved. Threshold sensitivity analyses indicated that a price reduction of at least 53%, or application in a group of patients resulting in the relative reduction in the mortality rate of at least 39%, ought to augment the economic value of this regimen. Sipuleucel-T immunotherapy treatment at the current price with 96.5% certainty is not cost-effective. The specific group of patients who will benefit more from the treatment should be revealed and treated, or the cost of the vaccine should be lowered significantly to increase its economic value. Accounting for crossover treatment in control patients improves sipuleucel-T's value (US$132,000 per QALY saved) although further investigation is necessary.

  13. Aurora A regulates expression of AR-V7 in models of castrate resistant prostate cancer.

    PubMed

    Jones, Dominic; Noble, Martin; Wedge, Steve R; Robson, Craig N; Gaughan, Luke

    2017-02-16

    Androgen receptor variants (AR-Vs) provide a mechanism of therapy evasion in castrate-resistant prostate cancer (CRPC), yet mechanisms of regulation remain largely unknown. Here we investigate the role of Aurora A kinase on AR-Vs in models of CRPC and show depletion of Aurora A reduces AR-V target gene expression. Importantly, knockdown of Aurora A reconfigures splicing of AR pre-mRNA to discriminately down-regulate synthesis of AR-V transcripts, including AR-V7, without effecting full-length AR mRNA; and as a consequence, AR-V-driven proliferation and survival of CRPC cells is markedly reduced. Critically, these effects are reproduced by Aurora A inhibition. We show that Aurora A levels increase in advanced disease and AURKA is an AR-V target gene demonstrating a positive feedback mechanism of androgenic signalling in CRPC. In all, our data suggests that Aurora A plays a pivotal role in regulation of AR-V7 expression and represents a new therapeutic target in CRPC.

  14. FOXA1 regulates androgen receptor variant activity in models of castrate-resistant prostate cancer

    PubMed Central

    Nakjang, Sirintra; Chaytor, Lewis; Grey, James; Robson, Craig N.; Gaughan, Luke

    2015-01-01

    Retention of androgen receptor (AR) signalling in castrate-resistant prostate cancer (CRPC) highlights the requirement for the development of more effective AR targeting therapies. A key mechanism of resistance to anti-androgens is through expression of constitutively active AR variants (AR-Vs) that are refractory to next-generation therapies, including Enzalutamide and Abiraterone. By maintaining an androgenic gene signature, AR-Vs drive tumour survival and progression in castrate conditions. Critically, however, our understanding of the mechanics of AR-V-driven transcription is limited, particularly with respect to dependency on pioneer factor function. Here we show that depletion of FOXA1 in the CWR22Rv1 CRPC cell line abrogates the oncogenic potential of AR-Vs. Gene expression profiling reveals that approximately 41% of the AR-V transcriptome requires FOXA1 and that depletion of FOXA1 attenuates AR-V binding at a sub-set of analysed co-regulated genes. Interestingly, AR-V levels are elevated in cells depleted of FOXA1 as a consequence of attenuated negative feedback on the AR gene, but is insufficient to maintain cell growth as evidenced by marked anti-proliferative effects in FOXA1 knockdown cells. In all, our data suggests that AR-Vs are dependent on FOXA1 for sustaining a pro-proliferative gene signature and agents targeting FOXA1 may represent novel therapeutic options for CRPC patients. PMID:26336819

  15. FOXA1 regulates androgen receptor variant activity in models of castrate-resistant prostate cancer.

    PubMed

    Jones, Dominic; Wade, Mark; Nakjang, Sirintra; Chaytor, Lewis; Grey, James; Robson, Craig N; Gaughan, Luke

    2015-10-06

    Retention of androgen receptor (AR) signalling in castrate-resistant prostate cancer (CRPC) highlights the requirement for the development of more effective AR targeting therapies. A key mechanism of resistance to anti-androgens is through expression of constitutively active AR variants (AR-Vs) that are refractory to next-generation therapies, including Enzalutamide and Abiraterone. By maintaining an androgenic gene signature, AR-Vs drive tumour survival and progression in castrate conditions. Critically, however, our understanding of the mechanics of AR-V-driven transcription is limited, particularly with respect to dependency on pioneer factor function. Here we show that depletion of FOXA1 in the CWR22Rv1 CRPC cell line abrogates the oncogenic potential of AR-Vs. Gene expression profiling reveals that approximately 41% of the AR-V transcriptome requires FOXA1 and that depletion of FOXA1 attenuates AR-V binding at a sub-set of analysed co-regulated genes. Interestingly, AR-V levels are elevated in cells depleted of FOXA1 as a consequence of attenuated negative feedback on the AR gene, but is insufficient to maintain cell growth as evidenced by marked anti-proliferative effects in FOXA1 knockdown cells. In all, our data suggests that AR-Vs are dependent on FOXA1 for sustaining a pro-proliferative gene signature and agents targeting FOXA1 may represent novel therapeutic options for CRPC patients.

  16. Downregulation of c-SRC kinase CSK promotes castration resistant prostate cancer and pinpoints a novel disease subclass.

    PubMed

    Yang, Chih-Cheng; Fazli, Ladan; Loguercio, Salvatore; Zharkikh, Irina; Aza-Blanc, Pedro; Gleave, Martin E; Wolf, Dieter A

    2015-09-08

    SRC kinase is activated in castration resistant prostate cancer (CRPC), phosphorylates the androgen receptor (AR), and causes its ligand-independent activation as a transcription factor. However, activating SRC mutations are exceedingly rare in human tumors, and mechanisms of ectopic SRC activation therefore remain largely unknown. Performing a functional genomics screen, we found that downregulation of SRC inhibitory kinase CSK is sufficient to overcome growth arrest induced by depriving human prostate cancer cells of androgen. CSK knockdown led to ectopic SRC activation, increased AR signaling, and resistance to anti-androgens. Consistent with the in vitro observations, stable knockdown of CSK conferred castration resistance in mouse xenograft models, while sensitivity to the tyrosine kinase inhibitor dasatinib was retained. Finally, CSK was found downregulated in a distinct subset of CRPCs marked by AR amplification and ETS2 deletion but lacking PTEN and RB1 mutations. These results identify CSK downregulation as a principal driver of SRC activation and castration resistance and validate SRC as a drug target in a molecularly defined subclass of CRPCs.

  17. Downregulation of c-SRC kinase CSK promotes castration resistant prostate cancer and pinpoints a novel disease subclass

    PubMed Central

    Yang, Chih-Cheng; Fazli, Ladan; Loguercio, Salvatore; Zharkikh, Irina; Aza-Blanc, Pedro; Gleave, Martin E.; Wolf, Dieter A.

    2015-01-01

    SRC kinase is activated in castration resistant prostate cancer (CRPC), phosphorylates the androgen receptor (AR), and causes its ligand-independent activation as a transcription factor. However, activating SRC mutations are exceedingly rare in human tumors, and mechanisms of ectopic SRC activation therefore remain largely unknown. Performing a functional genomics screen, we found that downregulation of SRC inhibitory kinase CSK is sufficient to overcome growth arrest induced by depriving human prostate cancer cells of androgen. CSK knockdown led to ectopic SRC activation, increased AR signaling, and resistance to anti-androgens. Consistent with the in vitro observations, stable knockdown of CSK conferred castration resistance in mouse xenograft models, while sensitivity to the tyrosine kinase inhibitor dasatinib was retained. Finally, CSK was found downregulated in a distinct subset of CRPCs marked by AR amplification and ETS2 deletion but lacking PTEN and RB1 mutations. These results identify CSK downregulation as a principal driver of SRC activation and castration resistance and validate SRC as a drug target in a molecularly defined subclass of CRPCs. PMID:26091350

  18. Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3

    PubMed Central

    Morris, Michael J.; Stadler, Walter M.; Higano, Celestia; Basch, Ethan; Fizazi, Karim; Antonarakis, Emmanuel S.; Beer, Tomasz M.; Carducci, Michael A.; Chi, Kim N.; Corn, Paul G.; de Bono, Johann S.; Dreicer, Robert; George, Daniel J.; Heath, Elisabeth I.; Hussain, Maha; Kelly, Wm. Kevin; Liu, Glenn; Logothetis, Christopher; Nanus, David; Stein, Mark N.; Rathkopf, Dana E.; Slovin, Susan F.; Ryan, Charles J.; Sartor, Oliver; Small, Eric J.; Smith, Matthew Raymond; Sternberg, Cora N.; Taplin, Mary-Ellen; Wilding, George; Nelson, Peter S.; Schwartz, Lawrence H.; Halabi, Susan; Kantoff, Philip W.; Armstrong, Andrew J.

    2016-01-01

    Purpose Evolving treatments, disease phenotypes, and biology, together with a changing drug development environment, have created the need to revise castration-resistant prostate cancer (CRPC) clinical trial recommendations to succeed those from prior Prostate Cancer Clinical Trials Working Groups. Methods An international expert committee of prostate cancer clinical investigators (the Prostate Cancer Clinical Trials Working Group 3 [PCWG3]) was reconvened and expanded and met in 2012-2015 to formulate updated criteria on the basis of emerging trial data and validation studies of the Prostate Cancer Clinical Trials Working Group 2 recommendations. Results PCWG3 recommends that baseline patient assessment include tumor histology, detailed records of prior systemic treatments and responses, and a detailed reporting of disease subtypes based on an anatomic pattern of metastatic spread. New recommendations for trial outcome measures include the time to event end point of symptomatic skeletal events, as well as time to first metastasis and time to progression for trials in the nonmetastatic CRPC state. PCWG3 introduces the concept of no longer clinically benefiting to underscore the distinction between first evidence of progression and the clinical need to terminate or change treatment, and the importance of documenting progression in existing lesions as distinct from the development of new lesions. Serial biologic profiling using tumor samples from biopsies, blood-based diagnostics, and/or imaging is also recommended to gain insight into mechanisms of resistance and to identify predictive biomarkers of sensitivity for use in prospective trials. Conclusion PCWG3 moves drug development closer to unmet needs in clinical practice by focusing on disease manifestations most likely to affect prognosis adversely for therapeutics tested in both nonmetastatic and metastatic CRPC populations. Consultation with regulatory authorities is recommended if a trial is intended to seek

  19. Treatment of castration-resistant prostate cancer and bone metastases with radium-223 dichloride

    PubMed Central

    Lien, Lise Marie E; Tvedt, Birger; Heinrich, Daniel

    2015-01-01

    Radium-223 dichloride (Ra-223) is the first α-particle emitting radiopharmaceutical to be approved for the treatment of patients with castration-resistant prostate cancer and associated bone metastases, and the first bone-targeting agent to significantly improve patient overall survival whilst reducing pain and the symptomatic skeletal events (SSEs) associated with bone metastases. Ra-223 exhibits a favourable safety profile, with low myelosuppression rates and fewer adverse events than placebo. Compared with other approved radiopharmaceuticals, the α-particle emitting Ra-223 has a high biological efficiency and a short penetration range, potentially sparing bone marrow toxicity and limiting unwanted exposure. Ra-223 has a short half-life and decays to a stable product, reducing the problem of storage and disposal associated with radiopharmaceuticals. Ra-223 offers a new treatment option with great potential in this setting. However, concerns remain amongst patients, their families and health care professionals over the use of radiopharmaceuticals. This article, which draws on the experiences of health care workers during the ALSYMPCA (ALpharadin in SYMtomatic Prostate CAncer) study, reviews the clinical development of Ra-223, highlighting the key issues for the uro-oncology nurse who has a pivotal role within the multi-disciplinary team (MDT) to ensure safe and effective treatment to the patient. The role of the uro-oncology nurse is multifaceted, including patient pre-assessment and post-treatment monitoring and coordination of the MDT. In addition, their role in communicating with and educating those involved with Ra-223 on what to expect from the agent can alleviate fears associated with its use. PMID:26097500

  20. Crosstalk of the Androgen Receptor with Transcriptional Collaborators: Potential Therapeutic Targets for Castration-Resistant Prostate Cancer

    PubMed Central

    Obinata, Daisuke; Takayama, Kenichi; Takahashi, Satoru; Inoue, Satoshi

    2017-01-01

    Prostate cancer is the second leading cause of death from cancer among males in Western countries. It is also the most commonly diagnosed male cancer in Japan. The progression of prostate cancer is mainly influenced by androgens and the androgen receptor (AR). Androgen deprivation therapy is an established therapy for advanced prostate cancer; however, prostate cancers frequently develop resistance to low testosterone levels and progress to the fatal stage called castration-resistant prostate cancer (CRPC). Surprisingly, AR and the AR signaling pathway are still activated in most CRPC cases. To overcome this problem, abiraterone acetate and enzalutamide were introduced for the treatment of CRPC. Despite the impact of these drugs on prolonged survival, CRPC acquires further resistance to keep the AR pathway activated. Functional molecular studies have shown that some of the AR collaborative transcription factors (TFs), including octamer transcription factor (OCT1), GATA binding protein 2 (GATA2) and forkhead box A1 (FOXA1), still stimulate AR activity in the castration-resistant state. Therefore, elucidating the crosstalk between the AR and collaborative TFs on the AR pathway is critical for developing new strategies for the treatment of CRPC. Recently, many compounds targeting this pathway have been developed for treating CRPC. In this review, we summarize the AR signaling pathway in terms of AR collaborators and focus on pyrrole-imidazole (PI) polyamide as a candidate compound for the treatment of prostate cancer. PMID:28264478

  1. Epithelial mesenchymal-like transition occurs in a subset of cells in castration resistant prostate cancer bone metastases.

    PubMed

    Haider, Maahum; Zhang, Xiaotun; Coleman, Ilsa; Ericson, Nolan; True, Lawrence D; Lam, Hung-Ming; Brown, Lisha G; Ketchanji, Melanie; Nghiem, Belinda; Lakely, Bryce; Coleman, Roger; Montgomery, Bruce; Lange, Paul H; Roudier, Martine; Higano, Celestia S; Bielas, Jason H; Nelson, Peter S; Vessella, Robert L; Morrissey, Colm

    2016-03-01

    TGFβ is a known driver of epithelial-mesenchymal transition (EMT) which is associated with tumor aggressiveness and metastasis. However, EMT has not been fully explored in clinical specimens of castration-resistant prostate cancer (CRPC) metastases. To assess EMT in CRPC, gene expression analysis was performed on 149 visceral and bone metastases from 62 CRPC patients and immunohistochemical analysis was performed on 185 CRPC bone and visceral metastases from 42 CRPC patients. In addition, to assess the potential of metastases to seed further metastases the mitochondrial genome was sequenced at different metastatic sites in one patient. TGFβ was increased in bone versus visceral metastases. While primarily cytoplasmic; nuclear and cytoplasmic Twist were significantly higher in bone than in visceral metastases. Slug and Zeb1 were unchanged, with the exception of nuclear Zeb1 being significantly higher in visceral metastases. Importantly, nuclear Twist, Slug, and Zeb1 were only present in a subset of epithelial cells that had an EMT-like phenotype. Underscoring the relevance of EMT-like cells, mitochondrial sequencing revealed that metastases could seed additional metastases in the same patient. In conclusion, while TGFβ expression and EMT-associated protein expression is present in a considerable number of CRPC visceral and bone metastases, nuclear Twist, Slug, and Zeb1 localization and an EMT-like phenotype (elongated nuclei and cytoplasmic compartment) was only present in a small subset of CRPC bone metastases. Mitochondrial sequencing from different metastases in a CRPC patient provided evidence for the seeding of metastases from previously established metastases, highlighting the biological relevance of EMT-like behavior in CRPC metastases.

  2. Registered report: the androgen receptor induces a distinct transcriptional program in castration-resistant prostate cancer in man

    PubMed Central

    Chronscinski, Denise; Cherukeri, Srujana; Tan, Fraser; Lomax, Joelle; Iorns, Elizabeth

    2015-01-01

    The Prostate Cancer Foundation-Movember Foundation Reproducibility Initiative (PCFMFRI) seeks to address growing concerns about reproducibility in scientific research by conducting replications of recent papers in the field of prostate cancer. This Registered Report describes the proposed replication plan of key experiments from “The Androgen Receptor Induces a Distinct Transcriptional Program in Castration-Resistant Prostate Cancer in Man” by Sharma and colleagues (2013), published in Cancer Cell in 2013. Of thousands of targets for the androgen receptor (AR), the authors elucidated a subset of 16 core genes that were consistently downregulated with castration and re-emerged with castration resistance. These 16 AR binding sites were distinct from those observed in cells in culture. The authors suggested that cellular context can have dramatic effects on downstream transcriptional regulation of AR binding sites. The present study will attempt to replicate Fig. 7C by comparing gene expression of the 16 core genes identified by Sharma and colleagues in xenograft tumor tissue compared to androgen treated LNCaP cells in vitro. The Prostate Cancer Foundation-Movember Foundation Reproducibility Initiative is a collaboration between the Prostate Cancer Foundation, the Movember Initiative, and Science Exchange, and the results of the replications will be published by PeerJ. PMID:26401447

  3. Curcumin induces apoptosis and protective autophagy in castration-resistant prostate cancer cells through iron chelation

    PubMed Central

    Yang, Chunguang; Ma, Xueyou; Wang, Zhihua; Zeng, Xing; Hu, Zhiquan; Ye, Zhangqun; Shen, Guanxin

    2017-01-01

    Background Curcumin induces apoptosis and autophagy in different cancer cells. Moreover, chemical and biological experiments have evidenced that curcumin is a biologically active iron chelator and induces cytotoxicity through iron chelation. We thus hypothesized that curcumin may induce apoptosis and autophagy in castration-resistant prostate cancer (CRPC) cells through its iron-chelating properties. Materials and methods CRPC cells were loaded with curcumin alone or in combination with ferric ammonium citrate (FAC). Cytotoxicity was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was assessed by flow cytometry, terminal deoxynucleotidyl transferase nick end labeling (TUNEL) assay and caspase activity. Autophagy status was analyzed by the detection of autophagosomes and light chain 3-II (LC3-II) using transmission electron microscopy and Western blot. Iron-binding activity of curcumin was assessed by spectrophotometry and MTT assay. The expression levels of transferrin receptor 1 (TfR1) and iron regulatory protein 1 (IRP1) were examined by Western blot. Results Curcumin induced apoptosis and autophagy in CRPC cells. Combining curcumin with autophagy inhibitors (3-methyladenine [3-MA]) synergized the apoptotic effect of curcumin. Moreover, curcumin bound to FAC at a ratio of ~1:1, as assessed by spectrophotometry and MTT assay. Apoptosis and autophagy induced by curcumin were counteracted by equal amounts of FAC. At apoptosis- and autophagy-inducing concentrations, curcumin enhanced the expression levels of TfR1 and IRP1, indicative of iron deprivation induced by curcumin. Conclusion Together, our results indicate that curcumin induces apoptosis and protective autophagy in CRPC cells, which are at least partially dependent on its iron-chelating properties. PMID:28243065

  4. Uncarboxylated Osteocalcin and Gprc6a Axis Produce Intratumoral Androgens in Castration-Resistant Prostate Cancer

    DTIC Science & Technology

    2015-03-01

    at metastatic sites by the activity of androgen biosynthetic enzymes . Recent study shows that Gprc6a/Osteocalcin axis regulates physiological... enzymes . This data suggest that prostate cancer bone tumors hijack Osteocalcin/Gprc6a axis for the production of intratumoral androgens via...overexpression of certain androgen biosynthetic enzyme expression. Bone tumor expressed androgens promote disease progression via tumoral androgen production

  5. [Alpha emitter radium-223 dichloride: new therapy in castration-resistant prostate cancer with symptomatic bone metastases].

    PubMed

    Heinzer, H; König, F; Klutmann, S

    2014-04-01

    Radium-223 dichloride (Ra-223) is an alpha emitter with low toxicity for the treatment of patients with castrations-resistant prostate cancer (CRPC) and symptomatic bone metastases showing a 30% reduction in the risk of death, as compared to placebo. Because of the favorable physical and chemical characteristics, Ra-223 can be handled easily in daily practice based on interdisciplinary co-operation between urology and nuclear medicine. Ra-223 has been approved under the product name Xofigo® by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

  6. The Stromal Contribution to the Development of Resistance to New-Generation Drugs by Castration-Resistant Prostate Cancer

    DTIC Science & Technology

    2015-10-01

    AD______________ AWARD NUMBER: W81XWH-13-1-0379 TITLE: The Stromal Contribution to the Development of Resistance to New-Generation Drugs by...Generation Drugs by Castration-Resistant Prostate Cancer 5b. GRANT NUMBER W81XWH-13-1-0379 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Lubik, Amy Anne, PhD 5d...supports renewed activity of the androgen receptor (AR) in tumor cells thus enabling tumor re-growth(3). While new generation of drugs (abiraterone [abi] or

  7. State-of-the-Art Management for the Patient with Castration-Resistant Prostate Cancer in 2012.

    PubMed

    Sartor, Oliver

    2012-01-01

    Much progress has been made in metastatic castration-resistant prostate cancer (CRPC), and multiple new U.S. Food and Drug Administration (FDA)-approved survival-prolonging drugs are now available. In 2004, docetaxel/prednisone was the first therapy shown to prolong survival. In 2010 and 2011, sipuleucel-T, cabazitaxel/prednisone, and abiraterone/prednisone were FDA approved. Two new agents, radium-223 and MDV-3100, have recently reported large phase III trials prolonging overall survival and will be submitted for regulatory approval in 2012. One can now begin to ask, is there an optimal sequence for therapies in metastatic CRPC? Despite the recent progress, there is much we do not know and virtually no information on this important question. We know that abiraterone/prednisone and cabazitaxel/prednisone are appropriate choices for a patient after receiving docetaxel, but we do not know what, if anything, represents the optimal sequence for abiraterone and cabazitaxel. In fact we do not understand how one therapy may affect the response to a subsequent therapy. We are also aware that the pre- and postdocetaxel spaces represent regulatory rather than biologic divisions. In addition, despite the proven role of docetaxel/prednisone, many patients with CRPC are not considered to be suitable for chemotherapy, and worldwide many never receive any form of chemotherapy. What is the optimal management for these patients? Taken together it is reasonable to assess patient preferences, prior therapies and response/tolerance to prior therapies, burden of disease, comorbidities, current symptoms, drug toxicities, out-of-pocket costs, etc., in clinical decision making. Given the many factors we do not know, it is hard to be dogmatic in approaching the therapeutic options for the patient with CRPC. We will likely soon move beyond the current sequencing paradigm and begin to assess new combinations in a systematic and rational fashion. Perhaps one day, in the not too distant future

  8. N-Cadherin in Prostate Cancer: Downstream Pathways and Their Translational Application for Castrate-Resistant Prostate Cancer

    DTIC Science & Technology

    2012-09-01

    primary prostate cancer, although some patients will experience disease recurrence. Standard treatment for recurrent prostate cancer is androgen... diseases : lessons from a rapid autopsy program. Cancer Res. 2004;64(24):9209-16. PubMed PMID: 15604294. -19- A r t i c l e s 1414 VOLUME 16 | NUMBER 12...DECEMBER 2010 nAture medicine Men with prostate cancer die predominantly from metastatic disease that is resistant to androgen deprivation therapy

  9. Inhibition of Pten deficient Castration Resistant Prostate Cancer by Targeting of the SET - PP2A Signaling axis.

    PubMed

    Hu, Xiaoyong; Garcia, Consuelo; Fazli, Ladan; Gleave, Martin; Vitek, Michael P; Jansen, Marilyn; Christensen, Dale; Mulholland, David J

    2015-11-13

    The PP2A signaling axis regulates multiple oncogenic drivers of castration resistant prostate cancer (CRPC). We show that targeting the endogenous PP2A regulator, SET (I2PP2A), is a viable strategy to inhibit prostate cancers that are resistant to androgen deprivation therapy. Our data is corroborated by analysis of prostate cancer patient cohorts showing significant elevation of SET transcripts. Tissue microarray analysis reveals that elevated SET expression correlates with clinical cancer grading, duration of neoadjuvant hormone therapy (NHT) and time to biochemical recurrence. Using prostate regeneration assays, we show that in vivo SET overexpression is sufficient to induce hyperplasia and prostatic intraepithelial neoplasia. Knockdown of SET induced significant reductions in tumorgenesis both in murine and human xenograft models. To further validate SET as a therapeutic target, we conducted in vitro and in vivo treatments using OP449 - a recently characterized PP2A-activating drug (PAD). OP449 elicits robust anti-cancer effects inhibiting growth in a panel of enzalutamide resistant prostate cancer cell lines. Using the Pten conditional deletion mouse model of prostate cancer, OP449 potently inhibited PI3K-Akt signaling and impeded CRPC progression. Collectively, our data supports a critical role for the SET-PP2A signaling axis in CRPC progression and hormone resistant disease.

  10. Inhibition of Pten deficient Castration Resistant Prostate Cancer by Targeting of the SET - PP2A Signaling axis

    PubMed Central

    Hu, Xiaoyong; Garcia, Consuelo; Fazli, Ladan; Gleave, Martin; Vitek, Michael P.; Jansen, Marilyn; Christensen, Dale; Mulholland, David J

    2015-01-01

    The PP2A signaling axis regulates multiple oncogenic drivers of castration resistant prostate cancer (CRPC). We show that targeting the endogenous PP2A regulator, SET (I2PP2A), is a viable strategy to inhibit prostate cancers that are resistant to androgen deprivation therapy. Our data is corroborated by analysis of prostate cancer patient cohorts showing significant elevation of SET transcripts. Tissue microarray analysis reveals that elevated SET expression correlates with clinical cancer grading, duration of neoadjuvant hormone therapy (NHT) and time to biochemical recurrence. Using prostate regeneration assays, we show that in vivo SET overexpression is sufficient to induce hyperplasia and prostatic intraepithelial neoplasia. Knockdown of SET induced significant reductions in tumorgenesis both in murine and human xenograft models. To further validate SET as a therapeutic target, we conducted in vitro and in vivo treatments using OP449 - a recently characterized PP2A-activating drug (PAD). OP449 elicits robust anti-cancer effects inhibiting growth in a panel of enzalutamide resistant prostate cancer cell lines. Using the Pten conditional deletion mouse model of prostate cancer, OP449 potently inhibited PI3K-Akt signaling and impeded CRPC progression. Collectively, our data supports a critical role for the SET-PP2A signaling axis in CRPC progression and hormone resistant disease. PMID:26563471

  11. The N-terminal domain of the androgen receptor drives its nuclear localization in castration-resistant prostate cancer cells

    PubMed Central

    Dar, Javid A.; Masoodi, Khalid Z.; Eisermann, Kurtis; Isharwal, Sudhir; Ai, Junkui; Pascal, Laura E.; Nelson, Joel B.; Wang, Zhou

    2014-01-01

    Androgen-independent nuclear localization is required for androgen receptor (AR) transactivation in castration-resistant prostate cancer (CRPC) and should be a key step leading to castration resistance. However, mechanism(s) leading to androgen-independent AR nuclear localization are poorly understood. Since the N-terminal domain (NTD) of AR plays a role in transactivation under androgen-depleted conditions, we investigated the role of NTD in AR nuclear localization in CRPC. Deletion mutagenesis was used to identify amino acid sequences in the NTD essential for its androgen-independent nuclear localization in C4-2, a widely used CRPC cell line. Deletion mutants of AR tagged with green fluorescent protein (GFP) at the 5`-end were generated and their signal distribution was investigated in C4-2 cells by fluorescent microscopy. Our results showed that the region of a.a. 294–556 was required for androgen-independent AR nuclear localization whereas a.a. 1–293 mediates Hsp90 regulation of AR nuclear localization in CRPC cells. Although a.a. 294–556 does not contain a nuclear import signal, it was able to enhance DHT-induced import of the ligand binding domain (LBD). Also, transactivation of the NTD could be uncoupled from its modulation of AR nuclear localization in C4-2 cells. These observations suggest an important role of NTD in AR intracellular trafficking and androgen-independent AR nuclear localization in CRPC cells. PMID:24662325

  12. MicroRNAs and Androgen Receptor 3′ Untranslated Region: A Missing Link in Castration-resistant Prostate Cancer?

    PubMed Central

    Sikand, Kavleen; Barik, Sailen; Shukla, Girish C.

    2012-01-01

    The ligand-activated transcription factor, androgen receptor (AR) plays a central role in the development and progression of prostate cancer. Prostate cancer initiates as an androgen-dependent disease and further accumulation of multiple sequential genetic and epigenetic alterations transform it into an aggressive, castration-resistant prostate cancer (CRPC). The molecular basis of the transition from androgen-dependent prostate cancer to CRPC remains unclear. However, it is apparent that AR plays a pivotal role in this alteration. The recent discovery that microRNAs (miRNAs) can target the function of AR suggests a functional role of these non-coding RNAs in the pathogenesis of prostate cancer. miRNAs usually function by targeting the 3′ untranslated region (UTR) of a mRNA by base-pairing interactions and modulate translation either by destabilizing the message or by repression of protein synthesis in actively translating ribosomes. Here, we discuss the potential molecular pathways through which AR targeting miRNAs may promote CRPC. Modulation of AR expression by miRNAs presents a novel therapeutic option for prostate cancer, albeit it will likely be used in combination with the existing therapies. PMID:22468168

  13. Gradual reduction of testosterone using a gonadotropin-releasing hormone vaccination delays castration resistance in a prostate cancer model.

    PubMed

    Barranco, Jesús A Junco; Millar, Robert P; Fuentes, Franklin; Bover, Eddy; Pimentel, Eulogio; Basulto, Roberto; Calzada, Lesvia; Morán, Rolando; Rodríguez, Ayni; Garay, Hilda; Reyes, Osvaldo; Castro, Maria D; Bringas, Ricardo; Arteaga, Niurka; Toudurí, Henio; Rabassa, Mauricio; Fernández, Yairis; Serradelo, Andrés; Hernández, Eduardo; Guillén, Gerardo E

    2016-08-01

    In a previous study aimed to design a novel prostate cancer vaccine, the authors of the present study demonstrated the advantage of combining the adjuvants Montanide ISA 51 with very small size proteoliposomes (VSSP) to promote a significant humoral immune response to gonadotropin-releasing hormone (GnRH) in healthy animals. The present study compared the efficacy of this vaccine formulation versus the standard treatment currently available in terms of preventing the development of tumors in DD/S mice injected with Shionogi carcinoma (SC) 115 cells. The results demonstrated that 5 non-vaccinated control mice exhibited a fast tumor growth, and succumbed to the disease within 19-31 days. Mice immunized with the GnRH/Montanide ISA 51/VSSP vaccine exhibited a moderate decline in testosterone levels that was associated with a decrease in anti-GnRH antibody titers, which lead to a sustained tumor growth inhibition. In total, 2 mice in the immunized group exhibited complete remission of the tumor for the duration of the present study. In addition, castrated mice, which were used as a control for standard hormonal therapy, exhibited an accelerated decrease in tumor size. However, tumor relapse was observed between days 50 and 54, and between days 65 and 85, following the injection of SC 155 cells. Therefore, these mice were sacrificed at day 90. The present study concludes that the slow and moderate reduction of testosterone levels observed using the GnRH-based vaccine may delay the appearance of castration resistance in a Shionogi prostate cancer model. These findings suggest that this vaccine may be used to delay castration resistance in patients with prostate cancer.

  14. Gradual reduction of testosterone using a gonadotropin-releasing hormone vaccination delays castration resistance in a prostate cancer model

    PubMed Central

    Barranco, Jesús A. Junco; Millar, Robert P.; Fuentes, Franklin; Bover, Eddy; Pimentel, Eulogio; Basulto, Roberto; Calzada, Lesvia; Morán, Rolando; Rodríguez, Ayni; Garay, Hilda; Reyes, Osvaldo; Castro, Maria D.; Bringas, Ricardo; Arteaga, Niurka; Toudurí, Henio; Rabassa, Mauricio; Fernández, Yairis; Serradelo, Andrés; Hernández, Eduardo; Guillén, Gerardo E.

    2016-01-01

    In a previous study aimed to design a novel prostate cancer vaccine, the authors of the present study demonstrated the advantage of combining the adjuvants Montanide ISA 51 with very small size proteoliposomes (VSSP) to promote a significant humoral immune response to gonadotropin-releasing hormone (GnRH) in healthy animals. The present study compared the efficacy of this vaccine formulation versus the standard treatment currently available in terms of preventing the development of tumors in DD/S mice injected with Shionogi carcinoma (SC) 115 cells. The results demonstrated that 5 non-vaccinated control mice exhibited a fast tumor growth, and succumbed to the disease within 19–31 days. Mice immunized with the GnRH/Montanide ISA 51/VSSP vaccine exhibited a moderate decline in testosterone levels that was associated with a decrease in anti-GnRH antibody titers, which lead to a sustained tumor growth inhibition. In total, 2 mice in the immunized group exhibited complete remission of the tumor for the duration of the present study. In addition, castrated mice, which were used as a control for standard hormonal therapy, exhibited an accelerated decrease in tumor size. However, tumor relapse was observed between days 50 and 54, and between days 65 and 85, following the injection of SC 155 cells. Therefore, these mice were sacrificed at day 90. The present study concludes that the slow and moderate reduction of testosterone levels observed using the GnRH-based vaccine may delay the appearance of castration resistance in a Shionogi prostate cancer model. These findings suggest that this vaccine may be used to delay castration resistance in patients with prostate cancer. PMID:27446378

  15. A novel HSP90 inhibitor delays castrate resistant prostate cancer without altering serum PSA levels and inhibits osteoclastogenesis

    PubMed Central

    Lamoureux, Francois; Thomas, Christian; Yin, Min-Jean; Kuruma, Hidetoshi; Fazli, Ladan; Gleave, Martin E; Zoubeidi, Amina

    2015-01-01

    Purpose Prostate cancer responds initially to anti-androgen therapies, however, progression to castration resistant disease frequently occurs. Therefore there is an urgent need for novel therapeutic agents that can prevent the emergence of castration resistant prostate cancer (CRPC). Hsp90 is a molecular chaperone involved in the stability of many client proteins including Akt and androgen receptor (AR). 17-AAG have been reported to inhibit tumor growth in various cancers, however induces tumor progression in the bone microenvironment. Methods Cell growth, apoptosis, and AR transactivation were examined by crystal violet assay, flow cytometry and luciferase assays respectively. The consequence of HSP90 therapy in vivo was evaluated in LNCaP xenograft model. The consequence of PF-04928473 therapy on bone metastasis was studied using an osteoclastogenesis in vitro assay. Results PF-04928473 inhibits cell growth in a panel of prostate cancer cells, induces cell cycle arrest at sub-G1 and leads to apoptosis and increased caspase-3 activity. These biologic events were accompanied by decreased activation of Akt and Erk as well as decreased expression of Her2, and decreased AR expression and activation in vitro. In contrast to 17-AAG, PF-04928473 abrogates RANKL-induced osteoclast differentiation by affecting NF-kB activation and Src phosphorylation. Finally, PF-04929113 inhibited tumor growth and prolonged survival compared to controls. Surprisingly, PF-04929113 did not reduce serum PSA levels in vivo in parallel these decreases in tumor volume. Conclusion These data identify significant anti-cancer activity of PF-04929113 in CRPC but suggest that serum PSA may not prove useful as pharmaco-dynamic tool for this drug. PMID:21349995

  16. Targeting of CYP17A1 Lyase by VT-464 Inhibits Adrenal and Intratumoral Androgen Biosynthesis and Tumor Growth of Castration Resistant Prostate Cancer

    PubMed Central

    Maity, Sankar N.; Titus, Mark A.; Gyftaki, Revekka; Wu, Guanglin; Lu, Jing-Fang; Ramachandran, S.; Li-Ning-Tapia, Elsa M.; Logothetis, Christopher J.; Araujo, John C.; Efstathiou, Eleni

    2016-01-01

    Cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) is a validated treatment target for the treatment of metastatic castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA) inhibits both 17α-hydroxylase (hydroxylase) and 17,20-lyase (lyase) reactions catalyzed by CYP17A1 and thus depletes androgen biosynthesis. However, coadministration of prednisone is required to suppress the mineralocorticoid excess and cortisol depletion that result from hydroxylase inhibition. VT-464, a nonsteroidal small molecule, selectively inhibits CYP17A1 lyase and therefore does not require prednisone supplementation. Administration of VT-464 in a metastatic CRPC patient presenting with high tumoral expression of both androgen receptor (AR) and CYP17A1, showed significant reduction in the level of both dehydroepiandrosterone (DHEA) and serum PSA. Treatment of a CRPC patient-derived xenograft, MDA-PCa-133 expressing H874Y AR mutant with VT-464, reduced the increase in tumor volume in castrate male mice more than twice as much as the vehicle (P < 0.05). Mass spectrometry analysis of post-treatment xenograft tumor tissues showed that VT-464 significantly decreased intratumoral androgens but not cortisol. VT-464 also reduced AR signaling more effectively than abiraterone in cultured PCa cells expressing T877A AR mutant. Collectively, this study suggests that VT-464 therapy can effectively treat CRPC and be used in precision medicine based on androgen receptor mutation status. PMID:27748439

  17. SRRM4 Expression and the Loss of REST Activity May Promote the Emergence of the Neuroendocrine Phenotype in Castration-Resistant Prostate Cancer

    PubMed Central

    Zhang, Xiaotun; Coleman, Ilsa M.; Brown, Lisha G.; True, Lawrence D.; Kollath, Lori; Lucas, Jared M.; Lam, Hung-Ming; Dumpit, Ruth; Corey, Eva; Chéry, Lisly; Lakely, Bryce; Higano, Celestia S.; Montgomery, Bruce; Roudier, Martine; Lange, Paul H.; Nelson, Peter S.; Vessella, Robert L.; Morrissey, Colm

    2015-01-01

    Purpose The neuroendocrine (NE) phenotype is associated with the development of metastatic castration-resistant prostate cancer (CRPC). Our objective was to characterize the molecular features of the NE phenotype in CRPC. Experimental Design Expression of chromogranin A (CHGA), synaptophysin (SYP), androgen receptor (AR), and prostate-specific antigen (PSA) was analyzed by immunohistochemistry (IHC) in 155 CRPC metastases from 50 patients and in 24 LuCaP prostate cancer patient-derived xenografts (PDX). Seventy-one of 155 metastases and the 24 LuCaP xenograft lines were analyzed by whole genome microarrays. REST splicing was verified by PCR. Results Co-expression of CHGA and SYP in >30% of cells was observed in 22 of 155 metastases (9 patients); 11 of the 22 metastases were AR+/PSA+ (6 patients), 11/22 were AR−/PSA− (4 patients), and 4/24 LuCaP PDXs were AR−/PSA−. By IHC, of the 71 metastases analyzed by whole genome microarrays, 5 metastases were CHGA+/SYP+/AR− and 5 were CHGA+/SYP+/AR+. Only CHGA+/SYP+ metastases had a NE transcript signature. The neuronal transcriptional regulator SRRM4 transcript was associated with the NE signature in CHGA+/SYP+ metastases and all CHGA+/SYP+ LuCaP xenografts. Additionally, expression of SRRM4 in LuCaP NE xenografts correlated with a splice variant of REST that lacks the transcriptional repressor domain. Conclusions (a) metastatic NE status can be heterogeneous in the same patient, (b) the CRPC NE molecular phenotype can be defined by CHGA+/SYP+ dual positivity, (c) the NE phenotype is not necessarily associated with the loss of AR activity, and (d) the splicing of REST by SRRM4 could promote the NE phenotype in CRPC. PMID:26071481

  18. Targeting autophagy overcomes Enzalutamide resistance in castration-resistant prostate cancer cells and improves therapeutic response in a xenograft model

    PubMed Central

    Nguyen, H G; Yang, J C; Kung, H-J; Shi, X-B; Tilki, D; Lara, P N; DeVere White, R W; Gao, A C; Evans, C P

    2014-01-01

    Macro-autophagy is associated with drug resistance in various cancers and can function as an adaptive response to maintain cell survival under metabolic stresses, including androgen deprivation. Androgen deprivation or treatment with androgen receptor (AR) signaling inhibitor (ARSI), Enzalutamide (MDV-3100, ENZA) or bicalutamide induced autophagy in androgen-dependent and in castration-resistant CaP (castration-resistant prostate cancer (CRPC)) cell lines. The autophagic cascade triggered by AR blockage, correlated with the increased light chain 3-II/I ratio and ATG-5 expression. Autophagy was observed in a subpopulation of C4-2B cells that developed insensitivity to ENZA after sustained exposure in culture. Using flow cytometry and clonogenic assays, we showed that inhibiting autophagy with clomipramine (CMI), chloroquine or metformin increased apoptosis and significantly impaired cell viability. This autophagic process was mediated by AMP-dependent protein kinase (AMPK) activation and the suppression of mammalian target of rapamycin (mTOR) through Raptor phosphorylation (Serine 792). Furthermore, small interfering RNA targeting AMPK significantly inhibited autophagy and promoted cell death in CaP cells acutely or chronically exposed to ENZA or androgen deprivation, suggesting that autophagy is an important survival mechanism in CRPC. Lastly, in vivo studies with mice orthotopically implanted with ENZA-resistant cells demonstrated that the combination of ENZA and autophagy modulators, CMI or metformin significantly reduced tumor growth when compared with control groups (P<0.005). In conclusion, autophagy is as an important mechanism of resistance to ARSI in CRPC. Antiandrogen-induced autophagy is mediated through the activation of AMPK pathway and the suppression of mTOR pathway. Blocking autophagy pharmacologically or genetically significantly impairs prostate cancer cell survival in vitro and in vivo, implying the therapeutics potential of autophagy inhibitors

  19. Hypoxic tumor kinase signaling mediated by STAT5A in development of castration-resistant prostate cancer.

    PubMed

    Røe, Kathrine; Bratland, Åse; Vlatkovic, Ljiljana; Ragnum, Harald Bull; Saelen, Marie Grøn; Olsen, Dag Rune; Marignol, Laure; Ree, Anne Hansen

    2013-01-01

    In this study, we hypothesized that androgen-deprivation therapy (ADT) in prostate cancer, although initially efficient, induces changes in the tumor kinome, which subsequently promote development of castration-resistant (CR) disease. Recognizing the correlation between tumor hypoxia and poor prognosis in prostate cancer, we further hypothesized that such changes might be influenced by hypoxia. Microarrays with 144 kinase peptide substrates were applied to analyze CWR22 prostate carcinoma xenograft samples from ADT-naïve, androgen-deprived (AD), long-term AD (ADL), and CR disease stages. The impact of hypoxia was assessed by matching the xenograft kinase activity profiles with those acquired from hypoxic and normoxic prostate carcinoma cell cultures, whereas the clinical relevance was evaluated by analyzing prostatectomy tumor samples from patients with locally advanced disease, either in ADT-naïve or early CR disease stages. By using this novel peptide substrate microarray method we revealed high kinase activity mediated by signal transducer and activator of transcription 5A (STAT5A) in CR prostate cancer. Additionally, we uncovered high STAT5A kinase activity already in regressing ADL xenografts, before renewed CR growth was evidenced. Finally, since increased STAT5A kinase activity also was detected after exposing prostate carcinoma cells to hypoxia, we propose long-term ADT to induce tumor hypoxia and stimulate STAT5A kinase activity, subsequently leading to renewed CR tumor growth. Hence, the study detected STAT5A as a candidate to be further investigated for its potential as marker of advanced prostate cancer and as possible therapeutic target protein.

