Management Of Castration-resistant Prostate Cancer Research Articles

Nuclear Receptor LRH-1 Functions to Promote Castration-Resistant Growth of Prostate Cancer via Its Promotion of Intratumoral Androgen Biosynthesis.

Targeting of steroidogenic enzymes (e.g., abiraterone acetate targeting CYP17A1) has been developed as a novel therapeutic strategy against metastatic castration-resistant prostate cancer (CRPC). However, resistance to steroidal inhibitors inevitably develops in patients, the mechanisms of which remain largely unknown. Liver receptor homolog-1 (LRH-1, NR5A2) is a nuclear receptor, originally characterized as an important regulator of some liver-specific metabolic genes. Here, we report that LRH-1, which exhibited an increased expression pattern in high-grade prostate cancer and CRPC xenograft models, functions to promote de novo androgen biosynthesis via its direct transactivation of several key steroidogenic enzyme genes, elevating intratumoral androgen levels and reactivating AR signaling in CRPC xenografts as well as abiraterone-treated CRPC tumors. Pharmacologic inhibition of LRH-1 activity attenuated LRH-1-mediated androgen deprivation and anti-androgen resistance of prostate cancer cells. Our findings not only demonstrate the significant role of LRH-1 in the promotion of intratumoral androgen biosynthesis in CRPC via its direct transcriptional control of steroidogenesis, but also suggest targeting LRH-1 could be a potential therapeutic strategy for CRPC management.Significance: These findings not only demonstrate the significant role of the nuclear receptor LRH-1 in the promotion of intratumoral androgen biosynthesis in CRPC via its direct transcriptional control of steroidogenesis, but also suggest targeting LRH-1 could be a potential therapeutic strategy for CRPC management. Cancer Res; 78(9); 2205-18. ©2018 AACR.

Are clinical guidelines designed according to guidelines? Cross-sectional assessment of quality and transparency of clinical guidelines in urology.

Guidelines and recommendations become increasingly important in clinical urologic practice. This study aims to inform clinicians using guidelines on how to evaluate the quality of the methodology and transparency of these documents. The guidelines on management of castration-resistant prostate cancer of the American Urology Association, European Association of Urology, National Comprehensive Cancer Network, National Institute for Health and Care Excellence, European Society of Medical Oncology were reviewed using the AGREE-II tool (Appraisal of Guidelines for Research and Evaluation). We reported and compared the domain scores for the domains 1 scope and purpose, 2 stakeholder involvement, 3 rigor of development, 4 clarity of presentation, 5 applicability, and 6 editorial independence (100% indicates highest-best quality score). The domains evaluated highest and with lowest variability were 'editorial independence' (92% {88-95%}) and 'clarity of presentation' (83% {72-90%}), while the domains with the lowest scores and most variability were 'stakeholder involvement' (56% {36-79%}) and 'applicability' (40% {30-63%}). Length and extent of detail of guidelines vary considerably, each with its own strengths and limitations and adapted to target users. Standard external review using AGREE criteria may be preferable. A formal search strategy was not performed. Findings may be outdated by guidelines' updates. Clinicians using practice guidelines need to be aware of the different domains of methodology and transparency used to assess the quality of guidelines contents and recommendations. Urologists increasingly use guidelines for support in evidence-based recommendations in clinical practice. It is very important to know how to assess these documents. This study applies standard criteria to compare the design and background of different available guidelines on prostate cancer no longer responding to hormonal treatment.

