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Representative in vitro model systems that accurately model response to therapy and allow the identification of new targets are important for improving our treatment of prostate cancer. Here we describe molecular characterization and drug testing in a panel of 20 prostate cancer cell lines. The cell lines cluster into distinct subsets based on RNA expression, which is largely driven by functional Androgen Receptor (AR) expression. KLK3, the AR-responsive gene that encodes prostate specific antigen, shows the greatest variability in expression across the cell line panel. Other common prostate cancer associated genes such as TMPRSS2 and ERG show similar expression patterns. Copy number analysis demonstrates that many of the most commonly gained (including regions containing TERC and MYC) and lost regions (including regions containing TP53 and PTEN) that were identified in patient samples by the TCGA are mirrored in the prostate cancer cell lines. Assessment of response to the anti-androgen enzalutamide shows a distinct separation of responders and non-responders, predominantly related to status of wild-type AR. Surprisingly, several AR-null lines responded to enzalutamide. These AR-null, enzalutamide-responsive cells were characterized by high levels of expression of glucocorticoid receptor (GR) encoded by NR3C1. Treatment of these cells with the anti-GR agent mifepristone showed that they were more sensitive to this drug than enzalutamide, as were several of the enzalutamide non-responsive lines. This is consistent with several recent reports that suggest that GR expression is an alternative signaling mechanism that can bypass AR blockade. This study reinforces the utility of large cell line panels for the study of cancer and identifies several cell lines that represent ideal models to study AR-null cells that have upregulated GR to sustain growth.

Despite advances in prostate cancer screening and treatment, available therapy options, particularly in later stages of the disease, remain limited and the treatment-resistant setting represents a serious unmet medical need. Moreover, disease heterogeneity and disparities in patient access to medical advances result in significant variability in outcomes across patients. Disease classification based on genomic sequencing is a promising approach to identify patients whose tumors exhibit actionable targets and make more informed treatment decisions. Here we discuss how we can accelerate precision oncology to inform broader genomically-driven clinical decisions for men with advanced prostate cancer, drug development and ultimately contribute to new treatment paradigms., Competing Interests: Competing Interests Statement. J.M. reports advisory board participation for Amgen, AstraZeneca, Roche, Janssen, MSD and Clovis Oncology; research funding from AstraZeneca and Pfizer Oncology; W.A. reports consulting /advisory for Clovis, Janssen, More Health, ORIC, Daiichi Sankyo; research funding from AstraZeneca, Zenith Epigenetics, Clovis, GlaxoSmithKline, ORIC, Epizyme; travel from GlaxoSmithKline, Clovis, ORIC; and honoraria from CARET. R.R.M. received research funding from Bayer, Pfizer, Tempus; serves on Advisory Board for Bayer, Bristol Myers Squib, Exelixis, Janssen, Novartis, Pfizer, Sanofi, Tempus; is a consultant for Dendreon, Vividion. R.A. reports advisory board participation and research funding from Merck, AstraZeneca, and Janssen; B.M. reports research funding from AstraZeneca, Janssen, Clovis, Astellas, Beigene; M.R. reports consulting: Amgen, Ambryx, Constellation; educational writing and consulting: Plexus; speaking: Bayer, Janssen; funding and clinical research support: Novartis, Astellas, Medivation, Merck; D.B.S. has consulted for/received honoraria from Pfizer, Loxo Oncology, Lilly Oncology, BioBridge, Vivideon Therapeutics, and Illumina; E.V. reports advisory/consulting: Tango Therapeutics, Genome Medical, Invitae, Enara Bio, Janssen, Manifold Bio, Monte Rosa; research support: Novartis, BMS; Equity: Tango Therapeutics, Genome Medical, Syapse, Enara Bio, Manifold Bio, Microsoft, Monte Rosa; travel reimbursement: Roche/Genentech; institutional patents on chromatin mutations and immunotherapy response, and methods for clinical interpretation; D.V. reports honoraria from Clovis Oncology. H.B. reports advisory/consulting from Janssen, Amgen, Astra Zeneca, Pfizer, Astellas, Sanofi Genzyme and research funding from Janssen, Abbvie Stemcentryx, Eli Lilly, Millenium, Astellas. J.V. is employed by the Prostate Cancer Clinical Trials Consortium. H.R.S., J.W.S., and A.K.M. are employed by the Prostate Cancer Foundation.

