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

// David E. Korenchan 1 , Robert Bok 1 , Renuka Sriram 1 , Kristina Liu 5 , Romelyn Delos Santos 1 , Hecong Qin 1 , Iryna Lobach 2 , Natalie Korn 1 , David M. Wilson 1 , John Kurhanewicz 1 , 3 , 4 and Robert R. Flavell 1 , 3 1 Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA 2 Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA 3 Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA 4 Department of Urology, University of California, San Francisco, CA, USA 5 Department of Physical Chemistry, Technical University of Munich, Munich, Germany Correspondence to: Robert R. Flavell, email: Robert.Flavell@ucsf.edu Keywords: prostate cancer; extracellular pH; hyperpolarization; MRI; metabolism Received: August 01, 2019     Accepted: September 10, 2019     Published: October 22, 2019 ABSTRACT 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) 13 C 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 [ 13 C] bicarbonate MRI for pH e , with 1 H apparent diffusion coefficient (ADC) mapping and HP [1- 13 C] 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.