Orphan nuclear receptor TLX contributes to androgen insensitivity in castration-resistant prostate cancer via its repression of androgen receptor transcription

The metastatic castration-resistant prostate cancer (CRPC) is a lethal form of prostate cancer, in which the expression of androgen receptor (AR) is highly heterogeneous. Indeed, lower AR expression and attenuated AR signature activity is shown in CRPC tissues, especially in the subset of neuroendocrine prostate cancer (NEPC) and prostate cancer stem-like cells (PCSCs). However, the significance of AR downregulation in androgen insensitivity and de-differentiation of tumor cells in CRPC is poorly understood and much neglected. Our previous study shows that the orphan nuclear receptor TLX (NR2E1), which is upregulated in prostate cancer, plays an oncogenic role in prostate carcinogenesis by suppressing oncogene-induced senescence. In the present study, we further established that TLX exhibited an increased expression in metastatic CRPC. Further analyses showed that overexpression of TLX could confer resistance to androgen deprivation and anti-androgen in androgen-dependent prostate cancer cells in vitro and in vivo, whereas knockdown of endogenous TLX could potentiate the sensitivity to androgen deprivation and anti-androgen in prostate cancer cells. Our study revealed that the TLX-induced resistance to androgen deprivation and anti-androgen was mediated through its direct suppression of AR gene transcription and signaling in both androgen-stimulated and -unstimulated prostate cancer cells. We also characterized that TLX could bind directly to AR promoter and repress AR transcription by recruitment of histone modifiers, including HDAC1, HDAC3, and LSD1. Together, our present study shows, for the first time, that TLX can contribute to androgen insensitivity in CRPC via repression of AR gene transcription and signaling, and also implicates that targeting the druggable TLX may have a potential therapeutic significance in CRPC management, particularly in NEPC and PCSCs.

Integrative transcriptional analysis of enzalutamide-resistant castration resistant prostate cancer cells using RNA sequencing.

284 Background: Enzalutamide (ENZ)-resistance is a clinically challaengeable issue for management of castration-resistant prostate cancer (CRPC) patients. Here, we aimed to investigate the distinct features of transcriptional expression in ENZ-resistant CRPC cells using RNA sequencing, focusing on the histone modification enzymes as AR co-regulators. Methods: We chronically treated various concentration of ENZ (1 to 40 µM) for 6 to 9 months to establish ENZ-resistant CRPC cells by using C4-2B cells. To explore the phenotypic features of ENZ-resistant CRPC cells (ENZ-R), we analyzed the gene expression patterns, particularly AR target genes, following ENZ treatment. We performed cell viability assay, clonogenic assay, apotosis assay and tumor sphere formation assay. To examine the distinct features of transcriptional expression in ENZ-resistant CRPC cells, we conducted RNA sequencing and classified the key differential expression genes (DEG) according to Gene Ontology Database. Results: ENZ-R cells showed a higher cell viability and clonogenic proliferation compared to control cells following ENZ treatment. Also, ENZ-R cells showed higher gene expression of AR target gens (KLK2, KLK3, TTMPRSS) than those in control cells after dihydrotestosterone treatment. Of note, ENZ-R cells significantly expressed full length AR as well as AR splicing variant 7. Moreover, RNA sequencing revealed that 367 up-regulated genes and 223 down-regulated genes were identified as DEG compared to control cells. We further analyzed these DEG of histone modification enzyme as AR co-regulators, and therefore; we finally determined the candidate 28 target genes of histone modification enzyme (23 up-regulated and 5 down-regulated genes). We validated the differential expression of these key histone modification enzyme genes in ENZ-R cells by using real-time PCR. Conclusions: In sum, we established the ENZ-R cells and identified the 28 candidate DEG of histone modification enzyme in ENZ-R cells by performing RNA sequencing analysis. Our study can offer the valuable information for exploring the ENZ-resistant mechanisms, particularly focusing on the imbalance of AR co-regulators.

Androgen receptor-independent prostate cancer: an emerging clinical entity

ABSTRACTAndrogen deprivation therapy remains the backbone of prostate cancer treatment given its pivotal role in the pathogenesis of prostate cancer. The growing knowledge of androgen receptor-independent (i.e. AR-null) prostate cancer cells, however, might advance the treatment paradigm of prostate cancer. Here, we examined the results of two recent studies, published in Cancer Cell by Bluemn and Shukla et al., and their impact in the future management of castration-resistant prostate cancer.

