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Abstract The androgen receptor (AR) is central in prostate tissue identity and differentiation, and controls normal growth-suppressive, prostate-specific gene expression. It also drives prostate tumorigenesis when hijacked for oncogenic transcription. The execution of growth-suppressive AR transcriptional programs in prostate cancer (PCa) and the potential for reactivation remain unclear. Here, we use a genome-wide approach to modulate canonical androgen response element (ARE) motifs—the classic DNA binding elements for AR—to delineate distinct AR transcriptional programs. We find that activating these AREs promotes differentiation and growth-suppressive transcription, potentially leading to AR+ PCa cell death, while ARE repression is tolerated by PCa cells but deleterious to normal prostate cells. Gene signatures driven by ARE activity correlate with improved prognosis and luminal phenotypes in PCa patients. Canonical AREs maintain a normal, lineage-specific transcriptional program that can be reengaged in PCa cells, offering therapeutic potential and clinical relevance.

Abstract Metastatic castration-resistant prostate cancer (mCRPC) is a lethal form of prostate cancer. Although long-noncoding RNAs (lncRNAs) have been implicated in mCRPC, past studies have relied on bulk sequencing methods with low depth and lack of single-cell resolution. Hence, we performed a lncRNA-focused analysis of single-cell RNA-sequencing data (n = 14) from mCRPC biopsies followed by integration with bulk multi-omic datasets. This yielded 389 cell-enriched lncRNAs in prostate cancer cells and the tumor microenvironment (TME). These lncRNAs demonstrated enrichment with regulatory elements and exhibited alterations during prostate cancer progression. Prostate-lncRNAs were correlated with AR mutational status and response to treatment with enzalutamide, while TME-lncRNAs were associated with RB1 deletions and poor prognosis. Finally, lncRNAs identified between prostate adenocarcinomas and neuroendocrine tumors exhibited distinct expression and methylation profiles. Our findings demonstrate the ability of single-cell analysis to refine our understanding of lncRNAs in mCRPC and serve as a resource for future mechanistic studies.

Abstract The testicular androgen biosynthesis is well understood, however, how cancer cells gauge dwindling androgen to dexterously initiate its de novo synthesis remained elusive. We uncover dual-phosphorylated form of sterol regulatory element-binding protein 1 (SREBF1), pY673/951-SREBF1 that acts as an androgen sensor, and dissociates from androgen receptor (AR) in androgen deficient environment, followed by nuclear translocation. SREBF1 recruits KAT2A/GCN5 to deposit epigenetic marks, histone H2A Lys130-acetylation (H2A-K130ac) in SREBF1, reigniting de novo lipogenesis & steroidogenesis. Androgen prevents SREBF1 nuclear translocation, promoting T cell exhaustion. Nuclear SREBF1 and H2A-K130ac levels are significantly increased and directly correlated with late-stage prostate cancer, reversal of which sensitizes castration-resistant prostate cancer (CRPC) to androgen synthesis inhibitor, Abiraterone. Further, we identify a distinct CRPC lipid signature resembling lipid profile of prostate cancer in African American (AA) men. Overall, pY-SREBF1/H2A-K130ac signaling explains cancer sex bias and reveal synchronous inhibition of KAT2A and Tyr-kinases as an effective therapeutic strategy.

Immune checkpoint blockade is showing promise in cancer immune therapy, but many solid tumours are resistant. Authors here identify a pathway in T cells that leads to increased activity of C-terminal Src kinase, a negative regulator of T cell activity, thus disabling tumour infiltrating T cells and causing immune therapy resistance.

