Metabolic and imaging phenotypes associated with RB1 loss in castrate resistant prostate cancer

Ahmad, F.; White, M.; Yamamoto, K.; Crooks, D. R.; Agarwal, S.; Yang, Y.; Capaldo, B.; Raj, S.; Alilin, A. N.; Ton, A.; Adler, S.; Seidel, J.; Olkowski, C.; Cherukuri, M. K.; Choyke, P. L.; Kelly, K.; Brender, J. R.

doi:10.1101/2023.11.15.567250

bioRxiv · 10.1101/2023.11.15.567250

Metabolic and imaging phenotypes associated with RB1 loss in castrate resistant prostate cancer

Ahmad, F.·White, M.·Yamamoto, K.·Crooks, D. R.·Agarwal, S.·Yang, Y.·Capaldo, B.·Raj, S.·Alilin, A. N.·Ton, A.·Adler, S.·Seidel, J.·Olkowski, C.·Cherukuri, M. K.·Choyke, P. L.·Kelly, K.·Brender, J. R.

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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.

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Ahmad, F., White, M., Yamamoto, K., Crooks, D. R., Agarwal, S., Yang, Y., Capaldo, B., Raj, S., Alilin, A. N., Ton, A., Adler, S., Seidel, J., Olkowski, C., Cherukuri, M. K., Choyke, P. L., Kelly, K., Brender, J. R.. 2023-11-17. Metabolic and imaging phenotypes associated with RB1 loss in castrate resistant prostate cancer. https://doi.org/10.1101/2023.11.15.567250

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