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Updated: Jan 16, 2026
Hyperpolarized 13C Metabolic Magnetic Resonance Spectroscopy and Imaging
Published on: December 30, 2016
Metabolic and imaging phenotypes associated with RB1 and TP53 loss in prostate cancer
Fahim Ahmad1,2,3, Margaret White1,3, Kazutoshi Yamamoto2
1Molecular Imaging Branch, NCI/NIH, Bethesda, MD-20892.
Abstract:
Advanced prostate cancer is treated with androgen receptor (AR) signaling inhibitors, which are initially effective, but most patients eventually develop resistance and progress to castrate-resistant prostate cancer (CRPC). Loss of RB1 in CRPC tumors is correlated with rapid progression and poor patient survival and, in combination with TP53 loss, predisposes patients to the development of transitional neuroendocrine prostate cancer (NEPC). Although progressive CRPC is clinically associated with higher 18FDG-PET SUVmax values, it is unknown whether inactivation of RB1 and/or TP53 is a driver of increased glucose import. Using a cohort of patient-derived xenograft (PDX)-derived CRPC organoids, we found that NEPC could not be conclusively distinguished from adenocarcinoma by 18FDG uptake alone, and PSMA protein levels did not correlate with cancer phenotype or 18FDG uptake. Castration-resistant models showed higher 18FDG uptake, but lower pyruvate-to-lactate conversion compared to their castration-sensitive counterparts. In parallel studies using castration-sensitive prostate cancer models, RB1/TP53 knockdown did not affect 18FDG uptake, but increased basal respiration and glycolytic activity, with combined depletion leading to glucose diversion into glycogenesis. These metabolic changes were reflected in increased lactate dehydrogenase flux detected by 13C-hyperpolarized magnetic resonance spectroscopy upon RB1 loss, but not in 18FDG uptake. The metabolic heterogeneity revealed here suggests that a multimodal molecular imaging approach can improve tumor characterization, potentially leading to a better prognosis in cancer treatment.
Insights
Loss of RB1 and TP53 in prostate cancer alters cellular metabolism, impacting glucose processing and lactate production. This metabolic shift, not solely glucose uptake, may drive disease progression in advanced prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Metabolic Imaging
Background:
- Advanced prostate cancer (PC) treatment involves androgen receptor (AR) inhibitors, but resistance leads to castrate-resistant prostate cancer (CRPC).
- Loss of RB1, particularly with TP53 loss, is linked to CRPC 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 if RB1 and/or TP53 inactivation drives increased glucose uptake in prostate cancer.
- To characterize the metabolic alterations associated with RB1/TP53 loss in CRPC and NEPC.
- To assess the utility of metabolic imaging in distinguishing PC subtypes and predicting outcomes.
Main Methods:
- Utilized patient-derived xenograft (PDX)-derived CRPC organoids and castration-sensitive PC models.
- Performed 18FDG-PET imaging and measured PSMA protein levels.
- Assessed metabolic activity using 13C-hyperpolarized magnetic resonance spectroscopy and analyzed respiration and glycolysis.
Main Results:
- Neuroendocrine PC (NEPC) could not be distinguished from adenocarcinoma solely by 18FDG uptake; PSMA levels did not correlate with phenotype or uptake.
- Castration-resistant models showed higher 18FDG uptake but lower pyruvate-to-lactate conversion than castration-sensitive models.
- RB1/TP53 knockdown increased basal respiration and glycolysis, diverting glucose to glycogenesis and increasing lactate dehydrogenase flux, without altering 18FDG uptake.
Conclusions:
- RB1/TP53 inactivation influences glucose metabolism and lactate production, rather than solely increasing glucose import.
- Metabolic heterogeneity in CRPC suggests limitations of 18FDG uptake alone for tumor characterization.
- A multimodal molecular imaging approach is recommended for improved tumor characterization and patient prognosis in advanced prostate cancer.
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