Abstract Background The aim of this study is to elucidate the difference in absorbed dose (Dabs) patterns in radiopharmaceutical therapies between alpha emitters (225Ac) and beta emitters (177Lu) when targeting cancer-associated fibroblasts (CAF) or tumor cells. Five spherical models with 3 mm diameter were created, representing spherical tumor masses that contain tumor clusters, interspersed with CAFs. The mean distance from a tumor cell to the nearest CAF (Lmean) varied throughout these models from 92 to 1030 µm. Dabs calculations were performed while selecting either CAFs or tumor cells as sources, with Convolution/Superposition with 177Lu and Monte Carlo simulations (GATE) with 225Ac. Analyses were conducted with Dose Volume Histograms and efficacy ratios (ER), which represents the ratio of mean Dabs that is deposited in the target volume. Results 225Ac is the most optimal radionuclide when CAFs are both targeted and irradiating themselves, as ERs increase from 1.5 to 3.7 when Lmean increases from 92 to 1030 µm. With 177Lu, these numbers vary from 1.2 to 2.7. Conversely, when CAFs are sources and tumors are targets with 225Ac, ERs decreased from 0.8 to 0.1 when Lmean increases from 92 to 1030 µm. With 177Lu, these numbers vary from 0.9 to 0.3 Conclusion When targeting CAFs to irradiate tumors, the efficacy of using 225Ac decreases as the average size of the tumor clusters (or Lmean) increases. In such situations, 177Lu will be more effective than 225Ac when targeting CAFs due to the longer beta particle range.

Lineage plasticity is increasingly recognized as an emergent resistance mechanism after treatment with androgen receptor signalling inhibitors. To understand determinants of resistance, the authors analyzed the transcriptomes of patient tumor biopsies before enzalutamide treatment and at progression and identified a gene expression program associated with lineage plasticity risk and poor outcomes.

Prostate cancer is a highly heterogeneous disease, understanding the crosstalk between complex genomic and epigenomic alterations will aid in developing targeted therapeutics. We demonstrate that, even though snail family transcriptional repressor 2 (SNAI2) is frequently amplified in prostate cancer, it is epigenetically silenced in this disease, with dynamic changes in SNAI2 levels showing distinct clinical relevance. Integrative clinical data from 18 prostate cancer cohorts and experimental evidence showed that gene fusion between transmembrane serine protease 2 (TMPRSS2) and ETS transcription factor ERG (ERG) (TMPRSS2–ERG fusion) is involved in the silencing of SNAI2. We created a silencer score to evaluate epigenetic repression of SNAI2, which can be reversed by treatment with DNA methyltransferase inhibitors and histone deacetylase inhibitors. Silencing of SNAI2 facilitated tumor cell proliferation and luminal differentiation. Furthermore, SNAI2 has a major influence on the tumor microenvironment by reactivating tumor stroma and creating an immunosuppressive microenvironment in prostate cancer. Importantly, SNAI2 expression levels in part determine sensitivity to the cancer drugs dasatinib and panobinostat. For the first time, we defined the distinct clinical relevance of SNAI2 expression at different disease stages. We elucidated how epigenetic silencing of SNAI2 controls the dynamic changes of SNAI2 expression that are essential for tumor initiation and progression and discovered that restoring SNAI2 expression by treatment with panobinostat enhances dasatinib sensitivity, indicating a new therapeutic strategy for prostate cancer.

Abstract Prostate cancer is the most frequent cancer in men and a leading cause of cancer death. Determining a patient’s optimal therapy is a challenge, where oncologists must select a therapy with the highest likelihood of success and the lowest likelihood of toxicity. International standards for prognostication rely on non-specific and semi-quantitative tools, commonly leading to over- and under-treatment. Tissue-based molecular biomarkers have attempted to address this, but most have limited validation in prospective randomized trials and expensive processing costs, posing substantial barriers to widespread adoption. There remains a significant need for accurate and scalable tools to support therapy personalization. Here we demonstrate prostate cancer therapy personalization by predicting long-term, clinically relevant outcomes using a multimodal deep learning architecture and train models using clinical data and digital histopathology from prostate biopsies. We train and validate models using five phase III randomized trials conducted across hundreds of clinical centers. Histopathological data was available for 5654 of 7764 randomized patients (71%) with a median follow-up of 11.4 years. Compared to the most common risk-stratification tool—risk groups developed by the National Cancer Center Network (NCCN)—our models have superior discriminatory performance across all endpoints, ranging from 9.2% to 14.6% relative improvement in a held-out validation set. This artificial intelligence-based tool improves prognostication over standard tools and allows oncologists to computationally predict the likeliest outcomes of specific patients to determine optimal treatment. Outfitted with digital scanners and internet access, any clinic could offer such capabilities, enabling global access to therapy personalization.

