Previously Unrecognized Steroids as Wild-Type AR Ligands in Castration-Resistant Prostate Cancer
Abstract
This proposal responds to the Fiscal Year 2013 Prostate Cancer Research Program overarching challenge of developing effective treatments and addressing mechanisms of resistance for men with metastatic prostate cancer and responds to the focus areas of therapy and tumor biology. The importance of residual androgens in activating the androgen receptor (AR) and driving disease progression in men with castration-resistant prostate cancer (CRPC) is now well understood, as evidenced by the dramatic responses observed in men treated with potent androgen synthesis inhibitors such abiraterone (ABI) or AR blockers such as enzalutamide (ENZ). While these oral agents have been a great step forward in the care of men with advanced prostate cancer, not all men respond, the duration of response is variable, and nearly all men eventually demonstrate rising PSA (prostate specific antigen) (indicative of persistent/resurgent AR activity) with clinical disease progression. Notably, metastatic tumor samples from men treated with these drugs continue to show strong nuclear (central) localization of AR, indicative of ongoing AR activation (AR is located in the cytoplasmic (peripheral) area of the cell and must bind androgen and enter the nucleus to activate DNA/gene expression). Nuclear localization of AR after treatment with ABI or ENZ may be attributed, in part, to the induction of variant AR isoforms that can enter the nucleus and activate DNA without the requirement for binding androgen. However, it is still not clear how prevalent these variant AR isoforms really are in CRPC tumors. We propose, instead, the novel hypothesis that persistent AR activation in CRPC tumors resistant to ABI or ENZ reflects the presence of a previously unrecognized and unmeasured pool of steroids that are capable of binding and driving nuclear localization and activation of wild-type AR. Specifically, an adrenal androgen called 11-hydroxy-androstenedione (11OH-AED) is secreted by the adrenal gland at levels similar to the classic adrenal androgen androstenedione (AED). While 11OH-AED itself cannot activate the AR, recent data have shown that prostate cancer cell lines are able to convert it to downstream metabolites that can activate the AR as potently as the classical tumor androgens, testosterone and DHT (dihydrotestosterone). Moreover, available data demonstrate that even though ABI markedly suppresses serum and tissue levels of adrenal androgens, levels of adrenal precursors are still high enough for adrenal production of 11OH-AED. This hypothesis is especially important because it suggests that only measuring the classical androgens testosterone and DHT significantly underestimates the role and magnitude of residual androgens capable of stimulating the AR in CRPC. It also suggests that by competing for binding to the AR, these previously unrecognized androgenic metabolites of 11OH-AED can overcome the ability of AR antagonists such as ENZ to block the AR, leading to resistance and disease progression. The objective of this proposal is to delineate the presence and activity of the 11OH-AED pathway in localized and advanced prostate cancer, thereby illuminating a previously unrecognized mechanism of resistance to AR-axis inhibition and identifying CYP11B1 (the critical enzyme in producing 11OH-AED from AED) as a key target for novel therapeutic combinations. Importantly, drugs targeting this pathway have already been used to treat other adrenal disorders, and newer, more specific inhibitors have recently been developed, such that successfully achieving the aims of this proposal would provide compelling data for rapid instigation of clinical studies with these agents. Ultimately, combining inhibitors of this pathway with currently used drugs targeting the AR axis could significantly decrease the overall (and underappreciated) androgen activity of the CRPC tumor microenvironment, thereby improving efficacy of all strategies targeting the AR axis. Mo
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510150
Entities
People
- Elahe Mostaghel
Organizations
- Fred Hutchinson Cancer Center
- United States Army