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Polyamine Metabolism as a Metabolic Vulnerability in Prostate Cancer Treated with Supraphysiological Androgens.

Mohammadreza Alizadeh-Ghodsi·Andrew S Goldstein
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Abstract

Prostate cancer progression is predominantly driven by androgen receptor (AR) signaling, and despite initial benefits of androgen deprivation therapy (ADT), most patients eventually develop lethal castration-resistant disease. Cyclic administration of supraphysiologic androgen (SPA) with ADT paradoxically suppresses tumor growth; however, responses are heterogeneous, and the mechanisms underlying the antitumor effects of SPA remain incompletely understood. In this issue of Cancer Research, Kumar and colleagues demonstrate that SPA induces a distinct metabolic response, characterized by AR-dependent induction of polyamine biosynthesis via ODC1 and AMD1. This metabolic rewiring elevates polyamine synthesis while concurrently depleting the methyl donor S-adenosylmethionine (SAM). Although increased polyamine metabolism by SPA may promote adaptive resistance, genetic or pharmacologic inhibition of ODC1 using difluoromethylornithine (DFMO) enhances SPA-induced growth suppression by disrupting protective polyamine pools and further exacerbating SAM depletion, revealing a metabolic vulnerability in SPA-treated prostate cancer cells. Supporting these findings, a clinical trial combining DFMO with bipolar androgen therapy (BAT) demonstrated reduced circulating polyamines in patients, confirming polyamine pathway suppression in patients with different genomic features. Together, this study uncovers a mechanistic link among androgen signaling, polyamine metabolism, and therapeutic response, providing a rationale for targeting metabolic dependencies to improve SPA efficacy. See related article by Kumar et al., p. 1148.

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MaleHumansPolyaminesProstatic NeoplasmsAndrogensReceptors, AndrogenEflornithineAnimalsJournal ArticleComment

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Mohammadreza Alizadeh-Ghodsi, Andrew S Goldstein. 2026-03-02. Polyamine Metabolism as a Metabolic Vulnerability in Prostate Cancer Treated with Supraphysiological Androgens.. https://doi.org/10.1158/0008-5472.can-25-4807

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