Androgen receptor drives polyamine synthesis creating a vulnerability for prostate cancer.

Supraphysiological androgen (SPA) treatment can paradoxically restrict growth of castration-resistant prostate cancer with high androgen receptor (AR) activity, which is the basis for use of Bipolar Androgen Therapy (BAT) for patients with this disease. While androgens are widely appreciated to enhance anabolic metabolism, how SPA-mediated metabolic changes alter prostate cancer progression and therapy response is unknown. Here, we report that SPA markedly increased intracellular and secreted polyamines in prostate cancer models. AR binding at enhancer sites upstream of the ODC1 promoter increased the abundance of ornithine decarboxylase (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 efficacy of SPA. Mechanistically, AR activation combined with loss of negative feedback by polyamines increased the activity of S-adenosylmethionine decarboxylase 1 (AMD1), 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 castration-resistant prostate cancer. Pharmacodynamic studies of this therapeutic combination in the first five patients on trial indicated that this approach effectively depleted polyamines in plasma. Thus, the AR potently stimulates polyamine synthesis, which constitutes a vulnerability in prostate cancer treated with SPA that can be targeted therapeutically.