  20. Persistent Neutrophil to Lymphocyte Ratio >3 during Treatment with Enzalutamide and Clinical Outcome in Patients with Castration-Resistant Prostate Cancer

    PubMed Central

    Conteduca, Vincenza; Crabb, Simon J.; Jones, Robert J.; Caffo, Orazio; Elliott, Tony; Scarpi, Emanuela; Fabbri, Paolo; Derosa, Lisa; Massari, Francesco; Numico, Gianmauro; Zarif, Sunnya; Hanna, Catherine; Maines, Francesca; Joyce, Helen; Lolli, Cristian; De Giorgi, Ugo

    2016-01-01

    The baseline value of neutrophil to lymphocyte ratio (NLR) has been found to be prognostic in patients with metastatic castration resistant prostate cancer (CRPC). We evaluated the impact of baseline NLR and its change in patients receiving enzalutamide. We included consecutive metastatic CRPC patients treated with enzalutamide after docetaxel and studies the change of NLR (>3 vs ≤3) after week 4 and 12 weeks. Progression-free survival (PFS), overall survival (OS) and their 95% Confidence Intervals (95% CI) were estimated by the Kaplan-Meier method and compared with the log-rank test. The impact of NLR on PFS and OS was evaluated by Cox regression analyses and on prostate-specific antigen response rates (PSA RR; PSA decline >50%) were evaluated by binary logistic regression. Data collected on 193 patients from 9 centers were evaluated. Median age was 73.1 years (range, 42.8–90.7). The median baseline NLR was 3.2. The median PFS was 3.2 months (95% CI = 2.7–4.2) in patients with baseline NLR >3 and 7.4 months (95% CI = 5.5–9.7) in those with NLR ≤3, p < 0.0001. The median OS was 10.4 months (95% CI = 6.5–14.9) in patients with baseline NLR >3 and 16.9 months (95% CI = 11.2–20.9) in those with baseline NLR ≤3, p < 0.0001. In multivariate analysis, changes in NLR at 4 weeks were significant predictors of both PFS [hazard ratio (HR) 1.24, 95% confidence interval (95% CI) 1.07–1.42, p = 0.003, and OS (HR 1.29, 95% CI 1.10–1.51, p = 0.001. A persistent NLR >3 during treatment with enzalutamide seems to have both prognostic and predictive value in CRPC patients. PMID:27434372

  1. PTEN loss in circulating tumour cells correlates with PTEN loss in fresh tumour tissue from castration-resistant prostate cancer patients

    PubMed Central

    Punnoose, Elizabeth A; Ferraldeschi, Roberta; Szafer-Glusman, Edith; Tucker, Eric K; Mohan, Sankar; Flohr, Penelope; Riisnaes, Ruth; Miranda, Susana; Figueiredo, Ines; Rodrigues, Daniel Nava; Omlin, Aurelius; Pezaro, Carmel; Zhu, Jin; Amler, Lukas; Patel, Premal; Yan, Yibing; Bales, Natalee; Werner, Shannon L; Louw, Jessica; Pandita, Ajay; Marrinucci, Dena; Attard, Gerhardt; de Bono, Johann

    2015-01-01

    Background: PTEN gene loss occurs frequently in castration-resistant prostate cancer (CRPC) and may drive progression through activation of the PI3K/AKT pathway. Here, we developed a novel CTC-based assay to determine PTEN status and examined the correlation between PTEN status in CTCs and matched tumour tissue samples. Methods: PTEN gene status in CTCs was evaluated on an enrichment-free platform (Epic Sciences) by fluorescence in situ hybridisation (FISH). PTEN status in archival and fresh tumour tissue was evaluated by FISH and immunohistochemistry. Results: Peripheral blood was collected from 76 patients. Matched archival and fresh cancer tissue was available for 48 patients. PTEN gene status detected in CTCs was concordant with PTEN status in matched fresh tissues and archival tissue in 32 of 38 patients (84%) and 24 of 39 patients (62%), respectively. CTC counts were prognostic (continuous, P=0.001). PTEN loss in CTCs associated with worse survival in univariate analysis (HR 2.05; 95% CI 1.17–3.62; P=0.01) and with high lactate dehydrogenase (LDH) in metastatic CRPC patients. Conclusions: Our results illustrate the potential use of CTCs as a non-invasive, real-time liquid biopsy to determine PTEN gene status. The prognostic and predictive value of PTEN in CTCs warrants investigation in CRPC clinical trials of PI3K/AKT-targeted therapies. PMID:26379078

  2. CH5137291, an androgen receptor nuclear translocation-inhibiting compound, inhibits the growth of castration-resistant prostate cancer cells.

    PubMed

    Ishikura, Nobuyuki; Kawata, Hiromitsu; Nishimoto, Ayako; Nakamura, Ryo; Tsunenari, Toshiaki; Watanabe, Miho; Tachibana, Kazutaka; Shiraishi, Takuya; Yoshino, Hitoshi; Honma, Akie; Emura, Takashi; Ohta, Masateru; Nakagawa, Toshito; Houjo, Takao; Corey, Eva; Vessella, Robert L; Aoki, Yuko; Sato, Haruhiko

    2015-04-01

    Resistance of prostate cancer to castration is currently an unavoidable problem. The major mechanisms underlying such resistance are androgen receptor (AR) overexpression, androgen-independent activation of AR, and AR mutation. To address this problem, we developed an AR pure antagonist, CH5137291, with AR nuclear translocation-inhibiting activity, and compared its activity and characteristics with that of bicalutamide. Cell lines corresponding to the mechanisms of castration resistance were used: LNCaP-BC2 having AR overexpression and LNCaP-CS10 having androgen-independent AR activation. VCaP and LNCaP were used as hormone-sensitive prostate cancer cells. In vitro functional assay clearly showed that CH5137291 inhibited the nuclear translocation of wild-type ARs as well as W741C- and T877A-mutant ARs. In addition, it acted as a pure antagonist on the transcriptional activity of these types of ARs. In contrast, bicalutamide did not inhibit the nuclear translocation of these ARs, and showed a partial/full agonistic effect on the transcriptional activity. CH5137291 inhibited cell growth more strongly than bicalutamide in VCaP and LNCaP cells as well as in LNCaP-BC2 and LNCaP-CS10 cells in vitro. In xenograft models, CH5137291 strongly inhibited the tumor growth of LNCaP, LNCaP-BC2, and LNCaP-CS10, whereas bicalutamide showed a weaker effect in LNCaP and almost no effect in LNCaP-BC2 and LNCaP-CS10 xenografts. Levels of prostate-specific antigen (PSA) in plasma correlated well with the antitumor effect of both agents. CH5137291 inhibited the growth of LNCaP tumors that had become resistant to bicalutamide treatment. A docking model suggested that CH5137291 intensively collided with the M895 residue of helix 12, and therefore strongly inhibited the folding of helix 12, a cause of AR agonist activity, in wild-type and W741C-mutant ARs. In cynomolgus monkeys, the serum concentration of CH5137291 increased dose-dependently and PSA level decreased 80% at 100 mg/kg. CH

  3. c-MYC drives histone demethylase PHF8 during neuroendocrine differentiation and in castration-resistant prostate cancer

    PubMed Central

    Liu, Qi; Fazli, Ladan; Tyler, Scott; Nasir, Moman; Dong, Xuesen; Qi, Hank Heng

    2016-01-01

    Epigenetic factors play critical roles in prostate cancer (PCa) development. However, how they contribute to neuroendocrine differentiation (NED) and castration-resistant PCa (CRPC) is not fully understood. Using bioinformatics and biochemical approaches to analyze cell-based models of NED and CRPC, we found a cluster of epigenetic factors whose expression is downregulated during NED and upregulated in CRPC (i.e. follow a Down-Up pattern). Two histone demethylases within this cluster, PHF8 and KDM3A, are post-transcriptionally regulated by c-MYC through miR-22, which targets both PHF8 and KDM3A. We also found that the c-MYC/miR-22/PHF8 axis is downstream of androgen receptor (AR) signaling in CRPC cells. The co-expression of PHF8 with AR in clinical CRPC samples, normal mouse prostate, and adenocarcinomas of the prostate during PCa progression in a transgenic (TRAMP) mouse model supports the connection between PHF8 and AR. Knockdown of PHF8 impedes cell cycle progression in CRPC cells and has more profound effects on their growth than on the parental LNCaP cell line. Furthermore, PHF8 knockdown sensitizes LNCaP-Abl cells to the AR antagonist enzalutamide. Our data reveal novel mechanisms that underlie the regulation of PHF8 and KDM3A during NED and in CRPC, and support the candidacy of PHF8 as a therapeutic target in CRPC. PMID:27689328

  4. c-MYC drives histone demethylase PHF8 during neuroendocrine differentiation and in castration-resistant prostate cancer.

    PubMed

    Maina, Peterson Kariuki; Shao, Peng; Liu, Qi; Fazli, Ladan; Tyler, Scott; Nasir, Moman; Dong, Xuesen; Qi, Hank Heng

    2016-11-15

    Epigenetic factors play critical roles in prostate cancer (PCa) development. However, how they contribute to neuroendocrine differentiation (NED) and castration-resistant PCa (CRPC) is not fully understood. Using bioinformatics and biochemical approaches to analyze cell-based models of NED and CRPC, we found a cluster of epigenetic factors whose expression is downregulated during NED and upregulated in CRPC (i.e. follow a Down-Up pattern). Two histone demethylases within this cluster, PHF8 and KDM3A, are post-transcriptionally regulated by c-MYC through miR-22, which targets both PHF8 and KDM3A. We also found that the c-MYC/miR-22/PHF8 axis is downstream of androgen receptor (AR) signaling in CRPC cells. The co-expression of PHF8 with AR in clinical CRPC samples, normal mouse prostate, and adenocarcinomas of the prostate during PCa progression in a transgenic (TRAMP) mouse model supports the connection between PHF8 and AR. Knockdown of PHF8 impedes cell cycle progression in CRPC cells and has more profound effects on their growth than on the parental LNCaP cell line. Furthermore, PHF8 knockdown sensitizes LNCaP-Abl cells to the AR antagonist enzalutamide. Our data reveal novel mechanisms that underlie the regulation of PHF8 and KDM3A during NED and in CRPC, and support the candidacy of PHF8 as a therapeutic target in CRPC.

  5. UGT2B17 Expedites Progression of Castration-Resistant Prostate Cancers by Promoting Ligand-Independent AR Signaling.

    PubMed

    Li, Haolong; Xie, Ning; Chen, Ruiqi; Verreault, Mélanie; Fazli, Ladan; Gleave, Martin E; Barbier, Olivier; Dong, Xuesen

    2016-11-15

    Castration-resistant prostate cancer (CRPC) is characterized by a shift in androgen receptor (AR) signaling from androgen-dependent to androgen (ligand)-independent. UDP-glucuronosyltransferase 2B17 (UGT2B17) is a key enzyme that maintains androgen homeostasis by catabolizing AR agonists into inactive forms. Although enhanced UGT2B17 expression by antiandrogens has been reported in androgen-dependent prostate cancer, its roles in regulating AR signaling transformation and CRPC progression remain unknown. In this study, we show that higher UGT2B17 protein expression in prostate tumors is associated with higher Gleason score, metastasis, and CRPC progression. UGT2B17 expression and activity were higher in androgen-independent compared to androgen-dependent cell lines. UGT2B17 stimulated cancer cell proliferation, invasion, and xenograft progression to CRPC after prolonged androgen deprivation. Gene microarray analysis indicated that UGT2B17 suppressed androgen-dependent AR transcriptional activity and enhanced of ligand-independent transcriptional activity at genes associated with cell mitosis. These UGT2B17 actions were mainly mediated by activation of the c-Src kinase. In CRPC tumors, UGT2B17 expression was associated positively with c-Src activation. These results indicate that UGT2B17 expedites CRPC progression by enhancing ligand-independent AR signaling to activate cell mitosis in cancer cells. Cancer Res; 76(22); 6701-11. ©2016 AACR.

  6. Lipocalin 2 over-expression facilitates progress of castration-resistant prostate cancer via improving androgen receptor transcriptional activity

    PubMed Central

    Feng, Chenchen; Jiang, Haowen; Xu, Jianfeng; Ding, Qiang

    2016-01-01

    Background Castration-resistant prostate cancer (CRPC) is the lethal phenotype of prostate cancer. Lipocalin 2 (LCN2) is aberrantly expressed in many cancers including primary prostate cancer (PCa), but its role in CRPC has not been reported. Results LCN2 expression was upregulated in human primary PCa and CRPC tissues. Overexpression of LCN2 promoted C4-2B and 22RV1 cell proliferation while knockdown of LCN2 markedly inhibited C4-2B and 22RV1 cell growth. LCN2 overexpression led to increased AR downstream gene SLC45A3 without upregulating AR expression. In the xenograft model, overexpression of LCN2 significantly promoted tumor growth. Methods LCN2 expression was detected in primary PCa and CRPC tissues and cell lines C4-2B and 22RV1 using immunohistochemistry and western blotting, respectively. Serum LCN2 level was detected vi ELISA. Lentiviruses-mediated over-expression of LCN2 and LCN2 knockdown were performed in CRPC cell lines. Expressions of androgen receptor (AR) downstream genes was examined in cell lines, in CRPC tissues, and in animal models. Conclusion LCN2 could facilitate cell proliferation of CRPC via AR transcriptional activity. LCN2 could be a novel target in CRPC. PMID:27602760

  7. Sipuleucel-T and Androgen Receptor-Directed Therapy for Castration-Resistant Prostate Cancer: A Meta-Analysis

    PubMed Central

    Yi, Renliang; Duan, Peng; Shen, Huanyu; Liu, Qun; Yuan, Chen; Ou, Weilin

    2016-01-01

    New treatments, such as sipuleucel-T and androgen receptor- (AR-) directed therapies (enzalutamide (Enz) and abiraterone acetate (AA)), have emerged and been approved for the management of castration-resistant prostate cancer (CRPC). There are still debates over their efficacy and clinical benefits. This meta-analysis aimed to investigate the efficacy and safety of sipuleucel-T and AR-directed therapies in patients with CRPC. RevMan 5.1 was used for pooled analysis and analysis of publication bias. Seven studies were included in the meta-analysis, with three studies in sipuleucel-T (totally 737 patients, 488 patients in treatment group, and 249 patients in placebo group) and four in AR-directed therapies (totally 5,199 patients, 3,015 patients in treatment group, and 2,184 patients in placebo group). Treatment with sipuleucel-T significantly improved overall survival in patients with CRPC and was not associated with increased risk of adverse event of grade ≥3 (p > 0.05). However, treatment with sipuleucel-T did not improve time-to-progression and reduction of prostate-specific antigen (PSA) level ≥50% was not significantly different from that with placebo. AR-directed therapies significantly improved overall survival in patients with CRPC and improved time-to-progression and reduction of PSA level ≥50%. AR-directed therapies did not increase risk of adverse event of grade ≥3 (p > 0.05). PMID:28058266

  8. Sipuleucel-T and Androgen Receptor-Directed Therapy for Castration-Resistant Prostate Cancer: A Meta-Analysis.

    PubMed

    Yi, Renliang; Chen, Baoxin; Duan, Peng; Zheng, Chanjiao; Shen, Huanyu; Liu, Qun; Yuan, Chen; Ou, Weilin; Zhou, Zhiheng

    2016-01-01

    New treatments, such as sipuleucel-T and androgen receptor- (AR-) directed therapies (enzalutamide (Enz) and abiraterone acetate (AA)), have emerged and been approved for the management of castration-resistant prostate cancer (CRPC). There are still debates over their efficacy and clinical benefits. This meta-analysis aimed to investigate the efficacy and safety of sipuleucel-T and AR-directed therapies in patients with CRPC. RevMan 5.1 was used for pooled analysis and analysis of publication bias. Seven studies were included in the meta-analysis, with three studies in sipuleucel-T (totally 737 patients, 488 patients in treatment group, and 249 patients in placebo group) and four in AR-directed therapies (totally 5,199 patients, 3,015 patients in treatment group, and 2,184 patients in placebo group). Treatment with sipuleucel-T significantly improved overall survival in patients with CRPC and was not associated with increased risk of adverse event of grade ≥3 (p > 0.05). However, treatment with sipuleucel-T did not improve time-to-progression and reduction of prostate-specific antigen (PSA) level ≥50% was not significantly different from that with placebo. AR-directed therapies significantly improved overall survival in patients with CRPC and improved time-to-progression and reduction of PSA level ≥50%. AR-directed therapies did not increase risk of adverse event of grade ≥3 (p > 0.05).

  9. Global analysis of transcription in castration-resistant prostate cancer cells uncovers active enhancers and direct androgen receptor targets

    PubMed Central

    Toropainen, Sari; Niskanen, Einari A.; Malinen, Marjo; Sutinen, Päivi; Kaikkonen, Minna U.; Palvimo, Jorma J.

    2016-01-01

    Androgen receptor (AR) is a male sex steroid-activated transcription factor (TF) that plays a critical role in prostate cancers, including castration-resistant prostate cancers (CRPC) that typically express amplified levels of the AR. CRPC-derived VCaP cells display an excessive number of chromatin AR-binding sites (ARBs) most of which localize to distal inter- or intragenic regions. Here, we analyzed direct transcription programs of the AR in VCaP cells using global nuclear run-on sequencing (GRO-seq) and integrated the GRO-seq data with the ARB and VCaP cell-specific TF-binding data. Androgen immediately activated transcription of hundreds of protein-coding genes, including IGF-1 receptor and EGF receptor. Androgen also simultaneously repressed transcription of a large number of genes, including MYC. As functional enhancers have been postulated to produce enhancer-templated non-coding RNAs (eRNAs), we also analyzed the eRNAs, which revealed that only a fraction of the ARBs reside at functional enhancers. Activation of these enhancers was most pronounced at the sites that also bound PIAS1, ERG and HDAC3, whereas binding of HDAC3 and PIAS1 decreased at androgen-repressed enhancers. In summary, our genome-wide data of androgen-regulated enhancers and primary target genes provide new insights how the AR can directly regulate cellular growth and control signaling pathways in CPRC cells. PMID:27641228

  10. LncRNA MALAT1 enhances oncogenic activities of EZH2 in castration-resistant prostate cancer

    PubMed Central

    Wang, Liguo; Zhao, Yu; Sun, Zhifu; Karnes, R. Jeffrey; Zhang, Jun; Huang, Haojie

    2015-01-01

    The Polycomb protein enhancer of zeste homolog 2 (EZH2) is frequently overexpressed in advanced human prostate cancer (PCa), especially in lethal castration-resistant prostate cancer (CRPC). However, the signaling pathways that regulate EZH2 functions in PCa remain incompletely defined. Using EZH2 antibody-based RNA immunoprecipitation-coupled high throughput sequencing (RIP-seq), we demonstrated that EZH2 binds to MALAT1, a long non-coding RNA (lncRNA) that is overexpressed during PCa progression. GST pull-down and RIP assays demonstrated that the 3′ end of MALAT1 interacts with the N-terminal of EZH2. Knockdown of MALAT1 impaired EZH2 recruitment to its target loci and upregulated expression of EZH2 repressed genes. Further studies indicated that MALAT1 plays a vital role in EZH2-enhanced migration and invasion in CRPC cell lines. Meta-analysis and RT-qPCR of patient specimens demonstrated a positive correlation between MALAT1 and EZH2 expression in human CRPC tissues. Finally, we showed that MALAT1 enhances expression of PRC2-independent target genes of EZH2 in CRPC cells in culture and patient-derived xenografts. Together, these data indicate that MALAT1 may be a crucial RNA cofactor of EZH2 and that the EZH2-MALAT1 association may provide a new avenue for development new strategies for treatment of CRPC. PMID:26516927

  11. Using a Novel Transgenic Mouse Model to Study c-Myc Oncogenic Pathway in Castration Resistance and Chemoresistance of Prostate Cancer

    DTIC Science & Technology

    2014-10-01

    AWARD NUMBER: W81XWH-13-1-0162 TITLE: Using a Novel Transgenic Mouse Model to Study c-Myc...CONTRACT NUMBER Using a Novel Transgenic Mouse Model to Study c-Myc Oncogenic Pathway in Castration Resistance and Chemoresistance of Prostate Cancer...Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT We previously generated a PB-Cre4/CAG-SMIL transgenic model allowing Cre

  12. Predictors of long-term response to abiraterone in patients with metastastic castration-resistant prostate cancer: a retrospective cohort study

    PubMed Central

    Verzoni, Elena; Giorgi, Ugo De; Derosa, Lisa; Caffo, Orazio; Boccardo, Francesco; Facchini, Gaetano; Porcu, Luca; Vincenzo, Fabio De; Zaniboni, Alberto; Chiuri, Vincenzo Emanuele; Fratino, Lucia; Santini, Daniele; Adamo, Vincenzo; Vivo, Rocco De; Dinota, Angelo; Messina, Caterina; Ricotta, Riccardo; Caserta, Claudia; Scavelli, Claudio; Susi, Marina; Tartarone, Alfredo; Surace, Giuseppe; Mosca, Alessandra; Bruno, Michele; Barni, Sandro; Grassi, Paolo; Procopio, Giuseppe

    2016-01-01

    We aimed to identify clinical predictors of long-term response to abiraterone (defined as >12 months drug exposure) in a retrospective cohort of metastatic castration-resistant prostate cancer patients treated in post-docetaxel setting at 24 Italian centers. The Cox proportional hazards model was used to analyze the association between clinical features and the duration of drug exposure. Results were expressed as hazard ratios (HR) with associated 95% confidence intervals (CI). A total of 143 patients met the inclusion criteria. Their median age was 73 years, median Gleason score 8 and median abiraterone exposure 20 months. At the univariate analysis, a significant correlation with the duration of abiraterone exposure was found for Gleason score (HR 0.82, 95% CI 0.71-0.96; p=0.012), PSA (HR 1.10, 95% CI 1.03-1.18; p=0.08) and lactic dehydrogenase levels (HR 1.22, 95% CI 1.02-1.46; p=0.027), while the association between lower alkaline phosphatase levels and treatment duration was marginally significant (HR 1.07, 95% CI 0.99-1.16; p=0.074). Only PSA and Gleason score were predictive of long-term treatment duration in the multivariate analysis. No other clinical factors resulted to be predictive of sustained response to abiraterone, including metastatic disease at diagnosis and visceral disease, suggesting that all subgroups of patients may derive a substantial clinical benefit from abiraterone treatment. These findings need to be validated in prospective, larger studies. PMID:27223078

  13. Predictors of long-term response to abiraterone in patients with metastastic castration-resistant prostate cancer: a retrospective cohort study.

    PubMed

    Verzoni, Elena; De Giorgi, Ugo; Derosa, Lisa; Caffo, Orazio; Boccardo, Francesco; Facchini, Gaetano; Porcu, Luca; De Vincenzo, Fabio; Zaniboni, Alberto; Chiuri, Vincenzo Emanuele; Fratino, Lucia; Santini, Daniele; Adamo, Vincenzo; De Vivo, Rocco; Dinota, Angelo; Messina, Caterina; Ricotta, Riccardo; Caserta, Claudia; Scavelli, Claudio; Susi, Marina; Tartarone, Alfredo; Surace, Giuseppe; Mosca, Alessandra; Bruno, Michele; Barni, Sandro; Grassi, Paolo; Procopio, Giuseppe

    2016-06-28

    We aimed to identify clinical predictors of long-term response to abiraterone (defined as >12 months drug exposure) in a retrospective cohort of metastatic castration-resistant prostate cancer patients treated in post-docetaxel setting at 24 Italian centers. The Cox proportional hazards model was used to analyze the association between clinical features and the duration of drug exposure. Results were expressed as hazard ratios (HR) with associated 95% confidence intervals (CI). A total of 143 patients met the inclusion criteria. Their median age was 73 years, median Gleason score 8 and median abiraterone exposure 20 months. At the univariate analysis, a significant correlation with the duration of abiraterone exposure was found for Gleason score (HR 0.82, 95% CI 0.71-0.96; p=0.012), PSA (HR 1.10, 95% CI 1.03-1.18; p=0.08) and lactic dehydrogenase levels (HR 1.22, 95% CI 1.02-1.46; p=0.027), while the association between lower alkaline phosphatase levels and treatment duration was marginally significant (HR 1.07, 95% CI 0.99-1.16; p=0.074). Only PSA and Gleason score were predictive of long-term treatment duration in the multivariate analysis. No other clinical factors resulted to be predictive of sustained response to abiraterone, including metastatic disease at diagnosis and visceral disease, suggesting that all subgroups of patients may derive a substantial clinical benefit from abiraterone treatment. These findings need to be validated in prospective, larger studies.

  14. Alterations of androgen receptor-regulated enhancer RNAs (eRNAs) contribute to enzalutamide resistance in castration-resistant prostate cancer

    PubMed Central

    Zhao, Jingwen; Zhao, Yu; Wang, Liguo; Zhang, Jun; Karnes, R. Jeffrey; Kohli, Manish; Wang, Guixia; Huang, Haojie

    2016-01-01

    Enzalutamide is a second-generation anti-androgen for treatment of castration-resistant prostate cancer (CPRC). It prolongs survival of CRPC patients, but its overall survival benefit is relatively modest (4.8 months) and by 24 months most patients progress on enzalutamide. To date, however, the molecular mechanisms underlying enzalutamide resistance remain elusive. Herein, we report enzalutamide treatment-induced alterations of androgen receptor (AR)-regulated enhancer RNAs (AR-eRNAs) and their roles in enzalutamide-resistant growth and survival of CRPC cells. AR chromatin immunoprecipitation and high throughput sequencing (ChIP-seq) and RNA-seq analyses revealed that 188 and 227 AR-eRNAs were differentially expressed in enzalutamide-resistant LNCaP and C4-2 cells, respectively. The AR-eRNAs upregulated in C4-2 cells and downregulated in LNCaP cells were selected through meta-analysis. Expression of AR-eRNAs and related mRNAs in the loci of FTO, LUZP2, MARC1 and NCAM2 were further verified by real-time RT-PCR. Silencing of LUZP2 inhibited, but silencing of MARC1 increased the growth of enzalutamide-resistant C4-2 cells. Intriguingly, meta-analysis showed that expression of LUZP2 mRNA increased in primary tumors compared to normal prostate tissues, but decreased again in metastatic CRPC. Our findings suggest that eRNA alteration profiling is a viable new approach to identify functional gene loci that may not only contribute to enzalutamide-resistant growth of CRPC, but also serve as new targets for CRPC therapy. PMID:27221037

  15. Early Prediction of Therapy Response to Abiraterone Acetate Using PSA Subforms in Patients with Castration Resistant Prostate Cancer

    PubMed Central

    Schlack, Katrin; Krabbe, Laura-Maria; Fobker, Manfred; Schrader, Andres Jan; Semjonow, Axel; Boegemann, Martin

    2016-01-01

    The purpose of this study was to evaluate the prognostic ability of early changes of total prostate specific antigen (tPSA), free PSA (fPSA), [−2]proPSA and the Prostate Health Index (PHI) following initiation of Abiraterone-therapy in men with castration resistant prostate cancer (mCRPC). In 25 patients, PSA-subforms were analyzed before and at 8–12 weeks under therapy as prognosticators of progression-free-survival (PFS) and overall survival (OS). Comparing patients with a PFS < vs. ≥12 months by using Mann–Whitney–Wilcoxon Tests, the relative-median-change of tPSA (−0.1% vs. −86.8%; p = 0.02), fPSA (12.1% vs. −55.3%; p = 0.03) and [−2]proPSA (8.1% vs. −59.3%; p = 0.05) differed significantly. For men with ≤ vs. >15 months of OS there was a non-significant trend for a difference in the relative-median-change of fPSA (17.0% vs. −46.3%; p = 0.06). In Kaplan–Meier analyses, declining fPSA and [−2]proPSA were associated with a longer median PFS (13 months, 95% confidence interval (CI): 9.6–16.4 vs. 10 months, 95% CI: 3.5–16.5; p = 0.11), respectively. Correspondingly, decreasing fPSA and [−2]proPSA values indicated an OS of 32 months (95% CI: not reached (NR)) compared to 21 months in men with rising values (95% CI: 7.7–34.3; p = 0.14), respectively. We concluded that the addition of fPSA- and [−2]proPSA-changes to tPSA-information might be further studied as potential markers of early Abiraterone response in mCRPC patients. PMID:27618028

  16. Early Prediction of Therapy Response to Abiraterone Acetate Using PSA Subforms in Patients with Castration Resistant Prostate Cancer.

    PubMed

    Schlack, Katrin; Krabbe, Laura-Maria; Fobker, Manfred; Schrader, Andres Jan; Semjonow, Axel; Boegemann, Martin

    2016-09-09

    The purpose of this study was to evaluate the prognostic ability of early changes of total prostate specific antigen (tPSA), free PSA (fPSA), [-2]proPSA and the Prostate Health Index (PHI) following initiation of Abiraterone-therapy in men with castration resistant prostate cancer (mCRPC). In 25 patients, PSA-subforms were analyzed before and at 8-12 weeks under therapy as prognosticators of progression-free-survival (PFS) and overall survival (OS). Comparing patients with a PFS < vs. ≥12 months by using Mann-Whitney-Wilcoxon Tests, the relative-median-change of tPSA (-0.1% vs. -86.8%; p = 0.02), fPSA (12.1% vs. -55.3%; p = 0.03) and [-2]proPSA (8.1% vs. -59.3%; p = 0.05) differed significantly. For men with ≤ vs. >15 months of OS there was a non-significant trend for a difference in the relative-median-change of fPSA (17.0% vs. -46.3%; p = 0.06). In Kaplan-Meier analyses, declining fPSA and [-2]proPSA were associated with a longer median PFS (13 months, 95% confidence interval (CI): 9.6-16.4 vs. 10 months, 95% CI: 3.5-16.5; p = 0.11), respectively. Correspondingly, decreasing fPSA and [-2]proPSA values indicated an OS of 32 months (95% CI: not reached (NR)) compared to 21 months in men with rising values (95% CI: 7.7-34.3; p = 0.14), respectively. We concluded that the addition of fPSA- and [-2]proPSA-changes to tPSA-information might be further studied as potential markers of early Abiraterone response in mCRPC patients.

  17. Activation of P-TEFb by Androgen Receptor-Regulated Enhancer RNAs in Castration-Resistant Prostate Cancer.

    PubMed

    Zhao, Yu; Wang, Liguo; Ren, Shancheng; Wang, Lan; Blackburn, Patrick R; McNulty, Melissa S; Gao, Xu; Qiao, Meng; Vessella, Robert L; Kohli, Manish; Zhang, Jun; Karnes, R Jeffrey; Tindall, Donald J; Kim, Youngsoo; MacLeod, Robert; Ekker, Stephen C; Kang, Tiebang; Sun, Yinghao; Huang, Haojie

    2016-04-19

    The androgen receptor (AR) is required for castration-resistant prostate cancer (CRPC) progression, but the function and disease relevance of AR-bound enhancers remain unclear. Here, we identify a group of AR-regulated enhancer RNAs (e.g., PSA eRNA) that are upregulated in CRPC cells, patient-derived xenografts (PDXs), and patient tissues. PSA eRNA binds to CYCLIN T1, activates P-TEFb, and promotes cis and trans target gene transcription by increasing serine-2 phosphorylation of RNA polymerase II (Pol II-Ser2p). We define an HIV-1 TAR RNA-like (TAR-L) motif in PSA eRNA that is required for CYCLIN T1 binding. Using TALEN-mediated gene editing we further demonstrate that this motif is essential for increased Pol II-Ser2p occupancy levels and CRPC cell growth. We have uncovered a P-TEFb activation mechanism and reveal altered eRNA expression that is related to abnormal AR function and may potentially be a therapeutic target in CRPC.

  18. Understanding and overcoming the mechanisms of primary and acquired resistance to abiraterone and enzalutamide in castration resistant prostate cancer.

    PubMed

    Buttigliero, Consuelo; Tucci, Marcello; Bertaglia, Valentina; Vignani, Francesca; Bironzo, Paolo; Di Maio, Massimo; Scagliotti, Giorgio Vittorio

    2015-12-01

    In recent years, in castration resistant prostate cancer (CRPC), several new drugs have been approved that prolong overall survival, including enzalutamide and abiraterone, two new-generation hormonal therapies. Despite the demonstrated benefit of these agents, not all patients with CRPC are responsive to treatment, the gain in median progression-free survival with these therapies compared to standard of care is, rather disappointingly, still less than six months and the appearance of acquired resistance is almost universal. Approximately one third of patients treated with abiraterone and 25% of those treated with enzalutamide show primary resistance to these agents. Even if the mechanisms of resistance to these agents are not fully defined, many hypotheses are emerging, including systemic and intratumoral androgen biosynthesis up-regulation, androgen receptor (AR) gene mutations and amplifications, alteration of pathways involved in cross-talk with AR signaling, glucocorticoid receptor overexpression, neuroendocrine differentiation, immune system deregulation and others. The aim of this paper is to review currently available data about mechanisms of resistance to abiraterone and enzalutamide, and to discuss how these mechanisms could be potentially overcome through novel therapeutic agents.

  19. Exploitation of Castration-Resistant Prostate Cancer Transcription Factor Dependencies by the Novel BET Inhibitor ABBV-075.

    PubMed

    Faivre, Emily J; Wilcox, Denise; Lin, Xiaoyu; Hessler, Paul; Torrent, Maricel; He, Wei; Uziel, Tamar; Albert, Daniel H; McDaniel, Keith; Kati, Warren; Shen, Yu

    2017-01-01

    Competitive inhibitors of acetyl-lysine binding to the bromodomains of the BET (bromodomain and extra terminal) family are being developed for the treatment of solid and hematologic malignancies. The function of BET family member BRD4 at enhancers/superenhancers has been shown to sustain signal-dependent or pathogenic gene expression programs. Here, the hypothesis was tested that the transcription factor drivers of castration-resistant prostate cancer (CRPC) clinical progression, including the androgen receptor (AR), are critically dependent on BRD4 and thus represent a sensitive solid tumor indication for the BET inhibitor ABBV-075. DHT-stimulated transcription of AR target genes was inhibited by ABBV-075 without significant effect on AR protein expression. Furthermore, ABBV-075 disrupted DHT-stimulated recruitment of BET family member BRD4 to gene-regulatory regions cooccupied by AR, including the well-established PSA and TMPRSS2 enhancers. Persistent BET inhibition disrupted the composition and function of AR-occupied enhancers as measured by a reduction in AR and H3K27Ac ChIP signal and inhibition of enhancer RNA transcription. ABBV-075 displayed potent antiproliferative activity in multiple models of resistance to second-generation antiandrogens and inhibited the activity of the AR splice variant AR-V7 and ligand-binding domain gain-of-function mutations, F877L and L702H. ABBV-075 was also a potent inhibitor of MYC and the TMPRSS2-ETS fusion protein, important parallel transcription factor drivers of CRPC.

  20. Denosumab and Bone Metastasis-Free Survival in Men With Castration-Resistant Prostate Cancer: Results of a Global Phase 3, Randomised, Placebo-Controlled Trial

    PubMed Central

    Smith, Matthew R; Saad, Fred; Coleman, Robert; Shore, Neal; Fizazi, Karim; Tombal, Bertrand; Miller, Kurt; Sieber, Paul; Karsh, Lawrence; Damião, Ronaldo; Tammela, Teuvo L; Egerdie, Blair; Van Poppel, Hendrik; Chin, Joseph; Morote, Juan; Gómez-Veiga, Francisco; Borkowski, Tomasz; Ye, Zhishen; Kupic, Amy; Dansey, Roger; Goessl, Carsten

    2013-01-01

    Background Bone metastases are a major cause of morbidity and mortality in men with prostate cancer. Preclinical studies suggest that osteoclast inhibition may prevent bone metastases. This phase 3 study evaluated denosumab, a fully human anti-RANKL monoclonal antibody, to prevent bone metastasis or death from any cause in men with non-metastatic castration-resistant prostate cancer (CRPC). Methods Men with non-metastatic CRPC at high risk for bone metastasis (PSA ≥8.0 ng/mL and/or PSA doubling time ≤10.0 months) were enrolled in 319 centers from 30 countries. Patients were randomised 1:1 in blinded fashion using an interactive voice response system to receive monthly subcutaneous denosumab 120 mg or placebo. The primary endpoint was bone metastasis-free survival, a composite endpoint determined by time to first occurrence of bone metastasis (symptomatic or asymptomatic) or death. Results 1432 patients were randomised, 716 to receive denosumab and 716 to receive placebo. Denosumab significantly increased bone metastasis-free survival by a median of 4.2 months over placebo (hazard ratio 0.85 [0.73–0.98]; P=0.028). Denosumab also significantly delayed time to first bone metastasis (hazard ratio 0.84 [0.71–0.98]; P=0.032). Overall survival was similar between groups (hazard ratio 1.01 [0.85–1.20]; P=0.91). Rates of adverse events (AEs) and serious AEs were generally similar between groups, except for osteonecrosis of jaw (ONJ) and hypocalcemia. Yearly cumulative incidence of ONJ for denosumab was: 1%, 3%, 4% in years 1, 2, 3, respectively; overall, less than 5% (n=33). Hypocalcemia occurred in under 2% (n=12) of denosumab and under 1% (n=2) of placebo patients. The blinded treatment phase has been completed. Conclusion In men with CRPC, denosumab significantly prolonged bone metastasis-free survival and delayed time to bone metastasis. This is the first large randomised study to demonstrate that targeting the bone microenvironment prevents bone metastasis in

  1. 11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored

    PubMed Central

    Pretorius, Elzette; Africander, Donita J.; Vlok, Maré; Quanson, Jonathan

    2016-01-01

    Dihydrotestosterone (DHT) is regarded as the most potent natural androgen and is implicated in the development and progression of castration resistant prostate cancer (CRPC). Under castrate conditions, DHT is produced from the metabolism of the adrenal androgen precursors, DHEA and androstenedione. Recent studies have shown that the adrenal steroid 11β-hydroxyandrostenedione (11OHA4) serves as the precursor to the androgens 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT). In this study we comprehensively assess the androgenic activity of 11KT and 11KDHT. This is the first study, to our knowledge, to show that 11KT and 11KDHT, like T and DHT, are potent and efficacious agonists of the human androgen receptor (AR) and induced both the expression of representative AR-regulated genes as well as cellular proliferation in the androgen dependent prostate cancer cell lines, LNCaP and VCaP. Proteomic analysis revealed that 11KDHT regulated the expression of more AR-regulated proteins than DHT in VCaP cells, while in vitro conversion assays showed that 11KT and 11KDHT are metabolized at a significantly lower rate in both LNCaP and VCaP cells when compared to T and DHT, respectively. Our findings show that 11KT and 11KDHT are bona fide androgens capable of inducing androgen-dependant gene expression and cell growth, and that these steroids have the potential to remain active longer than T and DHT due to the decreased rate at which they are metabolised. Collectively, our data demonstrates that 11KT and 11KDHT likely play a vital, but overlooked, role in the development and progression of CRPC. PMID:27442248

  2. Phase-1 study of abiraterone acetate in chemotherapy-naïve Japanese patients with castration-resistant prostate cancer.

    PubMed

    Matsubara, Nobuaki; Uemura, Hiroji; Fukui, Iwao; Niwakawa, Masashi; Yamaguchi, Akito; Iizuka, Koho; Akaza, Hideyuki

    2014-10-01

    Persistent androgen synthesis under castration status in adrenal gland, testes and tumor cells is thought to be one of the major causes of development and progression of castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA), the prodrug of abiraterone, which is an inhibitor of androgen synthesis enzymes, was evaluated for pharmacokinetics, pharmacodynamics, preliminary efficacy and safety in Japanese patients with CRPC in a phase-1, open-label and dose-escalation study. Chemotherapy-naïve Japanese CRPC patients (N = 27) received one of four AA daily doses (250 mg [n = 9], 500 mg [n = 6], 1000 [1 h premeal] mg [n = 6] and 1000 [2 h postmeal] mg [n = 6]) continuously through 28-day treatment cycles. In the first cycle, AA monotherapy was given on days 1-7 for pharmacokinetics, and AA plus prednisone (5 mg twice daily) from days 8 to 28. Of 27 patients, 9 continued treatment with AA until the data cut-off date (18 July 2013). Over the evaluated dose range, plasma abiraterone concentrations increased with dose, with median tmax 2-3 h. At each dose level, mean serum corticosterone concentrations increased, while testosterone and dehydroepiandrosterone sulfate concentrations rapidly decreased following a single AA dose and were further reduced to near the quantification limit on day 8 regardless of the dose. At least 3 patients from each dose-group experienced ≥50% prostate-specific antigen reduction, suggesting clinical benefit from AA in Japanese CRPC patients. AA was generally well-tolerated, and, therefore, the recommended AA dosage regimen in Japanese CRPC patients is 1000 mg oral dose under modified fasting conditions (at least 1 h premeal or 2 h postmeal). This study is registered at ClinicalTrials.gov: NCT01186484.

