@article{c4379f1e45dd463dacf6cfb514f54019,
title = "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.",
author = "Sena, {Laura A.} and Rajendra Kumar and Sanin, {David E.} and Thompson, {Elizabeth A.} and Rosen, {D. Marc} and Dalrymple, {Susan L.} and Lizamma Antony and Yuhan Yang and Carolina Gomes-Alexandre and Hicks, {Jessica L.} and Tracy Jones and Bowers, {Kiara A.} and Eskra, {Jillian N.} and Jennifer Meyers and Anuj Gupta and Alyza Skaist and Srinivasan Yegnasubramanian and Jun Luo and Brennen, {W. Nathaniel} and Kachhap, {Sushant K.} and Antonarakis, {Emmanuel S.} and {De Marzo}, {Angelo M.} and Isaacs, {John T.} and Markowski, {Mark C.} and Denmeade, {Samuel R.}",
note = "Funding Information: We thank the patients and caregivers who participated in the clinical trial described. We thank the members of the Sidney Kimmel Comprehensive Cancer Center{\textquoteright}s Experimental and Computational Genomics Core, supported by NIH/NCI grant P30CA006973, for support in carrying out RNA-Seq experiments and analysis of the paired biopsy specimens. We thank the members of the Johns Hopkins University Transcriptomics and Deep Sequencing Core for support in performing ATAC-Seq experiments. This work was funded by the Department of Defense (W81XWH2010079 to LAS, W81XWH2210118 to RK, W81XWH1910724 to SKK, W81XWH1910692 to MCM), the Johns Hopkins Clinician-Scientist Award (to LAS), the Prostate Cancer Foundation (to RK, ESA, and SKK), and the National Institute of Health (1R01CA243184-01A1 to SKK and P50CA058236 to SRD). Funding Information: Authorship note: LAS and RK are co–first authors. MCM and SRD are co–senior authors. Conflict of interest: ESA is a paid consultant/advisor to Janssen, Astellas, Sanofi, Dendreon, Pfizer, Amgen, Lilly, Bayer, AstraZeneca, Bristol-Myers Squibb, Clovis, and Merck; he has received research funding to his institution from Janssen, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novartis, Tokai, Bristol Myers-Squibb, Astra-Zeneca, Clovis, and Merck; and he is the coinventor of an AR-V7 biomarker technology that has been licensed to Qiagen. SRD has received research funding to his institution from Astellas. AMD is a paid consultant/advisor to Merck and Cepheid and has received research funding from Janssen and Myriad for unrelated work. SY receives research funding to his institution from Bristol-Myers Squibb and Celgene, Janssen, and Cepheid for unrelated work and has served as a consultant for Cepheid. He owns founder{\textquoteright}s equity in Brahm Astra Therapeutics and Digital Harmonic. MCM is a paid consultant to Clovis and Exelixis. Copyright: {\textcopyright} 2022, Sena et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. Submitted: June 7, 2022; Accepted: September 29, 2022; Published: December 1, 2022. Reference information: J Clin Invest. 2022;132(23):e162396. https://doi.org/10.1172/JCI162396. Publisher Copyright: Copyright: {\textcopyright} 2022, Sena et al.",
year = "2022",
month = dec,
day = "1",
doi = "10.1172/JCI162396",
language = "English (US)",
volume = "132",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "23",
}