Abstract 6177: Deciphering the molecular determinants of testosterone paradox in prostate cancer

Abstract Androgen deprivation therapy (ADT) is the mainstay of PC treatment for lethal, recurrent and metastatic prostate cancer (PCa). Although the initial response rate to ADT is high, the therapy invariably fails as cancer cells become resistant to therapy and progress into a castration-resistant stage called castration-resistant prostate cancer (CRPC). Based on a long-standing paradoxical observation that the growth of PCa could be inhibited by supraphysiologic testosterone (SupraT) treatment, we devised a therapy called the bipolar androgen therapy (BAT) to treat the CRPC. BAT involves a rapid cycling of testosterone between two polar extremes from supraphysiological to near castrate levels with each cycle lasting 28 days. Following the significant clinical efficacy of BAT in a subset of men with metastatic CRPC, we elucidated that SupraT can induce a non-apoptotic cell death called ferroptosis and activate innate immune genes in SupraT-sensitive PCa cells. The current study aims to identify molecular determinants of SupraT-induced cell death and immune activation. This study sheds light on the molecular mechanisms involved in the BAT therapeutic response. Understanding and characterizing the molecular determinants of PC response to BAT is crucial as it will help us stratify patients who would benefit from the therapy and also devise novel combination therapies with BAT including immunotherapeutics, for an enhanced clinical outcome. Citation Format: Abhishek Shetty, Lillian Wilson, Deven Topiwala, Vaishnavi Anand, Zhen Wong, Yuhan Yang, Chandana Kruthiventi, Sai Harshitha Dakoor, Virginia Bencosme, Taylor Blanco, Boan Yang, Sayyada Kazim, Olutosin Owoyemi, Nathaniel Brennen, Eugene Shenderov, Michael Carducci, Samuel Denmeade, Sushant Kachhap. Deciphering the molecular determinants of testosterone paradox in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6177.