  3. Understanding and Targeting Tumor Microenvironment in Prostate Cancer to Inhibit Tumor Progression and Castration Resistance

    DTIC Science & Technology

    2015-10-01

    SUBJECT TERMS Prostate cancer, myeloid-derived suppressor cell (MDSC), Pten, Smad4, genetically engineered mouse model, Gr-1, peptide-Fc fusion protein...KEYWORDS Prostate cancer, myeloid-derived suppressor cell (MDSC), Pten, Smad4, genetically engineered mouse model, Gr-1, peptide-Fc fusion protein 3...which should provide a genetic method for MDSC functional evaluation. Currently, the compound mouse Ptenpc-/- Smad4pc-/- CD11b-DTR+ are still in

  4. Safety of long-term exposure to abiraterone acetate in patients with castration-resistant prostate cancer and concomitant cardiovascular risk factors

    PubMed Central

    Verzoni, Elena; Grassi, Paolo; Ratta, Raffaele; Niger, Monica; De Braud, Filippo; Valdagni, Riccardo; Procopio, Giuseppe

    2016-01-01

    Background: We aimed to evaluate the long-term safety profile of abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) with controlled cardiovascular comorbidities or risk factors. Methods: We retrospectively analysed the clinical charts of consecutive mCRPC patients with cardiac disorders/risk factors who had been treated with abiraterone 1000 mg once daily plus prednisone 5 mg twice daily for a median duration of 16 months at an oncology referral centre between April 2011 and July 2015. Patients underwent an electrocardiogram (ECG) and echocardiographic assessments, including measurement of left ventricular ejection fraction (LVEF) at baseline and at the end of treatment. Blood pressure (BP) was measured daily at home. During follow up (median 24 months), all adverse events were recorded. Cardiac events (CEs) were defined, according to Common Terminology Criteria for Adverse Events version 4.0, as the appearance of a symptomatic CE that required medical intervention. Results: A total of 51 patients (median age 71 years) were evaluated. Pre-existing cardiovascular conditions included hypertension (41%), cardiac ischaemia (12%), stroke (9%), dyslipidaemia (18%) and type 2 diabetes mellitus (12%). No CEs were recorded and no changes in LVEF were observed. The most frequently reported adverse events were Grade 1–2 fluid retention (18%), hypertension (16%) and asthenia (16%). No patients permanently discontinued abiraterone due to cardiac events. Conclusions: Long-term abiraterone treatment was well tolerated in mCRPC patients with controlled cardiovascular comorbidities/risk factors, with no apparent worsening of cardiovascular conditions from baseline over an extended observation period. PMID:27583024

  5. Epidermal Growth Factor Receptor Status in Circulating Tumor Cells as a Predictive Biomarker of Sensitivity in Castration-Resistant Prostate Cancer Patients Treated with Docetaxel Chemotherapy

    PubMed Central

    Okegawa, Takatsugu; Itaya, Naoshi; Hara, Hidehiko; Tambo, Mitsuhiro; Nutahara, Kikuo

    2016-01-01

    Objective: We examined whether epidermal growth factor receptor (EGFR) expression in circulating tumor cells (CTCs) can be used to predict survival in a population of bone-metastatic castration-resistant prostate cancer (mCRPC) patients treated with docetaxel chemotherapy. Methods: All patients with mCRPC who had experienced treatment failure with androgen-deprivation therapy and had received docetaxel chemotherapy were eligible. CTCs and EGFR expression in CTCs were enumerated with the CellSearch System in whole blood. This system is a semi-automated system that detects and enriches epithelial cells from whole blood using an EpCAM antibody-based immunomagnetic capture. In addition, the EGFR-positive CTCs were assessed using CellSearch® Tumor Phenotyping Reagent EGFR. Results: The median CTC count at baseline before starting trial treatment was eight CTCs per 7.5 mL of blood (range 0–184). There were 37 patients (61.7%) who had ≥5 CTCs, with median overall survival of 11.5 months compared with 20.0 months for 23 patients (38.3%) with <5 CTCs (p < 0.001). A total of 15 patients (40.5%, 15/37) with five or more CTCs were subjected to automated immunofluorescence staining and cell sorting for EGFR protein. Patients with EGFR-positive CTCs had a shorter overall survival (OS) (5.5 months) than patients with EGFR-negative CTCs (20.0 months). CTCs, EGFR-positive CTCs, and alkaline phosphatase (ALP) were independent predictors of overall survival time (p = 0.002, p < 0.001, and p = 0.017, respectively). Conclusion: CTCs may be an independent predictor of OS in CRPC treated with docetaxel chemotherapy. The EGFR expression detected in CTCs was important for assessing the response to chemotherapy and predicting disease outcome. PMID:27916908

  6. Radioisotopes in management of metastatic prostate cancer

    PubMed Central

    Raval, Amar; Dan, Tu D.; Williams, Noelle L.; Pridjian, Andrew; Den, Robert B.

    2016-01-01

    Introduction: Metastatic prostate cancer continues to be a leading cause of morbidity and mortality in men with prostate cancer. Over the last decade, the treatment landscape for patients with castrate-resistant disease has drastically changed, with several novel agents demonstrating an improvement in overall survival in large, multi-institutional randomized trials. Traditional treatment with radioisotopes has largely been in the palliative setting. However, the first in class radiopharmaceutical radium-223 has emerged as the only bone-directed treatment option demonstrating an improvement in overall survival. Methods: Medline publications from 1990 to 2016 were searched and reviewed to assess the use of currently approved radioisotopes in the management of prostate cancer including emerging data regarding integration with novel systemic therapies. New positron emission tomography-based radiotracers for advanced molecular imaging of prostate cancer were also queried. Results: Radioisotopes play a crucial role in the diagnosis and treatment of prostate cancer in the definitive and metastatic setting. Molecular imaging of prostate cancer and theranostics are currently being investigated in the clinical arena. Conclusions: The use of modern radioisotopes in selected patients with mCRPC is associated with improvements in overall survival, pain control, and quality of life. PMID:27843209

  7. Dual-Targeting of AR and Akt Pathways by Berberine in Castration-Resistant Prostate Cancer

    DTIC Science & Technology

    2014-08-01

    suppression of AR signaling in prostate cancer. Clin Cancer Res 2009; 15: 4792-8. [3] Pienta KJ, Bradley D. Mechanisms underlying the development of...Yu J, Chen Z, Beroukhim R, Wang H, Lupien M, Wu T, Regan MM, Meyer CA, Carroll JS, Manrai AK, Janne OA et al. Androgen receptor regulates a

  8. Investigating Genomic Mechanisms of Treatment Resistance in Castration Resistant Prostate Cancer

    DTIC Science & Technology

    2013-05-01

    Sensitive Prostate Cancer”. Oncol. Rep. 2012 Jan;27(1):3-9. 4. Friedlander TW, Ryan CJ. Editorial Comment on “ Adrenocorticotropic hormone (ACTH...warranting an elevated dose (1000mg twice daily). Blood is currently being collected for serum hormone levels, SNPs in androgen synthesis genes...Bladder Cancer, genomics, microarrays, pharmacogenetics, circulating tumor cells, androgen biosynthesis inhibitors, hormonal therapy, clinical trials

  9. Low β₂-adrenergic receptor level may promote development of castration resistant prostate cancer and altered steroid metabolism.

    PubMed

    Braadland, Peder Rustøen; Grytli, Helene Hartvedt; Ramberg, Håkon; Katz, Betina; Kellman, Ralf; Gauthier-Landry, Louis; Fazli, Ladan; Krobert, Kurt Allen; Wang, Wanzhong; Levy, Finn Olav; Bjartell, Anders; Berge, Viktor; Rennie, Paul S; Mellgren, Gunnar; Mælandsmo, Gunhild Mari; Svindland, Aud; Barbier, Olivier; Taskén, Kristin Austlid

    2016-01-12

    The underlying mechanisms responsible for the development of castration-resistant prostate cancer (CRPC) in patients who have undergone androgen deprivation therapy are not fully understood. This is the first study to address whether β2-adrenergic receptor (ADRB2)- mediated signaling may affect CRPC progression in vivo. By immunohistochemical analyses, we observed that low levels of ADRB2 is associated with a more rapid development of CRPC in a Norwegian patient cohort. To elucidate mechanisms by which ADRB2 may affect CRPC development, we stably transfected LNCaP cells with shRNAs to mimic low and high expression of ADRB2. Two UDP-glucuronosyltransferases, UGT2B15 and UGT2B17, involved in phase II metabolism of androgens, were strongly downregulated in two LNCaP shADRB2 cell lines. The low-ADRB2 LNCaP cell lines displayed lowered glucuronidation activities towards androgens than high-ADRB2 cells. Furthermore, increased levels of testosterone and enhanced androgen responsiveness were observed in LNCaP cells expressing low level of ADRB2. Interestingly, these cells grew faster than high-ADRB2 LNCaP cells, and sustained their low glucuronidation activity in castrated NOD/SCID mice. ADRB2 immunohistochemical staining intensity correlated with UGT2B15 staining intensity in independent TMA studies and with UGT2B17 in one TMA study. Similar to ADRB2, we show that low levels of UGT2B15 are associated with a more rapid CRPC progression. We propose a novel mechanism by which ADRB2 may affect the development of CRPC through downregulation of UGT2B15 and UGT2B17.

  10. Low β2-adrenergic receptor level may promote development of castration resistant prostate cancer and altered steroid metabolism

    PubMed Central

    Katz, Betina; Kellman, Ralf; Gauthier-Landry, Louis; Fazli, Ladan; Krobert, Kurt Allen; Wang, Wanzhong; Levy, Finn Olav; Bjartell, Anders; Berge, Viktor; Rennie, Paul S.; Mellgren, Gunnar; Mælandsmo, Gunhild Mari; Svindland, Aud; Barbier, Olivier; Taskén, Kristin Austlid

    2016-01-01

    The underlying mechanisms responsible for the development of castration-resistant prostate cancer (CRPC) in patients who have undergone androgen deprivation therapy are not fully understood. This is the first study to address whether β2-adrenergic receptor (ADRB2)- mediated signaling may affect CRPC progression in vivo. By immunohistochemical analyses, we observed that low levels of ADRB2 is associated with a more rapid development of CRPC in a Norwegian patient cohort. To elucidate mechanisms by which ADRB2 may affect CRPC development, we stably transfected LNCaP cells with shRNAs to mimic low and high expression of ADRB2. Two UDP-glucuronosyltransferases, UGT2B15 and UGT2B17, involved in phase II metabolism of androgens, were strongly downregulated in two LNCaP shADRB2 cell lines. The low-ADRB2 LNCaP cell lines displayed lowered glucuronidation activities towards androgens than high-ADRB2 cells. Furthermore, increased levels of testosterone and enhanced androgen responsiveness were observed in LNCaP cells expressing low level of ADRB2. Interestingly, these cells grew faster than high-ADRB2 LNCaP cells, and sustained their low glucuronidation activity in castrated NOD/SCID mice. ADRB2 immunohistochemical staining intensity correlated with UGT2B15 staining intensity in independent TMA studies and with UGT2B17 in one TMA study. Similar to ADRB2, we show that low levels of UGT2B15 are associated with a more rapid CRPC progression. We propose a novel mechanism by which ADRB2 may affect the development of CRPC through downregulation of UGT2B15 and UGT2B17. PMID:26646591

  11. A Phase 2 Study of GW786034 (Pazopanib) with or without Bicalutamide in Patients with Castration Resistant Prostate Cancer

    PubMed Central

    Sridhar, Srikala S.; Joshua, Anthony M.; Gregg, Richard; Booth, Christopher M.; Murray, Nevin; Golubovic, Jovana; Wang, Lisa; Harris, Pamela; Chi, Kim N.

    2014-01-01

    Introduction Pazopanib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor. In this randomized open label phase II study, pazopanib alone or in combination with bicalutamide was evaluated in chemotherapy-naive castration resistant prostate cancer (CRPC) patients. Methods Patients received either pazopanib 800 mg daily (Arm A) or pazopanib 800 mg plus bicalutamide 50 mg daily (Arm B). A two-stage study design was used and the primary endpoint was PSA response rate (defined as a confirmed ≥50% decline from baseline). Results Twenty-three patients (Arm A 10, Arm B 13) were accrued. The main grade 3+ toxicities were hypertension, fatigue, decreased lymphocytes and increased ALT. Due to significant toxicity, the protocol was amended after the first 11 patients and the pazopanib starting dose was reduced to 600 mg daily. In arm A, of 9 evaluable patients there was 1(11%) patient with a PSA response, 3 (33%) with stable PSA, and 5 (56%) with PSA progression; in arm B of 12 evaluable patients: there were 2 (17%) patients with PSA responses, 6 (50%) with stable PSA and 4 (33%) with PSA progression. Median PFS (95%CI) was similar in both arms at 7.3 months (2.5 mo-not reached). Long term SD was seen in 4 patients who remained on treatment for 18 (Arm A), 26 (Arm A), 35 (Arm B) and 52 (Arm B) months. Conclusions In this unselected patient population, pazopanib either alone or in combination with bicalutamide failed to show sufficient activity to warrant further evaluation. However, four patients did had long-term benefit suggesting that targeting VEGFR pathway may still be relevant in selected patients, emphasizing the need for improved predictive markers for patients with CRPC. PMID:24993934

  12. Epithelial Plasticity in Castration-Resistant Prostate Cancer: Biology of the Lethal Phenotype

    DTIC Science & Technology

    2012-07-01

    little overexpression of this marker , despite its expression in stroma. In scored epithelial tumor cells for example, we only found overexpression of N...found these markers to be over-expressed in the circulating tumor cells from men with mCRPC and women with metastatic breast cancer (see below), and...outcomes. We have already developed and validated several EMT markers that will then be applied in the following order to the TMA in order to study the

  13. The tumor suppressor TERE1 (UBIAD1) prenyltransferase regulates the elevated cholesterol phenotype in castration resistant prostate cancer by controlling a program of ligand dependent SXR target genes

    PubMed Central

    Fredericks, William J.; Sepulveda, Jorge; Lal, Priti; Tomaszewski, John E.; Lin, Ming-Fong; McGarvey, Terry; Rauscher, Frank J; Malkowicz, S. Bruce

    2013-01-01

    Castrate-Resistant Prostate Cancer (CRPC) is characterized by persistent androgen receptor-driven tumor growth in the apparent absence of systemic androgens. Current evidence suggests that CRPC cells can produce their own androgens from endogenous sterol precursors that act in an intracrine manner to stimulate tumor growth. The mechanisms by which CRPC cells become steroidogenic during tumor progression are not well defined. Herein we describe a novel link between the elevated cholesterol phenotype of CRPC and the TERE1 tumor suppressor protein, a prenyltransferase that synthesizes vitamin K-2, which is a potent endogenous ligand for the SXR nuclear hormone receptor. We show that 50% of primary and metastatic prostate cancer specimens exhibit a loss of TERE1 expression and we establish a correlation between TERE1 expression and cholesterol in the LnCaP-C81 steroidogenic cell model of the CRPC. LnCaP-C81 cells also lack TERE1 protein, and show elevated cholesterol synthetic rates, higher steady state levels of cholesterol, and increased expression of enzymes in the de novo cholesterol biosynthetic pathways than the non-steroidogenic prostate cancer cells. C81 cells also show decreased expression of the SXR nuclear hormone receptor and a panel of directly regulated SXR target genes that govern cholesterol efflux and steroid catabolism. Thus, a combination of increased synthesis, along with decreased efflux and catabolism likely underlies the CRPC phenotype: SXR might coordinately regulate this phenotype. Moreover, TERE1 controls synthesis of vitamin K-2, which is a potent endogenous ligand for SXR activation, strongly suggesting a link between TERE1 levels, K-2 synthesis and SXR target gene regulation. We demonstrate that following ectopic TERE1 expression or induction of endogenous TERE1, the elevated cholesterol levels in C81 cells are reduced. Moreover, reconstitution of TERE1 expression in C81 cells reactivates SXR and switches on a suite of SXR target genes that

  14. BAY 1024767 blocks androgen receptor mutants found in castration-resistant prostate cancer patients

    PubMed Central

    Sugawara, Tatsuo; Lejeune, Pascale; Köhr, Silke; Neuhaus, Roland; Faus, Hortensia; Gelato, Kathy A.; Busemann, Matthias; Cleve, Arwed; Lücking, Ulrich; von Nussbaum, Franz; Brands, Michael; Mumberg, Dominik; Jung, Klaus; Stephan, Carsten; Haendler, Bernard

    2016-01-01

    Androgen receptor (AR) mutations arise in patients developing resistance to hormone deprivation therapies. Here we describe BAY 1024767, a thiohydantoin derivative with strong antagonistic activity against nine AR variants with mutations located in the AR ligand-binding domain (LBD), and against wild-type AR. Antagonism was maintained, though reduced, at increased androgen levels. Anti-tumor efficacy was evidenced in vivo in the KuCaP-1 prostate cancer model which bears the W741C bicalutamide resistance mutation and in the syngeneic prostate cancer rat model Dunning R3327-G. The prevalence of six selected AR mutations was determined in plasma DNA originating from 100 resistant patients and found to be at least 12%. Altogether the results show BAY 1024767 to be a strong antagonist for several AR mutants linked to therapy resistance, which opens the door for next-generation compounds that can benefit patients based on their mutation profile. PMID:26760770

  15. Dual-Targeting of AR and Akt Pathways by Berberine in Castration-Resistant Prostate Cancer

    DTIC Science & Technology

    2015-08-01

    prostate cancer driven by a constitutively active AR splice variant. While berberine treatment significantly inhibited the growth of tumor xenografts...or AR-V- promoted CRPC growth . BBR sensitizes ARv567es-expressing tumor xenografts to enzalutamide treatment. In the previous annual report...weeks before the animals were sacrificed. As shown in Fig. 1, the antiandrogen enzalutamide did not significantly change the growth of ARv567es

  16. Dual-Targeting of AR and Akt Pathways by Berberine in Castration-Resistant Prostate Cancer

    DTIC Science & Technology

    2015-08-01

    weeks before the animals were sacrificed. As shown in Fig. 1, the antiandrogen enzalutamide did not significantly change the growth of ARv567es...prostate cancer driven by a constitutively active AR splice variant. While berberine treatment significantly inhibited the growth of tumor xenografts...or AR-V- promoted CRPC growth . BBR sensitizes ARv567es-expressing tumor xenografts to enzalutamide treatment. In the previous annual report

  17. Quercetin-loaded nanomicelles to circumvent human castration-resistant prostate cancer in vitro and in vivo

    NASA Astrophysics Data System (ADS)

    Zhao, Jing; Liu, Juan; Wei, Tuo; Ma, Xiaowei; Cheng, Qiang; Huo, Shuaidong; Zhang, Chunqiu; Zhang, Yanan; Duan, Xianglin; Liang, Xing-Jie

    2016-02-01

    Prostate cancer is highly prevalent and has become the second leading cause of cancer-related death in men. Its treatment remains a challenge in the clinic, particularly in patients who have advanced to ``castration-resistant prostate cancer'' (CRPC). Thus, more effective therapeutic strategies are required. Quercetin (QCT) is a natural flavonoid compound that has attracted increasing interest due to its anticancer activity. However, the clinical application of quercetin is largely hampered by its poor water solubility and low bioavailability. The objective of this study was to evaluate the therapeutic potential of novel QCT-loaded nanomicelles (M-QCTs) assembled from DSPE-PEG2000 for prostate cancer treatment. Our results indicated that QCT was efficiently encapsulated into micelles up to 1 mg mL-1, which corresponds to a 450-fold increase of its water solubility. In vitro studies showed that the half-maximal inhibitory concentration (IC50) value (20.2 μM) of M-QCTs was much lower than free QCT (>200 μM). Thus, M-QCTs were considerably more effective than free QCT in proliferation inhibition and apoptosis induction of human androgen-independent PC-3 cells. Furthermore, M-QCTs showed superior antitumor efficacy and the tumor proliferation rate reduced by 52.03% compared to the control group in the PC-3 xenograft mouse model, possibly due to increased accumulation of M-QCTs at the tumor site by the enhanced permeability and retention (EPR) effect. Collectively, our studies demonstrated that M-QCTs significantly increase drug accumulation at the tumor site and exhibit superior anticancer activity in prostate cancer. Thus, our nanomicelle-based drug delivery system constitutes a promising and effective therapeutic strategy for clinical treatment.Prostate cancer is highly prevalent and has become the second leading cause of cancer-related death in men. Its treatment remains a challenge in the clinic, particularly in patients who have advanced to ``castration-resistant

  18. Selection and identification of ligand peptides targeting a model of castrate-resistant osteogenic prostate cancer and their receptors.

    PubMed

    Mandelin, Jami; Cardó-Vila, Marina; Driessen, Wouter H P; Mathew, Paul; Navone, Nora M; Lin, Sue-Hwa; Logothetis, Christopher J; Rietz, Anna Cecilia; Dobroff, Andrey S; Proneth, Bettina; Sidman, Richard L; Pasqualini, Renata; Arap, Wadih

    2015-03-24

    We performed combinatorial peptide library screening in vivo on a novel human prostate cancer xenograft that is androgen-independent and induces a robust osteoblastic reaction in bonelike matrix and soft tissue. We found two peptides, PKRGFQD and SNTRVAP, which were enriched in the tumors, targeted the cell surface of androgen-independent prostate cancer cells in vitro, and homed to androgen receptor-null prostate cancer in vivo. Purification of tumor homogenates by affinity chromatography on these peptides and subsequent mass spectrometry revealed a receptor for the peptide PKRGFQD, α-2-macroglobulin, and for SNTRVAP, 78-kDa glucose-regulated protein (GRP78). These results indicate that GRP78 and α-2-macroglobulin are highly active in osteoblastic, androgen-independent prostate cancer in vivo. These previously unidentified ligand-receptor systems should be considered for targeted drug development against human metastatic androgen-independent prostate cancer.

  19. Bone Metastases in Castration-Resistant Prostate Cancer: Associations between Morphologic CT Patterns, Glycolytic Activity, and Androgen Receptor Expression on PET and Overall Survival

    PubMed Central

    Wassberg, Cecilia; Fox, Josef J.; Wibmer, Andreas; Goldman, Debra A.; Kuk, Deborah; Gonen, Mithat; Larson, Steven M.; Morris, Michael J.; Scher, Howard I.; Hricak, Hedvig

    2014-01-01

    Purpose To compare the features of bone metastases at computed tomography (CT) to tracer uptake at fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) and fluorine 18 16β-fluoro-5-dihydrotestosterone (FDHT) PET and to determine associations between these imaging features and overall survival in men with castration-resistant prostate cancer. Materials and Methods This is a retrospective study of 38 patients with castration-resistant prostate cancer. Two readers independently evaluated CT, FDG PET, and FDHT PET features of bone metastases. Associations between imaging findings and overall survival were determined by using univariate Cox proportional hazards regression. Results In 38 patients, reader 1 detected 881 lesions and reader 2 detected 867 lesions. Attenuation coefficients at CT correlated inversely with FDG (reader 1: r = −0.3007; P < .001; reader 2: r = −0.3147; P < .001) and FDHT (reader 1: r = −0.2680; P = .001; reader 2: r = −0.3656; P < .001) uptake. The number of lesions on CT scans was significantly associated with overall survival (reader 1: hazard ratio [HR], 1.025; P = .05; reader 2: HR, 1.021; P = .04). The numbers of lesions on FDG and FDHT PET scans were significantly associated with overall survival for reader 1 (HR, 1.051–1.109; P < .001) and reader 2 (HR, 1.026–1.082; P ≤ .009). Patients with higher FDHT uptake (lesion with the highest maximum standardized uptake value) had significantly shorter overall survival (reader 1: HR, 1.078; P = .02; reader 2: HR, 1.092; P = .02). FDG uptake intensity was not associated with overall survival (reader 1, P = .65; reader 2, P = .38). Conclusion In patients with castration-resistant prostate cancer, numbers of bone lesions on CT, FDG PET, and FDHT PET scans and the intensity of FDHT uptake are significantly associated with overall survival. © RSNA, 2013 PMID:24475817

  20. [Radium-223 treatment of bone metastases from castration-resistant prostate cancer].

    PubMed

    Mortensen, Jann; Højgaard, Liselotte

    2014-07-21

    The alpha emitter Radium-223 ((22)3Ra-Cl2) is a bone-seeking radionuclide studied as a new treatment for patients with bone metastases from hormone refractory prostate cancer. More than 1,000 patients have been included in clinical phase I-III tests showing significant reduction in alkaline phosphatase- and PSA level and prolonged survival. Adverse events are usually mild to moderate and comprise gastrointestinal and myelotoxic symptoms. Intravenously administered (22)3Ra-Cl2 (half-life 11.4 days) will likely be given every four weeks for six treatments to out-patients.

  1. A low carbohydrate, high protein diet suppresses intratumoral androgen synthesis and slows castration-resistant prostate tumor growth in mice.

    PubMed

    Fokidis, H Bobby; Yieng Chin, Mei; Ho, Victor W; Adomat, Hans H; Soma, Kiran K; Fazli, Ladan; Nip, Ka Mun; Cox, Michael; Krystal, Gerald; Zoubeidi, Amina; Tomlinson Guns, Emma S

    2015-06-01

    Dietary factors continue to preside as dominant influences in prostate cancer prevalence and progression-free survival following primary treatment. We investigated the influence of a low carbohydrate diet, compared to a typical Western diet, on prostate cancer (PCa) tumor growth in vivo. LNCaP xenograft tumor growth was studied in both intact and castrated mice, representing a more advanced castration resistant PCa (CRPC). No differences in LNCaP tumor progression (total tumor volume) with diet was observed for intact mice (P = 0.471) however, castrated mice on the Low Carb diet saw a statistically significant reduction in tumor growth rate compared with Western diet fed mice (P = 0.017). No correlation with serum PSA was observed. Steroid profiles, alongside serum cholesterol and cholesteryl ester levels, were significantly altered by both diet and castration. Specifically, DHT concentration with the Low Carb diet was 58% that of the CRPC-bearing mice on the Western diet. Enzymes in the steroidogenesis pathway were directly impacted and tumors isolated from intact mice on the Low Carb diet had higher AKR1C3 protein levels and lower HSD17B2 protein levels than intact mice on the Western diet (ARK1C3: P = 0.074; HSD17B2: P = 0.091, with α = 0.1). In contrast, CRPC tumors from mice on Low Carb diets had higher concentrations of both HSD17B2 (P = 0.016) and SRD5A1 (P = 0.058 with α = 0.1) enzymes. There was no correlation between tumor growth in castrated mice for Low Carb diet versus Western diet and (a) serum insulin (b) GH serum levels (c) insulin receptor (IR) or (d) IGF-1R in tumor tissue. Intact mice fed Western diet had higher serum insulin which was associated with significantly higher blood glucose and tumor tissue IR. We conclude that both diet and castration have a significant impact on the endocrinology of mice bearing LNCaP xenograft tumors. The observed effects of diet on cholesterol and steroid regulation impact tumor tissue DHT specifically and are

  2. Subverting ER-stress towards apoptosis by nelfinavir and curcumin coexposure augments docetaxel efficacy in castration resistant prostate cancer cells.

    PubMed

    Mathur, Aditi; Abd Elmageed, Zakaria Y; Liu, Xichun; Kostochka, Mikhail L; Zhang, Haitao; Abdel-Mageed, Asim B; Mondal, Debasis

    2014-01-01

    Despite its side-effects, docetaxel (DTX) remains a first-line treatment against castration resistant prostate cancer (CRPC). Therefore, strategies to increase its anti-tumor efficacy and decrease its side effects are critically needed. Targeting of the constitutive endoplasmic reticulum (ER) stress in cancer cells is being investigated as a chemosensitization approach. We hypothesized that the simultaneous induction of ER-stress and suppression of PI3K/AKT survival pathway will be a more effective approach. In a CRPC cell line, C4-2B, we observed significant (p<0.005) enhancement of DTX-induced cytotoxicity following coexposure to thapsigargin and an AKT-inhibitor. However, since these two agents are not clinically approved, we investigated whether a combination of nelfinavir (NFR) and curcumin (CUR), known to target both these metabolic pathways, can similarly increase DTX cytotoxicity in CRPC cells. Within 24 hrs post-exposure to physiologic concentrations of NFR (5 µM) and CUR (5 µM) a significantly (p<0.005) enhanced cytotoxicity was evident with low concentration of DTX (10 nM). This 3-drug combination rapidly increased apoptosis in aggressive C4-2B cells, but not in RWPE-1 cells or in primary prostate epithelial cells (PrEC). Comparative molecular studies revealed that this 3-drug combination caused a more pronounced suppression of phosphorylated-AKT and higher induction in phosphorylated-eIF2α in C4-2B cells, as compared to RWPE-1 cells. Acute exposure (3-9 hrs) to this 3-drug combination intensified ER-stress induced pro-apoptotic markers, i.e. ATF4, CHOP, and TRIB3. At much lower concentrations, chronic (3 wks) exposures to these three agents drastically reduced colony forming units (CFU) by C4-2B cells. In vivo studies using mice containing C4-2B tumor xenografts showed significant (p<0.05) enhancement of DTX's (10 mg/kg) anti-tumor efficacy following coexposure to NFR (20 mg/kg) & CUR (100 mg/kg). Immunohistochemical (IHC) analyses of tumor sections

  3. Phase-1 study of abiraterone acetate in chemotherapy-naïve Japanese patients with castration-resistant prostate cancer

    PubMed Central

    Matsubara, Nobuaki; Uemura, Hiroji; Fukui, Iwao; Niwakawa, Masashi; Yamaguchi, Akito; Iizuka, Koho; Akaza, Hideyuki

    2014-01-01

    Persistent androgen synthesis under castration status in adrenal gland, testes and tumor cells is thought to be one of the major causes of development and progression of castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA), the prodrug of abiraterone, which is an inhibitor of androgen synthesis enzymes, was evaluated for pharmacokinetics, pharmacodynamics, preliminary efficacy and safety in Japanese patients with CRPC in a phase-1, open-label and dose-escalation study. Chemotherapy-naïve Japanese CRPC patients (N = 27) received one of four AA daily doses (250 mg [n = 9], 500 mg [n = 6], 1000 [1 h premeal] mg [n = 6] and 1000 [2 h postmeal] mg [n = 6]) continuously through 28-day treatment cycles. In the first cycle, AA monotherapy was given on days 1–7 for pharmacokinetics, and AA plus prednisone (5 mg twice daily) from days 8 to 28. Of 27 patients, 9 continued treatment with AA until the data cut-off date (18 July 2013). Over the evaluated dose range, plasma abiraterone concentrations increased with dose, with median tmax 2–3 h. At each dose level, mean serum corticosterone concentrations increased, while testosterone and dehydroepiandrosterone sulfate concentrations rapidly decreased following a single AA dose and were further reduced to near the quantification limit on day 8 regardless of the dose. At least 3 patients from each dose-group experienced ≥50% prostate-specific antigen reduction, suggesting clinical benefit from AA in Japanese CRPC patients. AA was generally well-tolerated, and, therefore, the recommended AA dosage regimen in Japanese CRPC patients is 1000 mg oral dose under modified fasting conditions (at least 1 h premeal or 2 h postmeal). This study is registered at ClinicalTrials.gov: NCT01186484. PMID:25117615

  4. HES6 drives a critical AR transcriptional programme to induce castration-resistant prostate cancer through activation of an E2F1-mediated cell cycle network

    PubMed Central

    Ramos-Montoya, Antonio; Lamb, Alastair D; Russell, Roslin; Carroll, Thomas; Jurmeister, Sarah; Galeano-Dalmau, Nuria; Massie, Charlie E; Boren, Joan; Bon, Helene; Theodorou, Vasiliki; Vias, Maria; Shaw, Greg L; Sharma, Naomi L; Ross-Adams, Helen; Scott, Helen E; Vowler, Sarah L; Howat, William J; Warren, Anne Y; Wooster, Richard F; Mills, Ian G; Neal, David E

    2014-01-01

    Castrate-resistant prostate cancer (CRPC) is poorly characterized and heterogeneous and while the androgen receptor (AR) is of singular importance, other factors such as c-Myc and the E2F family also play a role in later stage disease. HES6 is a transcription co-factor associated with stem cell characteristics in neural tissue. Here we show that HES6 is up-regulated in aggressive human prostate cancer and drives castration-resistant tumour growth in the absence of ligand binding by enhancing the transcriptional activity of the AR, which is preferentially directed to a regulatory network enriched for transcription factors such as E2F1. In the clinical setting, we have uncovered a HES6-associated signature that predicts poor outcome in prostate cancer, which can be pharmacologically targeted by inhibition of PLK1 with restoration of sensitivity to castration. We have therefore shown for the first time the critical role of HES6 in the development of CRPC and identified its potential in patient-specific therapeutic strategies. PMID:24737870

  5. Expression of AR-V7 in Circulating Tumour Cells Does Not Preclude Response to Next Generation Androgen Deprivation Therapy in Patients with Castration Resistant Prostate Cancer.

    PubMed

    Bernemann, Christof; Schnoeller, Thomas J; Luedeke, Manuel; Steinestel, Konrad; Boegemann, Martin; Schrader, Andres J; Steinestel, Julie

    2017-01-01

    The androgen receptor splice variant AR-V7 has recently been discussed as a predictive biomarker for nonresponse to next-generation androgen deprivation therapy (ADT) in patients with castration-resistant prostate cancer. However, we recently identified one patient showing a response from abiraterone despite expression of AR-V7 in his circulating tumour cells (CTC). Therefore, we precisely assessed the response in a cohort of 21 AR-V7 positive castration-resistant prostate cancer patients who had received therapy with abiraterone or enzalutamide. We detected a subgroup of six AR-V7 positive patients showing benefit from either abiraterone or enzalutamide. Their progression free survival was 26 d (censored) to 188 d. Four patients displayed a prostate-specific antigen decrease of >50%. When analysing prior therapies, we noticed that only one of the six patients had received next-generation ADT prior to CTC collection. As a result, we conclude that AR-V7 status in CTC cannot entirely predict nonresponse to next generation ADT and AR-V7-positive patients should not be systematically denied abiraterone or enzalutamide treatment, especially as effective alternative treatment options are still limited.

  6. New drug development in metastatic prostate cancer.

    PubMed

    Armstrong, Andrew J; George, Daniel J

    2008-01-01

    In 2007, drug development in castration-resistant metastatic prostate cancer (CRPC) remains challenging, due to the number of potentially viable molecular targets and clinical trials available, the lack of established surrogates for overall survival, and competing causes of mortality. This review will highlight the highest impact phase II and phase III trials of novel agents in the current CRPC landscape, and focus on both molecular targets and clinical trial designs that are more likely to demonstrate clinical benefit. The need for tissue correlative studies for target evaluation and drug mechanism is stressed to continue to advance the field and to define biomarkers that may identify patient populations that may derive a greater benefit from these molecular agents.

  7. The E3 Ubiquitin Ligase Siah2 Contributes to Castration-Resistant Prostate Cancer by Regulation of Androgen Receptor Transcriptional Activity

    PubMed Central

    Qi, Jianfei; Tripathi, Manisha; Mishra, Rajeev; Sahgal, Natasha; Fazil, Ladan; Ettinger, Susan; Placzek, William J.; Claps, Giuseppina; Chung, Leland W.K.; Bowtell, David; Gleave, Martin; Bhowmick, Neil; Ronai, Ze'ev A.

    2013-01-01

    SUMMARY Understanding the mechanism underlying the regulation of the androgen receptor (AR), a central player in the development of castration-resistant prostate cancer (CRPC), holds promise for overcoming the challenge of treating CRPC. We demonstrate that the ubiquitin ligase Siah2 targets a select pool of NCOR1-bound, transcriptionally-inactive AR for ubiquitin-dependent degradation, thereby promoting expression of select AR target genes implicated in lipid metabolism, cell motility, and proliferation. Siah2 is required for prostate cancer cell growth under androgen-deprivation conditions in vitro and in vivo, and Siah2 inhibition promotes prostate cancer regression upon castration. Notably, Siah2 expression is markedly increased in human CRPCs. Collectively, we find that selective regulation of AR transcriptional activity by the ubiquitin ligase Siah2 is important for CRPC development. PMID:23518348

  8. The E3 ubiquitin ligase Siah2 contributes to castration-resistant prostate cancer by regulation of androgen receptor transcriptional activity.

    PubMed

    Qi, Jianfei; Tripathi, Manisha; Mishra, Rajeev; Sahgal, Natasha; Fazli, Ladan; Fazil, Ladan; Ettinger, Susan; Placzek, William J; Claps, Giuseppina; Chung, Leland W K; Bowtell, David; Gleave, Martin; Bhowmick, Neil; Ronai, Ze'ev A

    2013-03-18

    Understanding the mechanism underlying the regulation of the androgen receptor (AR), a central player in the development of castration-resistant prostate cancer (CRPC), holds promise for overcoming the challenge of treating CRPC. We demonstrate that the ubiquitin ligase Siah2 targets a select pool of NCOR1-bound, transcriptionally-inactive AR for ubiquitin-dependent degradation, thereby promoting expression of select AR target genes implicated in lipid metabolism, cell motility, and proliferation. Siah2 is required for prostate cancer cell growth under androgen-deprivation conditions in vitro and in vivo, and Siah2 inhibition promotes prostate cancer regression upon castration. Notably, Siah2 expression is markedly increased in human CRPCs. Collectively, we find that selective regulation of AR transcriptional activity by the ubiquitin ligase Siah2 is important for CRPC development.

  9. The AhR Ligand, TCDD, Regulates Androgen Receptor Activity Differently in Androgen-Sensitive versus Castration-Resistant Human Prostate Cancer Cells

    PubMed Central

    Ghotbaddini, Maryam; Powell, Joann B.

    2015-01-01

    The reported biological effects of TCDD include induction of drug metabolizing enzymes, wasting syndrome and tumor promotion. TCDD elicits most of its effects through binding the aryl hydrocarbon receptor (AhR). TCDD induced degradation of AhR has been widely reported and requires ubiquitination of the protein. The rapid depletion of AhR following TCDD activation serves as a mechanism to modulate AhR mediated gene induction. In addition to inducing AhR degradation, TCDD has been reported to induce degradation of hormone receptors. The studies reported here, evaluate the effect of TCDD exposure on androgen receptor (AR) expression and activity in androgen-sensitive LNCaP and castration-resistant C4-2 prostate cancer cells. Our results show that TCDD exposure does not induce AhR or AR degradation in C4-2 cells. However, both AhR and AR are degraded in LNCaP cells following TCDD exposure. In addition, TCDD enhances AR phosphorylation and induces expression of AR responsive genes in LNCaP cells. Our data reveals that TCDD effect on AR expression and activity differs in androgen-sensitive and castration-resistant prostate cancer cell models. PMID:26154658

  10. Development of a New Class of Drugs to Inhibit All Forms of Androgen Receptor in Castration-Resistant Prostate Cancers

    DTIC Science & Technology

    2015-10-01

    AWARD NUMBERS: W81XWH-14-1-0518 TITLE: Development of a New Class of Drugs to Inhibit All Forms of Androgen Receptor in Castration-Resistant...COVERED 30 Sep 2014 - 29 Sep 2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Development of a New Class of Drugs to Inhibit All Forms of Androgen...designed to block AR activity that re- emerges during castration. However, despite a growing armamentarium of drugs targeting the androgen/AR signaling

  11. Development of a New Class of Drugs to Inhibit All Forms of Androgen Receptor in Castration Resistant Prostate Cancers

    DTIC Science & Technology

    2015-10-01

    AWARD NUMBERS: W81XWH-14-1-0520 TITLE: Development of a New Class of Drugs to Inhibit All Forms of Androgen Receptor in Castration-Resistant...COVERED 30 Sep 2014 - 29 Sep 2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-14-1-0520 Development of a New Class of Drugs to Inhibit All Forms...re- emerges during castration. However, despite a growing armamentarium of drugs targeting the androgen/AR signaling axis, progression of castration

  12. Nrdp1-mediated regulation of ErbB3 expression by the androgen receptor in androgen-dependent but not castrate-resistant prostate cancer cells

    PubMed Central

    Chen, Liqun; Siddiqui, Salma; Bose, Swagata; Mooso, Benjamin; Asuncion, Alfredo; Bedolla, Roble G.; Vinall, Ruth; Tepper, Clifford G.; Gandour-Edwards, Regina; Shi, XuBao; Lu, Xiao-Hua; Siddiqui, Javed; Chinnaiyan, Arul M.; Mehra, Rohit; deVere White, Ralph W.; Carraway, Kermit L.; Ghosh, Paramita M.

