Prostate cancer (PC) initially depends on androgen receptor (AR) signaling for survival and growth. Therapeutics designed to suppress AR activity serve as the primary intervention for advanced disease. However, supraphysiological androgen (SPA) concentrations can produce paradoxical responses leading to PC growth inhibition. We sought to discern the mechanisms by which SPA inhibits PC and to determine if molecular context associates with antitumor activity. SPA produced an AR-mediated, dose-dependent induction of DNA double-strand breaks, G₀/G₁ cell-cycle arrest, and cellular senescence. SPA repressed genes involved in DNA repair and delayed the restoration of damaged DNA, which was augmented by poly (ADP-ribose) polymerase 1 inhibition. SPA-induced double-strand breaks were accentuated in BRCA2-deficient patients with PC, and combining SPA with poly (ADP-ribose) polymerase or DNA-dependent protein kinase inhibition further repressed growth. Next-generation sequencing was performed on biospecimens from patients with PC receiving SPA as part of ongoing phase II clinical trials. Patients with mutations in genes mediating homology-directed DNA repair were more likely to exhibit clinical responses to SPA. These results provide a mechanistic rationale for directing SPA therapy to patients with PC who have AR amplification or DNA repair deficiency and for combining SPA therapy with poly (ADP-ribose) polymerase inhibition.

Solute Carrier (SLC) transporters are a large superfamily of transmembrane carriers involved in the regulated transport of metabolites, nutrients, ions and drugs across cellular membranes. A subset of these solute carriers play a significant role in the cellular uptake of many cancer therapeutics, ranging from chemotherapeutics such as antimetabolites, topoisomerase inhibitors, platinum-based drugs and taxanes to targeted therapies such as tyrosine kinase inhibitors. SLC transporters are co-expressed in groups and patterns across normal tissues, suggesting they may comprise a coordinated regulatory circuit serving to mediate normal tissue functions. In cancer however, there are dramatic changes in expression patterns of SLC transporters. This frequently serves to feed the increased metabolic demands of the tumor cell for amino acids, nucleotides and other metabolites, but also presents a therapeutic opportunity, as increased transporter expression may serve to increase intracellular concentrations of substrate drugs. In this review, we examine the regulation of drug transporters in cancer and how this impacts therapy response, and discuss novel approaches to targeting therapies to specific cancers via tumor-specific aberrations in transporter expression. We propose that among the oncogenic changes in SLC transporter expression there exist emergent vulnerabilities that can be exploited therapeutically, extending the application of precision medicine from tumor-specific drug targets to tumor-specific determinants of drug uptake.

Prostate cancer (PC) is driven by androgen receptor (AR) activity, a master regulator of prostate development and homeostasis. Frontline therapies for metastatic PC deprive the AR of the activating ligands testosterone (T) and dihydrotestosterone (DHT) by limiting their biosynthesis or blocking AR binding. Notably, AR signaling is dichotomous, inducing growth at lower activity levels, while suppressing growth at higher levels. Recent clinical studies have exploited this effect by administration of supraphysiological concentrations of T, resulting in clinical responses and improvements in quality of life. However, the use of T as a therapeutic agent in oncology is limited by poor drug-like properties as well as rapid and variable metabolism. Here, we investigated the antitumor effects of selective AR modulators (SARMs), which are small-molecule nonsteroidal AR agonists developed to treat muscle wasting and cachexia. Several orally administered SARMs activated the AR program in PC models. AR cistromes regulated by steroidal androgens and SARMs were superimposable. Coregulatory proteins including HOXB13 and GRHL2 comprised AR complexes assembled by both androgens and SARMs. At bioavailable concentrations, SARMs repressed MYC oncoprotein expression and inhibited the growth of castration-sensitive and castration-resistant PC in vitro and in vivo. These results support further clinical investigation of SARMs for treating advanced PC.

Clinical trials of high-dose androgen (HDA) therapy for prostate cancer (PC) have shown promising efficacy but are limited by lack of criteria to identify likely responders. To elucidate factors that govern the growth-repressive effects of HDAs, we applied an unbiased integrative approach using genetic screens and transcriptional profiling of PC cells with or without demonstrated phenotypic sensitivity to androgen-mediated growth repression. Through this comprehensive analysis, we identified genetic events and related signaling networks that determine the response to both HDA and androgen withdrawal. We applied these findings to develop a gene signature that may serve as an early indicator of treatment response and identify men with tumors that are amenable to HDA therapy.

202 Background: Recent clinical studies have taken advantage of the dichotomous ability of androgen receptor signaling to elicit growth-suppressive and differentiating effects by giving hyper-physiological levels of testosterone. This approach has demonstrated safety, improved quality of life, and met primary endpoints for efficacy in clinical trials; however, novel strategies to enhance and optimize the anti-tumor efficacy of this approach are needed. Methods: We performed high-throughput drug screening in PCa cell lines to identify agents showing synergy with high-dose androgen treatment. Results: The Survivin inhibitor YM155, demonstrated a potent synergy with high-dose androgen. YM155 IC50 values shifted from 24 nM without R1881 to 3.85 nM with 160 pM R1881.Using qRT-PCT and ChIP-qPCR we establish the mechanism of this synergy was due to the direct upregulation of YM155 transporter SLC35F2 by androgen receptor transcriptional activity. Knockdown and overexpression of SLC35F2 dramatically modulated sensitivity to YM155. In two xenograft models SLC35F2 and tumor DHT levels are highly correlated and castration-induced decreases in tumor androgens cause an identical decline in levels of SLC35F2. In CRPC metastases SLC35F2 expression significantly correlated with AR activity score (r = 0.62, p < 0.001). However, ~1/3 of tumors examined had transcripts for AR and SLC35F2, 1/3 AR+ but SLC35F2 negative, and 1/3 are negative for both. Conclusions: We describe a novel synergy between YM155 and high-dose androgen therapy mediated by the direct upregulation of YM155 transporter SLC35F2 by androgen receptor and implicate SLC35F2 expression as a potential biomarker for YM155 sensitivity. Whether ligand independent AR variants (AR-Vs) can constitutively mediate SLC35F2 expression is unknown, but if so would also provide a means of stratifying identifying men likely to respond to YM155.This study demonstrates a novel paradigm for precision medicine in the pharmacologic induction of drug sensitivity in a tissue restricted manner. Hormonal induction of carrier-mediated drug transport is a completely novel and unexplored concept that is poised to exploit androgen-based treatment strategies.