Abstract 3746: Targeting adrenal androgen to treat prostate cancer

Abstract

Abstract Background: Adrenal androgens are the most abundant androgens in humans, with dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S) being the major adrenal androgens in circulation. Significantly, adrenal androgens may serve as substrates for intratumoral (intracrine) production of testosterone (T) and/or dihydrotestosterone (DHT), the ligands for androgen receptor (AR). However, adrenal androgens also have functions that are independent of AR. The present study addressed the capability of prostate cancer tissue to use adrenal androgens for T/DHT production, delineated signaling pathways activated by adrenal androgens, and determined whether adrenal androgens sustained tumor growth after androgen-deprivation therapy (ADT). Experimental Procedures: Metabolism of adrenal androgen was evaluated ex vivo using fresh clinical prostate tissue specimens. The production of DHT or DHEA was determined using ELISA. Human prostate cancer cells lines were used for in vitro experiments. The effects of adrenal androgens on tumor growth were evaluated in vivo using xenografts of the human prostate cancer cell line VCaP in castrated or intact mice. Results: 1) Human prostate tissue was able to produce DHT using DHEA-S at a physiologic concentration (3.5 μM). The production of DHT from DHEA-S was absolutely dependent on the activity of steroid sulfatase (STS). DHEA at a physiologic concentration (10 nM) was not a suitable substrate for DHT production, but was used by prostate tissue when available at a supra-physiologic concentration (3.5 μM) to produce DHT. 2) DHEA-S was able to stimulate growth of prostate cancer cells in vitro. The growth stimulatory effect of DHEA-S was mediated by AR-dependent and AR-independent signaling pathways. A subset of the genes modulated specifically by DHEA-S were distinctive from the T-modulated genes. 3) DHEA sustained tumor growth after castration. DHEA-stimulated growth was attributed to activation of the insulin-like growth factor 1 receptor (IGF1R) signaling pathway. Conclusions: Prostate tissue can use adrenal androgens for DHT production. Adrenal androgens may stimulate prostate cancer growth using AR-dependent pathways that are mediated via intratumoral T/DHT production, or using AR-independent signaling pathways such as the IGF1R signaling pathway. Identification of targets and therapeutics to block the adrenal androgen-stimulated pathways may help develop novel strategies to treat prostate cancer. Citation Format: Yue Wu, Jianmin Wang, Li Tang, Elena Pop, John J. Stocking, Kristopher M. Attwood, Gary J. Smith. Targeting adrenal androgen to treat prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3746.