    2010-01-01

    Patients with advanced prostate cancer (PCa) are initially susceptible to androgen withdrawal (AW), but ultimately develop resistance to this therapy (castration-resistant PCa, CRPC). Here we show that AW can promote CRPC development by increasing the levels of the receptor tyrosine kinase (RTK) ErbB3 in androgen-dependent PCa, resulting in AW-resistant cell cycle progression and increased androgen receptor (AR) transcriptional activity. CRPC cell lines and human prostate cancer tissue overexpressed ErbB3, whereas downregulation of ErbB3 prevented CRPC cell growth. Investigation of the mechanism by which AW augments ErbB3, using normal prostate derived pRNS-1-1 cells, and androgen-dependent PCa lines LNCaP, PC346C and CWR22 mouse xenografts, revealed that the AR suppresses ErbB3 protein levels, while AW relieves this suppression, demonstrating for the first time negative regulation of ErbB3 by AR. We show that AR activation promotes ErbB3 degradation in androgen-dependent cells, and that this effect is mediated by AR-dependent transcriptional upregulation of Nrdp1, an E3 ubiquitin ligase that targets ErbB3 for degradation but whose role in PCa has not been previously examined. Therefore, AW decreases Nrdp1 expression, promoting ErbB3 protein accumulation, and leading to AR-independent proliferation. However, in CRPC sublines of LNCaP and CWR22 which strongly overexpress the AR, ErbB3 levels remain elevated due to constitutive suppression of Nrdp1, which prevents AR regulation of Nrdp1. Our observations point to a model of CRPC development where progression of PCa to castration-resistance is associated with the inability of AR to transcriptionally regulate Nrdp1, and predict that inhibition of ErbB3 during AW may impair CRPC development. PMID:20587519

  13. Development of Potent and Selective Indomethacin Analogues for the Inhibition of AKR1C3 (Type 5 17β-Hydroxysteroid Dehydrogenase/Prostaglandin F Synthase) in Castrate-Resistant Prostate Cancer

    PubMed Central

    2013-01-01

    Castrate-resistant prostate cancer (CRPC) is a fatal, metastatic form of prostate cancer. CRPC is characterized by reactivation of the androgen axis due to changes in androgen receptor signaling and/or adaptive intratumoral androgen biosynthesis. AKR1C3 is upregulated in CRPC where it catalyzes the formation of potent androgens. This makes AKR1C3 a target for the treatment of CRPC. AKR1C3 inhibitors should not inhibit AKR1C1/AKR1C2, which inactivate 5α-dihydrotestosterone. Indomethacin, used to inhibit cyclooxygenase, also inhibits AKR1C3 and displays selectivity over AKR1C1/AKR1C2. Parallel synthetic strategies were used to generate libraries of indomethacin analogues, which exhibit reduced cyclooxygenase inhibitory activity but retain AKR1C3 inhibitory potency and selectivity. The lead compounds inhibited AKR1C3 with nanomolar potency, displayed >100-fold selectivity over AKR1C1/AKR1C2, and blocked testosterone formation in LNCaP-AKR1C3 cells. The AKR1C3·NADP+·2′-des-methyl-indomethacin crystal structure was determined, and it revealed a unique inhibitor binding mode. The compounds reported are promising agents for the development of therapeutics for CRPC. PMID:23432095

  14. Silencing CAPN2 Expression Inhibited Castration-Resistant Prostate Cancer Cells Proliferation and Invasion via AKT/mTOR Signal Pathway

    PubMed Central

    Li, Pu; Miao, Chenkui; Liang, Chao; Shao, Pengfei

    2017-01-01

    The mRNA expression of CAPN2 was upregulated in CRPC cells (DU145 and PC3) than that in non-CRPC cells. Silencing CAPN2 expression could inhibit DU145 and PC3 cells proliferation by cell cycle arrest at G1 phase. Knockdown of CPAN2 level suppressed the migration and invasion capacity of CRPC cells by reducing matrix metalloproteinase-2 (MMP-2) and MMP-9 activation, as well as repressing the phosphorylation protein expression of AKT and mTOR. In addition, we found that the expression of CAPN2 was elevated in Pca tissues than that in normal control tissues. Therefore, we showed the important roles of CAPN2 in the development and progression in CRPC cells, suggesting a new therapeutic intervention for treating castration-resistant prostate cancer patients. PMID:28280729

  15. Nrdp1-mediated regulation of ErbB3 expression by the androgen receptor in androgen-dependent but not castrate-resistant prostate cancer cells.

    PubMed

    Chen, Liqun; Siddiqui, Salma; Bose, Swagata; Mooso, Benjamin; Asuncion, Alfredo; Bedolla, Roble G; Vinall, Ruth; Tepper, Clifford G; Gandour-Edwards, Regina; Shi, Xubao; Lu, Xiao-Hua; Siddiqui, Javed; Chinnaiyan, Arul M; Mehra, Rohit; Devere White, Ralph W; Carraway, Kermit L; Ghosh, Paramita M

    2010-07-15

    Patients with advanced prostate cancer (PCa) are initially susceptible to androgen withdrawal (AW), but ultimately develop resistance to this therapy (castration-resistant PCa, CRPC). Here, we show that AW can promote CRPC development by increasing the levels of the receptor tyrosine kinase ErbB3 in androgen-dependent PCa, resulting in AW-resistant cell cycle progression and increased androgen receptor (AR) transcriptional activity. CRPC cell lines and human PCa tissue overexpressed ErbB3, whereas downregulation of ErbB3 prevented CRPC cell growth. Investigation of the mechanism by which AW augments ErbB3, using normal prostate-derived pRNS-1-1 cells, and androgen-dependent PCa lines LNCaP, PC346C, and CWR22 mouse xenografts, revealed that the AR suppresses ErbB3 protein levels, whereas AW relieves this suppression, showing for the first time the negative regulation of ErbB3 by AR. We show that AR activation promotes ErbB3 degradation in androgen-dependent cells, and that this effect is mediated by AR-dependent transcriptional upregulation of neuregulin receptor degradation protein-1 (Nrdp1), an E3 ubiquitin ligase that targets ErbB3 for degradation but whose role in PCa has not been previously examined. Therefore, AW decreases Nrdp1 expression, promoting ErbB3 protein accumulation, and leading to AR-independent proliferation. However, in CRPC sublines of LNCaP and CWR22, which strongly overexpress the AR, ErbB3 levels remain elevated due to constitutive suppression of Nrdp1, which prevents AR regulation of Nrdp1. Our observations point to a model of CRPC development in which progression of PCa to castration resistance is associated with the inability of AR to transcriptionally regulate Nrdp1, and predict that inhibition of ErbB3 during AW may impair CRPC development.

  16. YAP1 and AR interactions contribute to the switch from androgen-dependent to castration-resistant growth in prostate cancer

    PubMed Central

    Kuser-Abali, Gamze; Alptekin, Ahmet; Lewis, Michael; Garraway, Isla P.; Cinar, Bekir

    2017-01-01

    The transcriptional co-activator Yes-associated protein 1 (YAP1), a key nuclear effector of the Hippo pathway, is a potent oncogene, and yet, the interaction between YAP1 and androgen receptor (AR) remains unexplored. Here we identify YAP1 as a physiological binding partner and positive regulator of AR in prostate cancer. YAP1 and AR co-localize and interact with each other predominantly within cell nuclei by an androgen-dependent mechanism in a hormone naive and an androgen-independent mechanism in castration-resistant prostate cancer cells. The growth suppressor MST1 kinase modulates androgen-dependent and -independent nuclear YAP1–AR interactions through directly regulating YAP1 nuclear accumulation. Disruption of YAP1 signalling by genetic (RNAi) and pharmacological (Verteporfin) approaches suppresses AR-dependent gene expression and prostate cancer cell growth. These findings indicate that the YAP1–AR axis may have a critical role in prostate cancer progression and serves as a viable drug target. PMID:28230103

  17. Radium-223 for Advanced Prostate Cancer

    Cancer.gov

    A summary of results from a phase III trial that compared radium-223 dichloride plus the best standard of care versus a placebo plus the best standard of care in men with metastatic, castration-resistant prostate cancer.

  18. Detection of AR-V7 mRNA in whole blood may not predict the effectiveness of novel endocrine drugs for castration-resistant prostate cancer.

    PubMed

    Takeuchi, Takumi; Okuno, Yumiko; Hattori-Kato, Mami; Zaitsu, Masayoshi; Mikami, Koji

    2016-01-01

    A splice variant of androgen receptor (AR), AR-V7, lacks in androgen-binding portion and leads to aggressive cancer characteristics. Reverse transcription-polymerase chain reactions (PCRs) and subsequent nested PCRs for the amplification of AR-V7 and prostate-specific antigen (PSA) transcripts were done for whole blood of patients with prostate cancer and male controls. With primary reverse transcription PCRs, AR-V7 and PSA were detected in 4.5% and 4.7% of prostate cancer, respectively. With nested PCRs, AR-V7 messenger RNA (mRNA) was positive in 43.8% of castration-sensitive prostate cancer and 48.1% of castration-resistant prostate cancer (CRPC), while PSA mRNA was positive in 6.3% of castration-sensitive prostate cancer and 18.5% of CRPC. Whole-blood samples of controls showed AR-V7 mRNA expression by nested PCR. Based on multivariate analysis, expression of AR-V7 mRNA in whole blood was not significantly correlated with clinical parameters and PSA mRNA in blood, while univariate analysis showed a correlation between AR-V7 mRNA and metastasis at initial diagnosis. Detection of AR-V7 mRNA did not predict the reduction of serum PSA in patients with CRPC following abiraterone and enzalutamide administration. In conclusion, AR-V7 mRNA expression in normal hematopoietic cells may have annihilated the manifestation of aggressiveness of prostate cancer and the prediction of the effectiveness of abiraterone and enzalutamide by the assessment of AR-V7 mRNA in blood.

  19. Targeting ACLY sensitizes castration-resistant prostate cancer cells to AR antagonism by impinging on an ACLY-AMPK-AR feedback mechanism.

    PubMed

    Shah, Supriya; Carriveau, Whitney J; Li, Jinyang; Campbell, Sydney L; Kopinski, Piotr K; Lim, Hee-Woong; Daurio, Natalie; Trefely, Sophie; Won, Kyoung-Jae; Wallace, Douglas C; Koumenis, Constantinos; Mancuso, Anthony; Wellen, Kathryn E

    2016-07-12

    The androgen receptor (AR) plays a central role in prostate tumor growth. Inappropriate reactivation of the AR after androgen deprivation therapy promotes development of incurable castration-resistant prostate cancer (CRPC). In this study, we provide evidence that metabolic features of prostate cancer cells can be exploited to sensitize CRPC cells to AR antagonism. We identify a feedback loop between ATP-citrate lyase (ACLY)-dependent fatty acid synthesis, AMPK, and the AR in prostate cancer cells that could contribute to therapeutic resistance by maintaining AR levels. When combined with an AR antagonist, ACLY inhibition in CRPC cells promotes energetic stress and AMPK activation, resulting in further suppression of AR levels and target gene expression, inhibition of proliferation, and apoptosis. Supplying exogenous fatty acids can restore energetic homeostasis; however, this rescue does not occur through increased β-oxidation to support mitochondrial ATP production. Instead, concurrent inhibition of ACLY and AR may drive excess ATP consumption as cells attempt to cope with endoplasmic reticulum (ER) stress, which is prevented by fatty acid supplementation. Thus, fatty acid metabolism plays a key role in coordinating ER and energetic homeostasis in CRPC cells, thereby sustaining AR action and promoting proliferation. Consistent with a role for fatty acid metabolism in sustaining AR levels in prostate cancer in vivo, AR mRNA levels in human prostate tumors correlate positively with expression of ACLY and other fatty acid synthesis genes. The ACLY-AMPK-AR network can be exploited to sensitize CRPC cells to AR antagonism, suggesting novel therapeutic opportunities for prostate cancer.

  20. High-throughput cell-based compound screen identifies pinosylvin methyl ether and tanshinone IIA as inhibitors of castration-resistant prostate cancer

    PubMed Central

    Ketola, Kirsi; Viitala, Miro; Kohonen, Pekka; Fey, Vidal; Culig, Zoran; Kallioniemi, Olli; Iljin, Kristiina

    2016-01-01

    Current treatment options for castration-resistant prostate cancer (CRPC) are limited. In this study, a high-throughput screen of 4910 drugs and drug-like molecules was performed to identify antiproliferative compounds in androgen ablated prostate cancer cells. The effect of compounds on cell viability was compared in androgen ablated LNCaP prostate cancer cells and in LNCaP cells grown in presence of androgens as well as in two non-malignant prostate epithelial cells (RWPE-1 and EP156T). Validation experiments of cancer specific anti-proliferative compounds indicated pinosylvin methyl ether (PSME) and tanshinone IIA as potent inhibitors of androgen ablated LNCaP cell proliferation. PSME is a stilbene compound with no previously described anti-neoplastic activity whereas tanshinone IIA is currently used in cardiovascular disorders and proposed as a cancer drug. To gain insights into growth inhibitory mechanisms in CRPC, genome-wide gene expression analysis was performed in PSME- and tanshinone IIA-exposed cells. Both compounds altered the expression of genes involved in cell cycle and steroid and cholesterol biosynthesis in androgen ablated LNCaP cells. Decrease in androgen signalling was confirmed by reduced expression of androgen receptor and prostate specific antigen in PSME- or tanshinone IIA-exposed cells. Taken together, this systematic screen identified a novel anti-proliferative agent, PSME, for CRPC. Moreover, our screen confirmed tanshinone IIA as well as several other compounds as potential prostate cancer growth inhibitors also in androgen ablated prostate cancer cells. These results provide valuable starting points for preclinical and clinical studies for CRPC treatment. PMID:27891324

  1. Activation of AMPKα mediates additive effects of solamargine and metformin on suppressing MUC1 expression in castration-resistant prostate cancer cells

    PubMed Central

    Xiang, SongTao; Zhang, QiuHong; Tang, Qing; Zheng, Fang; Wu, JingJing; Yang, LiJun; Hann, Swei Sunny

    2016-01-01

    Prostate cancer is the second most common cause of cancer-related deaths worldwide. The mucin 1 (MUC1) oncoprotein is highly expressed in human prostate cancers with aggressive features. However, the role for MUC1 in occurrence and progression of castration-resistant prostate cancer (CRPC) remained elusive. In this study, we showed that solamargine, a major steroidal alkaloid glycoside, inhibited the growth of CRPC cells, which was enhanced in the presence of metformin. Furthermore, we found that solamargine increased phosphorylation of AMPKα, whereas reducing the protein expression and promoter activity of MUC1. A greater effect was observed in the presence of metformin. In addition, solamargine reduced NF-κB subunit p65 protein expression. Exogenously expressed p65 resisted solamargine-reduced MUC1 protein and promoter activity. Interestingly, exogenously expressed MUC1 attenuated solamargine-stimulated phosphorylation of AMPKα and, more importantly reversed solamargine-inhibited cell growth. Finally, solamargine increased phosphorylation of AMPKα, while inhibiting MUC1, p65 and tumor growth were observed in vivo. Overall, our results show that solamargine inhibits the growth of CRPC cells through AMPKα-mediated inhibition of p65, followed by reduction of MUC1 expression in vitro and in vivo. More importantly, metformin facilitates the antitumor effect of solamargine on CRPC cells. PMID:27830724

  2. Definition of a FoxA1 Cistrome that is Crucial for G1-S Phase Cell-Cycle Transit in Castration-Resistant Prostate Cancer

    PubMed Central

    Chen, Hongyan; Chen, Zhong; Thomas-Ahner, Jennifer M.; Zynger, Debra L.; Eeckhoute, Jérôme; Yu, Jindan; Luo, Jun; Brown, Myles; Clinton, Steven K.; Nephew, Kenneth P.; Huang, Tim H.-M.; Li, Wei; Wang, Qianben

    2014-01-01

    The enhancer pioneer transcription factor FoxA1 is a global mediator of steroid receptor (SR) action in hormone-dependent cancers. In castration-resistant prostate cancer (CRPC), FoxA1 acts as an androgen receptor co-factor to drive G2-M phase cell-cycle transit. Here we describe a mechanistically distinct SR-independent role for FoxA1 in driving G1-S phase cell-cycle transit in CRPC. By comparing FoxA1 binding sites in prostate cancer cell genomes, we defined a co-dependent set of FoxA1-MYBL2 and FoxA1-CREB1 binding sites within the regulatory regions of the Cyclin E2 and E2F1 genes that are critical for CRPC growth. Binding at these sites upregulate the Cyclin E2 and Cyclin A2 genes in CRPC but not in earlier stage androgen-dependent prostate cancer (ADPC), establishing a stage-specific role for this pathway in CRPC growth. Mechanistic investigations indicated that FoxA1, MYBL2 or CREB1 induction of histone H3 acetylation facilitated nucleosome disruption as the basis for co-dependent transcriptional activation and G1-S phase cell-cycle transit. Our findings establish FoxA1 as a pivotal driver of the cell-cycle in CRPC which promotes G1-S phase transit as well as G2-M phase transit through two distinct mechanisms. PMID:21900400

  3. Inhibition of NF-kappa B signaling restores responsiveness of castrate resistant prostate cancer cells to anti-androgen treatment by decreasing androgen receptor variants expression

    PubMed Central

    Jin, Renjie; Yamashita, Hironobu; Yu, Xiuping; Wang, Jingbin; Franco, Omar E.; Wang, Yufen; Hayward, Simon W.; Matusik, Robert J.

    2014-01-01

    Androgen receptor splicing variants (ARVs) which lack the ligand-binding domain (LBD) are associated with the development of castration-resistant prostate cancer (CRPC), including resistance to the new generation of high affinity anti-androgens. However, the mechanism by which ARVs expression is regulated is not fully understood. In this study, we show that activation of classical NF-κB signaling increases the expression of ARVs in prostate cancer (PCa) cells and converts androgen sensitive PCa cells to become androgen insensitive; while, downregulation of NF-κB signaling inhibits ARVs expression and restores responsiveness of CRPC to anti-androgen therapy. In addition, we demonstrated that combination of anti-androgen with NF-κB targeted therapy inhibits efficiently tumor growth of human CRPC xenografts. These results indicate that induction ARVs by activated NF-κB signaling in PCa cells is a critical mechanism by which the PCa progresses to CRPC. This has important implications since it can prolong the survival of CRPC patients by restoring the tumors to once again respond to conventional androgen-deprivation therapy (ADT). PMID:25220414

  4. Surgical castration efficiently delays the time of starting a systemic chemotherapy in castration-resistant prostate cancer patients refractory to initial androgen-deprivation therapy

    PubMed Central

    Kang, Minyong; Lee, Sangchul; Oh, Jong Jin; Hong, Sung Kyu; Lee, Sang Eun; Byun, Seok-Soo

    2015-01-01

    Background The aim of this study was to investigate the effects of surgical castration, particularly delaying the time to entrance of systemic chemotherapy, in castration-resistant prostate cancer (CRPC) patients who were refractory to initial combination androgen deprivation therapy. Materials and methods We analyzed the clinical data of 14 CRPC patients diagnosed at Seoul National University Bundang Hospital (SNUBH) from November 2008 through May 2015. After exclusion of three patients, we finally analyzed the baseline characteristics of 11 CRPC patients. We also assessed the delaying time of docetaxel administration, which was defined as response duration, after surgical castration. Results After bilateral orchiectomy, the treatment response rate was 45.4% and the median duration of response was 9 months (range 4–48 mo). Responders had less aggressive biopsy Gleason scores compared to nonresponders. Notably, responders showed the reducing pattern of serum prostate specific antigen levels, while nonresponders demonstrated increasing tendency after surgical castration. Moreover, responders also presented with a reduction pattern of serum testosterone levels, whereas nonresponders showed an increasing pattern of testosterone levels after bilateral orchiectomy. Conclusions In summary, despite the limited number of cases for convincing evidence, our results shed light again on the clinical benefits of surgical castration prior to the systemic chemotherapy in some CRPC patients after initial hormone therapy. PMID:26779458

  5. Uroncor consensus statement: Management of biochemical recurrence after radical radiotherapy for prostate cancer: From biochemical failure to castration resistance.

    PubMed

    López Torrecilla, José; Hervás, Asunción; Zapatero, Almudena; Gómez Caamaño, Antonio; Macías, Victor; Herruzo, Ismael; Maldonado, Xavier; Gómez Iturriaga, Alfonso; Casas, Francesc; González San Segundo, Carmen

    2015-01-01

    Management of patients who experience biochemical failure after radical radiotherapy with or without hormonal therapy is highly challenging. The clinician must not only choose the type of treatment, but also the timing and optimal sequence of treatment administration. When biochemical failure occurs, numerous treatment scenarios are possible, thus making it more difficult to select the optimal approach. Moreover, rapid and ongoing advances in treatment options require that physicians make decisions that could impact both survival and quality of life. The aim of the present consensus statement, developed by the Urological Tumour Working Group (URONCOR) of the Spanish Society of Radiation Oncology (SEOR), is to provide cancer specialists with the latest, evidence-based information needed to make the best decisions for the patient under all possible treatment scenarios. The structure of this consensus statement follows the typical development of disease progression after biochemical failure, with the most appropriate treatment recommendations given for each stage. The consensus statement is organized into three separate chapters, as follows: biochemical failure with or without local recurrence and/or metastasis; progression after salvage therapy; and treatment of castration-resistant patients.

  6. Uroncor consensus statement: Management of biochemical recurrence after radical radiotherapy for prostate cancer: From biochemical failure to castration resistance

    PubMed Central

    López Torrecilla, José; Hervás, Asunción; Zapatero, Almudena; Gómez Caamaño, Antonio; Macías, Victor; Herruzo, Ismael; Maldonado, Xavier; Gómez Iturriaga, Alfonso; Casas, Francesc; González San Segundo, Carmen

    2015-01-01

    Management of patients who experience biochemical failure after radical radiotherapy with or without hormonal therapy is highly challenging. The clinician must not only choose the type of treatment, but also the timing and optimal sequence of treatment administration. When biochemical failure occurs, numerous treatment scenarios are possible, thus making it more difficult to select the optimal approach. Moreover, rapid and ongoing advances in treatment options require that physicians make decisions that could impact both survival and quality of life. The aim of the present consensus statement, developed by the Urological Tumour Working Group (URONCOR) of the Spanish Society of Radiation Oncology (SEOR), is to provide cancer specialists with the latest, evidence-based information needed to make the best decisions for the patient under all possible treatment scenarios. The structure of this consensus statement follows the typical development of disease progression after biochemical failure, with the most appropriate treatment recommendations given for each stage. The consensus statement is organized into three separate chapters, as follows: biochemical failure with or without local recurrence and/or metastasis; progression after salvage therapy; and treatment of castration-resistant patients. PMID:26109913

  7. Early use of chemotherapy in metastatic prostate cancer.

    PubMed

    Markowski, Mark C; Carducci, Michael A

    2016-10-03

    Since 2010, five new antineoplastic therapies have been FDA approved for the treatment of metastatic prostate cancer. With additional treatment options, questions arose about the optimal sequence of these agents. Until recently, chemotherapy has been deferred until later in the disease course in favor of next-generation androgen deprivation therapy. Prior to the development of abiraterone acetate and enzalutamide, clinical trials were opened investigating the combination of chemotherapy with androgen deprivation therapy in patients with metastatic hormone-sensitive disease. With the development of new oral therapies used to treat castration-resistant disease, these trials were largely forgotten or felt to be obsolete. Recently, two trials have been reported showing an overall survival benefit of the early use of chemotherapy in patients with hormone-naive prostate cancer, changing the treatment paradigm for metastatic disease. Here we review the history of chemotherapy in treating prostate cancer and the emerging evidence favoring its use as first-line therapy against metastatic hormone-sensitive disease.

  8. Therapeutic vaccination with an interleukin-2-interferon-gamma-secreting allogeneic tumor vaccine in patients with progressive castration-resistant prostate cancer: a phase I/II trial.

    PubMed

    Brill, Thomas H; Kübler, Hubert R; Pohla, Heike; Buchner, Alexander; Fend, Falko; Schuster, Tibor; van Randenborgh, Heiner; Paul, Roger; Kummer, Tania; Plank, Christian; Eisele, Bernd; Breul, Jürgen; Hartung, Rudolf; Schendel, Dolores J; Gansbacher, Bernd

    2009-12-01

    Immunotherapy with whole cell cancer vaccines has been tested in various tumor types. This study investigated the safety profile and antitumor activity of an allogeneic prostate carcinoma cell line, LNCaP, expressing recombinant human interleukin-2 and human interferon-gamma. Thirty HLA-A*0201-matched patients with progressive, castration-resistant prostate cancer received four intradermal injections on days 1, 15, 29, and 92, and then every 90 days, as long as no tumor progression occurred. Three patients received a dose level of 7.5 million cells, and 27 patients received 15 million cells per injection. The primary study criteria were safety and the difference in prostate-specific antigen doubling time (PSA-DT), determined in the pretreatment phase (before the start of vaccination) and in the trial treatment phase (during vaccination). No dose-limiting or autoimmune toxicity was seen. During vaccination there was a significant prolongation of the PSA-DT compared with the prevaccination period (prolongation from 63 to 114 days; p < 0.01; intention to treat). In addition, results showed a period of PSA stabilization of at least 12 weeks, together with stable bone scans in 12 of 30 patients, and 3 patients sustained a >50% decrease in PSA versus baseline. The median overall survival time from first vaccination was 32 months (mean value, 34 months). Immune monitoring revealed T cell stimulation in the majority of patients. This vaccine strategy was found to be safe and well tolerated and was accompanied by prolongation of PSA-DT. The results of this trial warrant clinical development of this vaccine.

  9. Inhibition of the HER2-YB1-AR axis with Lapatinib synergistically enhances Enzalutamide anti-tumor efficacy in castration resistant prostate cancer

    PubMed Central

    Shiota, Masaki; Bishop, Jennifer L.; Takeuchi, Ario; Nip, Ka Mun; Cordonnier, Thomas; Beraldi, Eliana; Kuruma, Hidetoshi; Gleave, Martin E.; Zoubeidi, Amina

    2015-01-01

    Incurable castration-resistant prostate cancer (CRPC) is driven by androgen receptor (AR) activation. Potent therapies that prevent AR signaling, such as Enzalutamide (ENZ), are mainstay treatments for CRPC; however patients eventually progress with ENZ resistant (ENZR) disease. In this study, we investigated one mechanism of ENZ resistance, and tried to improve therapeutic efficiency of ENZ. We found HER2 expression is increased in ENZR tumors and cell lines, and is induced by ENZ treatment of LNCaP cells. ENZ-induced HER2 overexpression was dependent on AKT-YB1 activation and modulated AR activity. HER2 dependent AR activation in LNCaP and ENZR cells was effectively blocked by treatment with the EGFR/HER2 inhibitor Lapatinib, which reduced cell viability and increased apoptosis. Despite efficacy in vitro, in vivo monotherapy with Lapatinib did not prevent ENZR tumor growth. However, combination treatment of Lapatinib with ENZ most effectively induced cell death in LNCaP cells in vitro and was more effective than ENZ alone in preventing tumor growth in an in vivo model of CRPC. These results suggest that while HER2 overexpression and subsequent AR activation is a targetable mechanism of resistance to ENZ, therapy using Lapatinib is only a rational therapeutic approach when used in combination with ENZ in CRPC. PMID:25871401

  10. ASC-J9(®) suppresses castration resistant prostate cancer progression via degrading the enzalutamide-induced androgen receptor mutant AR-F876L.

    PubMed

    Wang, Ronghao; Lin, Wanying; Lin, Changyi; Li, Lei; Sun, Yin; Chang, Chawnshang

    2016-08-28

    Androgen deprivation therapy (ADT) with the newly developed powerful anti-androgen enzalutamide (Enz, also known as MDV3100) has promising therapeutic effects to suppress castration resistant prostate cancer (CRPC) and extending patients' lives an extra 4.8 months. However, most Enz therapy eventually fails with the development of Enz resistance. The detailed mechanisms how CRPC develops Enz resistance remain unclear and may involve multiple mechanisms. Among them, the induction of the androgen receptor (AR) mutant AR-F876L in some CRPC patients may represent one driving force that confers Enz resistance. Here, we demonstrate that the AR degradation enhancer, ASC-J9(®), not only degrades wild-type AR, but also has the ability to target AR-F876L. The consequence of suppressing AR-F876L may then abrogate AR-F876L mediated CRPC cell proliferation and metastasis. Thus, developing ASC-J9(®) as a new therapeutic approach may represent a novel therapy to better suppress CRPC that has already developed Enz resistance.

  11. Solitary recurrence of castration-resistant prostate cancer with low or undetectable levels of prostate specific antigen salvaged with local ablative radiation therapy: A case report

    PubMed Central

    WANG, CHIACHIEN JAKE; YING, JAMES; KAPUR, PAYAL; WOHLFELD, BRYAN; ROEHRBORN, CLAUS; KIM, DONG W. NATHAN

    2016-01-01

    Prostate cancer recurrences are usually first detected by increased levels of prostate specific antigen (PSA), and systemic therapy is often initiated if distant metastasis is confirmed. However, low or nearly undetectable levels of PSA in the modern era of ultrasensitive PSA assay may be difficult to interpret in patients with a history of prostate cancer. Deciding whether to initiate additional systemic therapy in limited indolent metastatic disease while balancing the quality of life of the patient and ensuring the oncologic control of the disease may be challenging. In the present study, the case of a biopsy-confirmed solitary spine recurrence of prostate cancer with nearly undetectable but persistent levels of PSA (0.05 ng/ml) is reported. Treatment of the recurrence with local ablative radiotherapy improved the pain experienced by the patient, and reduced his levels of PSA to undetectable limits (<0.05 ng/ml). Repeated imaging analysis, PSA assay and clinical assessment demonstrated durable control of the disease without the requirement for additional systemic treatments. The present case highlighted the importance of initiating appropriate work-up according to the clinical scenario. Local treatment for solitary or oligometastatic recurrence of prostate cancer may enhance the effectiveness of current therapeutic strategies and benefit certain patients. PMID:26870272

  12. Denosumab Reduces Risk of Bone Side Effects in Advanced Prostate Cancer

    Cancer.gov

    The biological agent denosumab (Xgeva) is more effective than zoledronic acid at decreasing the risk of bone fractures and other skeletal-related events (SRE) in men with castration-resistant metastatic prostate cancer, according to results from a randomi

  13. MicroRNA expression signature of castration-resistant prostate cancer: the microRNA-221/222 cluster functions as a tumour suppressor and disease progression marker

    PubMed Central

    Goto, Yusuke; Kojima, Satoko; Nishikawa, Rika; Kurozumi, Akira; Kato, Mayuko; Enokida, Hideki; Matsushita, Ryosuke; Yamazaki, Kazuto; Ishida, Yasuo; Nakagawa, Masayuki; Naya, Yukio; Ichikawa, Tomohiko; Seki, Naohiko

    2015-01-01

    Background: Our present study of the microRNA (miRNA) expression signature in castration-resistant prostate cancer (CRPC) revealed that the clustered miRNAs microRNA-221 (miR-221) and microRNA-222 (miR-222) are significantly downregulated in cancer tissues. The aim of this study was to investigate the functional roles of miR-221 and miR-222 in prostate cancer (PCa) cells. Methods: A CRPC miRNA signature was constructed by PCR-based array methods. Functional studies of differentially expressed miRNAs were analysed using PCa cells. The association between miRNA expression and overall survival was estimated by the Kaplan–Meier method. In silico database and genome-wide gene expression analyses were performed to identify molecular targets regulated by the miR-221/222 cluster. Results: miR-221 and miR-222 were significantly downregulated in PCa and CRPC specimens. Kaplan–Meier survival curves showed that low expression of miR-222 predicted a short duration of progression to CRPC. Restoration of miR-221 or miR-222 in cancer cells revealed that both miRNAs significantly inhibited cancer cell migration and invasion. Ecm29 was directly regulated by the miR-221/222 cluster in PCa cells. Conclusions: Loss of the tumour-suppressive miR-221/222 cluster enhanced migration and invasion in PCa cells. Our data describing targets regulated by the tumour-suppressive miR-221/222 cluster provide insights into the mechanisms of PCa and CRPC progression. PMID:26325107

  14. Phase I trial of a cancer vaccine consisting of 20 mixed peptides in patients with castration-resistant prostate cancer: dose-related immune boosting and suppression.

    PubMed

    Noguchi, Masanori; Arai, Gaku; Matsumoto, Kazumasa; Naito, Seiji; Moriya, Fukuko; Suekane, Shigetaka; Komatsu, Nobukazu; Matsueda, Satoko; Sasada, Tetsuro; Yamada, Akira; Kakuma, Tatsuyuki; Itoh, Kyogo

    2015-04-01

    The heterogeneity expression of tumor-associated antigens (TAA) and variability of human T cell repertoire suggest that effective cancer vaccine requires induction of a wide breadth of cytotoxic T lymphocyte (CTL) specificities. This can be achieved with vaccines targeting multiple TAA. We evaluated the safety and immune dynamics of a cancer vaccine consisting of 20 mixed peptides (KRM-20) designed to induce CTLs against 12 different TAA in patients with castration-resistant prostate cancer (CRPC). Patients received each of three different randomly assigned doses of KRM-20 (6, 20, or 60 mg) once a week for 6 weeks. KRM-20 was applicable for patients with positive human leukocyte antigen (HLA) A2, A3, A11, A24, A26, A31 or A33 alleles, which cover the majority of the global population. To evaluate the minimum immunological effective dose (MIED), peptide-specific CTL and immunoglobulin G (IgG) responses, and immune suppressive subsets were evaluated during the vaccination. Total of 17 patients was enrolled. No serious adverse drug reactions were encountered. The MIED of KRM-20 in CTL or IgG response calculated by logistic regression model was set as 16 or 1.6 mg, respectively. The frequency of immune suppressive subsets was fewer in the 20 mg cohort than that in 6 or 60 mg cohort. Clinical responses determined by prostate-specific antigen levels were two partial responses (from the 20 mg cohort), five no changes and ten progressive diseases. Twenty milligrams of KRM-20 could be recommended for further studies because of the safety and ability to augment CTL activity.

  15. Significant and Sustained Antitumor Activity in Post-Docetaxel, Castration-Resistant Prostate Cancer With the CYP17 Inhibitor Abiraterone Acetate

    PubMed Central

    Reid, Alison H.M.; Attard, Gerhardt; Danila, Daniel C.; Oommen, Nikhil Babu; Olmos, David; Fong, Peter C.; Molife, L. Rhoda; Hunt, Joanne; Messiou, Christina; Parker, Christopher; Dearnaley, David; Swennenhuis, Joost F.; Terstappen, Leon W.M.M.; Lee, Gloria; Kheoh, Thian; Molina, Arturo; Ryan, Charles J.; Small, Eric; Scher, Howard I.; de Bono, Johann S.

    2010-01-01

    Purpose The principal objective of this trial was to evaluate the antitumor activity of abiraterone acetate, an oral, specific, irreversible inhibitor of CYP17 in docetaxel-treated patients with castration-resistant prostate cancer (CRPC). Patients and Methods In this multicenter, two-stage, phase II study, abiraterone acetate 1,000 mg was administered once daily continuously. The primary end point was achievement of a prostate-specific antigen (PSA) decline of ≥ 50% in at least seven of 35 patients. Per an attained phase II design, more than 35 patients could be enrolled if the primary end point was met. Secondary objectives included: PSA declines of ≥ 30% and ≥ 90%; rate of RECIST (Response Evaluation Criteria in Solid Tumors) responses and duration on study; time to PSA progression; safety and tolerability; and circulating tumor cell (CTC) enumeration. Results Docetaxel-treated patients with CRPC (N = 47) were enrolled. PSA declines of ≥ 30%, ≥ 50% and ≥ 90% were seen in 68% (32 of 47), 51% (24 of 47), and 15% (seven of 47) of patients, respectively. Partial responses (by RECIST) were reported in eight (27%) of 30 patients with measurable disease. Median time to PSA progression was 169 days (95% CI, 113 to 281 days). The median number of weeks on study was 24, and 12 (25.5%) of 47 patients remained on study ≥ 48 weeks. CTCs were enumerated in 34 patients; 27 (79%) of 34 patients had at least five CTCs at baseline. Eleven (41%) of 27 patients had a decline from at least five to less than 5 CTCs, and 18 (67%) of 27 had a ≥ 30% decline in CTCs after starting treatment with abiraterone acetate. Abiraterone acetate was well tolerated. Conclusion Abiraterone acetate has significant antitumor activity in post-docetaxel patients with CRPC. Randomized, phase III trials of abiraterone acetate are underway to define the future role of this agent. PMID:20159823

  16. Discovery of Novel N-alkyl 4-anilinofuro[2,3-b]quinoline Derivatives (CIL-102 Derivatives) Against Castration-resistant Human Prostate Cancers.

    PubMed

    Lo, We-Fen; Chou, Yu-Wei; Tseng, Chih-Hua; Shiu, Yia-Huei; Chen, Yu-Wen; Yang, Shyh-Chyun; Chen, Yeh-Long; Lin, Ming-Fong; Tzeng, Cherng-Chyi

    2015-01-01

    A number of N-alkylated 4-anilinofuro[2,3-b]quinoline derivatives were synthesized and evaluated in vitro against PC-3, A549, and MCF-7 cancer cells and M-10 normal human mammary epithelial cells. The known antimitotic CIL-102 was moderately active against the growth of PC-3 prostate cancer cells with an IC50 value of 2.69 μM while it was more potent against the growth of A549, MCF-7 and M-10 cells with IC50 values of 0.61, 0.31 and 0.95 μM, respectively. However, the cytotoxic profiles of its N-alkylated derivatives, 6a - 6c, were reversed and strongly inhibited PC-3 cell growth with IC50 values of less than 1.0 μM but only weakly against the growth of A549, MCF-7 and M-10 cells. These results indicated that N-alkylation of CIL-102 increased not only selectivity but also the antiproliferative potency against PC-3 cell growth. Among these derivatives synthesized, N-(4-acetylphenyl)-N-(furo[2,3-b]quinolin- 4-yl)methylamine (6a) and its N-ethyl counterpart 6b are the two most active CIL-102 derivatives against PC-3 cell growth with IC50 value of 0.22 and 0.20 μM, respectively. Compound 6a is less cytotoxic to normal human M-10 cells than 6b and therefore was selected for further mechanism studies. The flow cytometry studies clearly indicated that compound 6a induced cell accumulation in G2/M phase in a dose-dependent manner after 24 h-treatment. While the proliferation of LNCaP C-81 prostate cancer cells was also strongly suppressed by compound 6a; compound 11a exhibited better selective activity toward LNCaP C-81 prostate cancer cells over RWPE-1 non-cancerous prostate epithelia. Thus, this group of compounds has a potential of serving as therapeutic agents toward advanced castration-resistant prostate cancers.

  17. Biodegradable brush-type copolymer modified with targeting peptide as a nanoscopic platform for targeting drug delivery to treat castration-resistant prostate cancer.

    PubMed

    Liu, Tao; Huang, Qianxia

    2016-09-25

    Well-defined amphiphilic tumor-targeting brush-type copolymers, poly(oligo(ethylene glycol) monomethyl ether methacrylate-co-G3-C12)-g-poly(ε-caprolactone) (P(OEGMA-co-G3-C12)-g- PCL), were synthesized by the combination of ring-opening polymerization (ROP), reversible addition-fragmentation transfer (RAFT) polymerization and polymer post-functionalization, in which G3-C12 was castration-resistant prostate cancer (CRPC) targeting peptide. The obtained polymers were then employed for the targeted treatment of CRPC by delivering a hydrophobic anticancer drug (bufalin, BUF). Polymerizable monomer, 3-((2-(methacryloyloxy)ethyl)thio)propanoic acid (BSMA) and PCL-based macromolecular monomer (PCLMA) were synthesized at first. RAFT polymerization of OEGMA, BSMA, and PCLMA afforded amphiphilic brush-type copolymers, P(OEGMA-co-BSMA)-g-PCL. Post-functionalization of the obtained polymers with G3-C12 led to the formation of the final amphiphilic targeting brush-type copolymers, P(OEGMA-co-G3-C12)-g- PCL. In aqueous media, P(OEGMA-co-G3-C12)-g-PCL self-assembles into micelles with a hydrodynamic diameter (Dh) of ∼66.1±0.44nm. It was demonstrated that the obtained micellar nanoparticles exhibited good biocompatibility and biodegradability. Besides, BUF-loaded micellar nanoparticles assembled from P(OEGMA-co-G3-C12)-g-PCL, BUF-NP-(G3-C12), showed a controlled drug release in vitro and improved anticancer efficacy both in vitro and in vivo.

