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Metabolic and imaging phenotypes associated with RB1 and TP53 loss in prostate cancer

Fahim Ahmad1, Margaret White2, Kazutoshi Yamamoto3

  • 1Molecular Imaging Branch, NCI/NIH, Bethesda, MD 20892, United States; Radiation Biology Branch, NCI/NIH, Bethesda, MD 20892, United States; Laboratory of Genitourinary Cancer Pathogenesis, NCI/NIH, Bethesda, MD 20892, United States.

Neoplasia (New York, N.Y.)
|October 8, 2025
PubMed

Insights

Loss of RB1 and TP53 in prostate cancer alters cellular metabolism, increasing glucose use and lactate production, but not necessarily 18FDG uptake. This metabolic shift impacts tumor characterization and treatment prognosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Medical Imaging

Background:

  • Advanced prostate cancer treatment with AR inhibitors leads to resistance and castrate-resistant prostate cancer (CRPC).
  • Loss of RB1 and TP53 in CRPC is linked to disease progression and neuroendocrine prostate cancer (NEPC) development.
  • Increased 18FDG-PET SUVmax in progressive CRPC suggests metabolic changes, but the role of RB1/TP53 inactivation is unclear.

Purpose of the Study:

  • To investigate the metabolic impact of RB1 and/or TP53 inactivation in prostate cancer.
  • To determine if RB1/TP53 loss drives increased glucose uptake in CRPC.
  • To explore the utility of multimodal imaging for characterizing prostate cancer phenotypes.

Main Methods:

  • Utilized patient-derived xenograft (PDX)-derived CRPC organoids and castration-sensitive prostate cancer models.
  • Performed 18FDG-PET imaging, PSMA protein level analysis, and 13C-hyperpolarized magnetic resonance spectroscopy.
  • Conducted RB1/TP53 knockdown experiments to assess metabolic pathway alterations.

Main Results:

  • NEPC could not be distinguished from adenocarcinoma by 18FDG uptake alone; PSMA levels did not correlate with phenotype or 18FDG uptake.
  • Castration-resistant models exhibited higher 18FDG uptake but lower pyruvate-to-lactate conversion than castration-sensitive models.
  • RB1/TP53 knockdown increased basal respiration and glycolytic activity, with combined depletion causing glucose diversion to glycogenesis, reflected in lactate dehydrogenase flux.

Conclusions:

  • RB1/TP53 loss alters prostate cancer cell metabolism, increasing glycolysis and lactate production without necessarily increasing 18FDG uptake.
  • Metabolic heterogeneity in prostate cancer suggests multimodal imaging is crucial for accurate tumor characterization.
  • Improved tumor characterization through multimodal imaging may lead to better patient prognosis and treatment strategies.
Keywords:
FDG-PETMetabolic reprogramingMetabolismProstate cancerRB1TP53

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