Selective androgen receptor modulators activate the canonical prostate cancer androgen receptor program and repress cancer growth
Michael D. Nyquist, Lisa S. Ang, Alexandra Corella, Ilsa M. Coleman, Michael P. Meers, Anthony J. Christiani, Cordell Pierce, Derek H. Janssens, Hannah E. Meade, Arnab Bose, Lauren Brady, Timothy Howard, Navonil De Sarkar, Sander B. Frank, Ruth F. Dumpit, James T. Dalton, Eva Corey, Stephen R. Plymate, Michael C. Haffner, Elahe A. Mostaghel, Peter S. Nelson
Michael D. Nyquist, Lisa S. Ang, Alexandra Corella, Ilsa M. Coleman, Michael P. Meers, Anthony J. Christiani, Cordell Pierce, Derek H. Janssens, Hannah E. Meade, Arnab Bose, Lauren Brady, Timothy Howard, Navonil De Sarkar, Sander B. Frank, Ruth F. Dumpit, James T. Dalton, Eva Corey, Stephen R. Plymate, Michael C. Haffner, Elahe A. Mostaghel, Peter S. Nelson
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Research Article Oncology

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

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.

Authors

Michael D. Nyquist, Lisa S. Ang, Alexandra Corella, Ilsa M. Coleman, Michael P. Meers, Anthony J. Christiani, Cordell Pierce, Derek H. Janssens, Hannah E. Meade, Arnab Bose, Lauren Brady, Timothy Howard, Navonil De Sarkar, Sander B. Frank, Ruth F. Dumpit, James T. Dalton, Eva Corey, Stephen R. Plymate, Michael C. Haffner, Elahe A. Mostaghel, Peter S. Nelson

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Figure 7

SARMs activate AR signaling and repress PC growth in vitro and in vivo.

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SARMs activate AR signaling and repress PC growth in vitro and in vivo. ...
(A–D) Dose-response curves were generated for the steroidal androgens R1881 and T, the antiandrogen ENZ, the nonsteroidal AR agonists T8039, GTX-024, GTX-027, and SARM-2F for (A) VCaP, (B) 22PC-EP, and (C) APIPC cell lines (n = 4). Data represent the mean ± SD. (D) Dose-response curves for the survivin inhibitor YM155 in LNCaP cells with and without 5 μM SARM-2F (n = 4). Data represent the mean ± SD. (E) Tumor volume plot of LuCaP 35CR PDXs treated 5 times per week with vehicle (n = 10), 100 mg/kg SARM-2F (n = 10) (P = 0.045), or 30 mg/kg T8039 (n = 10) (P = 0.02), or with biweekly 40 mg/kg i.m. injections of T for 28 days (n = 10) (P = 0.047). Data represent the mean ± SEM. (F) Tumor volume plot of LuCaP 96 PDXs treated 3 times per week with the indicated doses of SARMs: 100 mg/kg SARM-2F (n = 8) (P = 0.04), or 30 mg/kg T8039 (n = 5) (P = 0.014), or biweekly with i.m. injections of 40 mg/kg T (n = 7) (P = 0.171) or vehicle (n = 7). Data represent the mean ± SEM. (G) Immunoblots of 35CR PDX lysates for p21, AR, and MYC. Lysates were harvested 48 hours after dosing. (H) IHC images of AR, KLK3, MYC, and Ki67 in 35CR PDX tumors analyzed 48 hours after dosing with vehicle, 40 mg/kg T, 30 mg/kg T8039, or 100 mg/kg SARM-2F. Scale bar: 100 μm. Original magnification, ×20. (I) Relative signal intensity for the AR by IHC (n = 4). (J) Relative signal intensity for PSA by IHC (n = 4). (K) Percentage of MYC-positive nuclei by IHC (n = 3). (L) Ki67-positive staining by IHC (n = 3). (I and J) Data represent the mean ± first and third interquartile range. *P < 0.05, by 1-way ANOVA with Dunnett’s multiple-comparison test.