  18. Cytochrome 450 1B1 (CYP1B1) polymorphisms associated with response to docetaxel in Castration-Resistant Prostate Cancer (CRPC) patients

    PubMed Central

    2010-01-01

    Background The selection of patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in Castration-Resistant Prostate Cancer (CRPC) patients. Functional polymorphisms within the cytochrome P450 1B1 (CYP1B1) gene have been associated with alterations in enzymatic expression and activity and may change sensitivity to the widely used docetaxel regimen. Methods CYP1B1 genotyping was performed on blood samples of 60 CRPC patients treated with docetaxel, using TaqMan probes-based assays. Association between CYP1B1-142C>G (leading to the 48ArgGly transition), 4326C>G (432LeuVal), and 4390A>G (453AsnSer) polymorphisms and treatment response, progression-free-survival (PFS) and overall-survival (OS) was estimated using Pearson χ2 test, Kaplan-Meier curves and Log-rank test. Results Patients carrying the CYP1B1-432ValVal genotype experienced a significantly lower response-rate (P = 0.014), shorter progression-free-survival (P = 0.032) and overall-survival (P < 0.001). Multivariate analyses and correction for multiple comparisons confirmed its prognostic significance for OS. No significant associations were found among other polymorphisms and both response and clinical outcome. Conclusions CYP1B1-4326C>G (432LeuVal) polymorphism emerged as possible predictive marker of response and clinical outcome to docetaxel in CRPC patients and may represent a potential new tool for treatment optimization. Larger prospective trials are warranted to validate these findings, which might be applied to the future practice of CRPC treatment. PMID:20875115

  19. Identification and Targeting of Candidate Pre-Existing Lurker Cells that Give Rise to Castration-Resistant Prostate Cancer

    DTIC Science & Technology

    2014-10-01

    propagation. Lgr5+ intestinal stem cells can initiate and maintain murine intestinal adenomas (6, 7). In mouse models of skin cancer, hair follicle bulge...initiated in Task 1 but further analysis will be collected in year 2 and a new approach will be added to Tasks 2 and 3 in year 2. Task 1. Test the in...vivo effects of castration on human luminal cancer subsets isolated from primary regenerated prostate tumors. Task 2. Test the in vivo growth

  20. Targeting the interleukin-11 receptor α in metastatic prostate cancer: A first-in-man study

    PubMed Central

    Pasqualini, Renata; Millikan, Randall E; Christianson, Dawn R; Cardó-Vila, Marina; Driessen, Wouter H P; Giordano, Ricardo J; Hajitou, Amin; Hoang, Anh G; Wen, Sijin; Barnhart, Kirstin F; Baze, Wallace B; Marcott, Valerie D; Hawke, David H; Do, Kim-Anh; Navone, Nora M; Efstathiou, Eleni; Troncoso, Patricia; Lobb, Roy R; Logothetis, Christopher J; Arap, Wadih

    2015-01-01

    BACKGROUND Receptors in tumor blood vessels are attractive targets for ligand-directed drug discovery and development. The authors have worked systematically to map human endothelial receptors (“vascular zip codes”) within tumors through direct peptide library selection in cancer patients. Previously, they selected a ligand-binding motif to the interleukin-11 receptor alpha (IL-11Rα) in the human vasculature. METHODS The authors generated a ligand-directed, peptidomimetic drug (bone metastasis-targeting peptidomimetic-11 [BMTP-11]) for IL-11Rα–based human tumor vascular targeting. Preclinical studies (efficacy/toxicity) included evaluating BMTP-11 in prostate cancer xenograft models, drug localization, targeted apoptotic effects, pharmacokinetic/pharmacodynamic analyses, and dose-range determination, including formal (good laboratory practice) toxicity across rodent and nonhuman primate species. The initial BMTP-11 clinical development also is reported based on a single-institution, open-label, first-in-class, first-in-man trial (National Clinical Trials number NCT00872157) in patients with metastatic, castrate-resistant prostate cancer. RESULTS BMTP-11 was preclinically promising and, thus, was chosen for clinical development in patients. Limited numbers of patients who had castrate-resistant prostate cancer with osteoblastic bone metastases were enrolled into a phase 0 trial with biology-driven endpoints. The authors demonstrated biopsy-verified localization of BMTP-11 to tumors in the bone marrow and drug-induced apoptosis in all patients. Moreover, the maximum tolerated dose was identified on a weekly schedule (20-30 mg/m2). Finally, a renal dose-limiting toxicity was determined, namely, dose-dependent, reversible nephrotoxicity with proteinuria and casts involving increased serum creatinine. CONCLUSIONS These biologic endpoints establish BMTP-11 as a targeted drug candidate in metastatic, castrate-resistant prostate cancer. Within a larger discovery

  1. Androgen Suppresses the Proliferation of Androgen Receptor-Positive Castration-Resistant Prostate Cancer Cells via Inhibition of Cdk2, CyclinA, and Skp2

    PubMed Central

    Jiang, Shih Sheng; Lin, Ching-Yu; Fukuchi, Junichi; Hiipakka, Richard A.; Chung, Chi-Jung; Chan, Tzu-Min; Liao, Shutsung; Chang, Chung-Ho; Chuu, Chih-Pin

    2014-01-01

    The majority of prostate cancer (PCa) patient receiving androgen ablation therapy eventually develop castration-resistant prostate cancer (CRPC). We previously reported that androgen treatment suppresses Skp2 and c-Myc through androgen receptor (AR) and induced G1 cell cycle arrest in androgen-independent LNCaP 104-R2 cells, a late stage CRPC cell line model. However, the mechanism of androgenic regulation of Skp2 in CRPC cells was not fully understood. In this study, we investigated the androgenic regulation of Skp2 in two AR-positive CRPC cell line models, the LNCaP 104-R1 and PC-3AR Cells. The former one is an early stage androgen-independent LNCaP cells, while the later one is PC-3 cells re-expressing either wild type AR or mutant LNCaP AR. Proliferation of LNCaP 104-R1 and PC-3AR cells is not dependent on but is suppressed by androgen. We observed in this study that androgen treatment reduced protein expression of Cdk2, Cdk7, Cyclin A, cyclin H, Skp2, c-Myc, and E2F-1; lessened phosphorylation of Thr14, Tyr15, and Thr160 on Cdk2; decreased activity of Cdk2; induced protein level of p27Kip1; and caused G1 cell cycle arrest in LNCaP 104-R1 cells and PC-3AR cells. Overexpression of Skp2 protein in LNCaP 104-R1 or PC-3AR cells partially blocked accumulation of p27Kip1 and increased Cdk2 activity under androgen treatment, which partially blocked the androgenic suppressive effects on proliferation and cell cycle. Analyzing on-line gene array data of 214 normal and PCa samples indicated that gene expression of Skp2, Cdk2, and cyclin A positively correlates to each other, while Cdk7 negatively correlates to these genes. These observations suggested that androgen suppresses the proliferation of CRPC cells partially through inhibition of Cyclin A, Cdk2, and Skp2. PMID:25271736

  2. Screening key microRNAs for castration-resistant prostate cancer based on miRNA/mRNA functional synergistic network.

    PubMed

    Zhu, Jin; Wang, Sugui; Zhang, Wenyu; Qiu, Junyi; Shan, Yuxi; Yang, Dongrong; Shen, Bairong

    2015-12-22

    High-throughput methods have been used to explore the mechanisms by which androgen-sensitive prostate cancer (ASPC) develops into castration-resistant prostate cancer (CRPC). However, it is difficult to interpret cryptic results by routine experimental methods. In this study, we performed systematic and integrative analysis to detect key miRNAs that contribute to CRPC development. From three DNA microarray datasets, we retrieved 11 outlier microRNAs (miRNAs) that had expression discrepancies between ASPC and CRPC using a specific algorithm. Two of the miRNAs (miR-125b and miR-124) have previously been shown to be related to CRPC. Seven out of the other nine miRNAs were confirmed by quantitative PCR (Q-PCR) analysis. MiR-210, miR-218, miR-346, miR-197, and miR-149 were found to be over-expressed, while miR-122, miR-145, and let-7b were under-expressed in CRPC cell lines. GO and KEGG pathway analyses revealed that miR-218, miR-197, miR-145, miR-122, and let-7b, along with their target genes, were found to be involved in the PI3K and AKT3 signaling network, which is known to contribute to CRPC development. We then chose five miRNAs to verify the accuracy of the analysis. The target genes of each miRNA were altered significantly upon transfection of specific miRNA mimics in the C4-2 CRPC cell line, which was consistent with our pathway analysis results. Finally, we hypothesized that miR-218, miR-145, miR-197, miR-149, miR-122, and let-7b may contribute to the development of CRPC through the influence of Ras, Rho proteins, and the SCF complex. Further investigation is needed to verify the functions of the identified novel pathways in CRPC development.

  3. Sipuleucel-T for the treatment of metastatic prostate cancer: promise and challenges.

    PubMed

    Paller, Channing J; Antonarakis, Emmanuel S

    2012-04-01

    In the past 18 mo, three new life-prolonging therapies have been approved by the US. Food and Drug Administration for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC), including sipuleucel-T, the first therapeutic vaccine approved for this disease. With very low toxicity and a demonstrable overall survival benefit, sipuleucel-T offers a promising new therapy and validates further investigation into other immunotherapy approaches for prostate cancer patients. However, questions about its mechanism of action, concerns about its cost, and its optimal sequencing in the prostate cancer treatment landscape may be limiting the adoption of sipuleucel-T. This review summarizes the state-of-the-science with respect to immunotherapy approaches for men with prostate cancer, provides information about the clinical development as well as the strengths and concerns associated with sipuleucel-T, and offers initial insights about where this promising treatment may best fit in the therapeutic landscape.

  4. Microtubule Control of Metabolism in Prostate Cancer

    DTIC Science & Technology

    2013-06-01

    Prostate Cancer PRINCIPAL INVESTIGATOR: Lynne Cassimeris CONTRACTING ORGANIZATION...Microtubule Control of Metabolism in Prostate Cancer 5b. GRANT NUMBER W81XWH-12-1-0071 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT...SUPPLEMENTARY NOTES 14. ABSTRACT The current standard chemotherapy treatment for metastatic castrate-resistant prostate cancer is the microtubule

  5. Networks of intergenic long-range enhancers and snpRNAs drive castration-resistant phenotype of prostate cancer and contribute to pathogenesis of multiple common human disorders

    PubMed Central

    Glinskii, Anna B; Ma, Shuang; Ma, Jun; Grant, Denise; Lim, Chang-Uk; Guest, Ian; Sell, Stewart; Buttyan, Ralph

    2011-01-01

    The mechanistic relevance of intergenic disease-associated genetic loci (IDAGL) containing highly statistically significant disease-linked SNPs remains unknown. Here, we present experimental and clinical evidence supporting the importantance of the role of IDAGL in human diseases. A targeted RT-PCR screen coupled with sequencing of purified PCR products detects widespread transcription at multiple IDAGL and identifies 96 small noncoding trans-regulatory RNAs of ∼100–300 nt in length containing SNPs (snpRNAs) associated with 21 common disorders. Multiple independent lines of experimental evidence support functionality of snpRNAs by documenting their cell type-specific expression and evolutionary conservation of sequences, genomic coordinates and biological effects. Chromatin state signatures, expression profiling experiments and luciferase reporter assays demonstrate that many IDAGL are Polycomb-regulated long-range enhancers. Expression of snpRNAs in human and mouse cells markedly affects cellular behavior and induces allele-specific clinically relevant phenotypic changes: NLRP1-locus snpRNAs rs2670660 exert regulatory effects on monocyte/macrophage transdifferentiation, induce prostate cancer (PC) susceptibility snpRNAs and transform low-malignancy hormone-dependent human PC cells into highly malignant androgen-independent PC. Q-PCR analysis and luciferase reporter assays demonstrate that snpRNA sequences represent allele-specific “decoy” targets of microRNAs that function as SNP allele-specific modifiers of microRNA expression and activity. We demonstrate that trans-acting RNA molecules facilitating resistance to androgen depletion (RAD) in vitro and castration-resistant phenotype (CRP) in vivo of PC contain intergenic 8q24-locus SNP variants (rs1447295; rs16901979; rs6983267) that were recently linked with increased risk of PC. Q-PCR analysis of clinical samples reveals markedly increased and highly concordant (r = 0.896; p < 0.0001) snpRNA expression

  6. Selection and characterization of DNA aptamer for metastatic prostate cancer recognition and tissue imaging

    PubMed Central

    Wu, Xiaoqiu; Sun, Yang; Li, Jianglin; Hu, Xiaoxiao; Lin, Wei; Han, Dongmei; Zhao, Yifan; Liu, Jing; Ye, Mao; Tan, Weihong

    2016-01-01

    Prostate cancer (PCa) is the second leading cause of death and most prevalent cancer in men. The absence of curative options for castration-resistant metastatic prostate cancer and biomarkers able to discriminate between indolent and aggressive tumors contribute to these statistics. In this study, a DNA aptamer termed DML-7 was successfully selected against human PCa cell line DU145 by using the cell-based systematic evolution of ligands by exponential enrichment (SELEX) method. The selected aptamer DML-7 was found to internalize into target cells in a temperature-dependent manner and exhibit high binding affinity for target cells with dissociation constants in the nanomolar range. Binding analysis further revealed that DML-7 only binds to DU145 and PC-3 cells with metastatic potential, but not to LNCaP or 22Rv1 cells with low or nonmetastatic potential, demonstrating that DML-7 has excellent selectivity for the recognition of the metastatic PCa cells. Clinical tissue imaging further confirmed these results. Therefore, both high binding affinity and specificity to metastatic PCa cells and tissues afford DML-7 with the potential for development into a novel tool for diagnosis and targeted drug delivery against metastatic prostate cancer. PMID:27183906

  7. Sirolimus, Docetaxel, and Carboplatin in Treating Patients With Metastatic Hormone-Resistant Prostate Cancer

    ClinicalTrials.gov

    2016-11-10

    Castration Levels of Testosterone; Hormone-Resistant Prostate Cancer; Metastatic Prostate Carcinoma; Prostate Carcinoma Metastatic in the Bone; PSA Progression; Recurrent Prostate Carcinoma; Stage IV Prostate Cancer

  8. Androgen pathway resistance in prostate cancer and therapeutic implications

    PubMed Central

    Maughan, Benjamin L

    2015-01-01

    Introduction Metastatic prostate cancer is an incurable disease that is treated with a variety of hormonal therapies targeting various nodes of the androgen receptor (AR) pathway. Invariably patients develop resistance and become castration resistant. Common treatments for castration-resistant disease include novel hormonal therapies, such as abiraterone and enzalutamide, chemotherapy, immunotherapy and radiopharmaceuticals. As this disease generally remains incurable, understanding the molecular underpinnings of resistance pathways is critical in designing therapeutic strategies to delay or overcome such resistance. Areas covered This review will explore the resistance mechanisms relevant to hormonal agents, such as AR-V7 expression and others, as well as discussing new approaches being developed to treat patients with castration-resistant prostate cancer that take advantage of these new insights. A literature search was performed to identify all published clinical trials related to androgen therapy mechanisms of drug resistance in metastatic castration-resistant prostate cancer. Expert opinion Androgen therapy resistance mechanisms are varied, and include modification of all nodes in the androgen signaling pathway. The optimal treatment for men with relapsed metastatic castration-resistant prostate cancer is uncertain at this time. The authors recommend using available clinical data to guide treatment decision making until more specific biomarkers are clinically available. PMID:26067250

  9. Duration of First Off-Treatment Interval Is Prognostic for Time to Castration Resistance and Death in Men With Biochemical Relapse of Prostate Cancer Treated on a Prospective Trial of Intermittent Androgen Deprivation

    PubMed Central

    Yu, Evan Y.; Gulati, Roman; Telesca, Donatello; Jiang, Peter; Tam, Stephen; Russell, Kenneth J.; Nelson, Peter S.; Etzioni, Ruth D.; Higano, Celestia S.

    2010-01-01

    Purpose This was an exploratory analysis of a trial of intermittent androgen deprivation (IAD) in men with biochemical relapse (BR) to establish first cycle characteristics prognostic for progression to castration-resistant prostate cancer (CRPC) and death. Patients and Methods Men with BR of prostate cancer after radical prostatectomy (RP) or radiation (RT) were treated with androgen deprivation therapy (ADT) comprised of leuprolide and flutamide. After 9 months on treatment, ADT was stopped, and monthly prostate-specific antigen (PSA) levels were observed during the off-treatment interval. When the PSA reached a threshold value (1 ng/mL for RP, 4 ng/mL for RT), ADT was resumed in a new cycle. Patients were treated intermittently in this manner until CRPC, which was defined as ≥ two consecutive increasing PSA values while on ADT with castrate testosterone levels. Results Seventy-two of 100 patients enrolled onto the study met criteria for this analysis. The duration of the first off-treatment interval (≤ v > 40 weeks) was associated with shorter time to CRPC (hazard ratio = 2.9; 95% CI, 1.1 to 7.7; P = .03) and death (hazard ratio = 3.8; 95% CI, 1.1 to 13.6; P = .04) after adjusting for age, stage, grade, and PSA at diagnosis. Conclusion In patients who completed the first cycle of IAD, a duration of the first off-treatment interval of ≤ 40 weeks defines a subset of patients at higher risk of CRPC and death. Conversely, patients with an off-treatment interval of more than 40 weeks have a significantly better long-term prognosis. PMID:20421544

  10. Reactive Oxygen Species Produced by Prostate Cancer Cells Cause Castrate-Resistant Cell Growth by Inducing B-cell Lymphotoxin Release

    DTIC Science & Technology

    2013-06-01

    and metabolites can be exchanged freely. We proposed to take a novel and innovative microfluidic approach for the co-culture to closely mimic the in...Gaussia luciferase reconstitution, high throughput screen , small molecule inhibitors, human prostate carcinoma cells, pharmacokinetcs, prostate cancer...where free exchange of nutrient and metabolites can be exchanged between two types of cells. To circumvent this problem, we used a microfluidic

  11. Vaccine Therapy and Pembrolizumab in Treating Patients With Hormone-Resistant, Metastatic Prostate Cancer

    ClinicalTrials.gov

    2016-11-23

    Hormone-Resistant Prostate Cancer; Metastatic Malignant Neoplasm in the Bone; Metastatic Malignant Neoplasm in the Soft Tissues; Metastatic Prostate Carcinoma; Prostate Adenocarcinoma; Recurrent Prostate Carcinoma; Stage IV Prostate Cancer

  12. A Rare Case of Omentum Invasive Prostate Cancer: Staging With PSMA PET/CT Imaging and Response to Systemic Therapy.

    PubMed

    Ladwa, Rahul; Gustafson, Sonja; McCaffrey, Elizabeth; Miles, Kenneth; O'Byrne, Kenneth

    2017-02-24

    The omentum is a rare metastatic site for prostatic adenocarcinoma. We present a case of metastatic castrate-resistant prostate cancer, with progressive omentum invasive prostate cancer identified on prostate-specific membrane antigen (PSMA) PET/CT scan. Omental biopsy revealed metastatic prostate adenocarcinoma, and cabazitaxel chemotherapy was instituted with a prostate-specific antigen biochemical response. Repeat PSMA PET/CT imaging revealed increased avidity in omental metastasis. Despite prostate-specific antigen response, PSMA PET/CT did not correlate with a therapeutic response.

  13. Galeterone and VNPT55 induce proteasomal degradation of AR/AR-V7, induce significant apoptosis via cytochrome c release and suppress growth of castration resistant prostate cancer xenografts in vivo.

    PubMed

    Kwegyir-Afful, Andrew K; Ramalingam, Senthilmurugan; Purushottamachar, Puranik; Ramamurthy, Vidya P; Njar, Vincent C O

    2015-09-29

    Galeterone (Gal) is a first-in-class multi-target oral small molecule that will soon enter pivotal phase III clinical trials in castration resistant prostate cancer (CRPC) patients. Gal disrupts androgen receptor (AR) signaling via inhibition of CYP17, AR antagonism and AR degradation. Resistance to current therapy is attributed to up-regulation of full-length AR (fAR), splice variants AR (AR-Vs) and AR mutations. The effects of gal and VNPT55 were analyzed on f-AR and AR-Vs (AR-V7/ARv567es) in LNCaP, CWR22Rv1 and DU145 (transfected with AR-Vs) human PC cells in vitro and CRPC tumor xenografts. Galeterone/VNPT55 decreased fAR/AR-V7 mRNA levels and implicates Mdm2/CHIP enhanced ubiquitination of posttranslational modified receptors, targeting them for proteasomal degradation. Gal and VNPT55 also induced significant apoptosis in PC cells via increased Bax/Bcl2 ratio, cytochrome-c release with concomitant cleavage of caspase 3 and PARP. More importantly, gal and VNPT55 exhibited strong in vivo anti-CRPC activities, with no apparent host toxicities. This study demonstrate that gal and VNPT55 utilize cell-based mechanisms to deplete both fAR and AR-Vs. Importantly, the preclinical activity profiles, including profound apoptotic induction and inhibition of CRPC xenografts suggest that these agents offer considerable promise as new therapeutics for patients with CRPC and those resistant to current therapy.

  14. YAP is closely correlated with castration-resistant prostate cancer, and downregulation of YAP reduces proliferation and induces apoptosis of PC-3 cells

    PubMed Central

    SHENG, XIA; LI, WEN-BIN; WANG, DE-LIN; CHEN, KE-HONG; CAO, JIAN-JIA; LUO, ZHAO; HE, JIANG; LI, MEI-CAI; LIU, WU-JIANG; YU, CHAO

    2015-01-01

    Yes-associated protein 65 (YAP65) has been implicated as an oncogene, and its expression is increased in human cancer. Previous studies have demonstrated that alterations in YAP activity may result in tumourigenesis of the prostate. With androgen deprivation therapies becoming progressively ineffective, often leading to life-threatening androgen-resistant prostate cancer (CRPC). The present study aimed to analyse the role of YAP in prostate cancer (PCa), particularly in CRPC. YAP protein was detected using immunohistochemistry and western blot analysis in different prostatic tissues. In addition, three specific RNA interference vectors targeting the human YAP gene were synthesised, and PC-3 cells with a stable inhibition of YAP were obtained by transfection. MTT, flow cytometry, reverse transcription-quantitative polymerase chain reaction and western blot assays were used to analyse the effects of YAP inhibition on the proliferation and apoptosis of PC-3 cells. The frequency of cells that were positive for YAP protein in PCa (78.13%) was significantly higher, compared with para-PCa (26.67%; P=0.007) and benign prostatic hyperplasia (0%; P=0.002). The frequency of cells, which were positive for the expression of YAP exhibited a positive correlation (P=0.008) with the Gleason score, the tumour-node-metastasis staging (P=0.033) and the level of prostate specific antigens (P=0.0032) in PCa. The proliferative capacity of the transfected group was significantly lower, compared with the negative control group (P=0.022). The cell-cycle of the transfected group was arrested in the G1 stage, which was detected using flow cytometry, and there was a significant increase in the apoptosis of cells in the transfected group (P=0.002). The mRNA and protein levels of TEA domain family member 1 were inhibited in the transfected group (P=0.001 and P=0.00, respectively). Therefore, it was concluded that gene transcription and protein expression of YAP may be involved in the development

  15. Serum testosterone level predicts the effective time of androgen deprivation therapy in metastatic prostate cancer patients.

    PubMed

    Wang, Yue; Dai, Bo; Ye, Ding-Wei

    2017-01-01

    Androgen deprivation therapy (ADT) is the standard of care for patients with metastatic prostate cancer. However, whether serum testosterone levels, using a cut-off point of 50 ng dl-1 , are related to the effective time of ADT in newly diagnosed prostate cancer patients remains controversial. Moreover, recent studies have shown that some patients may benefit from the addition of upfront docetaxel chemotherapy. To date, no studies have been able to distinguish patients who will benefit from the combination of ADT and docetaxel chemotherapy. This study included 206 patients who were diagnosed with metastatic prostate cancer and showed progression to castrate-resistance prostate cancer (CRPC). Serum testosterone levels were measured prospectively after ADT for 1, 3, and 6 months. The endpoint was the time to CRPC. In univariate and multivariate analyses, testosterone levels <50 ng dl-1 were not associated with the effective time of ADT. Receiver operating characteristic and univariate analysis showed that testosterone levels of ≤25 ng dl-1 after the first month of ADT offered the best overall sensitivity and specificity for prediction of a longer time to CRPC (adjusted hazard ratio [HR], 1.46; 95% confidence interval [95% CI], 1.08-1.96; P = 0.013). Our results show that serum testosterone level of 25 ng dl-1 plays a prognostic role in prostate cancer patients receiving ADT. A testosterone value of 25 ng dl-1 after the first month of ADT can distinguish patients who benefit from ADT effectiveness for only a short time. These patients may need to receive ADT and concurrent docetaxel chemotherapy.

  16. Serum testosterone level predicts the effective time of androgen deprivation therapy in metastatic prostate cancer patients

    PubMed Central

    Wang, Yue; Dai, Bo; Ye, Ding-Wei

    2017-01-01

    Androgen deprivation therapy (ADT) is the standard of care for patients with metastatic prostate cancer. However, whether serum testosterone levels, using a cut-off point of 50 ng dl−1, are related to the effective time of ADT in newly diagnosed prostate cancer patients remains controversial. Moreover, recent studies have shown that some patients may benefit from the addition of upfront docetaxel chemotherapy. To date, no studies have been able to distinguish patients who will benefit from the combination of ADT and docetaxel chemotherapy. This study included 206 patients who were diagnosed with metastatic prostate cancer and showed progression to castrate-resistance prostate cancer (CRPC). Serum testosterone levels were measured prospectively after ADT for 1, 3, and 6 months. The endpoint was the time to CRPC. In univariate and multivariate analyses, testosterone levels <50 ng dl−1 were not associated with the effective time of ADT. Receiver operating characteristic and univariate analysis showed that testosterone levels of ≤25 ng dl−1 after the first month of ADT offered the best overall sensitivity and specificity for prediction of a longer time to CRPC (adjusted hazard ratio [HR], 1.46; 95% confidence interval [95% CI], 1.08–1.96; P = 0.013). Our results show that serum testosterone level of 25 ng dl−1 plays a prognostic role in prostate cancer patients receiving ADT. A testosterone value of 25 ng dl−1 after the first month of ADT can distinguish patients who benefit from ADT effectiveness for only a short time. These patients may need to receive ADT and concurrent docetaxel chemotherapy. PMID:26975487

  17. The Activity of SN33638, an Inhibitor of AKR1C3, on Testosterone and 17β-Estradiol Production and Function in Castration-Resistant Prostate Cancer and ER-Positive Breast Cancer

    PubMed Central

    Yin, Yarong Diana; Fu, Melissa; Brooke, Darby G.; Heinrich, Daniel M.; Denny, William A.; Jamieson, Stephen M. F.

    2014-01-01

    AKR1C3 is a novel therapeutic target in castration-resistant prostate cancer (CRPC) and estrogen receptor (ER)-positive breast cancer because of its ability to produce testosterone and 17β-estradiol intratumorally, thus promoting nuclear receptor signaling and tumor progression. A panel of CRPC, ER-positive breast cancer and high/low AKR1C3-expressing cell lines were treated with SN33638, a selective inhibitor of AKR1C3, in the presence of hormone or prostaglandin (PG) precursors, prior to evaluation of cell proliferation and levels of 11β-PG F2α (11β-PGF2α), testosterone, 17β-estradiol, and prostate-specific antigen (PSA). A meta-analysis of AKR1C3 mRNA expression in patient samples was also conducted, which revealed that AKR1C3 mRNA was upregulated in CRPC, but downregulated in ER-positive breast cancer. 11β-PGF2α and testosterone levels in the cell line panel correlated with AKR1C3 protein expression. SN33638 prevented 11β-PGF2α formation in cell lines that expressed AKR1C3, but partially inhibited testosterone formation and subsequently cell proliferation and/or PSA expression only in high (LAPC4 AKR1C3-overexpressing cells) or moderate (22RV1) AKR1C3-expressing cell lines. SN33638 had little effect on 17β-estradiol production or estrone-stimulated cell proliferation in ER-positive breast cancer cell lines. Although SN33638 could prevent 11β-PGF2α formation, its ability to prevent testosterone and 17β-estradiol production and their roles in CRPC and ER-positive breast cancer progression was limited due to AKR1C3-independent steroid hormone production, except in LAPC4 AKR1C3 cells where the majority of testosterone was AKR1C3-dependent. These results suggest that inhibition of AKR1C3 is unlikely to produce therapeutic benefit in CRPC and ER-positive breast cancer patients, except possibly in the small subpopulation of CRPC patients with tumors that have upregulated AKR1C3 expression and are dependent on AKR1C3 to produce the testosterone required

  18. Role of chemotherapy in combination with hormonal therapy in first-line treatment of metastatic hormone-sensitive prostate cancer.

    PubMed

    Ceresoli, G L; De Vincenzo, F; Sauta, M G; Bonomi, M; Zucali, P A

    2015-12-01

    Prostate cancer (PC) is a heterogeneous disease, whose growth is driven by androgens and androgen receptors. Androgen deprivation therapy (ADT) is the standard treatment of hormone-naïve metastatic disease. The majority of patients are treated with medical castration with GnRH agonists or antagonists, which usually determines a profound PSA decline and a radiological and clinical benefit. However, essentially all patients experience progression to castration-resistant prostate cancer (CRPC), and overall prognosis remains disappointing. Early targeting of cells that survive hormonal therapy may potentially prevent the development of CRPC. Several trials have explored the use of combination therapy with ADT and chemotherapy, targeting both the androgen dependent and independent cells simultaneously. Docetaxel was administered in combination with ADT to men with hormone-naïve metastatic prostate cancer, in the attempt to improve the duration and quality of patient survival. Three large randomized trials (the GETUG-15, CHAARTED and more recently the STAMPEDE study) have assessed these endpoints, with partially conflicting results. Overall, the results from these trials seem to support the use of early docetaxel combined with ADT in selected hormone-naïve metastatic PC patients. Full publication of the results of all studies, with longer follow-up, and the results of other ongoing trials in this setting will hopefully further define the role and the indications of this therapeutic strategy.

  19. Sipuleucel-T for the treatment of advanced prostate cancer.

    PubMed

    Frohlich, Mark W

    2012-06-01

    Sipuleucel-T is an autologous cellular immunotherapy designed to stimulate an immune response to prostate cancer that prolongs the overall survival of men with asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer (CRPC). The clinical development program and key efficacy, safety, and immune response findings from the phase III studies are presented. The integration of sipuleucel-T into the treatment paradigm of advanced prostate cancer and future directions for research are discussed.

  20. Comparison of NaF and FDG PET/CT for assessment of treatment response in castrate-resistant prostate cancers with osseous metastases

    PubMed Central

    Simoncic, Urban; Perlman, Scott; Liu, Glenn; Staab, Mary Jane; Straus, Jane; Jeraj, Robert

    2014-01-01

    Background Assessment of skeletal metastases response to therapy is highly relevant, but unresolved clinical problem. The main goal of this work was to compare pharmacodynamic responses to therapy assessed with NaF and FDG PET/CT. Materials and Methods Prostate cancer patients with known osseous metastases were treated with Zibotentan (ZD4054) and imaged with combined dynamic NaF/FDG PET/CT prior to therapy (Baseline), after 4 weeks of therapy (Week 4) and after 2 weeks of treatment break (Week 6). Kinetic analysis allowed comparison of voxel-based tracer uptake rate parameter Ki, vasculature parameters K1 (measuring perfusion/permeability) and Vb (measuring vasculature fraction in the tissue) together with standardized uptake values (SUVs). Results Correlations were high for the NaF and FDG peak uptake parameters (Ki and SUV correlations ranged from 0.57 to 0.88) and for vasculature parameters (K1 and Vb correlations ranged from 0.61 to 0.81). Correlation between the NaF and FDG Week 4 Ki responses was low (ρ=0.35, p=0.084), but higher for NaF and FDG Week 6 Ki responses (ρ=0.72, p<0.0001). Correlations for vasculature responses were always low (ρ<0.35). NaF and FDG uptakes in the osseous metastases were spatially dislocated, with overlap in the range from 0% to 80%. Conclusions These results showed that late NaF and FDG uptake responses are consistently correlated, but earlier uptake responses and all vasculature responses can be unrelated. This study also proved that FDG and NaF uptakes are spatially dislocated. Although treatment responses assessed with NaF and FDG may be correlated, using both tracers provides additional information. PMID:25128349

  1. Management of progressive metastatic prostate cancer.

    PubMed

    Waselenko, J K; Dawson, N A

    1997-10-01

    Metastatic prostate cancer is a growing health problem and is the second leading cause of cancer death in men. While the response of patients with metastatic prostate cancer to initial hormonal manipulation is excellent, the majority of patients eventually progress. As a result, a growing number of patients and their physicians need-to-find acceptable therapeutic alternatives. Fortunately, the number of therapies in the management armamentarium is growing and includes: alternative hormonal therapies, chemotherapy, radioisotopes, and investigational agents. The major focus of treatment has shifted to palliation and quality of life. The decline of prostate-specific antigen (PSA) has become another important end point as evidence supporting a correlation with prolonged survival mounts. Enrolling eligible patients in clinical trials is critical to the development of new treatment strategies for this difficult disease.

  2. The Effects of Social Support on Health-Related Quality of Life of Patients with Metastatic Prostate Cancer.

    PubMed

    Colloca, Giuseppe; Colloca, Pasquale

    2016-06-01

    Patients with metastatic prostate cancer (PC) live longer than patients with metastatic tumours of other sites. Consequently, their social network can influence their quality of life (QoL) during a remarkable life span. The aim of this article is to present the findings of a systematic review of the studies that focused on social network supporting the quality of life of these patients. A systematic review for studies meeting specific criteria was undertaken on three databases. Some level of unmet psychological needs was present in 54 % of the patients. Depression and fatigue are highly prevalent, and the dyads, patient and partner, are at higher risk for distress symptoms. The efforts of individuals to cope with metastatic PC appear influenced by adaptative skills and specific types of family support. Psychological and relational problems predominate in the hormone-sensitive stage and are increasingly replaced by physical symptoms, social and spiritual needs in the later stages. In the early castration-resistant stage, patients will discuss with their doctors information about drugs, control of side effects and treatment strategies. In metastatic PC patients, needs change during the course of the disease. Social support plays a major role in maintaining or disrupting QoL and in the efficacy of psychosocial treatments. The trajectory of disease and its effect on the reduced QoL over the entire life expectancy should be kept in mind by health system providers and social workers.

  3. Immunotherapy in metastatic prostate cancer

    PubMed Central

    Slovin, Susan F.

    2016-01-01

    Introduction: Prostate cancer remains a challenge as a target for immunological approaches. The approval of the first cell-based immune therapy, Sipuleucel-T for prostate cancer introduced prostate cancer as a solid tumor with the potential to be influenced by the immune system. Methods: We reviewed articles on immunological management of prostate cancer and challenges that lie ahead for such strategies. Results: Treatments have focused on the identification of novel cell surface antigens thought to be unique to prostate cancer. These include vaccines against carbohydrate and blood group antigens, xenogeneic and naked DNA vaccines, and pox viruses used as prime-boost or checkpoint inhibitors. No single vaccine construct to date has resulted in a dramatic antitumor effect. The checkpoint inhibitor, anti-CTLA-4 has resulted in several long-term remissions, but phase III trials have not demonstrated an antitumor effect or survival benefit. Conclusions: Multiple clinical trials suggest that prostate cancer may not be optimally treated by single agent immune therapies and that combination with biologic agents, chemotherapies, or radiation may offer some enhancement of benefit. PMID:27843208

  4. Metastatic Prostate Cancer of Hand

    PubMed Central

    Oshima, Koji; Ishimaru, Daichi; Nishimoto, Yutaka; Ohno, Yoshiyuki; Hirakawa, Akihiro; Miyazaki, Tatsuhiko; Akiyama, Haruhiko

    2016-01-01

    Soft tissue metastases of prostate cancer to other sites are extremely rare, and, to our best knowledge, there have been no reports of metastasis to soft tissue of the hand. A 63-year-old man was diagnosed with prostatic cancer. During treatment, bone and soft tissue metastases to the right hand, appearing in the first web space, were observed. The tumor was resected, along with both the first and second metacarpal bones. The thumb was reconstructed by pollicization of the remaining index finger, enabling the patient to use the pollicized thumb for activities of daily living. This is the first case report of prostate cancer metastasizing to the soft tissue in hand. After wide resection, pollicization was able to reconstruct a functional hand and thumb. PMID:27843661

  5. Molecular Heterogeneity in Primary and Metastatic Prostate Tumor Tissue

    DTIC Science & Technology

    2014-10-01

    melatonin levels, sleep disruption, and risk of prostate cancer in elderly men. European Urology 2014 Advance online publication. doi: 10.1016/j.eururo...multi-focal and metastatic prostate cancer . Aim 1 focuses on a 4-gene signature of prostate cancer prognosis, and whether the signature differs...involved in metastatic progression of prostate cancer . Scope: In year 1, Dr. Batista has received IRB approval, completed a series of courses to augment

  6. Phase II Trial of Abiraterone Acetate Plus Prednisone in Black Men With Metastatic Prostate Cancer

    PubMed Central

    Sfakianos, John; Liaw, Bobby; Gimpel-Tetra, Kiev; Kemeny, Margaret; Bulone, Linda; Shahin, Mohammad; Oh, William Kyu; Galsky, Matthew David

    2016-01-01

    Lessons Learned The safety and activity findings of abiraterone acetate plus prednisone treatment in black men with mCRPC were similar to results from previously conducted studies with largely white populations. Poor trial accrual continues to be a challenge in black men with mCRPC and further efforts are needed to address such underrepresentation. Background. Self-identified black men have higher incidence and mortality from prostate cancer in the United States compared with white men but are dramatically underrepresented in clinical trials exploring novel therapies for metastatic castration-resistant prostate cancer (mCRPC). Methods. Black men with mCRPC were treated with abiraterone acetate (AA), 1,000 mg daily, and prednisone (P), 5 mg twice daily. The primary objective was to determine antitumor activity (defined by a ≥30% decline in prostate-specific antigen [PSA] level) and to correlate germline polymorphisms in androgen metabolism genes with antitumor activity. Secondary objectives included determining safety, post-treatment changes in measurable disease, and time to disease progression. Results. From April 2013 to March 2016, a total of 11 black men were enrolled and received AA plus P (AA+P); 7 of 10 evaluable patients were docetaxel naive. Post-treatment declines in PSA level of ≥30% were achieved in 90% of patients. The side effect profile was consistent with prior clinical trials exploring AA+P in mCRPC. Due to poor accrual, the study was closed prematurely with insufficient sample size for the planned pharmacogenetic analyses. Conclusion. In this small prospective study terminated for poor accrual, the safety and activity of AA+P in black men with mCRPC was similar to that reported in prior studies exploring AA in largely white populations. Further efforts are needed to address underrepresentation of black men in mCRPC trials. PMID:27742908

  7. Predictors of Metastatic Disease After Prostate Brachytherapy

    SciTech Connect

    Forsythe, Kevin; Burri, Ryan; Stone, Nelson; Stock, Richard G.

    2012-06-01

    Purpose: To identify predictors of metastatic disease after brachytherapy treatment for prostate cancer. Methods and Materials: All patients who received either brachytherapy alone (implant) or brachytherapy in combination with external beam radiation therapy for treatment of localized prostate cancer at The Mount Sinai Hospital between June 1990 and March 2007 with a minimum follow-up of 2 years were included. Univariate and multivariable analyses were performed on the following variables: risk group, Gleason score (GS), clinical T stage, pretreatment prostate-specific antigen level, post-treatment prostate-specific antigen doubling time (PSA-DT), treatment type (implant vs. implant plus external beam radiation therapy), treatment era, total biological effective dose, use of androgen deprivation therapy, age at diagnosis, and race. PSA-DT was analyzed in the following ordinate groups: 0 to 90 days, 91 to 180 days, 180 to 360 days, and greater than 360 days. Results: We included 1,887 patients in this study. Metastases developed in 47 of these patients. The 10-year freedom from distant metastasis (FFDM) rate for the entire population was 95.1%. Median follow-up was 6 years (range, 2-15 years). The only two significant predictors of metastatic disease by multivariable analyses were GS and PSA-DT (p < 0.001 for both variables). Estimated 10-year FFDM rates for GS of 6 or less, GS of 7, and GS of 8 or greater were 97.9%, 94.3%, and 76.1%, respectively (p < 0.001). Estimated FFDM rates for PSA-DT of 0 to 90 days, 91 to 180 days, 181 to 360 days, and greater than 360 days were 17.5%, 67.9%, 74%, and 94.8%, respectively (p < 0.001). Estimated 10-year FFDM rates for the low-, intermediate-, and high-risk groups were 98.6%, 96.2%, and 86.7%, respectively. A demographic shift to patients presenting with higher-grade disease in more recent years was observed. Conclusions: GS and post-treatment PSA-DT are both statistically significant independent predictors of metastatic

  8. The Genomic Evolution of Prostate Cancer

    DTIC Science & Technology

    2015-10-01

    addition, multiple genetic alterations are associated with disease evolution in response to therapy. This project aims to characterize evolution of...of castrate resistant metastatic cancer from primary foci. 15. SUBJECT TERMS Cancer genetics , tumor evolution, tumor heterogeneity, prostate cancer... genetic alterations are found more often in advanced disease. It is not known if these arise after metastases occur or are found in a subclone of the

  9. Molecular Heterogeneity in Primary and Metastatic Prostate Tumor Tissue

    DTIC Science & Technology

    2015-06-01

    AWARD NUMBER: W81XWH-12-1-0072 TITLE: Molecular Heterogeneity in Primary and Metastatic Prostate Tumor Tissue PRINCIPAL INVESTIGATOR: Dr. Julie...Molecular Heterogeneity in Primary and Metastatic Prostate Tumor Tissue 5a. CONTRACT NUMBER W81XWH-12-1-0072 5b. GRANT NUMBER 5c. PROGRAM ELEMENT...heterogeneity in PTEN loss in tumor tissue and prostate cancer prognosis. Aim 2 aimed to compare gene expression profiles between primary and lymph

  10. Commentary on "the E3 ubiquitin ligase Siah2 contributes to castration-resistant prostate cancer by regulation of androgen receptor transcriptional activity." Qi J, Tripathi M, Mishra R, Sahgal N, Fazli L, Ettinger S, Placzek WJ, Claps G, Chung LW, Bowtell D, Gleave M, Bhowmick N, Ronai ZA, Signal Transduction Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.: Cancer Cell 2013;23(6):332-46.

    PubMed

    Olumi, Aria F

    2014-02-01

    Understanding the mechanism underlying the regulation of the androgen receptor (AR), a central player in the development of castration-resistant prostate cancer (CRPC), holds promise for overcoming the challenge of treating CRPC. We demonstrate that the ubiquitin ligase Siah2 targets a select pool of NCOR1-bound, transcriptionally-inactive AR for ubiquitin-dependent degradation, thereby promoting expression of select AR target genes implicated in lipid metabolism, cell motility, and proliferation. Siah2 is required for prostate cancer cell growth under androgen-deprivation conditions in vitro and in vivo, and Siah2 inhibition promotes prostate cancer regression upon castration. Notably, Siah2 expression is markedly increased in human CRPCs. Collectively, we find that selective regulation of AR transcriptional activity by the ubiquitin ligase Siah2 is important for CRPC development.

  11. Enzalutamide Improves Survival in Patients with Metastatic Prostate Cancer

    Cancer.gov

    A summary of results from an international phase III trial that compared enzalutamide (Xtandi®) and placebo for the treatment of metastatic prostate cancer that had progressed during treatment with androgen deprivation therapy.

  12. Prostate specific membrane antigen (PSMA) from diagnostic to therapeutic target: radionuclide therapy comes of age in prostate cancer.

    PubMed

    Violet, John A; Hofman, Michael S

    2017-04-05

    Without doubt, molecular imaging using PET/CT directed against prostate specific membrane antigen (PSMA) has generated much interest for its impressive accuracy in detecting prostate cancer, particularly for biochemical recurrence[1]. PSMA expression is up regulated in advanced prostate cancer, including metastatic castration resistant prostate cancer (mCRPC), and provides a novel therapeutic target for radionuclide therapy directed towards PSMA-avid disease. Radionuclide therapy relies on the identification of a suitable tumour associated 'target' and an appropriate 'vehicle' that can bind to this with high selectivity and specificity to allow delivery of a therapeutic radionuclide. This article is protected by copyright. All rights reserved.

  13. The HGF/c-MET Axis as a Critical Driver of Resistance to Androgen Suppression in Metastatic Castrate-Resistant Prostate Cancer

    DTIC Science & Technology

    2015-10-01

    expression is increased after exposure to the AR antagonist enzalutamide and when cells are cultured in charcoal stripped medium (to remove AR hormonal...decreases MET expression under charcoal stripped conditions in an enzalutamide sensitive manner. Figure 6 Blockade of androgen signaling increases MET...MET and PSA protein levels. Right: Indicated cells were treated with charcoal stripped serum (CSS) for 48 hours prior to stimulation with DHT (10nM

  14. Bone-targeting agents in prostate cancer

    PubMed Central

    Suzman, Daniel L.; Boikos, Sosipatros A.; Carducci, Michael A.