Purpose The prevalence and features of treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC) are not well characterized in the era of modern androgen receptor (AR)-targeting therapy. We sought to characterize the clinical and genomic features of t-SCNC in a multi-institutional prospective study. Methods Patients with progressive, metastatic castration-resistant prostate cancer (mCRPC) underwent metastatic tumor biopsy and were followed for survival. Metastatic biopsy specimens underwent independent, blinded pathology review along with RNA/DNA sequencing. Results A total of 202 consecutive patients were enrolled. One hundred forty-eight (73%) had prior disease progression on abiraterone and/or enzalutamide. The biopsy evaluable rate was 79%. The overall incidence of t-SCNC detection was 17%. AR amplification and protein expression were present in 67% and 75%, respectively, of t-SCNC biopsy specimens. t-SCNC was detected at similar proportions in bone, node, and visceral organ biopsy specimens. Genomic alterations in the DNA repair pathway were nearly mutually exclusive with t-SCNC differentiation ( P = .035). Detection of t-SCNC was associated with shortened overall survival among patients with prior AR-targeting therapy for mCRPC (hazard ratio, 2.02; 95% CI, 1.07 to 3.82). Unsupervised hierarchical clustering of the transcriptome identified a small-cell-like cluster that further enriched for adverse survival outcomes (hazard ratio, 3.00; 95% CI, 1.25 to 7.19). A t-SCNC transcriptional signature was developed and validated in multiple external data sets with > 90% accuracy. Multiple transcriptional regulators of t-SCNC were identified, including the pancreatic neuroendocrine marker PDX1. Conclusion t-SCNC is present in nearly one fifth of patients with mCRPC and is associated with shortened survival. The near-mutual exclusivity with DNA repair alterations suggests t-SCNC may be a distinct subset of mCRPC. Transcriptional profiling facilitates the identification of t-SCNC and novel therapeutic targets.