A Systematic Review of Clinical Practice Guidelines for Castration-Resistant Prostate Cancer.

Cancer constitutes a huge burden on societies in countries with any level of economic development. Prostate cancer is the first most diagnosed cancer of men in developed countries and the forth one in developing countries in terms of incidence rate. It is also the third incident cancer of men in Iran along with a prevalence of about 10,000 cases. Castration-resistant prostate cancer (CRPC) is a severe stage of the disease with a number of newly discovered treatment options. These therapeutic alternatives including abiraterone acetate, enzalutamide, cabazitaxel, immunotherapy with sipuleucel-T, radiopharmaceuticals and bone-targeted therapies (zoledronic acid, denosumab) along with docetaxel have made the decision making process complex and challenging for clinicians. In addition to the challenges of selecting the best-fit treatment, high costs of new pharmaceuticals and technologies necessitates the health policy-makers to develop practice guidelines in adaptation with local resources and limitations. The aim of this paper is to review the clinical guidelines for the management of CRPC. For better comprehension of guideline recommendations, the main clinical trials on new treatments were also identified. The efficacy and safety outcomes including but not limited to overall survival, progression free survival, quality of life and adverse effects were summarized. The guidelines of American Urological Association (AUA), National Comprehensive Cancer Network (NCCN), European Association of Urology (EUA), Spanish Oncology Genitourinary Group (SOGG), Asian Oncology Summit, Saudi Oncology Society-Saudi Urology Association combined guideline, National Institute for Health and Care Excellence (NICE) and Canadian Urological Association-Canadian Urologic Oncology Group (CUA-CUOG) were covered in this paper.

Costunolide enhances doxorubicin-induced apoptosis in prostate cancer cells via activated mitogen-activated protein kinases and generation of reactive oxygen species.

The management of castration-resistant prostate cancer (CRPC) is challenging, attributable to a lack of efficacious therapies. Chemotherapy is one of the most important treatments for CRPC. Doxorubicin has been extensively used in many different tumors and is often combined with other drugs to enhance effects and reduce toxicity. Costunolide is a natural sesquiterpene lactone with anti-cancer properties. In this study, we first demonstrated that the combination of costunolide and doxorubicin induced apoptosis significantly more than either drug alone in prostate cancer cell lines. Costunolide combined with doxorubicin induced mitochondria-mediated apoptosis through a loss of mitochondrial membrane potential and modulation of Bcl-2 family proteins. We found that this drug combination significantly increased the production of reactive oxygen species (ROS), as well as phosphorylation of c-jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases, which play upstream roles in mitochondria-mediated apoptosis. Further studies showed that N-acetyl cysteine blocked JNK and p38 phosphorylation, suggesting that ROS were upstream activators of JNK and p38. However, a JNK inhibitor, but not a p38 inhibitor, blocked the increase in ROS observed in cells treated with a combination of costunolide and doxorubicin, suggesting that ROS and JNK could activate each other. In vivo, inhibition of tumor growth and induction of apoptosis were greater in mice treated with the costunolide and doxorubicin combination than in mice treated with either drug alone, without an increase in toxicity. Therefore, we suggested that costunolide in combination with doxorubicin was a new potential chemotherapeutic strategy for treating prostate cancer.

Research advances in prostate cancer stem cells and radiotherapy resistance of castration-resistant prostate cancer

Prostate cancer tends to progress to castration-resistant prostate cancer within 24 months after castration. For the management of castration-resistant prostate cancer, the biggest challenge is therapeutic resistance which includes radiotherapy resistance. Relevant studies suggest that the radiotherapy resistance of castration-resistant prostate cancer is associated with prostate cancer stem cells and miRNA related to prostate cancer stem cells. This article reviews the research advances in the radiotherapy resistance of castration-resistant prostate cancer in terms of the possible mechanisms of castration-resistant prostate cancer, prostate cancer stem cells, and miRNA related to prostate cancer stem cells. Key words: Castration Resistant Prostate Cancer; Cancer stem cell; Prostate cancer stem cell; Micro-ribonucleic acid