Prostate-specific membrane antigen (PSMA) is an important cell surface target in prostate cancer. There are limited data on the heterogeneity of PSMA tissue expression in metastatic castration-resistant prostate cancer (mCRPC). Furthermore, the mechanisms regulating PSMA expression (encoded by the FOLH1 gene) are not well understood. Here, we demonstrate that PSMA expression is heterogeneous across different metastatic sites and molecular subtypes of mCRPC. In a rapid autopsy cohort in which multiple metastatic sites per patient were sampled, we found that 13 of 52 (25%) cases had no detectable PSMA and 23 of 52 (44%) cases showed heterogeneous PSMA expression across individual metastases, with 33 (63%) cases harboring at least 1 PSMA-negative site. PSMA-negative tumors displayed distinct transcriptional profiles with expression of druggable targets such as MUC1. Loss of PSMA was associated with epigenetic changes of the FOLH1 locus, including gain of CpG methylation and loss of histone 3 lysine 27 (H3K27) acetylation. Treatment with histone deacetylase (HDAC) inhibitors reversed this epigenetic repression and restored PSMA expression in vitro and in vivo. Collectively, these data provide insights into the expression patterns and regulation of PSMA in mCRPC and suggest that epigenetic therapies — in particular, HDAC inhibitors — can be used to augment PSMA levels.

The changes that prostate cancer (PCa) induces in its microenvironment are not fully understood. Here the authors use single-cell RNA-seq and organoids to characterise how the microenvironment responds to PCa, and also identify tumour-associated epithelial cell states and club cells.

Abstract We are now in an era of molecular medicine, where specific DNA alterations can be used to identify patients who will respond to specific drugs. However, there are only a handful of clinically used predictive biomarkers in oncology. Herein, we describe an approach utilizing in vitro DNA and RNA sequencing and drug response data to create TreAtment Response Generalized Elastic-neT Signatures (TARGETS). We trained TARGETS drug response models using Elastic-Net regression in the publicly available Genomics of Drug Sensitivity in Cancer (GDSC) database. Models were then validated on additional in-vitro data from the Cancer Cell Line Encyclopedia (CCLE), and on clinical samples from The Cancer Genome Atlas (TCGA) and Stand Up to Cancer/Prostate Cancer Foundation West Coast Prostate Cancer Dream Team (WCDT). First, we demonstrated that all TARGETS models successfully predicted treatment response in the separate in-vitro CCLE treatment response dataset. Next, we evaluated all FDA-approved biomarker-based cancer drug indications in TCGA and demonstrated that TARGETS predictions were concordant with established clinical indications. Finally, we performed independent clinical validation in the WCDT and found that the TARGETS AR signaling inhibitors (ARSI) signature successfully predicted clinical treatment response in metastatic castration-resistant prostate cancer with a statistically significant interaction between the TARGETS score and PSA response (p = 0.0252). TARGETS represents a pan-cancer, platform-independent approach to predict response to oncologic therapies and could be used as a tool to better select patients for existing therapies as well as identify new indications for testing in prospective clinical trials.

Human prostate cancer can result from chromosomal rearrangements that lead to aberrant ETS gene expression. The mechanisms that lead to fusion-independent ETS factor upregulation and prostate oncogenesis remain relatively unknown. Here, we show that two neighboring transcription factors, Capicua (CIC) and ETS2 repressor factor (ERF), which are co-deleted in human prostate tumors can drive prostate oncogenesis. Concurrent CIC and ERF loss commonly occur through focal genomic deletions at chromosome 19q13.2. Mechanistically, CIC and ERF co-bind the proximal regulatory element and mutually repress the ETS transcription factor, ETV1. Targeting ETV1 in CIC and ERF-deficient prostate cancer limits tumor growth. Thus, we have uncovered a fusion-independent mode of ETS transcriptional activation defined by concurrent loss of CIC and ERF.