Purpose: Metastatic castration-resistant prostate cancer (CRPC) is the lethal form of the disease. Many groups have performed mutational or immunohistochemistry (IHC) testing in metastatic CRPC to identify treatment targets. However, the frequency with which mutational or IHC data have an impact on clinical decision making and the outcomes of molecularly guided therapy in CRPC are largely unknown. We report our institution's experience with mutational and IHC testing in patients with metastatic CRPC and its impact on clinical decision making and patient outcomes., Methods: Between 2012 and 2015, 59 patients with CRPC underwent metastatic tissue biopsies and were genotyped with a 37-cancer gene panel in a Clinical Laboratory Improvement Amendments-certified laboratory. PTEN expression by IHC testing was also measured in 35 of these samples. A retrospective chart review was performed to determine whether the genomic information was acted upon and the outcome of patients whose treatment was guided by molecular testing., Results: Forty-six of 59 patients with CRPC (78.0%) had biopsies with adequate tumor for mutational testing. Thirty-one of 46 subjects (67.4%) had mutations identified by sequencing. Of the 35 patients with CRPC whose biopsies were evaluated for PTEN expression by IHC testing, 13 had PTEN loss. Two patients had treatment on the basis of molecular testing, and one of these subjects had greater tumor control with molecularly guided therapy than his immediate prior therapy., Conclusion: Targeted sequencing and IHC can identify clinically informative molecular abnormalities in CRPC. Despite this, a small minority of patients in our series underwent therapies guided by mutational or IHC testing. Actionability of abnormalities identified in metastatic CRPC may be improved with access to clinical trials, insurance approval for unapproved uses of existing anticancer drugs, and larger gene sequencing panels that include more frequently mutated genes., Competing Interests: AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Molecular Testing in Patients With Castration-Resistant Prostate Cancer and Its Impact on Clinical Decision Making The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or po.ascopubs.org/site/ifc. Derrick L. Tao No relationship to disclose Shawna Bailey Research Funding: Janssen Research & Development (Inst), Medivation (Inst), Millennium (Inst), Aragon Pharmaceuticals (Inst), Bristol-Myers Squibb (Inst), OncoGenex (Inst), Astellas Scientific & Medical Affairs (Inst), Bayer (Inst), Myriad Genetics (Inst), SOTIO (Inst), Sanofi (Inst), Zenith Epigenetics (Inst), Boehringer Ingelheim Pharmaceuticals (Inst), Merck (Inst) Tomasz M. Beer Stock and Other Ownership Interests: Salarius Pharmaceuticals Consulting or Advisory Role: AstraZeneca, Churchill Pharmaceuticals, Dendreon, Janssen Biotech, Janssen Oncology, Janssen Research & Development, Johnson & Johnson, Janssen Japan, Roche Research Funding: Astellas Pharma (Inst), Bristol-Myers Squibb (Inst), Dendreon (Inst), Janssen Research & Development (Inst), Medivation (Inst), OncoGenex (Inst), SOTIO (Inst), SOTIO, Theraclone Sciences (Inst), Boehringer Ingelheim (Inst) Erik Foss Research Funding: Coinvestigator for a research grant from Moximed for magnetic resonance imaging of potential and postoperative patients undergoing KineSpring knee implant surgery (an orthopedic implant designed to alleviate degenerative joint pain). Brooke Beckett No relationship to disclose Alice Fung Speakers’ Bureau: Guerbet Bryan R. Foster Honoraria: CIVCO Medical Solutions Alexander Guimaraes Honoraria: Philips Healthcare 2015 ($1,500); Siemens Medical Solutions 2014 ($2,000) Speakers’ Bureau: Siemens Medical Solutions 2014 Travel, Accommodations, Expenses: Siemens Medical Solutions 2014, Philips Healthcare 2015 Jeremy P. Cetnar No relationship to disclose Julie N. Graff Honoraria: Bayer, Astellas Medivation, Janssen Oncology Consulting or Advisory Role: Exelixis Research Funding: Sanofi (Inst), Medivation (Inst), Bristol-Myers Squibb (Inst), Merck Sharp & Dohme (Inst), Janssen Oncology (Inst) Patents, Royalties, Other Intellectual Property: OncoResponse: Exceptional responders Travel, Accommodations, Expenses: Bayer, Merck Sharp & Dohme, Clovis Oncology Kristine M. Eilers No relationship to disclose Eric J. Small Stock and Other Ownership Interests: Fortis Therapeutics, Harpoon Therapeutics Honoraria: Janssen-Cilag Consulting or Advisory Role: Fortis Therapeutics, Gilead Sciences Research Funding: Janssen (Inst) Christopher L. Corless Honoraria: Roche Consulting or Advisory Role: Roche, Thermo Fisher Scientific Biomarkers Travel, Accommodations, Expenses: Roche, Thermo Fisher Scientific George V. Thomas No relationship to disclose Joshi J. Alumkal Consulting or Advisory Role: Astellas Pharma, Bayer Research Funding: Aragon Pharmaceuticals (Inst), Astellas Pharma (Inst), Millennium (Inst), Novartis (Inst), Zenith Epigenetics (Inst)

