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 4

BAT downregulates MYC in responding patients.

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BAT downregulates MYC in responding patients. (A) AR nuclear-to-cytoplas...
(A) AR nuclear-to-cytoplasmic ratio (AR N:C) in paired tumor biopsies (n = 24). (B) Percent change in AR N:C among nonresponders (NR) and responders (R) with median indicated by line. (C) MYC H-score in paired tumor biopsies (n = 24). (D) Percent change in MYC H-score among NR and R with median indicated by line. (E) Example of IHC for MYC in paired biopsy samples from a responding patient. Scale bar: 200 μm. (F) Correlation of MYC RNA change from C1D1 to C4D1 with MYC protein change from C1D1 to C4D1 (n = 15). (G) Ki-67 H-score in paired tumor biopsies (n = 24). (H) Percent change in Ki-67 H-score among NR and R with median indicated by line. (I) Example of IHC for Ki-67 in paired biopsy samples from a responding patient. (J) Correlation of percent change in tumor volume from C1D1 to C4D1 with MYC protein change from C1D1 to C4D1 (n = 23; 1 patient excluded for lack of measurable disease). (K) Correlation of percent change in Ki-67 H-score with percent change in MYC H-score (n = 24). (L) Percent change in MYC H-score stratified by ARAMW score (n = 15) with median indicated by line. (M) Correlation of change in expression of genes within the 8q24 TAD with change in MYC expression (n = 15). (A, C, G) P value determined by paired 2-tailed t test. (B, D, H) P value determined by unpaired 2-tailed t test. (F, J, K, and M) r and P values determined by Pearson’s correlation calculation.