Elahe A Mostaghel 1,2 , Ailin Zhang 2 , Susana Hernandez 2 , Brett T Marck 3 , Xiaotun Zhang 4 , Daniel Tamae 5 , Heather E Biehl 2 , Maria Tretiakova 6 , Jon Bartlett 2 , John Burns 2 , Ruth Dumpit 2 , Lisa Ang 2 , Alvin M Matsumoto 3 , Trevor M Penning 5 , Steven P Balk 7 , Colm Morrissey 4 , Eva Corey 4 , Lawrence D True 6 , Peter S Nelson 2 Show Affiliations »
Abstract
PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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). CONCLUSIONS: 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. ©2018 American Association for Cancer Research.
PURPOSE: Tumor androgens in castrat ion-resistant prostate cancer (CRPC) reflect de novo intratumoral synthesis or adrenal androgens . We used C.B.-17 SCID mice in which we observed adrenal CYP17 A activity to isolate the impact of adrenal steroids on CRPC tumors in vivo. EXPERIMEN TAL DESIGN: We evaluated tumor gr owth and androgens in LuCaP35CR and LuCaP96CR xenogr afts in response to adrenalectomy (ADX). We assessed pr otein expr ession of key steroid ogenic enzymes in 185 CRPC metastases from 42 patients . RESULTS: Adrenal glands of intact and castrat ed mice expr essed CYP17 A. Serum DHEA , androstenedione (AED ), and testosterone (T) in castrat ed mice became undetectable after ADX (all P < 0.05). ADX pr olonged median survival (days) in both CRPC models (33 vs. 179; 25 vs. 301) and suppr essed tumor steroids versus castrat ion 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 var iants, and glucocorticoid receptor (GR ). Metastases from 19 of 35 patients with AR positive tumors concurrently expr essed enzymes for adrenal androgen utilization and nine expr essed enzymes for de novo steroid ogenesis (HSD3B1 , CYP17 A, AKR1C3 , and HSD17B3 ). CONCLUSIONS: Mice ar e appr opr iate for evaluating adrenal impact of steroid ogenesis inhibitors. A subset of ADX-resistant CRPC tumors demonstrat e de novo androgen synthesis. Tumor gr owth and androgens were suppr essed more strongly by surgical ADX than pr ior studies using abiraterone , suggesting reduction in adrenally-derived androgens beyond that achieved by abiraterone may have clinical benefit. Pr oof-of-concept studies with agents capable of achieving true "nonsurgical ADX" ar e war ranted. ©2018 American Association for Cancer Resear ch.
Entities: CellLine
Chemical
Disease
Gene
Species
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Year: 2018
PMID： 30181386 PMCID： PMC6320302 DOI： 10.1158/1078-0432.CCR-18-1431
Source DB: PubMed Journal: Clin Cancer Res ISSN： 1078-0432 Impact factor: 12.531