Background: Immunotherapy with granulocyte-macrophage colony-stimulating factor (GM-CSF), an agent that previously demonstrated antitumor activity, was evaluated within an intermittent chemotherapy framework of docetaxel with prednisone (D+P) in metastatic castration-resistant prostate cancer (mCRPC)., Patients and Methods: mCRPC patients with ≥ 50% prostate-specific antigen (PSA) decline after 6 cycles of D+P were randomized to either GM-CSF or observation (Obs). At disease progression (PD), D+P was reinitiated for 6 cycles followed by the same "off chemotherapy" regimen in patients eligible for chemotherapy interruption. The sequence was repeated until PD during chemotherapy, lack of PSA response to chemotherapy, or unacceptable toxicity. The primary end point was time to chemotherapy resistance (TTCR)., Results: Of 125 patients enrolled, 52 (42%) experienced ≥ 50% PSA decline on induction D+P and were randomized to GM-CSF (n = 27) or Obs (n = 25). The median time to PD was 3.3 months (95% confidence interval [CI], 2.4-3.5) and 1.5 months (95% CI, 1.5-2.4) during the initial course of GM-CSF and Obs, respectively. Twelve of 26 (46%) patients responded to a second course of D+P. Eleven randomized patients (21%) experienced PD during chemotherapy, precluding accurate assessment of TTCR. The remaining 41 randomized patients discontinued study for lack of PSA response to chemotherapy (n = 8), patient choice to not restart chemotherapy with PSA PD (n = 13), toxicity (n = 7), or study withdrawal (n = 13)., Conclusion: Conducting a prospective study in mCRPC with maintenance immunotherapy within the framework of intermittent chemotherapy was feasible. The use of PSA instead of radiographic end points limited the number of evaluable patients. This study provides important insight into designing contemporary intermittent chemotherapy trials with maintenance immunotherapy in patients with advanced prostate cancer., (Copyright © 2015 Elsevier Inc. All rights reserved.)

DNA methylation occurs commonly in non-small cell lung cancer (NSCLC). We sought to determine the frequency and relationship of methylation of key genes involved in the pathways of mitotic checkpoint control, DNA damage repair, apoptosis, and growth factor signaling in these patients. We analyzed the DNA methylation status of eight genes (CHFR, FANCF, MGMT, p16, DAPK, ASC or TMS-1, RAR-B, and CRBP1) using nested methylation-specific PCR (MSP) on over 314 paraffin-embedded, human non-small cell lung cancer samples. We determined the methylation frequency of each gene in addition to the association of the methylation of each gene with other members of the panel. Methylation was a common event in these samples. Our methylation analysis showed frequencies of methylation of 10% for CHFR, 14% for FANCF, 30% for MGMT, 29% for p16, 17% for DAPK, 33% for ASC, 38% for RAR-B, and 7% for CRBP1. There was a strong correlation between methylation of the mitotic G2-M checkpoint gene, CHFR, and methylation of other genes in our panel involved in DNA damage repair (FANCF and MGMT) and apoptosis (DAPK and ASC) but not with other genes in our panel, including p16 (the G1-S checkpoint gene), CRBP1, or RAR-B. In addition, MGMT methylation strongly correlated with the pro-apoptotic gene, ASC. There are distinct associations of methylated genes in non-small cell lung cancer involving DNA damage repair, apoptosis, and the G2-M mitotic checkpoint control. Further studies are warranted to determine whether these methylation patterns have implications for prognosis in addition to prediction of response to chemotherapeutic agents commonly used in the treatment of non-small cell lung cancer, such as radiotherapy and platinum- or taxane-based chemotherapy.

We aimed to identify a prostate cancer DNA hypermethylation microarray signature (denoted as PHYMA) that differentiates prostate cancer from benign prostate hyperplasia (BPH), high from low-grade and lethal from non-lethal cancers. This is a non-randomized retrospective study in 111 local Asian men (87 prostate cancers and 24 BPH) treated from 1995 to 2009 in our institution. Archival prostate epithelia were laser-capture microdissected and genomic DNA extracted and bisulfite-converted. Samples were profiled using Illumina GoldenGate Methylation microarray, with raw data processed by GenomeStudio. A classification model was generated using support vector machine, consisting of a 55-probe DNA methylation signature of 46 genes. The model was independently validated on an internal testing dataset which yielded cancer detection sensitivity and specificity of 95.3% and 100% respectively, with overall accuracy of 96.4%. Second validation on another independent western cohort yielded 89.8% sensitivity and 66.7% specificity, with overall accuracy of 88.7%. A PHYMA score was developed for each sample based on the state of methylation in the PHYMA signature. Increasing PHYMA score was significantly associated with higher Gleason score and Gleason primary grade. Men with higher PHYMA scores have poorer survival on univariate (p = 0.0038, HR = 3.89) and multivariate analyses when controlled for (i) clinical stage (p = 0.055, HR = 2.57), and (ii) clinical stage and Gleason score (p = 0.043, HR = 2.61). We further performed bisulfite genomic sequencing on 2 relatively unknown genes to demonstrate robustness of the assay results. PHYMA is thus a signature with high sensitivity and specificity for discriminating tumors from BPH, and has a potential role in early detection and in predicting survival.

