Year: 2025
Type: article
Abstract: 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 negative feedback by polyamines increased the activity of S-adenosylmethionine decarboxylase 1, leading to the 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 of this therapeutic combination in the first five patients in the 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. SIGNIFICANCE: Increased polyamine synthesis is a prominent metabolic change induced by the androgen receptor that drives tumor progression and confers a targetable vulnerability in advanced prostate cancer. See related commentary by Alizadeh-Ghodsi and Goldstein, p. 1095.
Source: Cancer Research
Authors: Rajendra Kumar, Sheila Jonnatan, David E. Sanin, Varsha Vakkala, Anoushka Kadam, Shivani Kumar, D. Marc Rosen, Susan L. Dalrymple, Liang Zhao, Jackson R. Foley, Cassandra E. Holbert, Ashley Nwafor, Srushti Kittane, Elizabeth Penner, Petya Apostolova, Samuel Warner, Chi V. Dang, Eneda Toska, Elizabeth A. Thompson, John T. Isaacs, Angelo M. De Marzo, W. Nathaniel Brennen, Erika L. Pearce, Tracy Murray Stewart, Robert A. Casero, Samuel R. Denmeade, Laura A. Sena
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: EXPLORING THE ROLE OF FERROPTOSIS AS A TUMOR-INTRINSIC MOLECULAR DETERMINANT OF BIPOLAR ANDROGEN THERAPY, INVESTIGATING NONCANONICAL ROLES OF ANDROGEN RECEPTOR IN DRIVING GROWTH INHIBITION BY SUPRAPHYSIOLOGICAL ANDROGEN IN PROSTATE CANCER, G6902804345, THE ROLE OF POLYAMINE METABOLISM IN ADVANCED PROSTATE CANCER, Molecular features promoting sensitivity to LSD1i in castration-resistant prostate cancer, Training in Areas Fundamental to Cancer Research, SPORE in Prostate Cancer
OpenAlex ID: W4416516016