Title: Contribution of Adrenal Glands to Intratumor Androgens and Growth of Castration-Resistant Prostate Cancer.
Authors: Mostaghel, Elahe A; Zhang, Ailin; Hernandez, Susana; Marck, Brett T; Zhang, Xiaotun; Tamae, Daniel; Biehl, Heather E; Tretiakova, Maria; Bartlett, Jon; Burns, John; Dumpit, Ruth; Ang, Lisa; Matsumoto, Alvin M; Penning, Trevor M; Balk, Steven P; Morrissey, Colm; Corey, Eva; True, Lawrence D; Nelson, Peter S
Published In Clin Cancer Res, (2019 01 01)
Abstract: Tumor androgens in castration-resistant prostate cancer (CRPC) reflect de novo intratumoral 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.We evaluated tumor growth and androgens in LuCaP35CR and LuCaP96CR xenografts in response to adrenalectomy (ADX). 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, androstenedione (AED), and testosterone (T) in castrated mice became undetectable after ADX (all P < 0.05). ADX prolonged median survival (days) in both CRPC models (33 vs. 179; 25 vs. 301) and suppressed tumor steroids versus castration alone (T 0.64 pg/mg vs. 0.03 pg/mg; DHT 2.3 pg/mg vs. 0.23 pg/mg; and T 0.81 pg/mg vs. 0.03 pg/mg, DHT 1.3 pg/mg vs. 0.04 pg/mg; all P ≤ 0.001). A subset of tumors recurred with increased steroid levels, and/or induction of androgen receptor (AR), truncated AR variants, and glucocorticoid receptor (GR). Metastases from 19 of 35 patients with AR positive tumors concurrently expressed enzymes for adrenal androgen utilization and nine expressed enzymes for de novo steroidogenesis (HSD3B1, CYP17A, AKR1C3, and HSD17B3).Mice are appropriate for evaluating adrenal impact of steroidogenesis inhibitors. A subset of ADX-resistant CRPC tumors demonstrate de novo androgen synthesis. Tumor growth and androgens were suppressed more strongly by surgical ADX 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 "nonsurgical ADX" are warranted.
PubMed ID: 30181386
MeSH Terms: 17-Hydroxysteroid Dehydrogenases/genetics; Adrenal Glands/pathology; Adrenal Glands/surgery; Adrenalectomy; Aldo-Keto Reductase Family 1 Member C3/genetics; Androgens/biosynthesis; Androgens/genetics*; Animals; Cell Line, Tumor; Cell Proliferation/genetics*; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Male; Mice; Multienzyme Complexes/genetics; Neoplasm Recurrence, Local; Progesterone Reductase/genetics; Prostatic Neoplasms, Castration-Resistant/genetics*; Prostatic Neoplasms, Castration-Resistant/pathology; Prostatic Neoplasms, Castration-Resistant/surgery; Receptors, Androgen/genetics*; Steroid 17-alpha-Hydroxylase/genetics; Steroid Isomerases/genetics; Testosterone/genetics; Testosterone/metabolism