Faculty Collaboration Database

Selective androgen receptor modulators activate the canonical prostate cancer androgen receptor program and repress cancer growth. J Clin Invest 2021 May 17;131(10)

Date

05/18/2021

Pubmed ID

33998604

Pubmed Central ID

PMC8121509

DOI

10.1172/JCI146777

Scopus ID

2-s2.0-85106609999 (requires institutional sign-in at Scopus site)   22 Citations

Abstract

Prostate cancer (PC) is driven by androgen receptor (AR) activity, a master regulator of prostate development and homeostasis. Frontline therapies for metastatic PC deprive the AR of the activating ligands testosterone (T) and dihydrotestosterone (DHT) by limiting their biosynthesis or blocking AR binding. Notably, AR signaling is dichotomous, inducing growth at lower activity levels, while suppressing growth at higher levels. Recent clinical studies have exploited this effect by administration of supraphysiological concentrations of T, resulting in clinical responses and improvements in quality of life. However, the use of T as a therapeutic agent in oncology is limited by poor drug-like properties as well as rapid and variable metabolism. Here, we investigated the antitumor effects of selective AR modulators (SARMs), which are small-molecule nonsteroidal AR agonists developed to treat muscle wasting and cachexia. Several orally administered SARMs activated the AR program in PC models. AR cistromes regulated by steroidal androgens and SARMs were superimposable. Coregulatory proteins including HOXB13 and GRHL2 comprised AR complexes assembled by both androgens and SARMs. At bioavailable concentrations, SARMs repressed MYC oncoprotein expression and inhibited the growth of castration-sensitive and castration-resistant PC in vitro and in vivo. These results support further clinical investigation of SARMs for treating advanced PC.

Author List

Nyquist MD, Ang LS, Corella A, Coleman IM, Meers MP, Christiani AJ, Pierce C, Janssens DH, Meade HE, Bose A, Brady L, Howard T, De Sarkar N, Frank SB, Dumpit RF, Dalton JT, Corey E, Plymate SR, Haffner MC, Mostaghel EA, Nelson PS

Author

Navonil De Sarkar PhD Assistant Professor in the Pathology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Androgens
Animals
Cell Line, Tumor
Dihydrotestosterone
Humans
Male
Mice
Mice, Inbred NOD
Mice, SCID
Neoplasm Proteins
Prostatic Neoplasms
Receptors, Androgen
Signal Transduction