The androgen receptor (AR) is the principal therapeutic target in prostate cancer. For the past 70 years, androgen deprivation therapy (ADT) has been the major therapeutic focus. However, some patients do not benefit, and those tumors that do initially respond to ADT eventually progress. One recently described mechanism of such an effect is growth and survival-promoting effects of the AR that are exerted independently of the AR ligands, testosterone and dihydrotestosterone. However, specific ligand-independent AR target genes that account for this effect were not well characterized. We show here that c-Myc, which is a key mediator of ligand-independent prostate cancer growth, is a key ligand-independent AR target gene. Using microarray analysis, we found that c-Myc and AR expression levels strongly correlated with each other in tumors from patients with castration-resistant prostate cancer (CRPC) progressing despite ADT. We confirmed that AR directly regulates c-Myc transcription in a ligand-independent manner, that AR and c-Myc suppression reduces ligand-independent prostate cancer cell growth, and that ectopic expression of c-Myc attenuates the anti-growth effects of AR suppression. Importantly, treatment with the bromodomain inhibitor JQ1 suppressed c-Myc function and suppressed ligand-independent prostate cancer cell survival. Our results define a new link between two critical proteins in prostate cancer - AR and c-Myc - and demonstrate the potential of AR and c-Myc-directed therapies to improve prostate cancer control.

Purpose: To evaluate the efficacy, safety, biomarkers, and pharmacokinetics of rilotumumab, a fully human, monoclonal antibody against hepatocyte growth factor (HGF)/scatter factor, combined with mitoxantrone and prednisone (MP) in patients with castration-resistant prostate cancer (CRPC)., Experimental Design: This double-blinded phase II study randomized (1:1:1) patients with progressive, taxane-refractory CRPC to receive MP (12 mg/m(2) i.v. day 1, 5 mg twice a day orally days 1-21, respectively) plus 15 mg/kg rilotumumab, 7.5 mg/kg rilotumumab, or placebo (i.v. day 1) every 3 weeks. The primary endpoint was overall survival (OS)., Results: One hundred and forty-four patients were randomized. Median OS was 12.2 versus 11.1 months [HR, 1.10; 80% confidence interval (CI), 0.82-1.48] in the combined rilotumumab versus control arms. Median progression-free survival was 3.0 versus 2.9 months (HR, 1.02; 80% CI, 0.79-1.31). Treatment appeared well tolerated with peripheral edema (24% vs. 8%) being more common with rilotumumab. A trend toward unfavorable OS was observed in patients with high tumor MET expression regardless of treatment. Soluble MET levels increased in all treatment arms. Total HGF levels increased in the rilotumumab arms. Rilotumumab showed linear pharmacokinetics when co-administered with MP., Conclusions: Rilotumumab plus MP had manageable toxicities and showed no efficacy improvements in this estimation study. High tumor MET expression may identify patients with CRPC with poorer prognosis.

DNA methylation of promoter regions is a common event in prostate cancer, one of the most common cancers in men worldwide. Because prior reports demonstrating that DNA methylation is important in prostate cancer studied a limited number of genes, we systematically quantified the DNA methylation status of 1505 CpG dinucleotides for 807 genes in 78 paraffin-embedded prostate cancer samples and three normal prostate samples. The ERG gene, commonly repressed in prostate cells in the absence of an oncogenic fusion to the TMPRSS2 gene, was one of the most commonly methylated genes, occurring in 74% of prostate cancer specimens. In an independent group of patient samples, we confirmed that ERG DNA methylation was common, occurring in 57% of specimens, and cancer-specific. The ERG promoter is marked by repressive chromatin marks mediated by polycomb proteins in both normal prostate cells and prostate cancer cells, which may explain ERG's predisposition to DNA methylation and the fact that tumors with ERG DNA methylation were more methylated, in general. These results demonstrate that bead arrays offer a high-throughput method to discover novel genes with promoter DNA methylation such as ERG, whose measurement may improve our ability to more accurately detect prostate cancer.

