Androgen receptor activity in prostate cancer dictates efficacy of bipolar androgen therapy through MYC
Laura A. Sena, Rajendra Kumar, David E. Sanin, Elizabeth A. Thompson, D. Marc Rosen, Susan L. Dalrymple, Lizamma Antony, Yuhan Yang, Carolina Gomes-Alexandre, Jessica L. Hicks, Tracy Jones, Kiara A. Bowers, Jillian N. Eskra, Jennifer Meyers, Anuj Gupta, Alyza Skaist, Srinivasan Yegnasubramanian, Jun Luo, W. Nathaniel Brennen, Sushant K. Kachhap, Emmanuel S. Antonarakis, Angelo M. De Marzo, John T. Isaacs, Mark C. Markowski, Samuel R. Denmeade
Laura A. Sena, Rajendra Kumar, David E. Sanin, Elizabeth A. Thompson, D. Marc Rosen, Susan L. Dalrymple, Lizamma Antony, Yuhan Yang, Carolina Gomes-Alexandre, Jessica L. Hicks, Tracy Jones, Kiara A. Bowers, Jillian N. Eskra, Jennifer Meyers, Anuj Gupta, Alyza Skaist, Srinivasan Yegnasubramanian, Jun Luo, W. Nathaniel Brennen, Sushant K. Kachhap, Emmanuel S. Antonarakis, Angelo M. De Marzo, John T. Isaacs, Mark C. Markowski, Samuel R. Denmeade
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Research Article Oncology

Androgen receptor activity in prostate cancer dictates efficacy of bipolar androgen therapy through MYC

Abstract

Testosterone is the canonical growth factor of prostate cancer but can paradoxically suppress its growth when present at supraphysiological levels. We have previously demonstrated that the cyclical administration of supraphysiological androgen (SPA), termed bipolar androgen therapy (BAT), can result in tumor regression and clinical benefit for patients with castration-resistant prostate cancer. However, predictors and mechanisms of response and resistance have been ill defined. Here, we show that growth inhibition of prostate cancer models by SPA required high androgen receptor (AR) activity and were driven in part by downregulation of MYC. Using matched sequential patient biopsies, we show that high pretreatment AR activity predicted downregulation of MYC, improved clinical response, and prolonged progression-free and overall survival for patients on BAT. BAT induced strong downregulation of AR in all patients, which is shown to be a primary mechanism of acquired resistance to SPA. Acquired resistance was overcome by alternating SPA with the AR inhibitor enzalutamide, which induced adaptive upregulation of AR and resensitized prostate cancer to SPA. This work identifies high AR activity as a predictive biomarker of response to BAT and supports a treatment paradigm for prostate cancer involving alternating between AR inhibition and activation.

Authors

Laura A. Sena, Rajendra Kumar, David E. Sanin, Elizabeth A. Thompson, D. Marc Rosen, Susan L. Dalrymple, Lizamma Antony, Yuhan Yang, Carolina Gomes-Alexandre, Jessica L. Hicks, Tracy Jones, Kiara A. Bowers, Jillian N. Eskra, Jennifer Meyers, Anuj Gupta, Alyza Skaist, Srinivasan Yegnasubramanian, Jun Luo, W. Nathaniel Brennen, Sushant K. Kachhap, Emmanuel S. Antonarakis, Angelo M. De Marzo, John T. Isaacs, Mark C. Markowski, Samuel R. Denmeade

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Figure 7

Acquired resistance to SPA can be overcome by alternating between AR activation and inhibition.

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Acquired resistance to SPA can be overcome by alternating between AR act...
(A) Experimental design schematic. LNCaP-SPAR are LNCaP with acquired resistance to SPA; VEH, vehicle; ENZA, Enzalutamide (B) Viable cell number of LNCaP and LNCaP-SPAR cells following treatment with VEH, SPA, or ENZA for 5 days (n = 3 independent experiments). Biological replicates indicated in gray with mean of each independent experiment in color. Percent of VEH is indicated for ENZA-treated cells. (C) AR protein expression by Western blot of cells treated as indicated in A. Representative blot of n = 3 independent experiments. (D) MYC protein expression by Western blot of LNCaP and LNCaP-SPAR cells following treatment with VEH or ENZA for 5 days followed by VEH or SPA for 5 days. Representative blot of n = 3 independent experiments. (E) Viable cell number of cells treated as per D (n = 4 independent experiments). P values determined by unpaired 2-tailed t test. Biological replicates indicated in gray with mean of each independent experiment in color. (F) Tumor size of SKCaP-1R PDX following no treatment (Control; n = 4 mice), continuous testosterone (SPA; n = 4 mice), or SPA alternating with enzalutamide every 3 weeks (SPA-ENZA; n = 3 mice). P value determined by unpaired 2-tailed t test comparing final measurements. (G) AR and MYC protein expression by Western blot of SKCaP-1R untreated (control) or treated with SPA. (H) H&E staining and IHC for MYC and Ki-67 of SKCaP-1R following no treatment (Control), continuous SPA for 7 or 160 days, or SPA-ENZA for 160 days. Representative photograph of n = 3 mice per group. (I) RNA in situ hybridization for AR and AR-V7 in tumors of SKCaP-1R untreated (control) or treated with SPA for 30 days. Representative photograph of n = 3 mice per group. For Western blots, vinculin used as a loading control.