A Road Map to Comprehensive Androgen Receptor Axis Targeting for Castration-Resistant Prostate Cancer

Abstract

Gonadal androgen suppression (castration via orchiectomy or gonadotropin-releasing hormone analogues) suppresses circulating testosterone levels but does not achieve adequate androgen ablation within the prostate cancer microenvironment because it does not address adrenal and intratumoral steroid contributions. These residual extragonadal sources of androgens allow prostate cancer cells to survive, adapt, and evolve into castration-resistant prostate cancer (CRPC). The persistent significance of the androgen receptor (AR) axis in CRPC was recently validated by the clinical efficacy of androgen synthesis inhibitors (abiraterone) and novel, second-generation AR antagonists (enzalutamide). The appreciation that conventional therapeutic approaches achieve a suboptimal ablation of intratumoral androgens and AR axis signaling output opens transformative therapeutic opportunities. A treatment paradigm of comprehensive AR axis targeting at multiple levels (androgen synthesis, metabolism, and action) and at all relevant sites (gonadal, adrenal, intratumoral) simultaneously at the time of initiation of endocrine therapy (instead of the current approach of sequentially adding one agent at a time and only after disease progression) deserves examination in clinical trials to explore whether maximal first-line AR axis suppression via combination therapy can achieve maximal induction of cancer cell apoptosis (before they have the chance to adapt and evolve into CRPC) and thus, improve patient outcomes. Cancer Res; 73(15); 4599-605. Ó2013 AACR.

The context of prostate cancer genomics in personalized medicine

“…Individual patients have a distinct pattern of genetic alterations; therefore, treatment should be guided by the profile of diagnostic biomarkers (14,22,32). The AR signaling axis is a major target for numerous hormone therapies, throughout the stages of cancer (59)(60)(61). Once castration resistance develops, cancer cells harboring aberrant AR markedly evolve.…”

“…Once castration resistance develops, cancer cells harboring aberrant AR markedly evolve. Potent drugs, including AR antagonists and CYP17 inhibitors, may be used to inhibit the adapted AR and microenvironment due to androgen depletion (59,60). For ETS fusion-positive cancer, agents inhibiting fusion cofactors, such as DNA damage repair genes [poly(ADP-ribose) polymerase (PARP) 1, DNA-protein kinase (PK) and histone deacetylase 1], demonstrated a preferential effect in this subtype during clinical phase studies (61).…”

Mechanisms of Resistance to Intermittent Androgen Deprivation in Patients with Prostate Cancer Identified by a Novel Computational Method

“…Healthy prostatic epithelial cells and most malignant prostatic epithelial cells exhibit some degree of dependence on androgens, including testosterone and dihydrotestosterone (DHT), for proliferation and survival (1)(2)(3)(4)(5). The contribution androgens provide to cell proliferation and survival is mediated by the androgen receptor (AR) axis.…”

“…The contribution androgens provide to cell proliferation and survival is mediated by the androgen receptor (AR) axis. It is well known that AR signaling regulates expression of genes involved in proliferation and survival and is generally accepted to be the primary driver of tumor progression in adenocarcinomas (1,2,(4)(5)(6)(7). AR signaling inhibition, therefore, regresses tumors (2,4,8,9).…”

BETs abet Tam-R in ER-positive breast cancer

“…Using in vivo xenograft models of CRPC, we have demonstrated that JQ1 was significantly more effective than MDV3100 (Enzalutamide), a second-generation AR antagonist used clinically to treat advanced CRPC, in inhibiting tumor growth. Since the most common resistance mechanisms of endocrine therapy in prostate cancer arise due to aberrations of AR [7], the BET inhibitor-mediated abrogation of AR signaling downstream of the recep-npg tor has profound clinical implications in developing a durable treatment for CRPC. Since several BET inhibitors are currently in various stages of clinical development, we anticipate that our findings will spur prospective clinical trials to evaluate the efficacy of BET inhibitors in CRPC.…”