Contribution of Adrenal Glands to Intratumor Androgens and Growth of Castration-Resistant Prostate Cancer

Purpose: Tumor androgens in castration resistant prostate cancer (CRPC) reflect de novo intra-tumoral synthesis or adrenal androgens. We used C.B.-17 SCID mice in which we observed adrenal CYP17A activity to isolate the impact of adrenal steroids on CRPC tumors in vivo Experimental Design: We evaluated tumor growth and androgens in LuCaP35CR and LuCaP96CR xenografts in response to adrenalectomy. We assessed protein expression of key steroidogenic enzymes in 185 CRPC metastases from 42 patients. Results: Adrenal glands of intact and castrated mice expressed CYP17A. Serum DHEA, AED and T in castrated mice became undetectable after adrenalectomy (all p<0.05). Adrenalectomy prolonged median survival (days) in both CRPC models (33 vs 179; 25 vs 301) and suppressed tumor steroids vs castration alone (T 0.64 vs 0.03pg/mg; DHT 2.3 vs 0.23pg/mg; and T 0.81 vs 0.03pg/mg, DHT 1.3 vs 0.04pg/mg; all p <= 0.001). A subset of tumors recurred with increased steroid levels, and/or induction of AR, truncated AR variants, and GR. Metastases from 19 of 35 patients with AR positive tumors concurrently expressed enzymes for adrenal androgen utilization and 9 expressed enzymes for de novo steroidogenesis (HSD3B1, CYP17A, AKR1C3 and HSD17B3). Conclusions:Mice are appropriate for evaluating adrenal impact of steroidogenesis inhibitors. A subset of adrenalectomy-resistant CRPC tumors demonstrate de novo androgen synthesis. Tumor growth and androgens were suppressed more strongly by surgical adrenalectomy than prior studies using abiraterone, suggesting reduction in adrenally-derived androgens beyond that achieved by abiraterone may have clinical benefit. Proof-of-concept studies with agents capable of achieving true "non-surgical ADX" are warranted.