New horizons in the management of castrate-resistant prostate cancer

Castrate-resistant prostate cancer is an incurable disease. It continues to be an area of intense research to save prostate cancer patients’ lives. We aim from this review to explore the new lines of treatment that aim at extending disease-specific survival. We conducted a PubMed research on available literature pertaining to key words alone and in combination: prostate cancer, castrate-resistant, immunotherapy, hormonal therapy, chemotherapy, radiation therapy, metastasis, survival and quality of life. We also reviewed the following guidelines on castrate-resistant prostate cancer: National Comprehensive Cancer Network (NCCN), American Urological Association (AUA), the National Institute for Health and Care Excellence (NICE) and the European Association of Urology (EAU). There are four new lines of treatment in castrate-resistant prostate cancer. An immunotherapy, sipuleucel T (Provenge); new hormonal therapies – in the form of a new androgen receptor blocker, enzalutamide (Xtandi) and new adrenal androgen synthesis inhibitor, abiraterone acetate (Zytiga); a new chemotherapy, cabazitaxel (Jevtana) and new radioactive agent, radium 223 (Xofigo). There is an agreement between guidelines that patients with M0 castrate-resistant prostate cancer should not be offered any of these treatments. Similarly, patients with castrate-resistant prostate cancer and poor performance status should be offered only palliative care. There are several new lines of treatment that can be used in castrate-resistant prostate cancer, and hopefully in the near future castrate-resistant prostate cancer will be changing from a lethal disease to more of a chronic disease.

Inhibitor of H3K27 demethylase JMJD3/UTX GSK-J4 is a potential therapeutic option for castration resistant prostate cancer.

Androgen receptor (AR) mediates initiation and progression of prostate cancer (PCa); AR-driven transcription is activated by binding of androgens to the ligand-binding domain (LBD) of AR. Androgen ablation therapy offers only a temporary relief of locally advanced and metastatic PCa, and the disease eventually recurs as a lethal castration-resistant PCa (CRPC) as there is no effective treatment for CRPC patients. Thus, it is critical to identify novel targeted and combinatorial regimens for clinical management of CRPC.Reduction of the repressive epigenetic modification H3K27me2/3 correlates with PCa aggressiveness, while corresponding demethylases JMJD3/UTX are overexpressed in PCa. We found that JMJD3/UTX inhibitor GSK-J4 reduced more efficiently proliferation of AR-ΔLBD cells (CRPC model) compared with isogenic AR-WT cells. Inhibition of JMJD3/UTX protects demethylation of H3K27Me2/3, thus reducing levels of H3k27Me1. We observed that the reduction dynamics of H3K27Me1 was faster and achieved at lower inhibitor concentrations in AR-ΔLBD cells, suggesting that inhibition of JMJD3/UTX diminished proliferation of these cells by hindering AR-driven transcription. In addition, we observed synergy between GSK-J4 and Cabazitaxel, a taxane derivative that is approved for CRPC treatment. Collectively, our results point at the H3K27 demethylation pathway as a new potential therapeutic target in CRPC patients.

Radium-223 dichloride for the treatment of castration-resistant prostate cancer with symptomatic bone metastases

ABSTRACTIntroduction: Castration-resistant prostate cancer (CRPC) is associated with the development of bone metastases, increased mortality, and a reduction in the patient’s quality of life (QOL). The management of metastatic CRPC (mCRPC) has rapidly evolved over the past decade, with a number of available therapeutic agents improving overall survival. Radium-223 dichloride (radium-223), the first targeted alpha therapy, improves survival accompanied by QOL benefits with a favorable safety profile. It is approved in over 40 countries for the treatment of patients with CRPC with symptomatic bone metastases and no known visceral metastatic disease.Areas covered: The current management of CRPC in men with bone metastases, and in particular the role of radium-223 in this setting, is reviewed and discussed. A search of bibliographic databases for peer-reviewed literature and major meetings was conducted.Expert commentary: In treating patients with mCRPC, the best sequencing and/or combination of radium-223 with other agents has yet to be fully elucidated. The role of radium-223 in treating patients with hormone-sensitive metastatic prostate cancer who are candidates for chemotherapy should also be investigated in well-designed trials. The ability to tailor radium-223 therapy to both the clinical and genetic profiles of CRPC patients would be a promising development.

