2026 Sequencing Strategies for Population and Cancer Epidemiology Studies (SeqSPACE) : Submission #8

Abstract Summary Supraphysiologic androgen (SPA) treatment can paradoxically restrict the growth of castration-resistant prostate cancer (CRPC) with high androgen receptor (AR) activity, which is the basis for the use of bipolar androgen therapy (BAT) for patients with this disease. Although androgens are widely appreciated for enhancing anabolic metabolism, how SPA-mediated metabolic changes alter prostate cancer progression and therapy response is unknown. In this study, we report that SPA markedly increased intracellular and secreted polyamines in prostate cancer models. AR binding at enhancer sites upstream of the ornithine decarboxylase 1 (ODC1) promoter increased the abundance of ODC, a rate-limiting enzyme of polyamine synthesis, and de novo synthesis of polyamines from arginine. SPA-stimulated polyamines enhanced prostate cancer fitness, as dCas9-KRAB–mediated inhibition of AR regulation of ODC1 or direct ODC inhibition by difluoromethylornithine (DFMO) increased the efficacy of SPA. Mechanistically, AR activation, combined with the loss of polyamine-mediated negative feedback, increased S-adenosylmethionine decarboxylase 1 activity, leading to depletion of its substrate, S-adenosylmethionine, and global protein methylation. These data provided the rationale for a clinical trial testing the safety and efficacy of BAT in combination with DFMO for patients with metastatic CRPC. Pharmacodynamic studies in the first five patients in the trial indicated that this therapeutic combination effectively depleted plasma polyamines. Thus, the AR potently stimulates polyamine synthesis, which constitutes a vulnerability in prostate cancer treated with SPA that can be targeted therapeutically.