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

Purpose Advanced prostate cancer is treated with androgen receptor (AR) signaling inhibitors, which are initially effective, but the majority of 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 to the development of transitional neuroendocrine prostate cancer (NEPC). Although progressing 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. Experimental Design A cohort of patient-derived xenograft (PDX)-derived CRPC organoids was screened to assess 18FDG uptake in ARPC and NEPC, considering the influence of RB1 and TP53 status. Experimental loss of RB1 and/or TP53 was induced in an androgen sensitive and a castrate resistant model, and metabolic changes were evaluated using 18FDG-PET, 13C-hyperpolarized magnetic resonance spectroscopy, Seahorse, and ex vivo NMR. Results Knockdown of either RB1 or TP53 increased glycolysis and TCA cycle intermediates, while knockdown of both created a new phenotype where glucose was diverted to the pentose phosphate pathway and into glycogen synthesis. These large-scale metabolic changes were not reflected in 18FDG uptake, which was not increased upon knockdown of either gene. 13C-hyperpolarized magnetic resonance spectroscopy, on the other hand, showed significant differences in lactate dehydrogenase flux upon loss of RB1 . The metabolic heterogeneity revealed here suggests a multimodal molecular imaging approach can improve tumor characterization, potentially leading to better prognostics in cancer treatment. ### Competing Interest Statement The authors have declared no competing interest. * AR : Androgen receptor CR : castration-resistant CRPC : Castration resistant prostate cancer NEPC : Neuroendocrine prostate cancer ARPC : Androgen receptor positive adenocarcinoma HP-MRI : Hyperpolarized magnetic resonance imaging LDH : lactate dehydrogenase PDX : Patient derived xenograft PC : Principal component PLS-DA : Partial least-squares discriminant analysis