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Androgen Receptor Drives Polyamine Synthesis, Creating a Vulnerability for Prostate Cancer
Rajendra Kumar1, Sheila Jonnatan1, David E Sanin1
1Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
Supraphysiological androgens (SPA) boost polyamine synthesis in prostate cancer, fueling tumor growth. Inhibiting polyamine production enhances SPA efficacy, revealing a therapeutic vulnerability for Bipolar Androgen Therapy (BAT).
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metabolism
Background:
- Supraphysiological androgen (SPA) treatment, including Bipolar Androgen Therapy (BAT), paradoxically restricts castration-resistant prostate cancer (CRPC) growth.
- The metabolic effects of SPA on prostate cancer progression and therapy response remain largely unknown.
Purpose of the Study:
- To investigate the impact of SPA on metabolic changes in prostate cancer.
- To identify therapeutic strategies targeting SPA-induced metabolic alterations in CRPC.
Main Methods:
- Utilized prostate cancer models to assess the effects of SPA on polyamine synthesis.
- Employed genetic (dCas9-KRAB) and pharmacological (difluoromethylornithine - DFMO) inhibition of polyamine synthesis pathways.
- Conducted pharmacodynamic studies in patients undergoing a clinical trial combining BAT and DFMO.
Main Results:
- SPA significantly increased intracellular and secreted polyamines by upregulating ornithine decarboxylase (ODC) via androgen receptor (AR) binding.
- Inhibition of ODC1 or ODC activity enhanced the efficacy of SPA, demonstrating polyamines' role in prostate cancer fitness.
- Combined AR activation and polyamine feedback loss increased S-adenosylmethionine decarboxylase 1 (AMD1) activity, leading to S-adenosylmethionine depletion and global protein hypomethylation.
- Clinical trial data showed that BAT combined with DFMO effectively depleted plasma polyamines.
Conclusions:
- Androgen receptor (AR) activation potently stimulates polyamine synthesis in prostate cancer.
- SPA-induced polyamine synthesis represents a critical vulnerability in prostate cancer.
- Targeting polyamine synthesis offers a promising therapeutic strategy for CRPC treated with SPA/BAT.
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