    2014-01-01

    Bone metastases are present in the vast majority of men with advanced prostate cancer, representing the main cause for morbidity and mortality. Recurrent or metastatic disease is managed initially with androgen deprivation but the majority of the patients eventually will progress to castration-resistant prostate cancer, with patients developing bone metastases in most of the cases. Survival and growth of the metastatic prostate cancer cells is dependent on a complex microenvironment (onco-niche) that includes the osteoblasts, the osteoclasts, the endothelium, and the stroma. This review summarizes agents that target the pathways involved in this complex interaction between prostate cancer and bone micro-environment and aim to transform lethal metastatic prostate cancer into a chronic disease. PMID:24398856

  15. (-)-Gossypol reduces invasiveness in metastatic prostate cancer cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Acquisition of metastatic ability by prostatic cancer cells is the most lethal aspect of prostatic cancer progression. (-)-Gossypol, a polyphenolic compound present in cottonseeds, possesses anti-proliferation and pro-apoptotic effects in various cancer cells. In this study, the differences betwee...

  16. Circulating microRNA Profiling Identifies a Subset of Metastatic Prostate Cancer Patients with Evidence of Cancer-Associated Hypoxia

    PubMed Central

    Kroh, Evan M.; Dowell, Alexander E.; Chéry, Lisly; Siddiqui, Javed; Nelson, Peter S.; Vessella, Robert L.; Knudsen, Beatrice S.; Chinnaiyan, Arul M.; Pienta, Kenneth J.; Morrissey, Colm; Tewari, Muneesh

    2013-01-01

    MicroRNAs (miRNAs) are small (∼22 nucleotide) non-coding RNAs that regulate a myriad of biological processes and are frequently dysregulated in cancer. Cancer-associated microRNAs have been detected in serum and plasma and hold promise as minimally invasive cancer biomarkers, potentially for assessing disease characteristics in patients with metastatic disease that is difficult to biopsy. Here we used miRNA profiling to identify cancer-associated miRNAs that are differentially expressed in sera from patients with metastatic castration resistant prostate cancer (mCRPC) as compared to healthy controls. Of 365 miRNAs profiled, we identified five serum miRNAs (miR-141, miR-200a, miR-200c, miR-210 and miR-375) that were elevated in cases compared to controls across two independent cohorts. One of these, miR-210, is a known transcriptional target of the hypoxia-responsive HIF-1α signaling pathway. Exposure of cultured prostate cancer cells to hypoxia led to induction of miR-210 and its release into the extracellular environment. Moreover, we found that serum miR-210 levels varied widely amongst mCRPC patients undergoing therapy, and correlated with treatment response as assessed by change in PSA. Our results suggest that (i) cancer-associated hypoxia is a frequent, previously under-appreciated characteristic of mCRPC, and (ii) serum miR-210 may be further developed as a predictive biomarker in patients with this distinct disease biology. PMID:23935962

  17. Metastatic Prostate Cancer to the Duodenum: A Rare Case

    PubMed Central

    Kaswala, Dharmesh H.; Patel, Nitin; Jadallah, Sana; Wang, Weizheng

    2014-01-01

    Prostate cancer is the third most common cancer in man. About 1 in 6 males developed prostate cancer and 1 in 35 males die of this disease. Prostate cancer behavior ranges from microscopic tumors to aggressive cancer with metastatic potential. While metastasis to bone is relatively common, prostate cancer rarely metastasizes to the cecum, pituitary gland, small bowel, maxillary sinus and skin. Our case report presents a rare presentation of metastatic prostate cancer to the duodenum. Our search of the literature found only 2 cases of prostate metastases to duodenum published from 1966 to the present. To our knowledge this is the third case of metastatic prostate cancer presenting with duodenal metastasis. Although it is rare but in symptomatic patients small intestine metastasis should not be ignored with advanced prostate cancer. The case demonstrates a novel presentation of a common malignancy, and should raise awareness in clinicians and radiologists that prostate cancer can present with distant metastases in absence of any local lymphadenopathy. PMID:25161979

  18. Phenotypic and genetic heterogeneity of tumor tissue and circulating tumor cells in patients with metastatic castrationresistant prostate cancer: a report from the PETRUS prospective study

    PubMed Central

    Massard, Christophe; Oulhen, Marianne; Le Moulec, Sylvestre; Auger, Nathalie; Foulon, Stéphanie; Abou-Lovergne, Aurélie; Billiot, Fanny; Valent, Alexander; Marty, Virginie; Loriot, Yohann; Fizazi, Karim; Vielh, Philippe; Farace, Francoise

    2016-01-01

    Molecular characterization of cancer samples is hampered by tumor tissue availability in metastatic castration-resistant prostate cancer (mCRPC) patients. We reported the results of prospective PETRUS study of biomarker assessment in paired primary prostatic tumors, metastatic biopsies and circulating tumor cells (CTCs). Among 54 mCRPC patients enrolled, 38 (70%) had biopsies containing more than 50% tumour cells. 28 (52%) patients were analyzed for both tissue samples and CTCs. FISH for AR-amplification and TMPRSS2-ERG translocation were successful in 54% and 32% in metastatic biopsies and primary tumors, respectively. By comparing CellSearch and filtration (ISET)-enrichment combined to four color immunofluorescent staining, we showed that CellSearch and ISET isolated distinct subpopulations of CTCs: CTCs undergoing epithelial-to-mesenchymal transition, CTC clusters and large CTCs with cytomorphological characteristics but no detectable markers were isolated using ISET. Epithelial CTCs detected by the CellSearch were mostly lost during the ISET-filtration. AR-amplification was detected in CellSearch-captured CTCs, but not in ISET-enriched CTCs which harbor exclusively AR gain of copies. Eighty-eight percent concordance for ERG-rearrangement was observed between metastatic biopsies and CTCs even if additional ERG-alteration patterns were detected in ISET-enriched CTCs indicating a higher heterogeneity in CTCs. Molecular screening of metastatic biopsies is achievable in a multicenter context. Our data indicate that CTCs detected by the CellSearch and the ISET-filtration systems are not only phenotypically but also genetically different. Close attention must be paid to CTC characterization since neither approach tested here fully reflects the tremendous phenotypic and genetic heterogeneity present in CTCs from mCRPC patients. PMID:27391263

  19. A Phase I/II Study for Analytic Validation of 89Zr-J591 ImmunoPET as a Molecular Imaging Agent for Metastatic Prostate Cancer

    PubMed Central

    Pandit-Taskar, Neeta; O'Donoghue, Joseph A.; Durack, Jeremy C.; Lyashchenko, Serge K.; Cheal, Sarah M.; Beylergil, Volkan; Lefkowitz, Robert A.; Carrasquillo, Jorge A.; Martinez, Danny F.; Fung, Alex Mak; Solomon, Stephen B.; Gonen, Mithat; Heller, Glenn; Loda, Massimo; Nanus, David M.; Tagawa, Scott T.; Feldman, Jarett L.; Osborne, Joseph R.; Lewis, Jason S.; Reuter, Victor E.; Weber, Wolfgang A.; Bander, Neil H.; Scher, Howard I.; Larson, Steven M.; Morris, Michael J.

    2015-01-01

    Purpose Standard imaging for assessing osseous metastases in advanced prostate cancer remains focused on altered bone metabolism and is inadequate for diagnostic, prognostic, or predictive purposes. We performed a first-in-human phase I/II study of 89Zr-DFO-huJ591 (89Zr-J591) PET/CT immunoscintigraphy to assess performance characteristics for detecting metastases compared to conventional imaging modalities (CIMs) and pathology. Experimental Design Fifty patients with progressive metastatic castration-resistant prostate cancers were injected with 5 mCi of 89Zr-J591. Whole body PET/CT scans were obtained, and images were analyzed for tumor visualization. Comparison was made to contemporaneously obtained bone scintigraphy and cross-sectional imaging on a lesion-by-lesion basis, and with biopsies of metastatic sites. Results Median standardized uptake value for 89Zr-J591-positive bone lesions (n = 491) was 8.9; soft tissue lesions (n = 90): 4.8 (p < .00003). 89Zr-J591 detected 491 osseous sites compared to 339 by MDP, and 90 soft tissue lesions compared to 124 by CT. Compared to all CIMs combined, 89Zr-J591 detected an additional 99 osseous sites. Forty-six lesions (21 bone, 25 soft tissue) were biopsied in 34 patients; 18/19 89Zr-J591-positive osseous sites and 14/16 89Zr-J591-positive soft tissue sites were positive for prostate cancer. The overall accuracy of 89Zr-J591 was 95.2% (20/21) for osseous lesions and 60% (15/25) for soft tissue lesions. Conclusions 89Zr-J591 imaging demonstrated superior targeting of bone lesions relative to CIMs. Targeting soft tissue lesions was less optimal, although 89Zr-J591 had similar accuracy as individual CIMs. This study will provide benchmark data for comparing performance of proposed PSMA targeting agents for prostate cancer. PMID:26175541

  20. Gastrointestinal Bleeding from Metastatic Prostate Adenocarcinoma to the Stomach

    PubMed Central

    Koop, Andree; Brauhmbhatt, Bhaumik; Lewis, Jason

    2017-01-01

    We present a rare case of gastrointestinal (GI) bleeding associated with metastatic prostate adenocarcinoma to the stomach. Prostate cancer, which is the most common noncutaneous malignancy among men, rarely spreads to the stomach, with only 7 cases reported in the English literature. Symptoms may include abdominal pain, nausea, vomiting, and GI bleeding. Our patient was treated with epinephrine injection and bipolar cautery, but GI bleeding recurred 7 months later when he had worsening of his thrombocytopenia while using ibuprofen. PMID:28377935

  1. Metastatic Prostate Cancer to the Urethra Masquerading as Urothelial Carcinoma.

    PubMed

    Zardawi, Ibrahim; Chong, Peter

    2016-07-01

    Tumors of the urethra, whether primary or metastatic, are very rare. The true nature of urethral neoplasm is not always obvious clinically nor in routine histological sections. Immunostains should be performed on such lesions because of management implications. We present a case of multiple metastases to the urethra from a prostatic carcinoma, masquerading as multiple urothelial carcinomas. Pathologists and urologists should be aware of the possibility of metastasis from the prostate.

  2. SLCO2B1 and SLCO1B3 as New Targets for Enhancing Androgen Deprivation Therapy for Prostate Cancer

    DTIC Science & Technology

    2015-10-01

    the now 5 therapies approved for CRPC that improve survival including enzalutamide, abiraterone, cabazitaxel, radium -223, and sipuleucel-T. 29-35...metastatic castration-resistant prostate cancer - role of radium -223. Ther Clin Risk Manag 10:373-80, 2014 26. Pezaro C, Omlin A, Lorente D, et al...Abstracts 33:5020, 2015 29. Sartor AO, Heinrich D, Helle SI, et al: Radium -223 chloride impact on skeletal- related events in patients with

  3. Management Options in Advanced Prostate Cancer: What is the Role for Sipuleucel-T?

    PubMed

    Bitting, Rhonda L; Armstrong, Andrew J; George, Daniel J

    2011-01-01

    Most prostate cancer-related deaths occur in patients with castration-resistant prostate cancer (CRPC). Until recently, only therapy with docetaxel and prednisone has been shown to prolong survival in men with metastatic CRPC. With the United States Food and Drug Administration (US FDA) approvals of sipuleucel-T, cabazitaxel, and abiraterone acetate, all based on improvement in overall survival, the landscape for management of men with metastatic CRPC has dramatically changed. In this review we will discuss the pivotal clinical trial data leading to these approvals, with particular focus on the unique indication for sipuleucel-T and the implications for optimal management and sequencing of treatment in this patient population.

  4. LIGHT: A Novel Immunotherapy for Primary and Metastatic Prostate Cancer

    DTIC Science & Technology

    2013-09-01

    strong likelihood that combination treatment with LIGHT and immunotherapeutic vaccination will have an impact against primary and possibly metastatic...mediated by regulatory T cells while simultaneously activating tumor-specific immune responses, which we hope to demonstrate can be boosted by vaccination ...of PROVENGE, the first immunotherapeutic cell- based vaccine that can be prescribed for hormone-refractory prostate cancer patients, excitement is

  5. Extracellular Vesicles from Metastatic Rat Prostate Tumors Prime the Normal Prostate Tissue to Facilitate Tumor Growth

    PubMed Central

    Halin Bergström, Sofia; Hägglöf, Christina; Thysell, Elin; Bergh, Anders; Wikström, Pernilla; Lundholm, Marie

    2016-01-01

    Accumulating data indicates that tumor-derived extracellular vesicles (EVs) are responsible for tumor-promoting effects. However, if tumor EVs also prepare the tumor-bearing organ for subsequent tumor growth, and if this effect is different in low and high malignant tumors is not thoroughly explored. Here we used orthotopic rat Dunning R-3327 prostate tumors to compare the role of EVs from fast growing and metastatic MatLyLu (MLL) tumors with EVs from more indolent and non-metastatic Dunning G (G) tumors. Prostate tissue pre-conditioned with MLL-EVs in vivo facilitated G tumor establishment compared to G-EVs. MLL-EVs increased prostate epithelial proliferation and macrophage infiltration into the prostate compared to G-EVs. Both types of EVs increased macrophage endocytosis and the mRNA expression of genes associated with M2 polarization in vitro, with MLL-EVs giving the most pronounced effects. MLL-EVs also altered the mRNA expression of growth factors and cytokines in primary rat prostate fibroblasts compared to G-EVs, suggesting fibroblast activation. Our findings propose that EVs from metastatic tumors have the ability to prime the prostate tissue and enhance tumor growth to a higher extent than EVs from non-metastatic tumors. Identifying these differences could lead to novel therapeutic targets and potential prognostic markers for prostate cancer. PMID:27550147

  6. Radium-223 in Bone-Metastatic Prostate Cancer: Current Data and Future Prospects.

    PubMed

    Lewis, Brian; Chalhoub, Elie; Chalouhy, Carla; Sartor, Oliver

    2015-07-01

    Ra-223 (radium-223) is an alpha particle-emitting radiopharmaceutical with targeted uptake in areas of osteoblastic lesions. The combination of targeted skeletal uptake, short tissue-penetration range, and high energy of alpha particles allows for targeted cell killing and a low toxicity profile. A phase III trial (ALSYMPCA) demonstrated improvements in overall survival and symptomatic skeletal events in patients with castration-resistant prostate cancer and multifocal symptomatic bone metastases. Adverse events were limited but included both gastrointestinal and hematologic effects. This article will describe the historic background of Ra-223; outline the clinical studies which led to phase III trials of this agent; highlight key results of these phase III studies; and explore possible future directions for use of Ra-223 and other alpha particles--both in prostate cancer and for management of other diseases.

  7. The evolutionary history of lethal metastatic prostate cancer.

    PubMed

    Gundem, Gunes; Van Loo, Peter; Kremeyer, Barbara; Alexandrov, Ludmil B; Tubio, Jose M C; Papaemmanuil, Elli; Brewer, Daniel S; Kallio, Heini M L; Högnäs, Gunilla; Annala, Matti; Kivinummi, Kati; Goody, Victoria; Latimer, Calli; O'Meara, Sarah; Dawson, Kevin J; Isaacs, William; Emmert-Buck, Michael R; Nykter, Matti; Foster, Christopher; Kote-Jarai, Zsofia; Easton, Douglas; Whitaker, Hayley C; Neal, David E; Cooper, Colin S; Eeles, Rosalind A; Visakorpi, Tapio; Campbell, Peter J; McDermott, Ultan; Wedge, David C; Bova, G Steven

    2015-04-16

    Cancers emerge from an ongoing Darwinian evolutionary process, often leading to multiple competing subclones within a single primary tumour. This evolutionary process culminates in the formation of metastases, which is the cause of 90% of cancer-related deaths. However, despite its clinical importance, little is known about the principles governing the dissemination of cancer cells to distant organs. Although the hypothesis that each metastasis originates from a single tumour cell is generally supported, recent studies using mouse models of cancer demonstrated the existence of polyclonal seeding from and interclonal cooperation between multiple subclones. Here we sought definitive evidence for the existence of polyclonal seeding in human malignancy and to establish the clonal relationship among different metastases in the context of androgen-deprived metastatic prostate cancer. Using whole-genome sequencing, we characterized multiple metastases arising from prostate tumours in ten patients. Integrated analyses of subclonal architecture revealed the patterns of metastatic spread in unprecedented detail. Metastasis-to-metastasis spread was found to be common, either through de novo monoclonal seeding of daughter metastases or, in five cases, through the transfer of multiple tumour clones between metastatic sites. Lesions affecting tumour suppressor genes usually occur as single events, whereas mutations in genes involved in androgen receptor signalling commonly involve multiple, convergent events in different metastases. Our results elucidate in detail the complex patterns of metastatic spread and further our understanding of the development of resistance to androgen-deprivation therapy in prostate cancer.

  8. New Prostate Cancer Treatment Target

    Cancer.gov

    Researchers have identified a potential alternative approach to blocking a key molecular driver of an advanced form of prostate cancer, called androgen-independent or castration-resistant prostate cancer.

  9. [Corticosteroids in the management of advanced prostate cancer].

    PubMed

    Kübler, H

    2017-02-01

    Corticosteroids have been widely used for decades in cancer therapy, predominantly due to their anti-inflammatory activity. In the treatment of metastatic castration-resistant prostate cancer (mCRPC), corticosteroids play an important role both in the management of tumor-related symptoms, especially bone metastasis-related pain, and as concomitant treatment to counteract side effects associated with approved active prostatic anticancer agents such as docetaxel, cabazitaxel, and abiraterone acetate. In association with abiraterone acetate, low-dose corticosteroids (prednisone or prednisolone) reduce the mineralocorticoid side effects of abiraterone. In addition, corticosteroids may exert direct antitumoral activities, resulting in PSA decline.

  10. Immunotherapy for Prostate Cancer Enters Its Golden Age

    PubMed Central

    Boikos, Sosipatros A.; Antonarakis, Emmanuel S.

    2012-01-01

    In the United States, prostate cancer is the most frequent malignancy in men and ranks second in terms of mortality. Although recurrent or metastatic disease can be managed initially with androgen ablation, most patients eventually develop castration-resistant disease within a number of years, for which conventional treatments (eg, chemotherapy) provide only modest benefits. In the last few years, immunotherapy has emerged as an exciting therapeutic modality for advanced prostate cancer, and this field is evolving rapidly. Encouragingly, the US Food and Drug Administration (FDA) has recently approved two novel immunotherapy agents for patients with advanced cancer: the antigen presenting cell-based product sipuleucel-T and the anti-CTLA4 (cytotoxic T-lymphocyte antigen 4) antibody ipilimumab, based on improvements in overall survival in patients with castration-resistant prostate cancer and metastatic melanoma, respectively. Currently, a number of trials are investigating the role of various immunological approaches for the treatment of prostate cancer, many of them with early indications of success. As immunotherapy for prostate cancer enters its golden age, the challenge of the future will be to design rational combinations of immunotherapy agents with each other or with other standard prostate cancer treatments in an effort to improve patient outcomes further. PMID:22844202

  11. Evolving treatment paradigms for locally advanced and metastatic prostate cancer.

    PubMed

    Dorff, Tanya B; Quek, Marcus L; Daneshmand, Siamak; Pinski, Jacek

    2006-11-01

    While men with early stage prostate cancer typically enjoy long-term survival after definitive management, for those who present with locally advanced or metastatic disease, survival is compromised. Multimodality therapy can prolong survival in these patients, with state-of-the-art options including intensity-modulated radiation or brachytherapy in conjunction with androgen ablation, adjuvant androgen ablation and/or chemotherapy with radical retropubic prostatectomy. In addition, novel biological therapies are being explored to target the unique molecular changes in prostate cancer cells and their interactions with the microenvironment. With these advances the outlook will undoubtedly improve, even for patients presenting with advanced disease. Careful application of these emerging therapies to a select group of prostate cancer patients most likely to obtain benefit from them is the challenge for urologists, medical oncologists and radiation oncologists for the future.

  12. The Evolutionary History of Lethal Metastatic Prostate Cancer

    PubMed Central

    Gundem, Gunes; Van Loo, Peter; Kremeyer, Barbara; Alexandrov, Ludmil B.; Tubio, Jose M.C.; Papaemmanuil, Elli; Brewer, Daniel S.; Kallio, Heini M.L.; Högnäs, Gunilla; Annala, Matti; Kivinummi, Kati; Goody, Victoria; Latimer, Calli; O’Meara, Sarah; Dawson, Kevin J.; Isaacs, William; Emmert-Buck, Michael R; Nykter, Matti; Kote-Jarai, Zsofia; Whitaker, Hayley C.; Neal, David E.; Cooper, Colin S.; Eeles, Rosalind A.; Visakorpi, Tapio; Campbell, Peter J.

    2015-01-01

    Cancers emerge from an on-going Darwinian evolutionary process, often leading to multiple competing subclones within a single primary tumour1-4. This evolutionary process culminates in the formation of metastases, which is the cause of 90% of cancer-related deaths5. However, despite its clinical importance, little is known about the principles governing the dissemination of cancer cells to distant organs. Although the hypothesis that each metastasis originates from a single tumour cell is generally supported6-8, recent studies using mouse models of cancer demonstrated the existence of polyclonal seeding from and inter-clonal cooperation between multiple subclones9,10. In this study, we sought definitive evidence for the existence of polyclonal seeding in human malignancy and to establish the clonal relationship among different metastases in the context of androgen-deprived metastatic prostate cancer. Using whole genome sequencing, we characterised multiple metastases arising from prostate tumours in ten patients. Integrated analyses of subclonal architecture revealed the patterns of metastatic spread in unprecedented detail. Metastasis-to-metastasis spread was found to be common, either through de novo monoclonal seeding of daughter metastases or, in five cases, through the transfer of multiple tumour clones between metastatic sites. Lesions affecting tumour suppressor genes usually occur as single events, whereas mutations in genes involved in androgen receptor signalling commonly involve multiple, convergent events in different metastases. Our results elucidate in detail the complex patterns of metastatic spread and further our understanding of the development of resistance to androgen deprivation therapy in prostate cancer. PMID:25830880

  13. Stem cell and neurogenic gene-expression profiles link prostate basal cells to aggressive prostate cancer.

    PubMed

    Zhang, Dingxiao; Park, Daechan; Zhong, Yi; Lu, Yue; Rycaj, Kiera; Gong, Shuai; Chen, Xin; Liu, Xin; Chao, Hsueh-Ping; Whitney, Pamela; Calhoun-Davis, Tammy; Takata, Yoko; Shen, Jianjun; Iyer, Vishwanath R; Tang, Dean G

    2016-02-29

    The prostate gland mainly contains basal and luminal cells constructed as a pseudostratified epithelium. Annotation of prostate epithelial transcriptomes provides a foundation for discoveries that can impact disease understanding and treatment. Here we describe a genome-wide transcriptome analysis of human benign prostatic basal and luminal epithelial populations using deep RNA sequencing. Through molecular and biological characterizations, we show that the differential gene-expression profiles account for their distinct functional properties. Strikingly, basal cells preferentially express gene categories associated with stem cells, neurogenesis and ribosomal RNA (rRNA) biogenesis. Consistent with this profile, basal cells functionally exhibit intrinsic stem-like and neurogenic properties with enhanced rRNA transcription activity. Of clinical relevance, the basal cell gene-expression profile is enriched in advanced, anaplastic, castration-resistant and metastatic prostate cancers. Therefore, we link the cell-type-specific gene signatures to aggressive subtypes of prostate cancer and identify gene signatures associated with adverse clinical features.

  14. Stem cell and neurogenic gene-expression profiles link prostate basal cells to aggressive prostate cancer

    PubMed Central

    Zhang, Dingxiao; Park, Daechan; Zhong, Yi; Lu, Yue; Rycaj, Kiera; Gong, Shuai; Chen, Xin; Liu, Xin; Chao, Hsueh-Ping; Whitney, Pamela; Calhoun-Davis, Tammy; Takata, Yoko; Shen, Jianjun; Iyer, Vishwanath R.; Tang, Dean G.

    2016-01-01

    The prostate gland mainly contains basal and luminal cells constructed as a pseudostratified epithelium. Annotation of prostate epithelial transcriptomes provides a foundation for discoveries that can impact disease understanding and treatment. Here we describe a genome-wide transcriptome analysis of human benign prostatic basal and luminal epithelial populations using deep RNA sequencing. Through molecular and biological characterizations, we show that the differential gene-expression profiles account for their distinct functional properties. Strikingly, basal cells preferentially express gene categories associated with stem cells, neurogenesis and ribosomal RNA (rRNA) biogenesis. Consistent with this profile, basal cells functionally exhibit intrinsic stem-like and neurogenic properties with enhanced rRNA transcription activity. Of clinical relevance, the basal cell gene-expression profile is enriched in advanced, anaplastic, castration-resistant and metastatic prostate cancers. Therefore, we link the cell-type-specific gene signatures to aggressive subtypes of prostate cancer and identify gene signatures associated with adverse clinical features. PMID:26924072

  15. Molecular Indicators of Castration-Resistant Prostate Cancer

    DTIC Science & Technology

    2014-10-01

    associated RNA transcripts using multiplexed polymerase chain reaction (PCR). On the basis of detection of PCR signals for PSA, PSMA , or EGFR (very...negative for AR-V7. Both patients were positive for CTCs, as determined by the multiplex PCR assay (based on the examination of PSMA , PSA, EGFR and Actin

  16. Overcoming Autophagy to Induce Apoptosis in Castration Resistant Prostate Cancer

    DTIC Science & Technology

    2015-10-01

    I remained fairly steady with only marginal production of LC-3 II, so did the p-Akt. Because of the relative stable AR expression and yet...Figure 6. Enzalutamide and metformin monotherapies did not inhibit the orthotopic tumor growth significantly. However, combination of Enza and...that enzalutamide alone did not inhibit tumor growth. Serum PSA and tumor weight from the Enza group scored the highest among all. Metformin

  17. Molecular Indicators of Castration-Resistant Prostate Cancer

    DTIC Science & Technology

    2015-12-01

    not detected by the three RNA samples sequenced so far (Figure 1). These findings suggest that although other variants may contribute to CRPC, AR-V7... samples by means of gene-set enrichment analysis of RNA sequencing data (Figs. S9 and S10 in the Supplementary Appendix of the attached paper (5)), or by...paper (5)) revealed alterations consistent with a shift toward AR-V7–driven transcription in AR-V7–positive samples . Year 3: We have quantified the

  18. Laser immunotherapy in treatment of metastatic prostate tumors in rats

    NASA Astrophysics Data System (ADS)

    Chen, Wei R.; Ritchey, Jerry W.; Bartles, Kenneth E.; Lucroy, Michael D.; Liu, Hong; Nordquist, Robert E.

    2002-07-01

    Laser immunotherapy is a special cancer treatment modality using an intratumor injection of a special formulation consisting of a novel immunoadjuvant and a laser-absorbing dye, followed by a non-invasive near-IR laser irradiation. Our early experiments using a metastatic mammary rat tumor model showed that laser immunotherapy could cause acute selective photothermal tumor destruction and induce a systemic, long-term specific anti-tumor immunity. In the current study, laser immunotherapy was used to treat metastatic prostate tumors in Copenhagen male rats. The transplantable tumors metastasize mainly to the lung and the lung cancer is usually the cause of death. Two experimental were performed in our study. The first was to study the effect of laser immunotherapy on the tumor burdens, both the primary and the metastasis in the lung. The second was to study the effect of laser immunotherapy on the long-term survival of the tumor-bearing rats. For comparison, some rat tumors were also treated by the laser-dye combination to study the photothermal effect. Tour results showed that both the photothermal effect and the laser immunotherapy could slow the growth of primary tumors and the metastatic tumors. The laser-dye-immunoadjuvant treatment resulted in more than 20 percent long-term survival rate in tumor-bearing rats. Our experimental results indicate that the laser immunotherapy has a great potential in treating metastatic tumors.

  19. High Throughput Sequencing of Germline and Tumor from Men With Early-Onset Metastatic Prostate Cancer

    DTIC Science & Technology

    2014-10-01

    challenge, Dr. Tomlins has continued to develop state of the art technologies to use formalin-fixed paraffin-embedded (FFPE) prostate cancer specimens...men with early-onset, metastatic prostate cancer PRINCIPAL INVESTIGATOR: Kathleen A. Cooney, M.D. CONTRACTING ORGANIZATION...High-Throughput Sequencing of Germline and Tumor From Men with Early-Onset Metastatic Prostate Cancer 5b. GRANT NUMBER W81XWH-13-1-0371 5c

  20. Immunotherapy for Prostate Cancer – Recent Developments and Future Challenges

    PubMed Central

    Schweizer, Michael T.; Drake, Charles G.

    2014-01-01

    Since the approval of sipuleucel-T for men with metastatic castrate resistant prostate cancer in 2010, great strides in the development of anti-cancer immunotherapies have been made. Current drug development in this area has focused primarily on antigen specific [i.e. cancer vaccines and antibody based therapies)] or checkpoint inhibitor therapies, with the checkpoint inhibitors perhaps gaining the most attention as of late. Indeed, drugs blocking the inhibitory signal generated by the engagement of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) found on T-cells has emerged as potent means to combat the immunosuppressive milieu. The anti-CTLA-4 monoclonal antibody ipilimumab has already been approved in advanced melanoma and two phase III trials evaluating ipilimumab in men with metastatic castrate-resistant prostate cancer are underway. A phase III trial evaluating ProstVac-VF, a poxvirus-based therapeutic prostate cancer vaccine, is also underway. While there has been reason for encouragement over the past few years, many questions regarding the use of immunotherapies remain. Namely it is unclear what stage of disease is most likely to benefit from these approaches, how best to incorporate said treatments with each other and into our current treatment regimens and which therapy is most appropriate for which disease. Herein we review some of the recent advances in immunotherapy as related to the treatment of prostate cancer and outline some of the challenges that lie ahead. PMID:24477411

  1. Immune response to sipuleucel-T in prostate cancer.

    PubMed

    Thara, Eddie; Dorff, Tanya B; Averia-Suboc, Monica; Luther, Michael; Reed, Mary E; Pinski, Jacek K; Quinn, David I

    2012-04-18

    Historically, chemotherapy has remained the most commonly utilized therapy in patients with metastatic cancers. In prostate cancer, chemotherapy has been reserved for patients whose metastatic disease becomes resistant to first line castration or androgen deprivation. While chemotherapy palliates, decreases serum prostate specific antigen and improves survival, it is associated with significant side effects and is only suitable for approximately 60% of patients with castrate-resistant prostate cancer. On that basis, exploration of other therapeutic options such as active secondary hormone therapy, bone targeted treatments and immunotherapy are important. Until recently, immunotherapy has had no role in the treatment of solid malignancies aside from renal cancer and melanoma. The FDA-approved autologous cellular immunotherapy sipuleucel-T has demonstrated efficacy in improving overall survival in patients with metastatic castrate-resistant prostate cancer in randomized clinical trials. The proposed mechanism of action is reliant on activating the patients' own antigen presenting cells (APCs) to prostatic acid phosphatase (PAP) fused with granulocyte-macrophage colony stimulating factor (GM-CSF) and subsequent triggered T-cell response to PAP on the surface of prostate cancer cells in the patients body. Despite significant prolongation of survival in Phase III trials, the challenge to health care providers remains the dissociation between objective changes in serum PSA or on imaging studies after sipleucel-T and survival benefit. On that basis there is an unmet need for markers of outcome and a quest to identify immunologic or clinical surrogates to fill this role. This review focuses on the impact of sipuleucel-T on the immune system, the T and B cells, and their responses to relevant antigens and prostate cancer. Other therapeutic modalities such as chemotherapy, corticosteroids and GM-CSF and host factors can also affect immune response. The optimal timing for

  2. Immune Response to Sipuleucel-T in Prostate Cancer

    PubMed Central

    Thara, Eddie; Dorff, Tanya B.; Averia-Suboc, Monica; Luther, Michael; Reed, Mary E.; Pinski, Jacek K.; Quinn, David I.

    2012-01-01

    Historically, chemotherapy has remained the most commonly utilized therapy in patients with metastatic cancers. In prostate cancer, chemotherapy has been reserved for patients whose metastatic disease becomes resistant to first line castration or androgen deprivation. While chemotherapy palliates, decreases serum prostate specific antigen and improves survival, it is associated with significant side effects and is only suitable for approximately 60% of patients with castrate-resistant prostate cancer. On that basis, exploration of other therapeutic options such as active secondary hormone therapy, bone targeted treatments and immunotherapy are important. Until recently, immunotherapy has had no role in the treatment of solid malignancies aside from renal cancer and melanoma. The FDA-approved autologous cellular immunotherapy sipuleucel-T has demonstrated efficacy in improving overall survival in patients with metastatic castrate-resistant prostate cancer in randomized clinical trials. The proposed mechanism of action is reliant on activating the patients’ own antigen presenting cells (APCs) to prostatic acid phosphatase (PAP) fused with granulocyte-macrophage colony stimulating factor (GM-CSF) and subsequent triggered T-cell response to PAP on the surface of prostate cancer cells in the patients body. Despite significant prolongation of survival in Phase III trials, the challenge to health care providers remains the dissociation between objective changes in serum PSA or on imaging studies after sipleucel-T and survival benefit. On that basis there is an unmet need for markers of outcome and a quest to identify immunologic or clinical surrogates to fill this role. This review focuses on the impact of sipuleucel-T on the immune system, the T and B cells, and their responses to relevant antigens and prostate cancer. Other therapeutic modalities such as chemotherapy, corticosteroids and GM-CSF and host factors can also affect immune response. The optimal timing for

  3. Current Insights into Long Non-Coding RNAs (LncRNAs) in Prostate Cancer

    PubMed Central

    Smolle, Maria A.; Bauernhofer, Thomas; Pummer, Karl; Calin, George A.; Pichler, Martin

    2017-01-01

    The importance of long non-coding RNAs (lncRNAs) in the pathogenesis of various malignancies has been uncovered over the last few years. Their dysregulation often contributes to or is a result of tumour progression. In prostate cancer, the most common malignancy in men, lncRNAs can promote castration resistance, cell proliferation, invasion, and metastatic spread. Expression patterns of lncRNAs often change during tumour progression; their expression levels may constantly rise (e.g., HOX transcript antisense RNA, HOTAIR), or steadily decrease (e.g., downregulated RNA in cancer, DRAIC). In prostate cancer, lncRNAs likewise have diagnostic (e.g., prostate cancer antigen 3, PCA3), prognostic (e.g., second chromosome locus associated with prostate-1, SChLAP1), and predictive (e.g., metastasis-associated lung adenocarcinoma transcript-1, MALAT-1) functions. Considering their dynamic role in prostate cancer, lncRNAs may also serve as therapeutic targets, helping to prevent development of castration resistance, maintain stable disease, and prohibit metastatic spread. PMID:28241429

  4. C-Met/miR-130b axis as novel mechanism and biomarker for castration resistance state acquisition.

    PubMed

    Cannistraci, A; Federici, G; Addario, A; Di Pace, A L; Grassi, L; Muto, G; Collura, D; Signore, M; De Salvo, L; Sentinelli, S; Simone, G; Costantini, M; Nanni, S; Farsetti, A; Coppola, V; De Maria, R; Bonci, D

    2017-02-13

    Although a significant subset of prostate tumors remain indolent during the entire life, the advanced forms are still one of the leading cause of cancer-related death. There are not reliable markers distinguishing indolent from aggressive forms. Here we highlighted a new molecular circuitry involving microRNA and coding genes promoting cancer progression and castration resistance. Our preclinical and clinical data demonstrated that c-Met activation increases miR-130b levels, inhibits androgen receptor expression, promotes cancer spreading and resistance to hormone ablation therapy. The relevance of these findings was confirmed on patients' samples and by in silico analysis on an independent patient cohort from Taylor's platform. Data suggest c-Met/miR-130b axis as a new prognostic marker for patients' risk assessment and as an indicator of therapy resistance. Our results propose new biomarkers for therapy decision-making in all phases of the pathology. Data may help identify high-risk patients to be treated with adjuvant therapy together with alternative cure for castration-resistant forms while facilitating the identification of possible patients candidates for anti-Met therapy. In addition, we demonstrated that it is possible to evaluate Met/miR-130b axis expression in exosomes isolated from peripheral blood of surgery candidates and advanced patients offering a new non-invasive tool for active surveillance and therapy monitoring.Oncogene advance online publication, 13 February 2017; doi:10.1038/onc.2016.505.

  5. PROSTVAC® targeted immunotherapy candidate for prostate cancer.

    PubMed

    Shore, Neal D

    2014-01-01

    Targeted immunotherapies represent a valid strategy for the treatment of metastatic castrate-resistant prostate cancer. A randomized, double-blind, Phase II clinical trial of PROSTVAC® demonstrated a statistically significant improvement in overall survival and a large, global, Phase III trial with overall survival as the primary end point is ongoing. PROSTVAC immunotherapy contains the transgenes for prostate-specific antigen and three costimulatory molecules (designated TRICOM). Research suggests that PROSTVAC not only targets prostate-specific antigen, but also other tumor antigens via antigen cascade. PROSTVAC is well tolerated and has been safely combined with other cancer therapies, including hormonal therapy, radiotherapy, another immunotherapy and chemotherapy. Even greater benefits of PROSTVAC may be recognized in earlier-stage disease and low-disease burden settings where immunotherapy can trigger a long-lasting immune response.

  6. Cytoprotective Mitochondrial Chaperone TRAP-1 As a Novel Molecular Target in Localized and Metastatic Prostate Cancer

    PubMed Central

    Leav, Irwin; Plescia, Janet; Goel, Hira Lal; Li, Jing; Jiang, Zhong; Cohen, Ronald J.; Languino, Lucia R.; Altieri, Dario C.

    2010-01-01

    Molecular chaperones of the heat shock protein-90 (Hsp90) family promote cell survival, but the molecular requirements of this pathway in tumor progression are not understood. Here, we show that a mitochondria-localized Hsp90 chaperone, tumor necrosis factor receptor-associated protein-1 (TRAP-1), is abundantly and ubiquitously expressed in human high-grade prostatic intraepithelial neoplasia, Gleason grades 3 through 5 prostatic adenocarcinomas, and metastatic prostate cancer, but largely undetectable in normal prostate or benign prostatic hyperplasia in vivo. Prostate lesions formed in genetic models of the disease, including the transgenic adenocarcinoma of the mouse prostate and mice carrying prostate-specific deletion of the phosphatase tensin homolog tumor suppressor (Ptenpc−/−), also exhibit high levels of TRAP-1. Expression of TRAP-1 in nontransformed prostatic epithelial BPH-1 cells inhibited cell death, whereas silencing of TRAP-1 in androgen-independent PC3 or DU145 prostate cancer cells by small interfering RNA enhanced apoptosis. Targeting TRAP-1 with a novel class of mitochondria-directed Hsp90 inhibitors, ie, Gamitrinibs, caused rapid and complete killing of androgen-dependent or -independent prostate cancer, but not BPH-1 cells, whereas reintroduction of TRAP-1 in BPH-1 cells conferred sensitivity to Gamitrinib-induced cell death. These data identify TRAP-1 as a novel mitochondrial survival factor differentially expressed in localized and metastatic prostate cancer compared with normal prostate. Targeting this pathway with Gamitrinibs could be explored as novel molecular therapy in patients with advanced prostate cancer. PMID:19948822

  7. Collecting and Studying Blood and Tissue Samples From Patients With Locally Recurrent or Metastatic Prostate or Bladder/Urothelial Cancer

    ClinicalTrials.gov

    2016-12-06

    Healthy Control; Localized Urothelial Carcinoma of the Renal Pelvis and Ureter; Metastatic Malignant Neoplasm in the Bone; Metastatic Malignant Neoplasm in the Soft Tissues; Metastatic Urothelial Carcinoma of the Renal Pelvis and Ureter; Recurrent Bladder Carcinoma; Recurrent Prostate Carcinoma; Recurrent Urothelial Carcinoma of the Renal Pelvis and Ureter; Stage IV Bladder Cancer; Stage IV Bladder Urothelial Carcinoma; Stage IV Prostate Cancer

  8. The epigenome as a therapeutic target in prostate cancer.

    PubMed

    Perry, Antoinette S; Watson, R William G; Lawler, Mark; Hollywood, Donal

    2010-12-01

    During cancer development and progression, tumor cells undergo abnormal epigenetic modifications, including DNA methylation, histone deacetylation and nucleosome remodeling. Collectively, these aberrations promote genomic instability and lead to silencing of tumor-suppressor genes and reactivation of oncogenic retroviruses. Epigenetic modifications, therefore, provide exciting new avenues for prostate cancer research. Promoter hypermethylation is widespread during neoplastic transformation of prostate cells, which suggests that restoration of a 'normal' epigenome through treatment with inhibitors of the enzymes involved could be clinically beneficial. Global patterns of histone modifications are also being defined and have been associated with clinical and pathologic predictors of prostate cancer outcome. Although treatment for localized prostate cancer can be curative, the development of successful therapies for the management of castration-resistant metastatic disease is urgently needed. Reactivation of tumor-suppressor genes by demethylating agents and histone deacetylase inhibitors could be a potential treatment option for patients with advanced disease.