Prostate cancer is the most common cancer in men in the United States, and despite screening and early treatment, more than 27,000 men are predicted to die of the disease this year, almost all of whom will die of castrate-resistant, metastatic cancers that have progressed despite androgen deprivation therapy, also known as hormonal therapy. In recent years, an increased understanding of molecular mechanisms of prostate cancer progression and castration resistance has led to improved treatment strategies. This review focuses on emerging therapies for the treatment of castrate-resistant prostate cancer, with an emphasis on the importance of the drug targets as well as the state of current clinical trials, including those utilizing hormonal therapies, biological agents, and immunotherapy that are underway or have recently been completed.

Background: MDV3100 is an androgen-receptor antagonist that blocks androgens from binding to the androgen receptor and prevents nuclear translocation and co-activator recruitment of the ligand-receptor complex. It also induces tumour cell apoptosis, and has no agonist activity. Because growth of castration-resistant prostate cancer is dependent on continued androgen-receptor signalling, we assessed the antitumour activity and safety of MDV3100 in men with this disease., Methods: This phase 1-2 study was undertaken in five US centres in 140 patients. Patients with progressive, metastatic, castration-resistant prostate cancer were enrolled in dose-escalation cohorts of three to six patients and given an oral daily starting dose of MDV3100 30 mg. The final daily doses studied were 30 mg (n=3), 60 mg (27), 150 mg (28), 240 mg (29), 360 mg (28), 480 mg (22), and 600 mg (3). The primary objective was to identify the safety and tolerability profile of MDV3100 and to establish the maximum tolerated dose. The trial is registered with ClinicalTrials.gov, number NCT00510718., Findings: We noted antitumour effects at all doses, including decreases in serum prostate-specific antigen of 50% or more in 78 (56%) patients, responses in soft tissue in 13 (22%) of 59 patients, stabilised bone disease in 61 (56%) of 109 patients, and conversion from unfavourable to favourable circulating tumour cell counts in 25 (49%) of the 51 patients. PET imaging of 22 patients to assess androgen-receptor blockade showed decreased (18)F-fluoro-5alpha-dihydrotestosterone binding at doses from 60 mg to 480 mg per day (range 20-100%). The median time to progression was 47 weeks (95% CI 34-not reached) for radiological progression. The maximum tolerated dose for sustained treatment (>28 days) was 240 mg. The most common grade 3-4 adverse event was dose-dependent fatigue (16 [11%] patients), which generally resolved after dose reduction., Interpretation: We recorded encouraging antitumour activity with MDV3100 in patients with castration-resistant prostate cancer. The results of this phase 1-2 trial validate in man preclinical studies implicating sustained androgen-receptor signalling as a driver in this disease., Funding: Medivation, the Prostate Cancer Foundation, National Cancer Institute, the Howard Hughes Medical Institute, Doris Duke Charitable Foundation, and Department of Defense Prostate Cancer Clinical Trials Consortium., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Taxanes remain the only agents to extend survival in castration-resistant metastatic prostate cancer, but their impact on the natural history of this disease is modest. We sought to test the hypothesis that increased delivery of taxane chemotherapy to the tumor through the use of a macromolecular polymer-drug conjugate of paclitaxel modulated by estradiol could extend the utility of this class of drugs. Patients with metastatic adenocarcinoma of the prostate who progressed despite standard hormonal therapy and after docetaxel-containing chemotherapy were treated with transdermal estradiol (0.2 mg/24 h) for 4 weeks followed by the same dose of transdermal estradiol and paclitaxel poliglumex (PPX; 150 mg/m intravenous) every 28 days. The primary objective was to determine the level of activity of the regimen measured using a fraction of patients who experienced a confirmed decline in serum prostate-specific antigen (PSA) of 50% or more. A two-stage phase II study designed to identify a response rate of > or =25% required three responders among 21 patients in the first stage. Twenty-one patients who received a median of two earlier chemotherapy regimens were enrolled in the trial between March 2007 and May 2008. During the estradiol-only treatment phase, no patient had a PSA decline in excess of 50% and lesser PSA declines that ranged from 8.8 to 34.1% were seen in five patients. No patients achieved a > or =50% PSA decline following the addition of PPX and there were no responses in measurable disease. The median time to progression was 4 weeks. In conclusion, this regimen of low-dose transdermal estradiol induction followed by PPX does not have activity in taxane pretreated patients with castration-resistant prostate cancer.

