Abstract 1018: GnRH antagonists have direct inhibitory effects on castration-resistant prostate cancer via intracrine androgen and AR-V7 expression

Abstract

Abstract Hormone therapy is currently the mainstay in the management of locally advanced and metastatic prostate cancer (PCa). Degarelix (Firmagon, Deg), a GnRH receptor antagonist demonstrated some advantages over the LHRH agonist Leuprolide (Leup) by avoiding “testosterone flare” and lower FSH levels. We compared the effect of Deg and Leup on prostate cancer (PC) cell progression in vitro and in vivo. GnRHR2 was readily detectable in PC cells. AR transcriptional activity reported by PSA-Luc assay was modulated by both Leup and Deg. In LNCaP and C4-2B MDVR cells, 20µM Deg significantly reduced the cell viability (p<0.01). GnRH-antagonist (alone or in combination with AA or Enza) counteracted the transactivation activity of AR by reducing AR-FL and AR variants at the protein level. In C4-2BMDVR cells, Deg reduced AR-V7 protein expression by 26 to 40% alone or combined with AA and Enza compared to control. Leup, however, enhanced variant expression. Deg reduced AR-variant levels from 17 to 41% in monotherapy or combinations compared to control. In mice, Leup slightly suppressed tumor growth compared to controls (p>0.05). However, tumors in Deg-treated group were 1.5-fold smaller than Leup-treated group but 1.7-fold bigger than surgical castration-group. Ki67 IHC staining confirmed the difference in tumor proliferation among groups. Measurements of intratumoral steroids by LC-MS from tumors, serum samples or cell pellets confirmed that Deg decreased the levels of testosterone and steroidogenesis pathway intermediates, comparable to surgical castration; while Leup had no inhibitory effect. Our results suggest a selective mechanism of action of Deg against AR-variants. The present study provides additional molecular insights regarding the mechanism of Deg compared to GnRH agonist therapy which may have clinical implications. Citation Format: Vito Cucchiara, Joy C. Yang, Chengfei Liu, Hans Adomat, Emma Guns, Martin E. Gleave, Allen C. Gao, Christopher P. Evans. GnRH antagonists have direct inhibitory effects on castration-resistant prostate cancer via intracrine androgen and AR-V7 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1018.