Castration resistant prostate cancer (CRPC) first manifests as a sustained rise in the androgen-responsive gene, PSA, consistent with reactivation of a functioning androgen receptor (AR) axis. This observation led to the development of “second-line” therapies aimed at further blocking androgen/AR signaling. Unfortunately, resistance to these agents can also develop quickly. Paradoxically, several studies have suggested that the growth of AR-positive human CRPC cell lines may be inhibited by supraphysiologic levels of testosterone (SupT). These studies suggested that the adaptive reliance on AR signaling by CRPC cells becomes a therapeutic liability that can be exploited through the administration of SupT, which we termed as bipolar androgen therapy (BAT). Understanding how BAT works at the molecular and cellular levels might help in rationally combining BAT with other agents to achieve increased efficacy and tumor responses. Our data indicates that SupT induces autophagy mediated degradation of ferritin in prostate cancer (PCa) cells. Degradation of ferritin results in increase in labile iron pool increasing lipid peroxidation. Our data further indicates that SupT distinctly induces ferroptosis, a nonapoptotic regulated form of cell death induced by the accumulation of labile iron. Ferroptosis is thought to have tumor suppressing capabilities by clearing tumor cells via immune system activation. BAT has been discussed as a potential therapy for prostate cancer, but further research is needed to understand its full potential. Future combination of BAT with existing immunotherapeutics including immune checkpoint blockade may prove beneficial for treatment of CRPC.

Citation Format: Rajendra Kumar, Kavya Boyapati, Naiju Thomas, Deven Topiwala, Suthicha Kanacharoen, Olutosin Owoyemi, Max Coffey, Michael Carducci, Mark C. Markowski, Emmanuel S. Antonarakis, Drew Pardoll, Samuel Denmeade, Sushant K. Kachhap. Supraphysiological androgens induce ferroptotic cell death in prostate cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2410.