Background: Enzalutamide is an antiandrogen used to treat both metastatic and nonmetastatic prostate cancer. Here we present results from a phase 2 trial designed to determine the safety, tolerability, and efficacy of adding enzalutamide to standard androgen deprivation therapy with radiation therapy in high-risk localized or regional, nonmetastatic patients with prostate cancer. Methods and Materials: Enrollment criteria included at least 2 of the following: stage cT3a/b, prostate specific antigen (PSA) ≥20 ng/mL, Gleason grade 8 to 10, ≥33% core involvement on biopsy, or pelvic lymph node involvement on computed tomography or magnetic resonance imaging. Patients with metastatic disease were excluded. All patients received 24 months of leuprolide and enzalutamide, and 5 weeks of intensity modulated radiation therapy followed by a brachytherapy boost. Adverse events (AE), PSA, testosterone, and basic laboratory tests were then followed for up to 36 months. Primary outcomes were safety and tolerability and PSA complete response rate (PSA-CR, defined as PSA ≤0.3). Secondary outcomes included time to biochemical recurrence (BCR; nadir + 2 ng/mL). Results: Sixteen patients were enrolled; 2 were ineligible and 3 withdrew before starting treatment. Median age at enrollment was 69.0 years (interquartile range [IQR] 11.5). Median treatment duration was 24.0 months (IQR 11.9). Median follow-up time was 35.5 months (IQR 11.2), and 9 of 11 (81.8%) patients completed the 36 months of follow-up. One of 11 (9%) patients had grade 4 AE (seizure), and no grade 5 AE were reported. Four of 11 (36.4%) patients had grade 3 AE, such as erectile dysfunction and hot flashes. All patients achieved PSA-CR, and median time to PSA-CR was 4.2 months (IQR 1.4). At 24 months follow-up, 0 of 11 (0%) patients had a biochemical recurrence. At 36 months, 1 of 9 (11.1%) patient had a biochemical recurrence. Of note, this patient did not complete the full 24 months of enzalutamide and leuprolide due to AEs. Conclusions: Enzalutamide in combination with standard androgen deprivation therapy and radiation therapy was well-tolerated and effective warranting further study in a randomized controlled trial.

It is hypothesized that there are a number of tumor specific driver genes for metastatic prostate cancer. Here, the authors perform genome-wide CRISPRi screens and integrate these data with metastatic prostate cancer functional and clinical genomics data to show that KIF4A and WDR62 drive aggressive prostate cancer phenotypes.

Walter Rayford, Alp Tuna Beksac et al. investigated gene expression alterations in African-American and European-American men who underwent radical prostatectomy for prostate cancer. The observed differences include higher expression of inflammation genes and lower expression of mismatch repair genes in African-American men.

Abstract Background Androgen receptor (AR) is critical to the initiation, growth, and progression of prostate cancer. Once activated, the AR binds to cis-regulatory enhancer elements on DNA that drive gene expression. Yet, there are 10–100× more binding sites than differentially expressed genes. It is unclear how or if these excess binding sites impact gene transcription. Results To characterize the regulatory logic of AR-mediated transcription, we generated a locus-specific map of enhancer activity by functionally testing all common clinical AR binding sites with Self-Transcribing Active Regulatory Regions sequencing (STARRseq). Only 7% of AR binding sites displayed androgen-dependent enhancer activity. Instead, the vast majority of AR binding sites were either inactive or constitutively active enhancers. These annotations strongly correlated with enhancer-associated features of both in vitro cell lines and clinical prostate cancer samples. Evaluating the effect of each enhancer class on transcription, we found that AR-regulated enhancers frequently interact with promoters and form central chromosomal loops that are required for transcription. Somatic mutations of these critical AR-regulated enhancers often impact enhancer activity. Conclusions Using a functional map of AR enhancer activity, we demonstrated that AR-regulated enhancers act as a regulatory hub that increases interactions with other AR binding sites and gene promoters.

Prostate cancer risk-associated SNPs are enriched in noncoding CREs. Here the authors perform CRISPRi screens of CREs in prostate cancer cell lines to describe a causal mechanism synergistically driven by a risk SNP and DNA methylation-mediated 3D genome architecture.

Cryptochrome 1 (CRY1) is a transcriptional coregulator associated with the circadian clock. Here the authors reveal that CRY1 is hormone-regulated, stabilized by genomic insult, and promotes DNA repair and cell survival through temporal transcriptional regulation.