Biomarkers for the Management of Castration-Resistant Prostate Cancer: We Are Not There Yet.

In recent years, there has been a marked increase in the number of approved therapies that increase survival of patients with castration-resistant prostate cancer. Current treatment guidelines provide therapeutic management recommendations, but these are primarily based on clinical factors such as performance status or site of metastasis (bone vs. visceral), and not on underlying molecular or cellular features of disease that may predict response. The ability to tailor treatment based on molecular or cellular features of disease could potentially reduce the occurrence of unnecessary side effects and ineffective treatments, and thereby reduce both direct and indirect medical costs. As such, it is important to identify and validate new prognostic and predictive molecular biomarkers that can be used to direct cancer treatment. This review will focus on existing and potential biomarkers in the context of castration-resistant prostate cancer management and discuss the need for continued discovery and validation of new biomarkers and biomarker panels for prostate cancer.

The impact of continuing medical education (CME) programs in metastatic castration-resistant prostate cancer (CRPC).

e18280 Background: The concurrent development of many CRPC treatments within a short period of time has made prospective data on their sequential use and efficacy complicated, which have challenged clinician confidence, knowledge, and competency. Four hours of CME focused on the therapeutic management of CRPC were developed and participant responses analyzed to determine if these challenges were addressed. Methods: PlatformQ Health developed and executed 4 hours of virtual CME programs in CRPC. The 1st 2-hours, broadcast in May 2015 and offered online for 6 months, attracted a total of 545 learners. The 2nd 2-hours, broadcast in July 2016 and offered for 12 months, attracted a total of 345* learners. Survey-based evaluations targeted self-reported clinician data on satisfaction, clinical practice change and observed patient outcome. Clinician participation data and self-reported patients with CRPC seen per week were used in extrapolations of patients impacted by the CME education per week. Results: Between the 2015 and 2016 CME programs, learners gained confidence in their ability to employ a personalized, sequential approach to treat CRPC (12% vs 35%). Overall, 68% of all learners reported a positive clinical practice impact and 59% reported a positive impact on patient experience and/or outcomes as a result of CME participation. Learner commitment to change was consistently observed in both 2015 and 2016 programs in: medical and practice knowledge (90% and 94%, respectively), care attitudes (83% and 85%), practice behavior (79% and 77%), and their patients’ clinical outcomes (76% and 78%). An estimated 4,066 patients in 2015 and 3,374 patients in 2016 were impacted as a result of the education. Conclusions: Outcomes results of 2 years of education on evolving treatment paradigms of metastatic CRPC demonstrate learner improvements in both clinical practice and patient outcomes. Continuing education in the management of CRPC is recommended, particularly on strategies to appropriately sequence treatments, treatment of bone metastases, keeping abreast of new data, and understanding the rationale for investigational agents. *As of Jan 2017, data collection is ongoing

Why Targeting of PSMA Is a Valuable Addition to the Management of Castration-Resistant Prostate Cancer: The Urologist’s Point of View

Why Targeting of PSMA Is a Valuable Addition to the Management of Castration-Resistant Prostate Cancer: The Urologist’s Point of View

MP99-07 AP4 PROMOTES PROLIFERATION AND METASTASIS OF CASTRATION-RESISTANT PROSTATE CANCER THROUGH BINDING AND UP-REGULATION OF L-PLASTIN