  9. Prostate-specific membrane antigen-radioguided surgery for metastatic lymph nodes in prostate cancer.

    PubMed

    Maurer, Tobias; Weirich, Gregor; Schottelius, Margret; Weineisen, Martina; Frisch, Benjamin; Okur, Asli; Kübler, Hubert; Thalgott, Mark; Navab, Nassir; Schwaiger, Markus; Wester, Hans-Jürgen; Gschwend, Jürgen E; Eiber, Matthias

    2015-09-01

    With the advent of (68)Ga-labeled prostate-specific membrane antigen-N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid ((68)Ga-PSMA-HBED-CC) positron emission tomography (PET) hybrid imaging in prostate cancer (PCa), even small metastatic lymph nodes (LNs) can be visualized. However, intraoperative detection of such LNs may not be easy owing to their inconspicuous morphology and/or atypical localization. The aim of our feasibility study was to evaluate PSMA-radioguided surgery for detection of metastatic LNs. One patient with primary PCa and evidence of LN metastases and four PCa patients with evidence of recurrent disease to regional LNs on (68)Ga-PSMA-HBED-CC PET hybrid imaging received an intravenous injection of an (111)In-PSMA investigation and therapy agent 24h before surgery. Metastatic LNs were tracked intraoperatively using a gamma probe with acoustic and visual feedback. All radioactive-positive LN specimens detected in vivo were confirmed by ex vivo measurements and corresponded to PSMA-avid metastatic disease according to histopathology analysis. Intraoperative use of the gamma probe detected all PSMA-positive lesions identified on preoperative (68)Ga-PSMA-HBED-CC PET. Detection of small subcentimeter metastatic LNs was facilitated, and PSMA-radioguided surgery in two patients revealed additional lesions close to known tumor deposits that were not detected by preoperative (68)Ga-PSMA-HBED-CC PET. However, greater patient numbers and long-term follow-up data are needed to determine the future role of PSMA-radioguided surgery.

  10. Increased survival in men with metastatic prostate cancer receiving chemo and hormone therapy

    Cancer.gov

    Men with hormone-sensitive metastatic prostate cancer who received the chemotherapy drug docetaxel given at the start of standard hormone therapy lived longer than patients who received hormone therapy alone, according to early results from a NIH-supporte

  11. Hypoxia stabilizes GAS6/AXl signaling in metastatic prostate cancer

    PubMed Central

    Mishra, Anjali; Wang, Jingcheng; Shiozawa, Yusuke; McGee, Samantha; Kim, Jinkoo; Jung, Younghun; Joseph, Jeena; Berry, Janice E.; Havens, Aaron; Pienta, Kenneth J.; Taichman, Russell S.

    2012-01-01

    The receptor tyrosine kinase Axl is over-expressed in a variety of cancers and is known to play a role in proliferation and invasion. Previous data from our lab indicates that Axl and its ligand GAS6 may play a role in establishing metastatic dormancy in the bone marrow microenvironment. In the current study, we found that Axl is highly expressed in metastatic prostate cancer (PCa) cell lines PC3 and DU145 and has negligible levels of expression in a non-metastatic cancer cell line LNCaP. Knockdown of Axl in PC3 and DU145 cells resulted in decreased expression of several mesenchymal markers including Snail, Slug, and N-cadherin, and enhanced expression of the epithelial marker E-cadherin, suggesting that Axl is involved in the epithelial to mesenchymal transition in PCa cells. The Axl-knockdown PC3 and DU145 cells also displayed decreased in vitro migration and invasion. Interestingly, when PC3 and DU145 cells were treated with GAS6, Axl protein levels were down-regulated. Moreover, CoCl2, a hypoxia mimicking agent, prevented GAS6 mediated down-regulation of Axl in these cell lines. Immunochemical staining of human PCa tissue microarrays demonstrated that Axl, GAS6 and Hif1-α (indicator of hypoxia) were all co-expressed in PCa and in bone metastases, compared to normal tissues. Together, our studies indicate that Axl plays a crucial role in PCa metastasis, and that GAS6 regulates the expression of Axl. Importantly, in a hypoxic tumor microenvironment Axl expression maintained leading to enhanced signaling. PMID:22516347

  12. Sleeping Beauty screen reveals Pparg activation in metastatic prostate cancer.

    PubMed

    Ahmad, Imran; Mui, Ernest; Galbraith, Laura; Patel, Rachana; Tan, Ee Hong; Salji, Mark; Rust, Alistair G; Repiscak, Peter; Hedley, Ann; Markert, Elke; Loveridge, Carolyn; van der Weyden, Louise; Edwards, Joanne; Sansom, Owen J; Adams, David J; Leung, Hing Y

    2016-07-19

    Prostate cancer (CaP) is the most common adult male cancer in the developed world. The paucity of biomarkers to predict prostate tumor biology makes it important to identify key pathways that confer poor prognosis and guide potential targeted therapy. Using a murine forward mutagenesis screen in a Pten-null background, we identified peroxisome proliferator-activated receptor gamma (Pparg), encoding a ligand-activated transcription factor, as a promoter of metastatic CaP through activation of lipid signaling pathways, including up-regulation of lipid synthesis enzymes [fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), ATP citrate lyase (ACLY)]. Importantly, inhibition of PPARG suppressed tumor growth in vivo, with down-regulation of the lipid synthesis program. We show that elevated levels of PPARG strongly correlate with elevation of FASN in human CaP and that high levels of PPARG/FASN and PI3K/pAKT pathway activation confer a poor prognosis. These data suggest that CaP patients could be stratified in terms of PPARG/FASN and PTEN levels to identify patients with aggressive CaP who may respond favorably to PPARG/FASN inhibition.

  13. Sleeping Beauty screen reveals Pparg activation in metastatic prostate cancer

    PubMed Central

    Ahmad, Imran; Mui, Ernest; Galbraith, Laura; Patel, Rachana; Tan, Ee Hong; Salji, Mark; Rust, Alistair G.; Repiscak, Peter; Hedley, Ann; Markert, Elke; Loveridge, Carolyn; van der Weyden, Louise; Edwards, Joanne; Sansom, Owen J.; Adams, David J.; Leung, Hing Y.

    2016-01-01

    Prostate cancer (CaP) is the most common adult male cancer in the developed world. The paucity of biomarkers to predict prostate tumor biology makes it important to identify key pathways that confer poor prognosis and guide potential targeted therapy. Using a murine forward mutagenesis screen in a Pten-null background, we identified peroxisome proliferator-activated receptor gamma (Pparg), encoding a ligand-activated transcription factor, as a promoter of metastatic CaP through activation of lipid signaling pathways, including up-regulation of lipid synthesis enzymes [fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), ATP citrate lyase (ACLY)]. Importantly, inhibition of PPARG suppressed tumor growth in vivo, with down-regulation of the lipid synthesis program. We show that elevated levels of PPARG strongly correlate with elevation of FASN in human CaP and that high levels of PPARG/FASN and PI3K/pAKT pathway activation confer a poor prognosis. These data suggest that CaP patients could be stratified in terms of PPARG/FASN and PTEN levels to identify patients with aggressive CaP who may respond favorably to PPARG/FASN inhibition. PMID:27357679

  14. Role of Hsp90 in Androgen-Refractory Prostate Cancer

    DTIC Science & Technology

    2010-03-01

    Nelson, Zhou Wang: HDAC6 Regulates Androgen Receptor Hypersensitivity and Nuclear Localization via Modulating Hsp90 Acetylation in Castration... Hypersensitivity and Nuclear Localization via Modulating Hsp90 Acetylation in Castration-resistant Prostate Cancer, Molecular Endocrinology 2009, 23...1963-1972. HDAC6 Regulates Androgen Receptor Hypersensitivity and Nuclear Localization via Modulating Hsp90 Acetylation in Castration-Resistant

  15. Human Prostate Cancer Hallmarks Map.

    PubMed

    Datta, Dipamoy; Aftabuddin, Md; Gupta, Dinesh Kumar; Raha, Sanghamitra; Sen, Prosenjit

    2016-08-01

    Human prostate cancer is a complex heterogeneous disease that mainly affects elder male population of the western world with a high rate of mortality. Acquisitions of diverse sets of hallmark capabilities along with an aberrant functioning of androgen receptor signaling are the central driving forces behind prostatic tumorigenesis and its transition into metastatic castration resistant disease. These hallmark capabilities arise due to an intense orchestration of several crucial factors, including deregulation of vital cell physiological processes, inactivation of tumor suppressive activity and disruption of prostate gland specific cellular homeostasis. The molecular complexity and redundancy of oncoproteins signaling in prostate cancer demands for concurrent inhibition of multiple hallmark associated pathways. By an extensive manual curation of the published biomedical literature, we have developed Human Prostate Cancer Hallmarks Map (HPCHM), an onco-functional atlas of human prostate cancer associated signaling and events. It explores molecular architecture of prostate cancer signaling at various levels, namely key protein components, molecular connectivity map, oncogenic signaling pathway map, pathway based functional connectivity map etc. Here, we briefly represent the systems level understanding of the molecular mechanisms associated with prostate tumorigenesis by considering each and individual molecular and cell biological events of this disease process.

  16. Successful treatment of metastatic androgen-independent prostate carcinoma in a transsexual patient.

    PubMed

    Dorff, Tanya B; Shazer, Ronald L; Nepomuceno, Edward M; Tucker, Steven J

    2007-06-01

    The occurrence of prostate carcinoma in transsexual patients has rarely been reported. These cases present a unique challenge in that such patients are effectively receiving androgen deprivation therapy. By definition, their disease is androgen-independent prostate cancer, and the role of local therapy is undefined. We report on a male-to-female transsexual patient with metastatic prostate cancer treated successfully with combination chemotherapy after previous standard therapy failed.

  17. Role of stromal cell-derived factor 1α pathway in bone metastatic prostate cancer

    PubMed Central

    Gupta, Nisha; Duda, Dan G.

    2016-01-01

    Abstract Metastatic prostate cancer is one of the leading causes of cancer-related death in men. The primary site of metastasis from prostate cancers is the bone. During the last decade, multiple studies have pointed to the role of the stromal cell-derived factor 1 alpha (SDF1α)/CXCR4 axis in the metastatic spread of the disease, but the mechanisms that underlie this effect are still incompletely understood. In this review, we summarize the current understanding of the role of the SDF1α/CXCR4 pathway in bone metastatic prostate cancer. We also discuss the therapeutic potential of disrupting the interaction between prostate tumor cells and bone environment with focus on the SDF1α pathway. PMID:27533927

  18. Galeterone for the treatment of advanced prostate cancer: the evidence to date

    PubMed Central

    Bastos, Diogo A; Antonarakis, Emmanuel S

    2016-01-01

    Major advances have been achieved recently in the treatment of metastatic castration-resistant prostate cancer, resulting in significant improvements in quality of life and survival with the use of several new agents, including the next-generation androgen receptor (AR)-targeted drugs abiraterone and enzalutamide. However, virtually all patients will eventually progress on these therapies and most will ultimately die of treatment-refractory metastatic disease. Recently, several mechanisms of resistance to AR-directed therapies have been uncovered, including the AR splice variant 7 (AR-V7), which is a ligand-independent constitutionally-active form of the AR that has been associated with poor outcomes to abiraterone and enzalutamide. Galeterone, a potent anti-androgen with three modes of action (CYP17 lyase inhibition, AR antagonism, and AR degradation), is a novel agent under clinical development that could potentially target both full-length AR and aberrant AR, including AR-V7. In this manuscript, we will first discuss the biological mechanisms of action of galeterone and then review the safety and efficacy data from Phase I and II clinical studies of galeterone in patients with metastatic castration-resistant prostate cancer. A Phase III study of galeterone (compared against enzalutamide) in AR-V7-positive patients is currently underway, and represents the first pivotal trial using a biomarker-selection design in this disease. PMID:27486306

  19. A partial differential equation model of metastasized prostatic cancer.

    PubMed

    Friedman, Avner; Jain, Harsh Vardhan

    2013-06-01

    Biochemically failing metastatic prostate cancer is typically treated with androgen ablation. However, due to the emergence of castration-resistant cells that can survive in low androgen concentrations, such therapy eventually fails. Here, we develop a partial differential equation model of the growth and response to treatment of prostate cancer that has metastasized to the bone. Existence and uniqueness results are derived for the resulting free boundary problem. In particular, existence and uniqueness of solutions for all time are proven for the radially symmetric case. Finally, numerical simulations of a tumor growing in 2-dimensions with radial symmetry are carried in order to evaluate the therapeutic potential of different treatment strategies. These simulations are able to reproduce a variety of clinically observed responses to treatment, and suggest treatment strategies that may result in tumor remission, underscoring our model's potential to make a significant contribution in the field of prostate cancer therapeutics.

  20. Prostatic adenocarcinoma with mandibular metastatic lesion: case report.

    PubMed

    Reyes Court, Daniel; Encina, Susana; Levy, Irene

    2007-10-01

    Metastatic lesions of primary tumors, which originate in different parts of the body, comprise almost 1 % of different types of oral cancers. These lesions can affect either bones or soft tissues in the maxillofacial region. Whenever the maxillofacial area is affected, the most common location is in the molar region of the mandible. The clinical presentation of mandibular metastasis follows a clinical pattern characterized by irradiated dental pain in the third molar region. The most frequent sign is parethesia of the area innervated by the mandibular alveolar dental nerve. Differential diagnosis and treatment of these patients can be extremely difficult because there a number of pathologic conditions with similar symptoms and because diagnostic examination can be highly confusing. The aim of this article is to present a case of prostatic adenocarcinoma where the only metastasis was found in the jaw. A literature review will be presented, hoping to contribute to the scarce information regarding this lesion, due to its low frequency and atypical expression of this type of metastasis in terms of etiology, biological behavior and treatment.

  1. The Utility of 68Ga-PSMA PET/CT in Poorly Differentiated Metastatic Prostate Cancer.

    PubMed

    Demirkol, Mehmet Onur; Kiremit, Murat Can; Acar, Omer; Ucar, Burcu; Saglican, Yesim

    2017-03-17

    We aimed to emphasize how useful PSMA PET/CT findings can be while trying to restage prostate cancer after radical prostatectomy in the presence of low prostate-specific antigen values. A 64-year-old man with pT3b N1 M0 Gleason 7 adenocarcinoma of the prostate presented 5 years postoperatively with a palpable axillary mass, whereas his prostate-specific antigen was 0.08 ng/mL. Conventional imaging studies and histopathologic findings of the axillary mass biopsy revealed inconclusive results. Ga-PSMA PET/CT demonstrated PSMA-positive metastatic lesions, the largest one being located in the right axilla. This finding confirmed metastatic poorly differentiated prostate cancer, and androgen deprivation therapy was initiated.

  2. An overview of sipuleucel-T: autologous cellular immunotherapy for prostate cancer.

    PubMed

    Wesley, Johnna D; Whitmore, James; Trager, James; Sheikh, Nadeem

    2012-04-01

    Sipuleucel-T, the first autologous active cellular immunotherapy approved by the United States Food and Drug Administration, is designed to stimulate an immune response to prostate cancer. Sipuleucel-T is manufactured by culturing a patient's peripheral blood mononuclear cells (including antigen presenting cells) with a recombinant protein comprising a tumor-associated antigen (prostatic acid phosphatase) and granulocyte-macrophage colony stimulating factor. Treatment consists of 3 infusions at approximately 2-week intervals, resulting in a prime-boost pattern of immune activation, a robust antigen-specific cellular and humoral immune response, and, consequently, a survival benefit in subjects with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer. Adverse events are generally mild to moderate and resolve within 2 d. Serious adverse events occur at a low rate. As the first autologous cellular immunotherapy to demonstrate a survival benefit, sipuleucel-T is a novel oncologic therapeutic that warrants the reassessment of the current prostate cancer treatment paradigm.

  3. ARN-509: a novel antiandrogen for prostate cancer treatment.

    PubMed

    Clegg, Nicola J; Wongvipat, John; Joseph, James D; Tran, Chris; Ouk, Samedy; Dilhas, Anna; Chen, Yu; Grillot, Kate; Bischoff, Eric D; Cai, Ling; Aparicio, Anna; Dorow, Steven; Arora, Vivek; Shao, Gang; Qian, Jing; Zhao, Hong; Yang, Guangbin; Cao, Chunyan; Sensintaffar, John; Wasielewska, Teresa; Herbert, Mark R; Bonnefous, Celine; Darimont, Beatrice; Scher, Howard I; Smith-Jones, Peter; Klang, Mark; Smith, Nicholas D; De Stanchina, Elisa; Wu, Nian; Ouerfelli, Ouathek; Rix, Peter J; Heyman, Richard A; Jung, Michael E; Sawyers, Charles L; Hager, Jeffrey H

    2012-03-15

    Continued reliance on the androgen receptor (AR) is now understood as a core mechanism in castration-resistant prostate cancer (CRPC), the most advanced form of this disease. While established and novel AR pathway-targeting agents display clinical efficacy in metastatic CRPC, dose-limiting side effects remain problematic for all current agents. In this study, we report the discovery and development of ARN-509, a competitive AR inhibitor that is fully antagonistic to AR overexpression, a common and important feature of CRPC. ARN-509 was optimized for inhibition of AR transcriptional activity and prostate cancer cell proliferation, pharmacokinetics, and in vivo efficacy. In contrast to bicalutamide, ARN-509 lacked significant agonist activity in preclinical models of CRPC. Moreover, ARN-509 lacked inducing activity for AR nuclear localization or DNA binding. In a clinically valid murine xenograft model of human CRPC, ARN-509 showed greater efficacy than MDV3100. Maximal therapeutic response in this model was achieved at 30 mg/kg/d of ARN-509, whereas the same response required 100 mg/kg/d of MDV3100 and higher steady-state plasma concentrations. Thus, ARN-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists. Our findings offer preclinical proof of principle for ARN-509 as a promising therapeutic in both castration-sensitive and castration-resistant forms of prostate cancer.

  4. Adenosine deaminase complexing protein (ADCP) expression and metastatic potential in prostatic adenocarcinomas.

    PubMed

    Dinjens, W N; Ten Kate, J; Kirch, J A; Tanke, H J; Van der Linden, E P; Van den Ingh, H F; Van Steenbrugge, G J; Meera Khan, P; Bosman, F T

    1990-03-01

    The expression of the adenosine deaminase complexing protein (ADCP) was investigated by immunohistochemistry in the normal and hyperplastic human prostate, in 30 prostatic adenocarcinomas, and in seven human prostatic adenocarcinoma cell lines grown as xenografts in athymic nude mice. In the normal and hyperplastic prostate, ADCP was localized exclusively in the apical membrane and the apical cytoplasm of the glandular epithelial cells. In prostatic adenocarcinomas, four distinct ADCP expression patterns were observed: diffuse cytoplasmic, membranous, both cytoplasmic and membranous, and no ADCP expression. The expression patterns were compared with the presence of metastases. We found an inverse correlation between membranous ADCP immunoreactivity and metastatic propensity. Exclusively membranous ADCP immunoreactivity occurred only in non-metastatic tumours. In contrast, the metastatic tumours showed no or diffuse cytoplasmic ADCP immunoreactivity. This suggests that immunohistochemical detection of ADCP might predict the biological behaviour of prostatic cancer. However, the occurrence of membranous ADCP immunoreactivity in the xenograft of a cell line (PC-EW), derived from a prostatic carcinoma metastasis, indicates that not only the tendency to metastasize modulates ADCP expression.

  5. Checkpoint kinase 2 (CHK2) negatively regulates androgen sensitivity and prostate cancer cell growth

    PubMed Central

    Ta, Huy Q; Ivey, Melissa L; Frierson, Henry F; Conaway, Mark R; Dziegielewski, Jaroslaw; Larner, James M; Gioeli, Daniel

    2015-01-01

    Prostate cancer (PCa) is the second leading cause of cancer death in American men, and curing metastatic disease remains a significant challenge. Nearly all patients with disseminated PCa initially respond to androgen deprivation therapy (ADT), but virtually all patient will relapse and develop incurable castration-resistant prostate cancer (CRPC). A high-throughput RNAi screen to identify signaling pathways regulating PCa cell growth led to our discovery that Checkpoint Kinase 2 (CHK2) knockdown dramatically increased PCa growth and hypersensitized cells to low androgen levels. Mechanistic investigations revealed that the effects of CHK2 were dependent on the downstream signaling proteins CDC25C and CDK1. Moreover, CHK2 depletion increased androgen receptor (AR) transcriptional activity on androgen-regulated genes, substantiating the finding that CHK2 affects PCa proliferation, partly, through the AR. Remarkably, we further show that CHK2 is a novel AR-repressed gene, suggestive of a negative feedback loop between CHK2 and AR. Additionally, we provide evidence that CHK2 physically associates with the AR, and that cell cycle inhibition increased this association. Finally, immunohistochemical analysis of CHK2 in prostate cancer patient samples demonstrated a decrease in CHK2 expression in high-grade tumors. In conclusion, we propose that CHK2 is a negative regulator of androgen sensitivity and PCa growth, and that CHK2 signaling is lost during prostate cancer progression to castration resistance. Thus, perturbing CHK2 signaling may offer a new therapeutic approach for sensitizing CRPC to ADT and radiation. PMID:26573794

  6. What is the role of sipuleucel-T in the treatment of patients with advanced prostate cancer? An update on the evidence.

    PubMed

    Hu, Rachel; George, Daniel J; Zhang, Tian

    2016-08-01

    Prostate cancer is the most common cancer in men and the second most deadly. About one-third of patients with prostate cancer will develop metastatic disease. We discuss the six United States Food and Drug Administration (FDA) approved treatments for metastatic castrate-resistant prostate cancer (mCRPC) with a strong focus on sipuleucel-T. Sipuleucel-T is the first immunotherapy shown to improve survival in asymptomatic or minimally-symptomatic mCRPC. Herein, we discuss the proposed mechanism of sipuleucel-T and its synthesis. We describe in detail the three randomized controlled trials (RTCs) that led to its approval. We also compiled the newest research regarding use of sipuleucel-T with other agents and in different patient populations. Finally, we discuss the current ongoing trials.

  7. Generation of a syngeneic orthotopic transplant model of prostate cancer metastasis

    PubMed Central

    Ellis, Leigh; Lehet, Kristin; Ku, ShengYu; Azabdaftari, Gissou; Pili, Roberto

    2014-01-01

    Progression to metastatic disease is the primary cause of mortality in men with prostate cancer (PCa). Mouse models which progress with spontaneous metastasis are limited. Such models would allow for extensive studies of molecular mechanisms of metastasis, and more definite pre- clinical therapy trials. Orthotopic murine models have been described; however a limiting biology of these models is their lack of an intact immune system. Within, we describe the development of an androgen sensitive and castrate resistant tractable orthotopic murine syngeneic (immune competent) model of prostate cancer. Both models develop primary tumors which spontaneously progress to metastatic disease in lymph tissue. These models will allow for more complete mechanistic and therapeutic studies in a short time period. PMID:25485289

  8. Metastatic prostate cancer mimicking chronic subdural hematoma: a case report and review of the literature.

    PubMed

    Patil, Shashikant; Veron, Ayme; Hosseini, Pegah; Bates, Rachel; Brown, Benjamin; Guthikonda, Bharat; DeSouza, Rowena

    2010-01-01

    Cancer of the prostate is extremely common and is well known to metastasize to the pelvic lymph nodes and axial skeleton (vertebral column, pelvis, cranium, and proximal femur). However, reports of intracranial metastasis are rare and commonly discovered postmortem. Moreover, metastatic lesions mimicking subdural hematoma are extremely rare and are uncommonly reported in the literature. We found only three such cases in the literature. We present a unique case of metastatic prostate cancer presenting with headaches after head trauma with classic radiologic findings of subdural hematoma. The diagnosis may have been made sooner with preoperative magnetic resonance imaging.

  9. The relationship of TMPRSS2-ERG gene fusion between primary and metastatic prostate cancers.

    PubMed

    Guo, Charles C; Wang, Yan; Xiao, Li; Troncoso, Patricia; Czerniak, Bogdan A

    2012-05-01

    Recent studies have revealed the presence of TMPRSS2-ERG gene fusion in both primary and metastatic prostate cancers. However, the relationship between primary and corresponding metastatic prostate cancers with respect to the status of this gene fusion remains unclear. Using fluorescence in situ hybridization, we evaluated the rearrangement of the ERG gene in the radical prostatectomy specimens and corresponding lymph node metastases from 19 patients with prostate cancer. The mean age of the patients was 61 years, and the median Gleason score in the radical prostatectomy specimens was 7 (4 + 3). Prostate cancer was unifocal in 6 cases and multifocal in 13 cases, including 10 with 2 foci and 3 with 3 foci. In the primary prostate cancers, rearrangement of the ERG gene was observed in 13 cases and associated with deletion of the 5' ERG gene in 8 cases. In the metastases, the ERG rearrangement was present in 10 cases and associated with deletion of the 5' ERG gene in 6 cases. In unifocal prostate cancers, the status of the ERG rearrangement was concordant between the primary prostate cancer and metastasis in 5 of 6 cases. In multifocal prostate cancer, despite a significant interfocal discordance, the status of the ERG rearrangement was concordant between the index (largest) primary tumor focus and metastasis in all 13 cases. Our study demonstrates a close relationship of the TMPRSS2-ERG gene fusion status between primary and metastatic prostate cancer. The concordance of the ERG gene rearrangement status between the index primary tumor focus and metastasis suggests that metastasis most likely arises from the index tumor focus in multifocal prostate cancer.

  10. LIGHT: A Novel Immunotherapy for Primary and Metastatic Prostate Cancer

    DTIC Science & Technology

    2014-09-01

    effects due to the loss of testosterone (including fatigue, decreased sexual desire, weight gain, loss of muscle mass and osteoporosis ) and the well...beyond the prostate, immunotherapy may be the only way to treat it [6, 7]. A majority of clinical trials for the immunotherapy of prostate cancer...Localized Prostate Cancer. J Sex Med, 2012. 5. Fitzpatrick, J.M., Management of localized prostate cancer in senior adults : the crucial role of comorbidity

  11. International survey of androgen deprivation therapy (ADT) for non-metastatic prostate cancer in 19 countries

    PubMed Central

    Hallett, David C; Hope, Kirsty; Graham, Alex; Arellano, Jorge; Shahinian, Vahakn B

    2016-01-01

    Background Continuous androgen deprivation therapy (CADT) is commonly used for patients with non-metastatic prostate cancer as primary therapy for high-risk disease, adjuvant therapy together with radiation or for recurrence after initial local therapy. Intermittent ADT (IADT), a recently developed alternative strategy for providing ADT, is thought to potentially reduce adverse effects, but little is known about practice patterns relating to it. We aimed to describe factors related to physicians’ ADT use and modality for patients with non-metastatic prostate cancer. Methods A 45 min online survey was completed by urologists and oncologists responsible for treatment decisions for non-metastatic prostate cancer from 19 countries with high or increasing prevalence of non-metastatic prostate cancer. Results There were 441 treating physicians who completed the survey which represented 99 177 patients with prostate cancer under their care, of which 76 386 (77%) had non-metastatic prostate cancer. Of patients with non-metastatic prostate cancer, 38% received ADT (37% gonadotropin-releasing hormone (GnRH), 2% orchiectomy); among patients on GnRH, 54% received CADT (≥6 without >3 months interruption), 23% IADT and 23% <6 months. Highest rates of ADT were reported among oncologists (62%) and in Eastern Europe (Czech Republic, Hungary and Poland). Prostate-specific antigen (PSA) levels (65%), Gleason score (52%) and treatment guidelines (48%) were the most common reasons for CADT whereas PSA levels (54%), patient request (48%), desire to maintain sexual function (40%), patient age and comorbidities (38%) were cited most frequently as reasons for IADT. Conclusions This international survey with 441 treating physicians from 19 countries showed that ADT is commonly used in treating patients with non-metastatic prostate cancer, and type of ADT is influenced by high-risk criteria (PSA and Gleason), treatment guidelines and patient preferences. IADT use was primarily

  12. Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer

    DOE PAGES

    Hong, Matthew K. H.; Macintyre, Geoff; Wedge, David C.; ...

    2015-04-01

    Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones,more » even years after removal of the prostate. As a result, analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood.« less

  13. Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer

    PubMed Central

    Hong, Matthew K.H.; Macintyre, Geoff; Wedge, David C.; Van Loo, Peter; Patel, Keval; Lunke, Sebastian; Alexandrov, Ludmil B.; Sloggett, Clare; Cmero, Marek; Marass, Francesco; Tsui, Dana; Mangiola, Stefano; Lonie, Andrew; Naeem, Haroon; Sapre, Nikhil; Phal, Pramit M.; Kurganovs, Natalie; Chin, Xiaowen; Kerger, Michael; Warren, Anne Y.; Neal, David; Gnanapragasam, Vincent; Rosenfeld, Nitzan; Pedersen, John S.; Ryan, Andrew; Haviv, Izhak; Costello, Anthony J.; Corcoran, Niall M.; Hovens, Christopher M.

    2015-01-01

    Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones, even years after removal of the prostate. Analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood. PMID:25827447

  14. Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer

    SciTech Connect

    Hong, Matthew K. H.; Macintyre, Geoff; Wedge, David C.; Van Loo, Peter; Patel, Keval; Lunke, Sebastian; Alexandrov, Ludmil B.; Sloggett, Clare; Cmero, Marek; Marass, Francesco; Tsui, Dana; Mangiola, Stefano; Lonie, Andrew; Naeem, Haroon; Sapre, Nikhil; Phal, Pramit M.; Kurganovs, Natalie; Chin, Xiaowen; Kerger, Michael; Warren, Anne Y.; Neal, David; Gnanapragasam, Vincent; Rosenfeld, Nitzan; Pedersen, John S.; Ryan, Andrew; Haviv, Izhak; Costello, Anthony J.; Corcoran, Niall M.; Hovens, Christopher M.

    2015-04-01

    Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones, even years after removal of the prostate. As a result, analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood.

  15. Optical Strategies for Studying Metastatic Mechanisms, Tumor Cell Detection and Treatment of Prostate Cancer

    DTIC Science & Technology

    2006-10-01

    study we have used 2 prostate cancer cell lines. The LNCaP human prostate cancer cells initially isolated from a lymph node biopsy are useful for...cell line is fast growing, poorly differentiated, and metastatic to the lungs and lymph nodes. To determine if this subcurative PDT- induced decrease in...5 – PDT increases the fraction of animals with lymph node metastases. At the time of sacrifice the lungs, pelvic lymph nodes, liver and spines

  16. Functional screen identifies kinases driving prostate cancer visceral and bone metastasis.

    PubMed

    Faltermeier, Claire M; Drake, Justin M; Clark, Peter M; Smith, Bryan A; Zong, Yang; Volpe, Carmen; Mathis, Colleen; Morrissey, Colm; Castor, Brandon; Huang, Jiaoti; Witte, Owen N

    2016-01-12

    Mutationally activated kinases play an important role in the progression and metastasis of many cancers. Despite numerous oncogenic alterations implicated in metastatic prostate cancer, mutations of kinases are rare. Several lines of evidence suggest that nonmutated kinases and their pathways are involved in prostate cancer progression, but few kinases have been mechanistically linked to metastasis. Using a mass spectrometry-based phosphoproteomics dataset in concert with gene expression analysis, we selected over 100 kinases potentially implicated in human metastatic prostate cancer for functional evaluation. A primary in vivo screen based on overexpression of candidate kinases in murine prostate cells identified 20 wild-type kinases that promote metastasis. We queried these 20 kinases in a secondary in vivo screen using human prostate cells. Strikingly, all three RAF family members, MERTK, and NTRK2 drove the formation of bone and visceral metastasis confirmed by positron-emission tomography combined with computed tomography imaging and histology. Immunohistochemistry of tissue microarrays indicated that these kinases are highly expressed in human metastatic castration-resistant prostate cancer tissues. Our functional studies reveal the strong capability of select wild-type protein kinases to drive critical steps of the metastatic cascade, and implicate these kinases in possible therapeutic intervention.

  17. Predictive Comprehensive Geriatric Assessment in elderly prostate cancer patients: the prospective observational scoop trial results.

    PubMed

    Della Pepa, Chiara; Cavaliere, Carla; Rossetti, Sabrina; Di Napoli, Marilena; Cecere, Sabrina C; Crispo, Anna; De Sangro, Carlo; Rossi, Emanuela; Turitto, Dino; Germano, Domenico; Iovane, Gelsomina; Berretta, Massimiliano; D'Aniello, Carmine; Pisconti, Salvatore; Maiorino, Luigi; Daniele, Bruno; Gridelli, Cesare; Pignata, Sandro; Facchini, Gaetano

    2017-01-01

    The Comprehensive Geriatric Assessment (CGA) represents the future of the geriatric oncology to reduce toxicities and treatment-related hospitalization in the elderly. Most patients receiving docetaxel for metastatic castration-resistant prostate cancer are in their seventies or older. We explored the efficacy of the CGA in predicting chemotherapy feasibility and response to docetaxel in a cohort of 24 patients aged at least 70. This was an observational, prospective study involving 24 patients who were 70 years of age or older and about to start chemotherapy with docetaxel for metastatic castration-resistant prostate cancer; we performed a CGA including five domains and divided our patients into 'healthy' and 'frail'; the relations between general condition and (i) early chemotherapy discontinuation and (ii) response to docetaxel were explored. We found a statistically significant relationship between frailty assessed by CGA and early docetaxel discontinuation; we also found an association between frailty and response to chemotherapy, but this did not reach statistical significance. A geriatric assessment before starting chemotherapy may help clinicians to recognize frail patients, and hence to reduce toxicities and early treatment discontinuation. Further analyses are required to simplify the CGA tools and to facilitate its incorporation into routine clinical practice.

  18. Extracellular Vesicle-Mediated Reversal of Paclitaxel Resistance in Prostate Cancer

    PubMed Central

    Wang, Justin Q.; DeChalus, Austin; Chatterjee, Devin N.; Keller, Evan T.; Mizokami, Atsushi; Camussi, Giovanni; Mendelsohn, Andrew R.; Renzulli, Joseph F.; Quesenberry, Peter J.; Chatterjee, Devasis

    2017-01-01

    Prostate cancer (PCa) is the most common solid tumor in males and the second leading cause of cancer-related deaths in males in the United States. The current first line therapy for metastatic PCa is androgen deprivation therapy and is initially effective against the disease. However, castrate resistant prostate cancer (CRPC) develops in many men within 18–36 months, rendering this treatment ineffective. Chemotherapy, with a class of drugs known as taxanes is the standard-of-care cytotoxic option in metastatic castrate resistant PCa (mCRPC). However, the overall survival advantage for chemotherapy in mCRPC is only 2.2 months and the cancer cells often become resistant to these drugs as well. Once patients fail chemotherapy the progression to death is inevitable. Extracellular vesicles (EVs) are involved in cell signaling and play a role in cancer progression. Previous work has demonstrated that EVs are involved in the development of drug resistance in cancer cells. We report the reversal of taxane resistance and tumorigenic phenotype in PCa cells after EVs treatment. This study suggests that EVs represent a potentially novel therapeutic treatment option for CRPC. PMID:27279238

  19. Complementary traditional Chinese medicine therapy improves survival in patients with metastatic prostate cancer

    PubMed Central

    Liu, Jui-Ming; Lin, Po-Hung; Hsu, Ren-Jun; Chang, Ying-Hsu; Cheng, Kuan-Chen; Pang, See-Tong; Lin, Shun-Ku

    2016-01-01

    Abstract More than 50% of prostate cancer patients have used traditional Chinese medicine (TCM) in Taiwan. However, the long-term clinical efficacy of TCM in prostate cancer patients remains unclear. Here, we investigated the relationship between TCM use and the survival of prostate cancer patients. A retrospective nationwide cohort study of prostate cancer patients was conducted between 1998 and 2003 using the Taiwan National Health Insurance Research Database. Patients were classified as TCM users or nonusers, and monitored from the day of prostate cancer diagnosis to death or end of 2012. The association between death risk and TCM use was determined using Cox proportional-hazards models and Kaplan–Meier curves. Of the 1132 selected prostate cancer patients, 730 (64.5%) and 402 (35.5%) were TCM users and nonusers, respectively. The mean follow-up period was 8.38 years, and 292 (25.8%) deaths were reported. TCM users had a decreased mortality rate (21.9%) compared with nonusers (32.8%). A lower death risk was observed with longer TCM use, especially in patients who used TCM for ≧200 days (adjusted hazard ratio [aHR] 0.61, 95% confidence interval [CI] 0.44–0.84). TCM users with metastatic prostate cancer had a significant lower HR than nonusers (aHR 0.70, 95% CI 0.51–0.95). Chai-Hu-Jia-Long-Gu-Mu-Li-Tang was the most significant TCM formulae for improving survival in metastatic prostate cancer (aHR 0.18, 95% CI 0.04–0.94). The result suggested that complementary TCM therapy might be associated with a reduced risk of death in metastatic prostate cancer patients. PMID:27495088

  20. Dynein axonemal heavy chain 8 promotes androgen receptor activity and associates with prostate cancer progression

    PubMed Central

    Wang, Yu; Ledet, Russell J.; Imberg-Kazdan, Keren; Logan, Susan K.; Garabedian, Michael J.

    2016-01-01

    To gain insight into cellular factors regulating AR action that could promote castration resistant prostate cancer (CRPC), we performed a genome-wide RNAi screen for factors that promote ligand-independent AR transcriptional activity and integrated clinical databases for candidate genes that are positively associated with prostate cancer metastasis and recurrence. From this analysis, we identified Dynein Axonemal Heavy Chain 8 (DNAH8) as an AR regulator that displayed higher mRNA expression in metastatic than in primary tumors, and showed high expression in patients with poor prognosis. Axonemal dyneins function in cellular motility, but the function of DNAH8 in prostate cancer or other cell types has not been reported. DNAH8 is on chromosome 6q21.2, a cancer-associated amplicon, and is primarily expressed in prostate and testis. Its expression is higher in primary tumors compared to normal prostate, and is further increased in metastatic prostate cancers. Patients expressing high levels of DNAH8 have a greater risk of relapse and a poor prognosis after prostatectomy. Depletion of DNAH8 in prostate cancer cells suppressed AR transcriptional activity and proliferation. Androgen treatment increased DNAH8 mRNA expression, and AR bound the DNAH8 promoter sequence indicating DNAH8 is an AR target gene. Thus, DNAH8 is a new regulator of AR associated with metastatic tumors and poor prognosis. PMID:27363033

  1. Loss of Androgen-Regulated MicroRNA 1 Activates SRC and Promotes Prostate Cancer Bone Metastasis

    PubMed Central

    Barrett, Ben; Sheppard-Tillman, Heather; Li, Dongmei; Casey, Orla M.; Fang, Lei; Hynes, Paul G.; Ameri, Amir H.

    2015-01-01

    Bone metastasis is the hallmark of progressive and castration-resistant prostate cancers. MicroRNA 1 (miR-1) levels are decreased in clinical samples of primary prostate cancer and further reduced in metastases. SRC has been implicated as a critical factor in bone metastasis, and here we show that SRC is a direct target of miR-1. In prostate cancer patient samples, miR-1 levels are inversely correlated with SRC expression and a SRC-dependent gene signature. Ectopic miR-1 expression inhibited extracellular signal-regulated kinase (ERK) signaling and bone metastasis in a xenograft model. In contrast, SRC overexpression was sufficient to reconstitute bone metastasis and ERK signaling in cells expressing high levels of miR-1. Androgen receptor (AR) activity, defined by an AR output signature, is low in a portion of castration-resistant prostate cancer. We show that AR binds to the miR-1-2 regulatory region and regulates miR-1 transcription. Patients with low miR-1 levels displayed correlated low canonical AR gene signatures. Our data support the existence of an AR–miR-1–SRC regulatory network. We propose that loss of miR-1 is one mechanistic link between low canonical AR output and SRC-promoted metastatic phenotypes. PMID:25802280

  2. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer

    PubMed Central

    Pritchard, C.C.; Mateo, J.; Walsh, M.F.; De Sarkar, N.; Abida, W.; Beltran, H.; Garofalo, A.; Gulati, R.; Carreira, S.; Eeles, R.; Elemento, O.; Rubin, M.A.; Robinson, D.; Lonigro, R.; Hussain, M.; Chinnaiyan, A.; Vinson, J.; Filipenko, J.; Garraway, L.; Taplin, M-E.; AlDubayan, S.; Han, G.C.; Beightol, M.; Morrissey, C.; Nghiem, B.; Cheng, H.H.; Montgomery, B.; Walsh, T.; Casadei, S.; Berger, M.; Zhang, L.; Zehir, A.; Vijai, J.; Scher, H.I.; Sawyers, C.; Schultz, N.; Kantoff, P.W.; Solit, D.; Robson, M.; Van Allen, E.M.; Offit, K.; de Bono, J.; Nelson, P.S.

    2016-01-01

    BACKGROUND Inherited mutations in DNA-repair genes such as BRCA2 are associated with increased risks of lethal prostate cancer. Although the prevalence of germline mutations in DNA-repair genes among men with localized prostate cancer who are unselected for family predisposition is insufficient to warrant routine testing, the frequency of such mutations in patients with metastatic prostate cancer has not been established. METHODS We recruited 692 men with documented metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis. We isolated germline DNA and used multiplex sequencing assays to assess mutations in 20 DNA-repair genes associated with autosomal dominant cancer-predisposition syndromes. RESULTS A total of 84 germline DNA-repair gene mutations that were presumed to be deleterious were identified in 82 men (11.8%); mutations were found in 16 genes, including BRCA2 (37 men [5.3%]), ATM (11 [1.6%]), CHEK2 (10 [1.9% of 534 men with data]), BRCA1 (6 [0.9%]), RAD51D (3 [0.4%]), and PALB2 (3 [0.4%]). Mutation frequencies did not differ according to whether a family history of prostate cancer was present or according to age at diagnosis. Overall, the frequency of germline mutations in DNA-repair genes among men with metastatic prostate cancer significantly exceeded the prevalence of 4.6% among 499 men with localized prostate cancer (P<0.001), including men with high-risk disease, and the prevalence of 2.7% in the Exome Aggregation Consortium, which includes 53,105 persons without a known cancer diagnosis (P<0.001). CONCLUSIONS In our multicenter study, the incidence of germline mutations in genes mediating DNA-repair processes among men with metastatic prostate cancer was 11.8%, which was significantly higher than the incidence among men with localized prostate cancer. The frequencies of germline mutations in DNA-repair genes among men with metastatic disease did not differ significantly according to age at diagnosis or family

  3. AR-V7 and prostate cancer: The watershed for treatment selection?

    PubMed

    Ciccarese, Chiara; Santoni, Matteo; Brunelli, Matteo; Buti, Sebastiano; Modena, Alessandra; Nabissi, Massimo; Artibani, Walter; Martignoni, Guido; Montironi, Rodolfo; Tortora, Giampaolo; Massari, Francesco

    2016-02-01

    The androgen receptor (AR) plays a key role in progression to metastatic castration-resistant prostate cancer (mCRPC). Despite the recent progress in targeting persistent AR activity with the next-generation hormonal therapies (abiraterone acetate and enzalutamide), resistance to these agents limits therapeutic efficacy for many patients. Several explanations for response and/or resistance to abiraterone acetate and enzalutamide are emerging, but growing interest is focusing on importance of AR splice variants (AR-Vs) and in particular of AR-V7. Increasing evidences highlight the concept that variant expression could be used as a potential predictive biomarker and a therapeutic target in advanced prostate cancer. Therefore, understanding the mechanisms of treatment resistance or sensitivity can help to achieve a more effective management of mCRPC, increasing clinical outcomes and representing a promising and engaging area of prostate cancer research.