Abstract Whole genome sequencing (WGS) has enabled the discovery of genomic structural variants (SVs), including those targeting intergenic and intronic non-coding regions that eluded previous exome focused strategies. However, the field currently lacks an automated tool that analyzes SV candidates to identify recurrent SVs and their targeted sites (hotspot regions), visualizes these genomic events within the context of various functional elements, and evaluates their potential effect on gene expression. To address this, we developed SV-HotSpot, an automated tool that integrates SV candidates, copy number alterations, gene expression, and genome annotations (e.g. gene and regulatory elements) to discover, annotate, and visualize recurrent SVs and their targeted hotspot regions that may affect gene expression. We applied SV-HotSpot to WGS and matched transcriptome data from metastatic castration resistant prostate cancer patients and rediscovered recurrent SVs targeting coding and non-coding functional elements known to promote prostate cancer progression and metastasis. SV-HotSpot provides a valuable resource to integrate SVs, gene expression, and genome annotations for discovering biologically relevant SVs altering coding and non-coding genome. SV-HotSpot is available at https://github.com/ChrisMaherLab/SV-HotSpot .

Androgen receptor (AR) and its constitutively active variants (AR-Vs) have been extensively implicated in the progression and recurrence of prostate cancer, making them attractive targets in the treatment of this disease. Whether and how neddylation modification regulates AR, and the therapeutic implications of this potential regulation, are relatively unexplored areas of investigation. Here we report that neddylation inactivation by the pharmacological inhibitor MLN4924 or Lenti-shRNA-based genetic knockdown of neddylation activating enzyme (NAE) selectively suppressed growth and survival of prostate cancer cells with minor, if any, effect on normal prostate epithelial cells. MLN4924 also significantly suppressed the invasive capacity of prostate cancer cells. Furthermore, compared to monotherapy, the combination of MLN4924 with AR antagonist or castration significantly enhanced growth suppression of prostate cancer cells in vitro, and tumor growth in an in vivo xenograft model. Mechanistically, MLN4924 repressed the transcription of AR/AR-V7 and its downstream targets, and blocked MMP2 and MMP9 expression. Taken together, our study reveals that the neddylation pathway positively regulates AR/AR-V7 transcription, and that the neddylation inhibitor MLN4924 has therapeutic potential for the treatment of aggressive prostate cancers. Keywords: Neddylation, MLN4924, Androgen receptor, Prostate cancer, Targeted therapy

The androgen receptor (AR) is a master transcription factor that regulates prostate cancer (PC) development and progression. Inhibition of AR signaling by androgen deprivation is the first-line therapy with initial efficacy for advanced and recurrent PC. Paradoxically, supraphysiological levels of testosterone (SPT) also inhibit PC progression. However, as with any therapy, not all patients show a therapeutic benefit, and responses differ widely in magnitude and duration. In this study, we evaluated whether differences in the AR cistrome before treatment can distinguish between SPT-responding (R) and -nonresponding (NR) tumors. We provide the first preclinical evidence to our knowledge that SPT-R tumors exhibit a distinct AR cistrome when compared with SPT-NR tumors, indicating a differential biological role of the AR. We applied an integrated analysis of ChIP-Seq and RNA-Seq to the pretreatment tumors and identified an SPT-R signature that distinguishes R and NR tumors. Because transcriptomes of SPT-treated clinical specimens are not available, we interrogated available castration-resistant PC (CRPC) transcriptomes and showed that the SPT-R signature is associated with improved survival and has the potential to identify patients who would respond to SPT. These findings provide an opportunity to identify the subset of patients with CRPC who would benefit from SPT therapy.

In prostate cancer, investigating aberrant gene expression may shed light on disease etiology. Here, the authors imputed expression transcriptome-wide for 233,955 European ancestry men, discovering and replicating the associations between prostatic expression for select genes and prostate cancer risk, including the highly prevalent gene fusion partner TMPRSS2. The authors furthermore integrate diverse functional genomic datasets to interpret the epigenetic mechanisms by which the implicated risk variants and genes modulate disease risk.

