Selective androgen receptor modulators activate the canonical prostate cancer androgen receptor program and repress cancer growth

被引：35

作者：

Nyquist, Michael D. ^{[1
]}

Ang, Lisa S. ^{[1
]}

Corella, Alexandra ^{[1
]}

Coleman, Ilsa M. ^{[1
]}

Meers, Michael P. ^{[2
]}

Christiani, Anthony J. ^{[3
]}

Pierce, Cordell ^{[1
]}

Janssens, Derek H. ^{[2
]}

Meade, Hannah E. ^{[1
]}

Bose, Arnab ^{[1
]}

Brady, Lauren ^{[1
]}

Howard, Timothy ^{[1
]}

De Sarkar, Navonil ^{[1
]}

Frank, Sander B. ^{[1
]}

Dumpit, Ruth F. ^{[1
]}

Dalton, James T. ^{[4
]}

Corey, Eva ^{[5
]}

Plymate, Stephen R. ^{[3
,6
]}

Haffner, Michael C. ^{[1
,7
]}

Mostaghel, Elahe A. ^{[3
,6
,7
]}

Nelson, Peter S. ^{[1
,5
,6
,7
]}

机构：

[1] Fred Hutchinson Canc Res Ctr, Div Human Biol, Mailstop E2-152,1100 Fairview Ave N, Seattle, WA 98109 USA

[2] Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA

[3] VA Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA

[4] Univ Alabama, Off Acad Affairs, Tuscaloosa, AL USA

[5] Univ Washington, Dept Urol, Seattle, WA 98195 USA

[6] Univ Washington, Dept Med, Seattle, WA USA

[7] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2021年 / 131卷 / 10期

关键词：

INCREASED SURVIVAL; MASS-SPECTROMETRY; PHYSICAL FUNCTION; GENE-EXPRESSION; DOUBLE-BLIND; THERAPY; PHARMACOKINETICS; PROLIFERATION; DEPRIVATION; CELLS;

D O I：

10.1172/JCI146777

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页数：16

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