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Prostate Organoid Cultures as Tools to Translate Genotypes and Mutational Profiles to Pharmacological Responses
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Androgen receptor drives polyamine synthesis creating a vulnerability for prostate cancer

Rajendra Kumar, Sheila Jonnatan, David E Sanin

    Medrxiv : the Preprint Server for Health Sciences
    |December 23, 2024
    PubMed

    Insights

    Supraphysiological androgens (SPA) boost polyamine synthesis in prostate cancer by activating the androgen receptor (AR) to regulate ODC1. Inhibiting polyamine synthesis enhances SPA efficacy, revealing a therapeutic vulnerability.

    Area of Science:

    • Oncology
    • Molecular Biology
    • Metabolic Pathways

    Background:

    • Supraphysiological androgen (SPA) treatment, including Bipolar Androgen Therapy (BAT), paradoxically inhibits castration-resistant prostate cancer (CRPC) growth in AR-active tumors.
    • The metabolic alterations induced by SPA and their impact on CRPC progression and therapeutic response remain poorly understood.

    Purpose of the Study:

    • To investigate the metabolic changes, specifically polyamine synthesis, induced by SPA in prostate cancer models.
    • To elucidate the mechanism by which SPA influences polyamine metabolism and its role in CRPC progression.
    • To evaluate the therapeutic potential of targeting polyamine synthesis in combination with SPA.

    Main Methods:

    • Utilized prostate cancer models to assess the impact of SPA on intracellular and secreted polyamines.
    • Investigated the role of androgen receptor (AR) binding to enhancer sites upstream of the Ornithine Decarboxylase 1 (ODC1) promoter.
    • Employed dCas9-KRAB-mediated inhibition of AR regulation and difluoromethylornithine (DFMO) to inhibit ODC activity.
    • Assessed the effects of polyamine depletion on S-adenosylmethionine decarboxylase 1 (AMD1) activity and global protein methylation.
    • Conducted a Phase I clinical trial combining BAT and DFMO in metastatic CRPC patients, including pharmacodynamic studies.

    Main Results:

    • SPA significantly increased intracellular and secreted polyamines in prostate cancer models.
    • AR binding at enhancer sites increased ODC1 abundance, driving de novo polyamine synthesis from arginine.
    • Inhibition of AR-driven ODC1 or ODC activity with DFMO enhanced the efficacy of SPA treatment.
    • SPA increased AMD1 activity, partly due to AR stimulation and reduced polyamine feedback, leading to S-adenosylmethionine depletion and decreased global protein methylation.
    • Pharmacodynamic studies in patients showed effective plasma polyamine depletion with the BAT + DFMO combination.

    Conclusions:

    • Androgen receptor (AR) potently stimulates polyamine synthesis in prostate cancer.
    • SPA-induced polyamine synthesis represents a critical metabolic vulnerability in AR-driven prostate cancer.
    • Targeting polyamine synthesis, for example with DFMO, in combination with SPA (BAT) offers a promising therapeutic strategy for metastatic CRPC.

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