PurposeThe Expanded Prostate Cancer Index Composite (EPIC) is the most commonly used patient reported outcome (PRO) tool in prostate cancer (PC) clinical trials, but health utilities associated with the different health states assessed with this tool are unknown, limiting our ability to perform cost-utility analyses. This study aimed to map EPIC tool to EuroQoL-5D-3L (EQ5D) to generate EQ5D health utilities.Methods and materialsThis is a secondary analysis of a prospective, randomized non-inferiority clinical trial, conducted between 04/2006 and 12/2009 at cancer centers across the United States, Canada, and Switzerland. Eligible patients included men >18 years with a known diagnosis of low-risk PC. Patient HRQoL data were collected using EPIC and health utilities were obtained using EQ5D. Data were divided into an estimation sample (n = 765, 70%) and a validation sample (n = 327, 30%). The mapping algorithms that capture the relationship between the instruments were estimated using ordinary least squares (OLS), Tobit, and two-part models. Five-fold cross-validation (in-sample) was used to compare the predictive performance of the estimated models. Final models were selected based on root mean square error (RMSE).ResultsA total of 565 patients in the estimation sample had complete information on both EPIC and EQ5D questionnaires at baseline. Mean observed EQ5D utility was 0.90±0.13 (range: 0.28-1) with 55% of patients in full health. OLS models outperformed their counterpart Tobit and two-part models for all pre-determined model specifications. The best model fit was: "EQ5D utility = 0.248541 + 0.000748*(Urinary Function) + 0.001134*(Urinary Bother) + 0.000968*(Hormonal Function) + 0.004404*(Hormonal Bother)- 0.376487*(Zubrod) + 0.003562*(Urinary Function*Zubrod)"; RMSE was 0.10462.ConclusionsThis is the first study to identify a comprehensive set of mapping algorithms to generate EQ5D utilities from EPIC domain/ sub-domain scores. The study results will help estimate quality-adjusted life-years in PC economic evaluations.

Neuroendocrine prostate cancer (NEPC) is characterized by loss of androgen receptor (AR) signaling during neuroendocrine transdifferentiation, resulting in resistance to AR-targeted therapy. Here they report ONECUT2 to drive NEPC tumorigenesis via regulation of hypoxia signaling and tumor hypoxia, and find hypoxia directed therapy to be effective in NEPC.

Abstract PARP‐1 holds major functions on chromatin, DNA damage repair and transcriptional regulation, both of which are relevant in the context of cancer. Here, unbiased transcriptional profiling revealed the downstream transcriptional profile of PARP‐1 enzymatic activity. Further investigation of the PARP‐1‐regulated transcriptome and secondary strategies for assessing PARP‐1 activity in patient tissues revealed that PARP‐1 activity was unexpectedly enriched as a function of disease progression and was associated with poor outcome independent of DNA double‐strand breaks, suggesting that enhanced PARP‐1 activity may promote aggressive phenotypes. Mechanistic investigation revealed that active PARP‐1 served to enhance E2F1 transcription factor activity, and specifically promoted E2F1‐mediated induction of DNA repair factors involved in homologous recombination (HR). Conversely, PARP‐1 inhibition reduced HR factor availability and thus acted to induce or enhance “BRCA‐ness”. These observations bring new understanding of PARP‐1 function in cancer and have significant ramifications on predicting PARP‐1 inhibitor function in the clinical setting.

Summary: Meningioma is the most common primary intracranial tumor, but the molecular drivers of aggressive meningioma are incompletely understood. Using 280 human meningioma samples and RNA sequencing, immunohistochemistry, whole-exome sequencing, DNA methylation arrays, and targeted gene expression profiling, we comprehensively define the molecular profile of aggressive meningioma. Transcriptomic analyses identify FOXM1 as a key transcription factor for meningioma proliferation and a marker of poor clinical outcomes. Consistently, we discover genomic and epigenomic factors associated with FOXM1 activation in aggressive meningiomas. Finally, we define a FOXM1/Wnt signaling axis in meningioma that is associated with a mitotic gene expression program, poor clinical outcomes, and proliferation of primary meningioma cells. In summary, we find that multiple molecular mechanisms converge on a FOXM1/Wnt signaling axis in aggressive meningioma. : Using multiplatform molecular profiling, Vasudevan et al. comprehensively define the molecular profile of aggressive meningioma. They identify genomic, epigenomic, and transcriptomic mechanisms that converge on a FOXM1/Wnt signaling axis in aggressive meningioma that is associated with meningioma cell proliferation and is a marker of poor clinical outcomes across molecular subgroups. Keywords: DNA methylation, epigenome, FOXM1, genome, meningioma, NF2, RNA sequencing, transcriptome, whole-exome sequencing, Wnt

