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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
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Targeting arginine metabolism overcomes chemotherapy resistance in aggressive-variant prostate cancers

Elavarasan Subramani1, Patrick G Pilié2, Rebecca Slack-Tidwell3

  • 1Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Iscience
|June 15, 2026
PubMed

Insights

Aggressive-variant prostate cancers (AVPCs) show poor response to standard therapy. Arginine depletion combined with chemotherapy demonstrated enhanced efficacy in preclinical models, suggesting new treatment strategies.

Area of Science:

  • Oncology
  • Medical Research

Background:

  • Aggressive-variant prostate cancer (AVPC) exhibits poor response to anti-androgen therapies.
  • While sensitive to taxane-platinum chemotherapy, outcomes for AVPC remain suboptimal.

Purpose of the Study:

  • To evaluate the efficacy of induction cabazitaxel plus carboplatin (CabCarb) followed by olaparib maintenance versus observation in men with AVPC.
  • To identify predictors of early chemotherapy progression (ChemoPD) and explore novel therapeutic strategies.

Main Methods:

  • A phase 2 clinical trial was conducted involving patients with AVPC.
  • Patients received induction CabCarb followed by olaparib maintenance or observation.
  • Genomic, transcriptomic, and metabolomic analyses were performed on patient tumors and preclinical models.

Main Results:

  • The primary endpoint of improved progression-free survival (PFS) was not met, with 38.5% of patients experiencing ChemoPD before randomization.
  • No genomic alterations predicted ChemoPD; however, transcriptomic and metabolomic analyses revealed enrichment of metabolic pathways, including arginine metabolism, in ChemoPD tumors.
  • Arginine depletion using ADI-PEG20 enhanced CabCarb efficacy in preclinical AVPC models.

Conclusions:

  • AVPC exhibits significant heterogeneity, contributing to poor treatment outcomes.
  • Arginine metabolism pathways are implicated in chemotherapy resistance in AVPC.
  • Targeting arginine metabolism in combination with chemotherapy presents a promising strategy for overcoming treatment resistance in AVPC.
Keywords:
Health sciencesMedical specialtyMedicineOncology

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