Hyperpolarized in vivo pH imaging reveals grade-dependent acidification in prostate cancer

There is an unmet clinical need for new and robust imaging biomarkers to distinguish indolent from aggressive prostate cancer. Hallmarks of aggressive tumors such as a decrease in extracellular pH (pH_e) can potentially be used to identify aggressive phenotypes. In this study, we employ an optimized, high signal-to-noise ratio hyperpolarized (HP) ¹³C pH_e imaging method to discriminate between indolent and aggressive disease in a murine model of prostate cancer. Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice underwent a multiparametric MR imaging exam, including HP [¹³C] bicarbonate MRI for pH_e, with ¹H apparent diffusion coefficient (ADC) mapping and HP [1-¹³C] pyruvate MRI to study lactate metabolism. Tumor tissue was excised for histological staining and qRT-PCR to quantify mRNA expression for relevant glycolytic enzymes and transporters. We observed good separation in pH_e between low- and high-grade tumor regions, with high-grade tumors demonstrating a lower pH_e. The pH_e also correlated strongly with monocarboxylate transporter Mct4 gene expression across all tumors, suggesting that lactate export via MCT4 is associated with acidification in this model. Our results implicate extracellular acidification as an indicator of indolent-to-aggressive transition in prostate cancer and suggest feasibility of HP pH_e imaging to detect high-grade, clinically significant disease in men as part of a multiparametric MRI examination.