Background: We sought to determine temporal trends in the receipt of prostatectomy or locoregional radiation to the prostate for patients with metastatic prostate cancer and to identify predictors of receipt of local treatment. Methods: We identified 39,976 patients with metastatic prostate cancer diagnosed in 2004–2012 using the National Cancer Database (NCDB). We used logistic multivariable regression to determine trends in the receipt of prostate and/or pelvic radiation or radical prostatectomy after adjusting for demographic and clinical factors. Results: Patients with metastatic disease were less likely to receive locoregional treatment over time [7.88% in 2004 vs. 5.53% in 2012, adjusted odds ratio (AOR)=0.97 per year, 95% confidence interval (CI)=0.95–0.98; P

Radiation: Drug target found for radioresistance Drugs that block the androgen receptor (AR) protein can help make radiation-resistant breast tumors susceptible to ionizing therapy. Corey Speers from the University of Michigan, Ann Arbor, USA, and colleagues characterized the radiation sensitivity of 21 breast cancer cell lines and then paired the response data with the findings of a high-throughput drug screen to identify a medication called bicalutamide — an AR inhibitor — as one of the most potent agents for overcoming radiation resistance. The researchers then measured the expression of AR in more than 2100 human breast tumor samples and 51 breast cancer cell lines, and found that patients with triple-negative breast cancer, especially those who relapsed after radiation, had elevated levels of AR. Cell experiments with enzalutamide, a newer generation AR-blocking drug, confirmed that targeting AR helps reverse radiation resistance.

Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect. We also report that BRDs are overexpressed in CRPCs and that ATAD2 and BRD2 have prognostic value. Finally, we developed gene stratification signature (BROMO-10) for bromodomain response and PC prognostication, to inform current and future trials with drugs targeting these processes. Our findings provide a compelling rational for combination therapy targeting bromodomains in selected patients in which BRD-mediated TF binding is enhanced or modified as cancer progresses.

Increased rates of locoregional recurrence (LR) have been observed in triple negative breast cancer (TNBC) despite multimodality therapy, including radiation (RT). Recent data suggest inhibiting the androgen receptor (AR) may be an effective radiosensitizing strategy, and AR is expressed in 15–35% of TNBC tumors. The aim of this study was to determine whether seviteronel (INO-464), a novel CYP17 lyase inhibitor and AR antagonist, is able to radiosensitize AR-positive (AR+) TNBC models. In cell viability assays, seviteronel and enzalutamide exhibited limited effect as a single agent (IC50 > 10 μM). Using clonogenic survival assays, however, AR knockdown and AR inhibition with seviteronel were effective at radiosensitizing cells with radiation enhancement ratios of 1.20–1.89 in models of TNBC with high AR expression. AR-negative (AR−) models, regardless of their estrogen receptor expression, were not radiosensitized with seviteronel treatment at concentrations up to 5 μM. Radiosensitization of AR+ TNBC models was at least partially dependent on impaired dsDNA break repair with significant delays in repair at 6, 16, and 24 h as measured by immunofluorescent staining of γH2AX foci. Similar effects were observed in an in vivo AR+ TNBC xenograft model where there was a significant reduction in tumor volume and a delay to tumor doubling and tripling times in mice treated with seviteronel and radiation. Following combination treatment with seviteronel and radiation, increased binding of AR occurred at DNA damage response genes, including genes involved both in homologous recombination and non-homologous end joining. This trend was not observed with combination treatment of enzalutamide and RT, suggesting that seviteronel may have a different mechanism of radiosensitization compared to other AR inhibitors. Enzalutamide and seviteronel treatment also had different effects on AR and AR target genes as measured by immunoblot and qPCR. These results implicate AR as a mediator of radioresistance in AR+ TNBC models and support the use of seviteronel as a radiosensitizing agent in AR+ TNBC.

Management of men with prostate cancer is fraught with uncertainty as physicians and patients balance efficacy with potential toxicity and diminished quality of life. Utilization of genomics as a prognostic biomarker has improved the informed decision-making process by enabling more rationale treatment choices. Recently investigations have begun to determine whether genomic information from tumor transcriptome data can be used to impact clinical decision-making beyond prognosis. Here we discuss the potential of genomics to alter management of a patient who presented with high-risk prostate adenocarcinoma. We suggest that this information help selecting patients for advanced imaging, chemotherapies, or clinical trial.