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology IV1 Apr 2017MP99-07 AP4 PROMOTES PROLIFERATION AND METASTASIS OF CASTRATION-RESISTANT PROSTATE CANCER THROUGH BINDING AND UP-REGULATION OF L-PLASTIN Changhao Chen, TIanxin Lin, Thomas B Lam, Yue Zhao, and Jian Huang Changhao ChenChanghao Chen More articles by this author , TIanxin LinTIanxin Lin More articles by this author , Thomas B LamThomas B Lam More articles by this author , Yue ZhaoYue Zhao More articles by this author , and Jian HuangJian Huang More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.3093AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The transition from androgen-dependent to castration-resistant prostate cancer (CRPC) is a lethal event of uncertain molecular etiology. The aim of this study was to identify the mechanism that AP4 promotes the proliferation and metastasis of CRPC by upreguating of L-plastin. METHODS A total of 136 paired PCa and adjacent normal tissues were collected from patients who underwent prostatectomy between 2005 and 2015. The univariate and multivariate Cox regression analyses showed that AP4 expression was independent prognostic factor in patients with prostate cancer (PCa). The EMSA, supershift assays and CHIP-qPCR experiments noted that AP4 directly binds to L-plastin promoter. The in vitro and in vivo experiments were performed. RESULTS Previously, we reported that L-plastin is involved in the metastasis of PCa and up-regulated by androgen. Recently, we found that L-plastin is activated even after androgen deprivation, suggesting that androgen-independent factors might regulate its expression. Here, we noted that an androgen-independent factor, which locates in the area close to the transcription initiation site (-216 to +118) of L-plastin promoter, might facilitate the up-regulation of L-plastin. AP4 was then identified as a key transcription activator, which directly binds to L-plastin promoter. The microarray analysis noted that L-plastin is the differentially expressed downstream target gene of AP4. Furthermore, we demonstrated that AP4 upregulated L-plastin expression, which promotes the proliferation and metastatic of CRPC in vitro and in vivo. Importantly, AP4 level was increased in CRPC tissues compared with ASPC. Overexpression of AP4 was significantly correlated with poor survival, Gleason score over 7 and lymph node metastasis in a large cohort of PCa tissues (n=136). CONCLUSIONS Our study characterizes a new mechanism in CRPC, in which AP4 increases the progression of CRPC through binding L-plastin promoter. Strategies designed to target AP4 may provide novel therapeutic agents for the management of CRPC. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1322-e1323 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Changhao Chen More articles by this author TIanxin Lin More articles by this author Thomas B Lam More articles by this author Yue Zhao More articles by this author Jian Huang More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

The specific killing effect of matrine on castration-resistant prostate cancer cells by targeting the Akt/FoxO3a signaling pathway.

Matrine, a Sophora alkaloid, exhibits antiproliferative and anti-carcinogenic activities through several mechanisms. In a previous study, we found that matrine could effectively inhibit the proliferation of castration-resistant prostate cancer (CRPC). In the present study, the effect of matrine and LY294002 on the expression of the Akt/FoxO3a signaling pathway was examined by western blot analyses and RT-PCR. We discovered that matrine significantly inhibited the proliferation of both prostate cancer cell line PC-3 and prostate epithelial cell line RWPE1, induced apoptosis and induced cell cycle arrest. In addition, LY294002 was found to enhance the effect of matrine. Furthermore, the effects of matrine on the inhibition of proliferation and the induction of cell cycle arrest and cell apoptosis were more effective on PC-3 than on RWPE1 cells. Compared to RWPE1 cells, matrine exerted a more powerful influence on PC-3 cells in increasing the expression of the relevant protein. Our data suggested that FoxO3a-Bim and FoxO3a-P27 may mediate matrine-inhibited proliferation of CRPC cells by activating cell apoptosis and inducing cell cycle arrest. Matrine exhibited high selectivity in killing CRPC cells. Our findings demonstrated that matrine could be used in a potential therapeutic role in the management of CRPC in humans.

BIRC6 Targeting as Potential Therapy for Advanced, Enzalutamide-Resistant Prostate Cancer.

