Abstract IA004: Androgen receptor as a tumor suppressor in castration-resistant prostate cancer

Abstract Bipolar androgen therapy (BAT) is the use of testosterone as treatment for castration-resistant prostate cancer (CRPC). We and others have shown that BAT activates the androgen receptor (AR), which can suppress tumor growth in this context. This body of work suggests that AR can function as a tumor suppressor in CRPC. Contextual requirements for AR to behave as a tumor suppressor will be discussed, including high pre-treatment AR activity and limited tumor heterogeneity. A key mechanism by which BAT suppresses CRPC tumor growth is through inhibition of transcription of the proto-oncogene MYC, although MYC-independent mechanisms of BAT-mediated growth suppression also contribute. This downregulation of MYC relieves transcriptional interference with the AR, further amplifying AR activation by BAT. Our recent work suggests AR activation by BAT leads to metabolic reprogramming of CRPC with marked increase in polyamine synthesis and secretion. This occurs through AR binding at enhancer sites upstream of the ODC1 promoter to increase the abundance of ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine synthesis, and de novo synthesis of polyamines from arginine. AR stimulation of polyamine synthesis in prostate cancer is conserved from normal prostate, and in fact occurs even in cells of distinct embryological origin such as T lymphocytes. The increase in polyamine synthesis following BAT seems to facilitate therapeutic resistance, as genetic and pharmacologic blockade of ODC regulation by AR enhances therapeutic efficacy in models of CRPC. These data provided the rationale for an ongoing clinical trial testing the safety and efficacy of BAT in combination with an inhibitor of polyamine synthesis for patients with CRPC. Altogether, we hope these studies of the requirements and consequences of AR functioning as a tumor suppressor in CRPC will lead to new approaches to treatment of this disease. Citation Format: Laura A. Sena. Androgen receptor as a tumor suppressor in castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr IA004.