Abstract 3490: The effect of novel CYP17 inhibitor galeterone on gonadal and tumor progestogen and androgen levels in SCID mice bearing LNCaP prostate cancer xenografts

Prostate cancer growth is driven by androgen-dependent activation of the androgen receptor (AR). Inhibition of CYP17A1, a cytochrome P450 enzyme responsible for the conversion of progestogens to androgens, is a key strategy in the treatment of prostate cancer. CYP17A1 has both 17α-hydroxylase and 17,20-lyase function. The 17α-hydroxylase catalyzes the conversion of progesterone/pregnenolone to 17α-hydroxyprogesterone/17α-hydroxypregnenolone and the 17,20-lyase converts 17α-hydroxyprogesterone/17α-hydroxypregnenolone to androstenedione (AD)/dehydroepiandrosterone (DHEA). Galeterone, a novel AR degrader and antagonist, is also an inhibitor of CYP17A1 and has been shown to inhibit the growth of prostate cancer cells and tumors. However, the effects of galeterone on steroid levels affected by CYP17A1 inhibition have not been examined in vivo. Male SCID mice bearing LNCaP tumors were randomized to receive vehicle (30% beta-cyclodextran in saline) or 0.15mmol/kg galeterone (either po or sc). Mice were treated twice daily, seven days a week. Route of administration did not alter the efficacy of galeterone, which significantly reduced tumor volume (p = 0.044 and p = 0.049, sc, po). Upon completion of the experiment, tumors, testes, and plasma were collected for analysis of steroid levels. Analysis of intratumoral steroids showed an increase in progesterone (1.7- and 2-fold, sc, po) and a decrease in AD (89% and 77% reduction, sc, po). Similar results were observed in levels of pregnenolone which increased (1.4- and 3.0-fold, sc, po) while DHEA decreased (72% and 17% reduction, sc, po). Interestingly, levels of 17α-hydroxyprenenolone were increased in the sc treatment arm, suggesting selectivity of galeterone for the lyase over the hydroxylase catalytic function. Both routes of administration reduced intratumoral testosterone (97% and 77% reduction, sc, po). Intratesticular androgen levels showed similar trends compared to those in tumors. Following galeterone treatment, the levels of androgen precursors were higher in the testes than in the tumor (pregnenolone increased 2.3- and 1.5-fold sc, po; progesterone elevated 6.4- and 12.8-fold sc, po). Plasma androgen levels varied from those observed in the tumor and testes. However, galeterone treatment reduced the levels of AD (98% and 68% reduction, sc, po) and testosterone (99.6% and 99% reduction, sc, po). Together, these results show for the first time that galeterone specifically targets CYP17A1 in vivo as demonstrated by reduction of its enzymatic products DHEA, AD and testosterone. In addition, a selectivity for the lyase function was observed, as evidenced by greater decreases in DHEA and AD than in 17α-hydroxypregenelone. This is consistent with findings that patients treated with galeterone do not require cortisol replacement therapy and do not show symptoms of mineralocorticoid excess. Citation Format: Amanda J. Schech, Gauri J. Sabnis, Stephen Yu, Vincent C.O. Njar, Douglas B. Jacoby, Peter Nelson, Ruth Dumpit, Angela M.H. Brodie. The effect of novel CYP17 inhibitor galeterone on gonadal and tumor progestogen and androgen levels in SCID mice bearing LNCaP prostate cancer xenografts. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3490.