Purpose: Enzalutamide resistance has emerged as a major problem in the management of castration-resistant prostate cancer (CRPC). Research on therapy resistance of CRPCs has primarily focused on the androgen receptor pathway. In contrast, there is limited information on antiapoptotic mechanisms that may facilitate the treatment resistance. The inhibitor of apoptosis proteins (IAP) family is well recognized for its role in promoting treatment resistance of cancers by inhibiting drug-induced apoptosis. Here, we examined whether BIRC6, an IAP family member, has a role in enzalutamide resistance of CRPCs and could provide a therapeutic target for enzalutamide-resistant CRPC.Experimental Design: Use of enzalutamide-resistant CRPC models: (i) the transplantable, first high-fidelity LTL-313BR patient-derived enzalutamide-resistant CRPC tissue xenograft line showing primary enzalutamide resistance, (ii) MR42D and MR49F CRPC cells/xenografts showing acquired enzalutamide resistance. Specific BIRC6 downregulation in these models was produced using a BIRC6-targeting antisense oligonucleotide (ASO-6w2). Gene expression was determined by qRT-PCR and gene expression profiling. Molecular pathways associated with growth inhibition were assessed via gene enrichment analysis.Results: Of eight IAPs examined, BIRC6 was the only one showing elevated expression in both enzalutamide-resistant CRPC models. Treatment with ASO-6w2 markedly suppressed growth of LTL-313BR xenografts and increased tumor apoptosis without inducing major host toxicity. Pathway enrichment analysis indicated that GPCR and matrisome signaling were the most significantly altered pathways. Furthermore, ASO-6w2 inhibited expression of prosurvival genes that were upregulated in the LTL-313BR line.Conclusions:BIRC6 targeting inhibited the growth of enzalutamide-resistant CRPC models and may represent a new option for clinical treatment of advanced, enzalutamide-resistant prostate cancer. Clin Cancer Res; 23(6); 1542-51. ©2016 AACR.

Mechanisms of Therapeutic Resistance in Prostate Cancer.

Prostate cancer is the second leading cause of cancer deaths in the USA. The challenge in managing castration-resistant prostate cancer (CRPC) stems not from the lack of therapeutic options but from the limited duration of clinical and survival benefit offered by treatments in this setting due to primary and acquired resistance. The remarkable molecular heterogeneity and tumor adaptability in advanced prostate cancer necessitate optimization of such treatment strategies. While the future of CRPC management will involve newer targeted therapies in deliberately biomarker-selected patients, interventions using current approaches may exhibit improved clinical benefit if employed in the context of optimal sequencing and combinations. This review outlines our current understanding of mechanisms of therapeutic resistance in progression to and after the development of castration resistance, highlighting targetable and reversible mechanisms of resistance.

P090 - Prognostic factors for castration-resistant prostate cancer in men treated with abiraterone acetate

P090 - Prognostic factors for castration-resistant prostate cancer in men treated with abiraterone acetate

Immune Therapy for Prostate Cancer.

Immunotherapy for castration-resistant prostate cancer has continued to be an area of active research over the last several years. The enthusiasm of this approach has been based on the assumption of better tolerability and that using the body's own immune system may be more effective than either hormonal or chemotherapy. Sipuleucel-T, a dendritic cell-based vaccine, is the only approved agent in this class for the management of castrate-resistant prostate cancer. Although sipuleucel-T increases overall survival without any significant changes in progression-free survival, other forms of immunotherapy such as PSA-TRICOM, ipilimumab, and chimeric antigen receptor T cell therapy are in advanced stages of clinical development. Immune biomarkers are being developed to assess response to these treatments and also to understand how the immune system responds to these respective therapies. Combinations of immunotherapy with androgen deprivation, radiation therapy, and chemotherapy have also been explored with varying results. This review discusses the mechanisms, key preclinical and clinical data, and perspectives for immunotherapeutic agents in the treatment scheme for castrate-resistant prostate cancer.