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.
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).
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.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2018 Sep 04 [Epub ahead of print]
Elahe A Mostaghel, Ailin Zhang, Susana Hernandez, Brett Marck, Xiaotun Zhang, Daniel Tamae, Heather Biehl, Maria S Tretiakova, Jon Bartlett, John F Burns, Ruth F Dumpit, Lisa S Ang, Alvin M Matsumoto, Trevor M Penning, Steven P Balk, Colm Morrisey, Eva Corey, Lawrence True, Peter S Nelson
Geriatric Research, Education and Clinical Center, VA Puget Sound Health Care System ., Clinical Research, Fred Hutchinson Cancer Research Center., Fred Hutchinson Cancer Research Center., GRECC, V.A. Puget sound., Anatomic and Clinic Pathology, Mayo Clinic., Chemistry & Biochemistry, California State University Northridge., Pathology, University of Washington., Research, Fred Hutchinson Cancer Research Center., Human Biology, Fred Hutchinson Cancer Research Center., Clinical Research Division, Fred Hutchinson Cancer Research Center., Geriatric Research, Education and Clinical Center, VA Puget Sound Health Care System., Perelman School of Medicine, University of Pennsylvania., Beth Israel Deaconess Medical Center., University of Washington., Department of Urology, University of Washington., Department of Pathology, University of Washington., Division of Clinical Research, Fred Hutchinson Cancer Research Center.