  4. Molecular Heterogeneity in Primary and Metastatic Prostate Tumor Tissue

    DTIC Science & Technology

    2013-10-01

    PSMA ) and prostate cancer-specific mortality, Kasperzyk et al. found that PSMA was positively correlated with...expressed  in  prostate  tissue:  prostate  specific   membrane  antigen  ( PSMA ).  Utilizing  archival  prostate  tumor  tissue...from  two  US-­‐based  cohort   studies,  Kasperzyk  et  al.  found  that   PSMA  protein  expression  measured

  5. Exome sequencing identifies a spectrum of mutation frequencies in advanced and lethal prostate cancers

    PubMed Central

    Kumar, Akash; White, Thomas A.; MacKenzie, Alexandra P.; Clegg, Nigel; Lee, Choli; Dumpit, Ruth F.; Coleman, Ilsa; Ng, Sarah B.; Salipante, Stephen J.; Rieder, Mark J.; Nickerson, Deborah A.; Corey, Eva; Lange, Paul H.; Morrissey, Colm; Vessella, Robert L.; Nelson, Peter S.; Shendure, Jay

    2011-01-01

    To catalog protein-altering mutations that may drive the development of prostate cancers and their progression to metastatic disease systematically, we performed whole-exome sequencing of 23 prostate cancers derived from 16 different lethal metastatic tumors and three high-grade primary carcinomas. All tumors were propagated in mice as xenografts, designated the LuCaP series, to model phenotypic variation, such as responses to cancer-directed therapeutics. Although corresponding normal tissue was not available for most tumors, we were able to take advantage of increasingly deep catalogs of human genetic variation to remove most germline variants. On average, each tumor genome contained ∼200 novel nonsynonymous variants, of which the vast majority was specific to individual carcinomas. A subset of genes was recurrently altered across tumors derived from different individuals, including TP53, DLK2, GPC6, and SDF4. Unexpectedly, three prostate cancer genomes exhibited substantially higher mutation frequencies, with 2,000–4,000 novel coding variants per exome. A comparison of castration-resistant and castration-sensitive pairs of tumor lines derived from the same prostate cancer highlights mutations in the Wnt pathway as potentially contributing to the development of castration resistance. Collectively, our results indicate that point mutations arising in coding regions of advanced prostate cancers are common but, with notable exceptions, very few genes are mutated in a substantial fraction of tumors. We also report a previously undescribed subtype of prostate cancers exhibiting “hypermutated” genomes, with potential implications for resistance to cancer therapeutics. Our results also suggest that increasingly deep catalogs of human germline variation may challenge the necessity of sequencing matched tumor-normal pairs. PMID:21949389

  6. Metastatic superscan in prostate carcinoma on gallium-68-prostate-specific membrane antigen positron emission tomography/computed tomography scan.

    PubMed

    Agarwal, Krishan Kant; Tripathi, Madhavi; Kumar, Rajeev; Bal, Chandrasekhar

    2016-01-01

    We describe the imaging features of a metastatic superscan on gallium-68 Glu-NH-CO-NH-Lys-(Ahx)-[Ga-68(HBED-CC)], abbreviated as gallium-68-prostate-specific membrane antigen ((68)Ga-PSMA) positron emission tomography/computed tomography (PET/CT) imaging. (68)Ga-PSMA is novel radiotracer undergoing evaluation for PET/CT imaging of prostate carcinoma. This patient had a superscan of metastases on conventional bone scintigraphy and was referred for (68)Ga-PSMA PET/CT to evaluate the feasibility of (177)Lu-PSMA therapy.

  7. Prostate extracellular vesicles in patient plasma as a liquid biopsy platform for prostate cancer using nanoscale flow cytometry

    PubMed Central

    Al-Zahrani, Ali A.; Pardhan, Siddika; Brett, Sabine I.; Guo, Qiu Q.; Yang, Jun; Wolf, Philipp; Power, Nicholas E.; Durfee, Paul N.; MacMillan, Connor D.; Townson, Jason L.; Brinker, Jeffrey C.; Fleshner, Neil E.; Izawa, Jonathan I.; Chambers, Ann F.; Chin, Joseph L.; Leong, Hon S.

    2016-01-01

    Background Extracellular vesicles released by prostate cancer present in seminal fluid, urine, and blood may represent a non-invasive means to identify and prioritize patients with intermediate risk and high risk of prostate cancer. We hypothesize that enumeration of circulating prostate microparticles (PMPs), a type of extracellular vesicle (EV), can identify patients with Gleason Score≥4+4 prostate cancer (PCa) in a manner independent of PSA. Patients and Methods Plasmas from healthy volunteers, benign prostatic hyperplasia patients, and PCa patients with various Gleason score patterns were analyzed for PMPs. We used nanoscale flow cytometry to enumerate PMPs which were defined as submicron events (100-1000nm) immunoreactive to anti-PSMA mAb when compared to isotype control labeled samples. Levels of PMPs (counts/μL of plasma) were also compared to CellSearch CTC Subclasses in various PCa metastatic disease subtypes (treatment naïve, castration resistant prostate cancer) and in serially collected plasma sets from patients undergoing radical prostatectomy. Results PMP levels in plasma as enumerated by nanoscale flow cytometry are effective in distinguishing PCa patients with Gleason Score≥8 disease, a high-risk prognostic factor, from patients with Gleason Score≤7 PCa, which carries an intermediate risk of PCa recurrence. PMP levels were independent of PSA and significantly decreased after surgical resection of the prostate, demonstrating its prognostic potential for clinical follow-up. CTC subclasses did not decrease after prostatectomy and were not effective in distinguishing localized PCa patients from metastatic PCa patients. Conclusions PMP enumeration was able to identify patients with Gleason Score ≥8 PCa but not patients with Gleason Score 4+3 PCa, but offers greater confidence than CTC counts in identifying patients with metastatic prostate cancer. CTC Subclass analysis was also not effective for post-prostatectomy follow up and for

  8. Effects of Marine Phospholipids Extract on the Lipid Levels of Metastatic and Nonmetastatic Prostate Cancer Patients

    PubMed Central

    Taylor, Lenka A.; Kluth, Jessica; Hübschle, Tobias; Fritzsche, Jonas; Hildenbrand, Bernd; Pletschen, Lars; Schilli, Karin; Hodina, Arwen; Griffith, Lee S.; Breul, Jürgen

    2014-01-01

    High intake of omega-3 fatty acids (n-3 FAs) from fish has shown to reduce metastatic progression of prostate cancer. This clinical trial investigated the influence of high n-3 FA intake (marine phospholipids, MPL) on the FA composition of blood lipids, lysophosphatidylcholine (LPC), and on lipoproteins in prostate cancer patients and elderly men without prostate cancer. MPL supplementation resulted in a significant increase of n-3 FAs (eicosapentaenoic and docosahexaenoic acid) in blood lipids, while arachidonic acid (n-6 FA) decreased significantly. Low density lipoprotein (LDL) and high density lipoprotein (HDL) increased significantly, but the LDL increase was observed only in subjects with an inactive tumour. Similarly, LPC plasma concentration increased significantly only in patients without tumour. The missing increase of LDL and LPC after MPL supplementation in patients with actively growing (metastasizing) prostate cancer suggests that tumour cells have an elevated demand for LDL and LPC. Due to the MPL-induced increase of n-3 FAs in these blood lipids, it can be assumed that especially actively growing and metastasizing prostate cancer cells are provided with elevated amounts of these antimetastatic n-3 FAs. A hypothetic model explaining the lower incidence of metastatic progression in prostate cancer patients with high fish consumption is presented. PMID:27351011

  9. Analysis of autophagic flux in response to sulforaphane in metastatic prostate cancer cells

    PubMed Central

    Watson, Gregory W; Wickramasekara, Samanthi; Fang, Yufeng; Palomera-Sanchez, Zoraya; Maier, Claudia S; Williams, David E; Dashwood, Roderick H; Perez, Viviana I; Ho, Emily

    2015-01-01

    Scope The phytochemical sulforaphane has been shown to decrease prostate cancer metastases in a genetic mouse model of prostate carcinogenesis, though the mechanism of action is not fully known. Sulforaphane has been reported to stimulate autophagy, and modulation of autophagy has been proposed to influence sulforaphane cytotoxicity; however, no conclusions about autophagy can be drawn without assessing autophagic flux, which has not been characterized in prostate cancer cells following sulforaphane treatment. Methods and Results We conducted an investigation to assess the impact of sulforaphane on autophagic flux in two metastatic prostate cancer cell lines at a concentration shown to decrease metastasis in vivo. Autophagic flux was assessed by multiple autophagy related proteins and substrates. We found that sulforaphane can stimulate autophagic flux and cell death only at high concentrations, above what has been observed in vivo. Conclusion These results suggest that sulforaphane does not directly stimulate autophagy or cell death in metastatic prostate cancer cells under physiologically relevant conditions, but instead supports the involvement of in vivo factors as important effectors of sulforaphane- mediated prostate cancer suppression. PMID:26108801

  10. 68Ga PSMA PET/CT in a Rare Case of Metastatic Adenocarcinoma Prostate Presenting as Numb Chin Syndrome.

    PubMed

    Sasikumar, Arun; Joy, Ajith; Pillai, M R A; Gopal, Renuka; Thomas, Boben

    2017-03-01

    A 68-year-old man presented with right-side facial numbness. MRI showed an extra-axial mass infiltrating the right temporal bone. It was debulked surgically, and histopathology revealed metastatic adenocarcinoma. Ga PSMA PET/CT done in view of increased PSA levels and clinically suspicious hard lesion in prostate showed primary lesion in left side of prostate with metastases to the right temporal bone. Primary carcinoma of the prostate and metastases to the right temporal bone were proven histopathologically. Our case highlights the usefulness of Ga PSMA PET/CT in identifying the primary site in suspected prostate cancer and mapping the metastatic sites.

  11. Bone marrow adipocytes promote the Warburg phenotype in metastatic prostate tumors via HIF-1α activation

    PubMed Central

    Diedrich, Jonathan D.; Rajagurubandara, Erandi; Herroon, Mackenzie K.; Mahapatra, Gargi; Hüttemann, Maik; Podgorski, Izabela

    2016-01-01

    Metabolic adaptation is increasingly recognized as a key factor in tumor progression, yet its involvement in metastatic bone disease is not understood. Bone is as an adipocyte-rich organ, and a major site of metastasis from prostate cancer. Bone marrow adipocytes are metabolically active cells capable of shaping tumor metabolism via lipolysis and lipid transfer. In this study, using in vitro and in vivo models of marrow adiposity, we demonstrate that marrow fat cells promote Warburg phenotype in metastatic prostate cancer cells. We show increased expression of glycolytic enzymes, increased lactate production, and decreased mitochondrial oxidative phosphorylation in tumor cells exposed to adipocytes that require paracrine signaling between the two cell types. We also reveal that prostate cancer cells are capable of inducing adipocyte lipolysis as a postulated mechanism of sustenance. We provide evidence that adipocytes drive metabolic reprogramming of tumor cells via oxygen-independent mechanism of HIF-1α activation that can be reversed by HIF-1α downregulation. Importantly, we also demonstrate that the observed metabolic signature in tumor cells exposed to adipocytes mimics the expression patterns seen in patients with metastatic disease. Together, our data provide evidence for a functional relationship between marrow adipocytes and tumor cells in bone that has likely implications for tumor growth and survival within the metastatic niche. PMID:27588494

  12. How Precisely Can Prostate Cancer Be Managed?

    PubMed Central

    2016-01-01

    Progress has been made in applying genetic information to disease management in the postgenomic era, and precision medicine is emerging in prostate cancer management. The prostate health index, the 4-kallikrein (4K) score, and the PCA3, TMPRSS2-ERG, and Prostarix tests have potential for refining prostate cancer screening in conjunction with traditional prostate-specific antigen testing. The Confirm MDx and PCA3 tests have shown promise in identifying men who need be rebiopsied after a primary negative biopsy. Oncotype DX, Prolaris, the biopsy-based Decipher prostate cancer test, and ProMark may improve predictive risk stratification in addition to the traditional Gleason score and tumor stage. Decipher and Prolaris may predict biochemical recurrence and metastasis after radical prostatectomy and possibly help identify patients who need adjuvant therapy. Androgen receptor splice variant 7 appears effective in guiding the selection of second hormonal manipulation with abiraterone or enzalutamide versus chemotherapy when treating metastatic castration-resistant prostate cancer. PMID:27915475

  13. Cuprous oxide nanoparticles inhibit prostate cancer by attenuating the stemness of cancer cells via inhibition of the Wnt signaling pathway

    PubMed Central

    Wang, Ye; Yang, Qi-Wei; Yang, Qing; Zhou, Tie; Shi, Min-Feng; Sun, Chen-Xia; Gao, Xiu-Xia; Cheng, Yan-Qiong; Cui, Xin-Gang; Sun, Ying-Hao

    2017-01-01

    Disordered copper metabolism plays a critical role in the development of various cancers. As a nanomedicine containing copper, cuprous oxide nanoparticles (CONPs) exert ideal antitumor pharmacological effects in vitro and in vivo. Prostate cancer is a frequently diagnosed male malignancy prone to relapse, and castration resistance is the main reason for endocrine therapy failure. However, whether CONPs have the potential to treat castration-resistant prostate cancer is still unknown. Here, using the castration-resistant PC-3 human prostate cancer cell line as a model, we report that CONPs can selectively induce apoptosis and inhibit the proliferation of cancer cells in vitro and in vivo without affecting normal prostate epithelial cells. CONPs can also attenuate the stemness of cancer cells and inhibit the Wnt signaling pathway, both of which highlight the great potential of CONPs as a new clinical castration-resistant prostate cancer therapy.

  14. Droplet Digital PCR Based Androgen Receptor Variant 7 (AR-V7) Detection from Prostate Cancer Patient Blood Biopsies.

    PubMed

    Ma, Yafeng; Luk, Alison; Young, Francis P; Lynch, David; Chua, Wei; Balakrishnar, Bavanthi; de Souza, Paul; Becker, Therese M

    2016-08-04

    Androgen receptor splice variant V7 (AR-V7) was recently identified as a valuable predictive biomarker in metastatic castrate-resistant prostate cancer. Here, we report a new, sensitive and accurate screen for AR-V7 mRNA expression directly from circulating tumor cells (CTCs): We combined EpCAM-based immunomagnetic CTC isolation using the IsoFlux microfluidic platform with droplet digital polymerase chain reaction (ddPCR) to analyze total AR and AR-V7 expression from prostate cancer patients CTCs. We demonstrate that AR-V7 is reliably detectable in enriched CTC samples with as little as five CTCs, even considering tumor heterogeneity, and confirm detection of AR-V7 in CTC samples from advanced prostate cancer (PCa) patients with AR-V7 detection limited to castrate resistant disease status in our sample set. Sensitive molecular analyses of circulating tumor cells (CTCs) or circulating tumor nucleic acids present exciting strategies to detect biomarkers, such as AR-V7 from non-invasive blood samples, so-called blood biopsies.

  15. Sipuleucel-T in the treatment of prostate cancer: an evidence-based review of its place in therapy.

    PubMed

    Graff, Julie N; Chamberlain, Erin D

    2015-01-01

    Metastatic castration-resistant prostate cancer is the lethal form of cancer of the prostate. Five new agents that prolong survival in this group have emerged in the past 5 years, and sipuleucel-T is among them. Sipuleucel-T is the only immunotherapy shown to improve survival in prostate cancer. It is currently indicated in asymptomatic or mildly symptomatic patients, as it has never shown a direct cancer effect. This paper describes the process of creating the sipuleucel-T product from the manufacturing and patient aspects. It discusses the four placebo-controlled, randomized clinical trials (RCTs) of sipuleucel-T, focusing on survival and adverse events. There are three RCTs in metastatic castration-resistant prostate cancer, all of which showed improved overall survival without meaningful decreases in symptoms, tumor volumes, or prostate-specific antigen levels. One RCT in castration-sensitive, biochemically relapsed prostate cancer attempted to find a decrease in biochemical failure, but that endpoint was not reached. Adverse events in all four of these studies centered around cytokine release. This paper also reviews a Phase II study of sipuleucel-T given neoadjuvantly that speaks to its mechanism of action. Additionally, there is a registry study of sipuleucel-T that has been used to evaluate immunological parameters of the product in men ≥80 years of age and men who had previously been treated with palliative radiation. Attempts to find early markers of response to sipuleucel-T are described. Further ongoing studies that explore the efficacy of sipuleucel-T in combination with immune checkpoint inhibitors and second-generation hormonal therapies that are summarized. Finally, the only published economic analysis of sipuleucel-T is discussed.

  16. Cofilin drives cell-invasive and metastatic responses to TGF-β in prostate cancer.

    PubMed

    Collazo, Joanne; Zhu, Beibei; Larkin, Spencer; Martin, Sarah K; Pu, Hong; Horbinski, Craig; Koochekpour, Shahriar; Kyprianou, Natasha

    2014-04-15

    Cofilin (CFL) is an F-actin-severing protein required for the cytoskeleton reorganization and filopodia formation, which drives cell migration. CFL binding and severing of F-actin is controlled by Ser3 phosphorylation, but the contributions of this step to cell migration during invasion and metastasis of cancer cells are unclear. In this study, we addressed the question in prostate cancer cells, including the response to TGF-β, a critical regulator of migration. In cells expressing wild-type CFL, TGF-β treatment increased LIMK-2 activity and cofilin phosphorylation, decreasing filopodia formation. Conversely, constitutively active CFL (SerAla) promoted filipodia formation and cell migration mediated by TGF-β. Notably, in cocultures of prostate cancer epithelial cells and cancer-associated fibroblasts, active CFL promoted invasive migration in response to TGF-β in the microenvironment. Further, constitutively active CFL elevated the metastatic ability of prostate cancer cells in vivo. We found that levels of active CFL correlated with metastasis in a mouse model of prostate tumor and that in human prostate cancer, CFL expression was increased significantly in metastatic tumors. Our findings show that the actin-severing protein CFL coordinates responses to TGF-β that are needed for invasive cancer migration and metastasis.

  17. Gray level entropy matrix is a superior predictor than multiplex ELISA in the detection of reactive stroma and metastatic potential of high-grade prostatic adenocarcinoma.

    PubMed

    Jia, Xiaopeng; Sun, Yanan; Wang, Baozhi

    2014-12-01

    Recent reports have indicated that not only the primary glandular tissue but also the surrounding stromal tissue plays an active role in the progression of carcinoma. Such is true for cancer tissues arising in the prostate. However, the precise role of stromal tissue in benign prostatic hyperplasia (BPH) and prostate adenocarcinoma is not well described. We undertook this current investigation to examine the changes in orientation of the extracellular matrix and correlate with prostatic cancer progression. We used a novel form of image analysis called gray level entropy matrix (GLEM) texture analysis to evaluate morphometric changes in stromal tissues. We used normal prostatic tissue obtained from cadaveric specimen and compared with BPH, prostatic intraepithelium neoplastic, hormone responsive prostatic adenocarcinoma and castration-resistant prostatic adenocarcinoma tissues. GLEM showed higher entropy in disease-resistant prostatic tissues, compared with benign forms of all spectra of pathologically diagnosed prostatic tissues (P < 0.05, ANOVA, between groups). Higher entropy is reflective of the disorganized morphological organization of the stroma, possibly reflecting the reactive matrix. In contrast, ELISA revealed that although individually correlated with the progressive stages of benign and carcinomatous prostatic tissues and trend correlation between groups, intergroup comparisons failed to arrive at statistical significance of comparisons between markers of neovasculogenesis, vascular endothelial growth factor, epithelial-mesenchymal transition (beta1-integrin, E-cadherin, MMP3) and osteogenic metastasis (RANKL and osteoprotegerin). The results of our study demonstrate the potential of GLEM entropy of gray level pixel in providing quasiquantitative estimate of a reactive stroma in advance stages of prostatic adenocarcinoma and thus can be routinely used in clinical decision making.

  18. Development of a Gene Therapy Trial for Metastatic Prostate Cancer

    DTIC Science & Technology

    2006-07-01

    used to restrict adenovirus replication in hepatocellular and prostate carcinomas via alpha-fetoprotein and PSA promoters [21, 33]. Gene therapy with...control of PSES to direct adenovirus replication , and HSV-TK gene, a pro-drug enzyme gene, under the control of m6 enhancer to maximize cell-killing

  19. LIGHT: A Novel Immunotherapy for Primary and Metastatic Prostate Cancer

    DTIC Science & Technology

    2012-09-01

    suggests a strong likelihood that combination treatment with LIGHT and immunotherapeutic vaccination will have an impact against primary and... vaccination . This study may potentially provide a practical means of overcoming tumor-mediated immunosuppressive mechanisms in a variety of solid...immunotherapeutic cell- based vaccine that can be prescribed for hormone-refractory prostate cancer patients, excitement is dampened because there have been no

  20. Identification of a Gene on Chromosome 18q21 Involved in Suppressing Metastatic Prostate Cancer

    DTIC Science & Technology

    2005-12-01

    growth properties. In vivo analysis of the metastatic potential of PC-3 cells transfected with maspin reveals that maspin is involved in the seeding ...play a specific role in the ability of the PC-3 prostate cancer cells to seed to bone. PC-3 +18 PC-3 PC-3 C5 PC-3 B7...genomic clone and demonstrated that expression of maspin at endogenous levels affects the potential of PC-3 to seed to bone. • Abstract presented at the

  1. Oncogenic LINE-1 Retroelements Sustain Prostate Tumor Cells and Promote Metastatic Progression

    DTIC Science & Technology

    2015-10-01

    RNA -sequencing data that we are part way through processing, but suggests so far significant activation of non-coding RNA sequences derived from RNA ...metastasis tumor tissues in the UTHSCSA tissue bank, however the RNA was not considered of sufficient quality to submit for RNA sequencing. We did RNA ...sequencing of LNCaP cell line RNA as this is derived from a prostate cancer lymph node metastatic deposit, although the bioinformatics analysis has

  2. Successful whole-exome sequencing from a prostate cancer bone metastasis biopsy

    PubMed Central

    Van Allen, EM; Foye, A; Wagle, N; Kim, W; Carter, SL; McKenna, A; Simko, JP; Garraway, LA; Febbo, PG

    2015-01-01

    BACKGROUND Comprehensive molecular characterization of cancer that has metastasized to bone has proved challenging, which may limit the diagnostic and potential therapeutic opportunities for patients with bone-only metastatic disease. METHODS We describe successful tissue acquisition, DNA extraction, and whole-exome sequencing from a bone metastasis of a patient with metastatic, castration-resistant prostate cancer (PCa). RESULTS The resulting high-quality tumor sequencing identified plausibly actionable somatic genomic alterations that dysregulate the phosphoinostide 3-kinase pathway, as well as a theoretically actionable germline variant in the BRCA2 gene. CONCLUSIONS We demonstrate the feasibility of diagnostic bone metastases profiling and analysis that will be required for the widespread application of prospective ‘precision medicine’ to men with advanced PCa. PMID:24366412

  3. HDAC6 activity is not required for basal autophagic flux in metastatic prostate cancer cells

    PubMed Central

    Watson, Gregory W; Wickramasekara, Samanthi; Fang, Yufeng; Maier, Claudia S; Williams, David E; Dashwood, Roderick H; Perez, Viviana I

    2015-01-01

    Histone deacetylase 6 is a multifunctional lysine deacetylase that is recently emerging as a central facilitator of response to stress and may play an important role in cancer cell proliferation. The histone deacetylase 6-inhibitor tubacin has been shown to slow the growth of metastatic prostate cancer cells and sensitize cancer cells to chemotherapeutic agents. However, the proteins histone deacetylase 6 interacts with, and thus its role in cancer cells, remains poorly characterized. Histone deacetylase 6 deacetylase activity has recently been shown to be required for efficient basal autophagic flux. Autophagy is often dysregulated in cancer cells and may confer stress resistance and allow for cell maintenance and a high proliferation rate. Tubacin may therefore slow cancer cell proliferation by decreasing autophagic flux. We characterized the histone deacetylase 6-interacting proteins in LNCaP metastatic prostate cancer cells and found that histone deacetylase 6 interacts with proteins involved in several cellular processes, including autophagy. Based on our interaction screen, we assessed the impact of the histone deacetylase 6-inhibitor tubacin on autophagic flux in two metastatic prostate cancer cell lines and found that tubacin does not influence autophagic flux. Histone deacetylase 6 therefore influences cell proliferation through an autophagy-independent mechanism. PMID:26643866

  4. Catalytic inhibitors of DNA topoisomerase II suppress the androgen receptor signaling and prostate cancer progression

    PubMed Central

    Li, Haolong; Xie, Ning; Gleave, Martin E.; Dong, Xuesen

    2015-01-01

    Although the new generation of androgen receptor (AR) antagonists like enzalutamide (ENZ) prolong survival of metastatic castration-resistant prostate cancer (CRPC), AR-driven tumors eventually recur indicating that additional therapies are required to fully block AR function. Since DNA topoisomerase II (Topo II) was demonstrated to be essential for AR to initiate gene transcription, this study tested whether catalytic inhibitors of Topo II can block AR signaling and suppress ENZ-resistant CRPC growth. Using multiple prostate cancer cell lines, we showed that catalytic Topo II inhibitors, ICRF187 and ICRF193 inhibited transcription activities of the wild-type AR, mutant ARs (F876L and W741C) and the AR-V7 splice variant. ICRF187 and ICRF193 decreased AR recruitment to target promoters and reduced AR nuclear localization. Both ICRF187 and ICRF193 also inhibited cell proliferation and delayed cell cycling at the G2/M phase. ICRF187 inhibited tumor growth of castration-resistant LNCaP and 22RV1 xenografts as well as ENZ-resistant MR49F xenografts. We conclude that catalytic Topo II inhibitors can block AR signaling and inhibit tumor growth of CRPC xenografts, identifying a potential co-targeting approach using these inhibitors in combination with AR pathway inhibitors in CRPC. PMID:26009876

  5. The bifunctional role of steroid hormones: implications for therapy in prostate cancer.

    PubMed

    Mathew, Paul

    2014-05-01

    Ablation of the androgen-signaling axis is currently a dominant theme in developmental therapeutics in prostate cancer. Highly potent inhibitors of androgen biosynthesis and androgen receptor (AR) function have formally improved survival in castration-resistant metastatic disease. Resistance to androgen-ablative strategies arises through diverse mechanisms. Strategies to preserve and extend the success of hormonal therapy while mitigating the emergence of resistance have long been of interest. In preclinical models, intermittent hormonal ablative strategies delay the emergence of resistant stem-cell-driven phenotypes, but clinical studies in hormone-naive disease have not observed more than noninferiority over continual androgen ablation. In castration-resistant disease, response and improvement in subjective quality of life with therapeutic testosterone has been observed, but so too has symptomatic and life-threatening disease acceleration. The multifunctional and paradoxical role of steroid hormones in regulating proliferation and differentiation, as well as cell death, requires deeper understanding. The lack of molecular biomarkers that predict the outcome of hormone supplementation in a particular clinical context remains an obstacle to individualized therapy. Biphasic patterns of response to hormones are identifiable in vitro, and endocrine-regulated neoplasms that proliferate after prolonged periods of hormone deprivation appear preferentially sex steroid-suppressible. This review examines the relevance of a translational framework for studying therapeutic androgens in prostate cancer.

  6. Sequencing therapy in advanced prostate cancer: focus on sipuleucel-T.

    PubMed

    Quinn, David I; Vaishampayan, Ulka; Higano, Celestia S; Lin, Daniel W; Shore, Neal D; Beer, Tomasz M

    2014-01-01

    Immunotherapies such as sipuleucel-T present new and unique challenges for the optimal timing and sequencing of therapies for metastatic castration-resistant prostate cancer (mCRPC). Key considerations for the sequencing of sipuleucel-T are its unique proposed mechanism of action, the time required to generate a clinically relevant immune response, and the observed efficacy in Phase III trials in 'early' or asymptomatic or minimally symptomatic mCRPC. There are three broad timing and sequencing options for sipuleucel-T in patients with rising prostate-specific antigen and radiologic evidence of disease: immediately after androgen-deprivation therapy failure, after failure of secondary hormonal maneuvers, or after chemotherapy. There are several other agents in Phase III development in mCRPC and any future approvals will impact on the current treatment algorithm, and raise further questions regarding how to optimize sequencing and timing of therapies for better clinical outcomes.

  7. Profiling of differential expression of messenger RNA in normal, benign, and metastatic prostate cell lines.

    PubMed

    Chakrabarti, Ratna; Robles, Liza D; Gibson, Jane; Muroski, Megan

    2002-12-01

    To understand the phenotypic changes associated with prostate cancer development and metastasis, we investigated differential gene expression in primary and established prostate cell lines used as models. We have used a differential display of messenger RNA (DDRT-PCR) technique using 168 primer combinations and total RNA from BPH-1, LNCaP, and PC3 cells to identify filter-based cDNA microarrays containing 18,376 nonredundant clones of genes and expressed sequence tags (EST) using mRNA from PrEC and MDAPCa2a cells to identify genes that are differentially expressed in normal, benign, and cancerous prostate cell lines. Twenty-five cDNA with a significant difference in expression of 76 candidate cDNA, as identified by DDRT-PCR and confirmed by slot-blot analysis, were selected for sequence analysis. Of these, 14 cDNA were further confirmed by Northern blot analysis. Analysis of the cDNA microarray data showed that a variety of genes/EST were up- or down-regulated in the metastatic prostate tumor cells and a majority of these genes encode cytoskeletal proteins and proteins with regulatory function. Expression profile of two EST was confirmed by reverse transcription polymerase chain reaction. We also have identified a number of genes exhibiting differential expression in prostate cancer cells, which were not known earlier to be involved in prostate cancer. This report provides a comparative analysis of differential gene expression between normal prostatic epithelial cells and prostate cancer cells, and a foundation to facilitate in-depth studies on the mechanism of prostate cancer development and metastasis.

  8. Targeting Siah2 as Novel Therapy for Metastatic Prostate Cancer

    DTIC Science & Technology

    2015-10-01

    6. AUTHOR(S) Martin Gleave 5d. PROJECT NUMBER 5e. TASK NUMBER E-Mail: m.gleave@ubc.ca 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME(S...AND ADDRESS(ES) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER University of British Columbia 6190 Agronomy Road, Ste 102 Vancouver, BC...transplanted subcutaneously or orthotopically into the prostate site. The assessment of the Siah1/2 inhibitory peptide in genetic models of mouse as in

  9. Therapeutic Approaches Targeting MYC-Driven Prostate Cancer

    PubMed Central

    Rebello, Richard J.; Pearson, Richard B.; Hannan, Ross D.; Furic, Luc

    2017-01-01

    The transcript encoding the proto-oncogene MYC is commonly overexpressed in prostate cancer (PC). MYC protein abundance is also increased in the majority of cases of advanced and metastatic castrate-resistant PC (mCRPC). Accordingly, the MYC-directed transcriptional program directly contributes to PC by upregulating the expression of a number of pro-tumorigenic factors involved in cell growth and proliferation. A key cellular process downstream of MYC activity is the regulation of ribosome biogenesis which sustains tumor growth. MYC activity also cooperates with the dysregulation of the phosphoinositol-3-kinase (PI3K)/AKT/mTOR pathway to promote PC cell survival. Recent advances in the understanding of these interactions through the use of animal models have provided significant insight into the therapeutic efficacy of targeting MYC activity by interfering with its transcriptional program, and indirectly by targeting downstream cellular events linked to MYC transformation potential. PMID:28212321

  10. CCR5 receptor antagonists block metastasis to bone of v-Src-oncogene-transformed metastatic prostate cancer cell lines

    PubMed Central

    Sicoli, Daniela; Jiao, Xuanmao; Ju, Xiaoming; Velasco-Velazquez, Marco; Ertel, Adam; Addya, Sankar; Li, Zhiping; Ando, Sebastiano; Fatatis, Alessandro; Paudyal, Bishnuhari; Cristofanilli, Massimo; Thakur, Mathew L.; Lisanti, Michael P; Pestell, Richard G.

    2014-01-01

    Src family kinases (SFKs) integrate signal transduction for multiple receptors, regulating cellular proliferation invasion and metastasis in human cancer. Although Src is rarely mutated in human prostate cancer, SFK activity is increased in the majority of human prostate cancers. In order to determine the molecular mechanisms governing prostate cancer bone metastasis, FVB murine prostate epithelium was transduced with oncogenic v-Src. The prostate cancer cell lines metastasized in FVB mice to brain and bone. Gene expression profiling of the tumors identified activation of a CCR5 signaling module when the prostate epithelial cells (PEC) lines were grown in vivo vs. tissue cultures. The whole body, bone and brain metastatic prostate cancer burden was reduced by oral CCR5 antagonist. Clinical trials of CCR5 inhibitors may warrant consideration in patients with CCR5 activation in their tumors. PMID:25452256

  11. Fluid biopsy in patients with metastatic prostate, pancreatic and breast cancers

    NASA Astrophysics Data System (ADS)

    Marrinucci, Dena; Bethel, Kelly; Kolatkar, Anand; Luttgen, Madelyn S.; Malchiodi, Michael; Baehring, Franziska; Voigt, Katharina; Lazar, Daniel; Nieva, Jorge; Bazhenova, Lyudmila; Ko, Andrew H.; Korn, W. Michael; Schram, Ethan; Coward, Michael; Yang, Xing; Metzner, Thomas; Lamy, Rachelle; Honnatti, Meghana; Yoshioka, Craig; Kunken, Joshua; Petrova, Yelena; Sok, Devin; Nelson, David; Kuhn, Peter

    2012-02-01

    Hematologic spread of carcinoma results in incurable metastasis; yet, the basic characteristics and travel mechanisms of cancer cells in the bloodstream are unknown. We have established a fluid phase biopsy approach that identifies circulating tumor cells (CTCs) without using surface protein-based enrichment and presents them in sufficiently high definition (HD) to satisfy diagnostic pathology image quality requirements. This 'HD-CTC' assay finds >5 HD-CTCs mL-1 of blood in 80% of patients with metastatic prostate cancer (n = 20), in 70% of patients with metastatic breast cancer (n = 30), in 50% of patients with metastatic pancreatic cancer (n = 18), and in 0% of normal controls (n = 15). Additionally, it finds HD-CTC clusters ranging from 2 HD-CTCs to greater than 30 HD-CTCs in the majority of these cancer patients. This initial validation of an enrichment-free assay demonstrates our ability to identify significant numbers of HD-CTCs in a majority of patients with prostate, breast and pancreatic cancers.

  12. Impact of Hypoxia on the Metastatic Potential of Human Prostate Cancer Cells

    SciTech Connect

    Dai Yao; Bae, Kyungmi; Siemann, Dietmar W.

    2011-10-01

    Purpose: Intratumoral hypoxia is known to be associated with radioresistance and metastasis. The present study examined the effect of acute and chronic hypoxia on the metastatic potential of prostate cancer PC-3, DU145, and LNCaP cells. Methods and Materials: Cell proliferation and clonogenicity were tested by MTT assay and colony formation assay, respectively. 'Wound-healing' and Matrigel-based chamber assays were used to monitor cell motility and invasion. Hypoxia-inducible factor 1 alpha (HIF-1{alpha}) expression was tested by Western blot, and HIF-1-target gene expression was detected by real-time polymerase chain reaction. Secretion of matrix metalloproteinases (MMPs) was determined by gelatin zymography. Results: When PC-3 cells were exposed to 1% oxygen (hypoxia) for various periods of time, chronic hypoxia ({>=}24 h) decreased cell proliferation and induced cell death. In contrast, prostate cancer cells exposed to acute hypoxia ({<=}6 h) displayed increased motility, clonogenic survival, and invasive capacity. At the molecular level, both hypoxia and anoxia transiently stabilized HIF-1{alpha}. Exposure to hypoxia also induced the early expression of MMP-2, an invasiveness-related gene. Treatment with the HIF-1 inhibitor YC-1 attenuated the acute hypoxia-induced migration, invasion, and MMP-2 activity. Conclusions: The length of oxygen deprivation strongly affected the functional behavior of all three prostate cancer cell lines. Acute hypoxia in particular was found to promote a more aggressive metastatic phenotype.

  13. Using circulating tumor cells to inform on prostate cancer biology and clinical utility

    PubMed Central

    Li, Jing; Gregory, Simon G.; Garcia-Blanco, Mariano A.; Armstrong, Andrew J.

    2016-01-01

    Substantial advances in the molecular biology of prostate cancer have led to the approval of multiple new systemic agents to treat men with metastatic castration-resistant prostate cancer (mCRPC). These treatments encompass androgen receptor directed therapies, immunotherapies, bone targeting radiopharmaceuticals and cytotoxic chemotherapies. There is, however, great heterogeneity in the degree of patient benefit with these agents, thus fueling the need to develop predictive biomarkers that are able to rationally guide therapy. Circulating tumor cells (CTCs) have the potential to provide an assessment of tumor-specific biomarkers through a non-invasive, repeatable “liquid biopsy” of a patient’s cancer at a given point in time. CTCs have been extensively studied in men with mCRPC, where CTC enumeration using the Cellsearch® method has been validated and FDA approved to be used in conjunction with other clinical parameters as a prognostic biomarker in metastatic prostate cancer. In addition to enumeration, more sophisticated molecular profiling of CTCs is now feasible and may provide more clinical utility as it may reflect tumor evolution within an individual particularly under the pressure of systemic therapies. Here, we review technologies used to detect and characterize CTCs, and the potential biological and clinical utility of CTC molecular profiling in men with metastatic prostate cancer. PMID:26079252

  14. Disseminated intravascular coagulation in a patient with metastatic prostate cancer: Fatal outcome following strontium-89 therapy

    SciTech Connect

    Leong, C.; McKenzie, R.; Coupland, D.B.

    1994-10-01

    A patient with metastatic prostate cancer was found to have low-grade disseminated intravascular coagulation (DIC). He had significant bone pain despite external-beam radiotherapy and was given {sup 89}Sr with subsequent thrombocytopenia and epistaxis. The patient died from generalized hemorrhage 36 days postinjection. Although it is not possible to establish a causal relationship between {sup 89}Sr and DIC, practitioners should be alert to complications associated with the primary disorder which might occur at a time to raise concern about the intervention. 8 refs., 1 tab.

  15. Complete Response to Bicalutamide Withdrawal Prolonged for Almost 2 Years in Patients With Metastatic Prostate Cancer.

    PubMed

    Hongo, Hiroshi; Kosaka, Takeo; Oya, Mototsugu

    2014-09-01

    This is the first case report describing a complete response to bicalutamide withdrawal that lasted for almost 2 years in a patient with metastatic prostate cancer. An 80-year-old man who had prostate-specific antigen (PSA) level elevation (168.1 ng/mL) visited our hospital in February 2010. Bone scintigraphy showed pelvic metastases. We started hormonal therapy with leuprorelin and bicalutamide. The PSA concentration decreased to <0.1 ng/mL but started increasing again and reached 1.64 ng/mL in October 2012, at which time bicalutamide administration was discontinued. The PSA concentration decreased again and has remained below the limit of sensitivity for almost 2 years.

  16. A radiobiological model of metastatic burden reduction for molecular radiotherapy: application to patients with bone metastases

    NASA Astrophysics Data System (ADS)

    Denis-Bacelar, Ana M.; Chittenden, Sarah J.; Murray, Iain; Divoli, Antigoni; McCready, V. Ralph; Dearnaley, David P.; O’Sullivan, Joe M.; Johnson, Bernadette; Flux, Glenn D.

    2017-04-01

    Skeletal tumour burden is a biomarker of prognosis and survival in cancer patients. This study proposes a novel method based on the linear quadratic model to predict the reduction in metastatic tumour burden as a function of the absorbed doses delivered from molecular radiotherapy treatments. The range of absorbed doses necessary to eradicate all the bone lesions and to reduce the metastatic burden was investigated in a cohort of 22 patients with bone metastases from castration-resistant prostate cancer. A metastatic burden reduction curve was generated for each patient, which predicts the reduction in metastatic burden as a function of the patient mean absorbed dose, defined as the mean of all the lesion absorbed doses in any given patient. In the patient cohort studied, the median of the patient mean absorbed dose predicted to reduce the metastatic burden by 50% was 89 Gy (interquartile range: 83–105 Gy), whilst a median of 183 Gy (interquartile range: 107–247 Gy) was found necessary to eradicate all metastases in a given patient. The absorbed dose required to eradicate all the lesions was strongly correlated with the variability of the absorbed doses delivered to multiple lesions in a given patient (r  =  0.98, P  <  0.0001). The metastatic burden reduction curves showed a potential large reduction in metastatic burden for a small increase in absorbed dose in 91% of patients. The results indicate the range of absorbed doses required to potentially obtain a significant survival benefit. The metastatic burden reduction method provides a simple tool that could be used in routine clinical practice for patient selection and to indicate the required administered activity to achieve a predicted patient mean absorbed dose and reduction in metastatic tumour burden.

  17. A radiobiological model of metastatic burden reduction for molecular radiotherapy: application to patients with bone metastases.

    PubMed

    Denis-Bacelar, Ana M; Chittenden, Sarah J; Murray, Iain; Divoli, Antigoni; Ralph McCready, V; Dearnaley, David P; O'Sullivan, Joe M; Johnson, Bernadette; Flux, Glenn D

    2017-04-07

    Skeletal tumour burden is a biomarker of prognosis and survival in cancer patients. This study proposes a novel method based on the linear quadratic model to predict the reduction in metastatic tumour burden as a function of the absorbed doses delivered from molecular radiotherapy treatments. The range of absorbed doses necessary to eradicate all the bone le