Prostate cancer is the most common cancer in men in the United States, and it is the second leading cause of cancer-related death in American men. The Androgen receptor (AR), a nuclear hormone and transcription factor, is the most therapeutically relevant target in this disease. While most efforts in the clinic are still directed at lowering levels of androgens that activate AR, resistance to androgen deprivation eventually develops, and most prostate cancer deaths are attributable to this castration-resistant form of this disease. Recent work has shed light on the importance of epigenetic events including facilitation of AR signaling by histone-modifying enzymes and also on the role that enzymes such as HDAC6 play in stabilizing AR in prostate cancer cells. Herein, we summarize recent findings on the role of epigenetic enzymes in AR signaling and highlight examples on how interdiction of critical epigenetic enzymes may attenuate AR action in prostate cancer.

Anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) therapies represent a novel approach to cancer treatment via disruption of immune tolerance to antigens located on tumor cells. Disruption of immune tolerance, however, may occur at a cost. A host of immune related adverse events (IRAEs) are associated with anti-CTLA-4 therapy. Autoimmune hypophysitis has been reported in up to 17% of patients with melanoma and renal cell carcinoma treated with this therapy. Familiarity with the spectrum of IRAEs connected to these therapies is paramount for endocrinologists, oncologists and those involved in the care of these subjects. We review here key aspects of diagnosis and treatment of anti-CTLA-4 antibody therapy resultant IRAEs. We describe the first two cases of hypopituitarism in prostate cancer subjects undergoing experimental therapy with ipilimumab. The clinical evidence strongly suggests that the prostate cancer subjects developed autoimmune hypophysitis as a consequence of anti-CTLA-4 treatment. High dose glucocorticoid treatment resulted in markedly improved symptoms, and resolution of focal symptoms and diabetes insipidus. One subject recovered pituitary-thyroid axis function after 9 months; however, both continue to require GC replacement. These cases highlight the importance of early screening and treatment for hypopituitarism in all subjects undergoing treatment with anti-CTLA-4 therapy to prevent a potentially fatal outcome from secondary adrenal insufficiency, a readily treatable disease. We recommend mandatory long term follow-up to monitor the development of other hormonal deficits.

High consumption of cruciferous vegetables is associated with a reduced risk of prostate cancer in epidemiological studies. There is preliminary evidence that sulforaphane, derived from glucoraphanin found in a number of crucifers, may prevent and induce regression of prostate cancer and other malignancies in preclinical models, but the mechanisms that may explain these effects are not fully defined. Recent reports show that sulforaphane may impair prostate cancer growth through inhibition of histone deacetylases, which are up-regulated in cancer. Indeed, one of these enzymes, histone deacetylase 6 (HDAC6), influences the acetylation state of a key androgen receptor (AR) chaperone, HSP90. AR is the central signaling pathway in prostate cancer, and its inhibition is used for both prevention and treatment of this disease. However, it is not known whether the effects of sulforaphane involve suppression of AR. We hypothesized that sulforaphane treatment would lead to hyperacetylation of HSP90 and that this would destabilize AR and attenuate AR signaling. We confirmed this by demonstrating that sulforaphane enhances HSP90 acetylation, thereby inhibiting its association with AR. Moreover, AR is subsequently degraded in the proteasome, which leads to reduced AR target gene expression and reduced AR occupancy at its target genes. Finally, sulforaphane inhibits HDAC6 deacetylase activity, and the effects of sulforaphane on AR protein are abrogated by overexpression of HDAC6 and mimicked by HDAC6 siRNA. The inactivation by sulforaphane of HDAC6-mediated HSP90 deacetylation and consequent attenuation of AR signaling represents a newly defined mechanism that may help explain this agent's effects in prostate cancer.