LncRNAs have been associated with cancer. Here, the authors carry out a systematic review of lncRNAs in breast cancer and show that DSCAM-AS1is highly expressed in oestrogen receptor positive tumours and enhances cancer through an interaction with hnRNPL; and is also associated with tamoxifen resistance.

Rapid advances in the discovery of long noncoding RNAs (lncRNAs) have identified lineage- and cancer-specific biomarkers that may be relevant in the clinical management of prostate cancer (PCa). Here we assembled and analyzed a large RNA-seq dataset, from 585 patient samples, including benign prostate tissue and both localized and metastatic PCa to discover and validate differentially expressed genes associated with disease aggressiveness. We performed Sample Set Enrichment Analysis (SSEA) and identified genes associated with low versus high Gleason score in the RNA-seq database. Comparing Gleason 6 versus 9+ PCa samples, we identified 99 differentially expressed genes with variable association to Gleason grade as well as robust expression in prostate cancer. The top-ranked novel lncRNA PCAT14, exhibits both cancer and lineage specificity. On multivariate analysis, low PCAT14 expression independently predicts for BPFS (P = .00126), PSS (P = .0385), and MFS (P = .000609), with trends for OS as well (P = .056). An RNA in-situ hybridization (ISH) assay for PCAT14 distinguished benign vs malignant cases, as well as high vs low Gleason disease. PCAT14 is transcriptionally regulated by AR, and endogenous PCAT14 overexpression suppresses cell invasion. Thus, Using RNA-sequencing data we identify PCAT14, a novel prostate cancer and lineage-specific lncRNA. PCAT14 is highly expressed in low grade disease and loss of PCAT14 predicts for disease aggressiveness and recurrence.

PURPOSE: Increased murine double minute 2 (MDM2) expression, independent of p53 status, is associated with increased cancer-specific mortality for men with prostate cancer treated with radiotherapy. We assessed MI-219, a small molecule inhibitor of MDM2 with improved pharmacokinetics over nutlin-3, for sensitization of prostate cancer cells to radiotherapy and androgen deprivation therapy, a standard treatment option for men with high-risk prostate cancer. EXPERIMENTAL DESIGN: The effect of MDM2 inhibition by MI-219 was assessed in vitro and in vivo with mouse xenograft models across multiple prostate cancer cell lines containing varying p53 functional status. RESULTS: MDM2 inhibition by MI-219 resulted in dose- and time-dependent p53 activation and decreased clonogenic cell survival after radiation in a p53-dependent manner. Mechanistically, radiosensitization following inhibition of MDM2 was largely the result of p53-dependent increases in apoptosis and DNA damage as evidenced by Annexin V flow cytometry and γ-H2AX foci immunofluorescence. Similarly, treatment with MI-219 enhanced response to antiandrogen therapy via a p53-dependent increase in apoptotic cell death. Lastly, triple therapy with radiation, androgen deprivation therapy, and MI-219 decreased xenograft tumor growth compared with any single- or double-agent treatment. CONCLUSION: MDM2 inhibition with MI-219 results in p53-dependent sensitization of prostate cancer cells to radiation, antiandrogen therapy, and the combination. These findings support MDM2 small molecule inhibitor therapy as a therapy intensification strategy to improve clinical outcomes in high-risk localized prostate cancer. TRANSLATIONAL RELEVANCE: The combination of radiotherapy and androgen deprivation therapy is a standard treatment option for men with high-risk prostate cancer. Despite improvements in outcomes when androgen deprivation therapy is added to radiation, men with high-risk prostate cancer have significant risk for disease recurrence, progression, and even death within the first 10 years following treatment. We demonstrate that treatment with MI-219 (an inhibitor of MDM2) results in prostate cancer cell sensitization to radiation and androgen deprivation therapy in vitro and in vivo. Triple therapy with MI-219, radiation, and androgen deprivation therapy dramatically decreased tumor growth compared with any single- or double-agent therapy. These findings provide evidence that inhibition of MDM2 is a viable means by which to enhance the efficacy of both radiation and androgen deprivation therapy and thereby improve outcomes in the treatment of prostate cancer. As such, further investigation is warranted to translate these findings to the clinical setting.