Abstract 4106: Hyperpolarized [1-13C]-pyruvate/lactate magnetic resonance spectroscopic imaging of prostate cancer in vivo predicts response to lactate dehydrogenase inhibition
Authors: Bradley T. Scroggins, Masayuki Matsuo, Ayla O. White, Keita Saito, Jeeva P. Munasinghe, Carole Sourbier, Kazutoshi Yamamoto, Vivian Diaz, James B. Mitchell, Murali C. Krishna, Deborah E. Citrin
Journal: Cancer Research (2018)

Abstract Purpose: Non-invasive magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized (HP) 13C-labeled pyruvate and its metabolite lactate is being used to monitor the metabolic flux in solid tumors. In this study, we evaluate the potential of MRSI of HP [1-13C]-pyruvate and [1-13C]-lactate, in prostate cancer as a predictive biomarker for targeting lactate dehydrogenase. Experimental Design: Two human prostate cancer cell lines (DU145 and PC3) were grown as xenografts. The conversion of pyruvate to lactate in xenografts was measured, after intravenous delivery of hyperpolarized [1-13C] pyruvic acid, by MRSI. Steady state metabolomic analysis of xenograft tumors was performed by mass spectrometry and steady state lactate levels were measured with proton (1H) MRS. Perfusion and oxygenation of xenografts were measured with electron paramagnetic resonance (EPR) imaging. Tumor growth was assessed after lactate dehydrogenase (LDH) inhibition with FX-11 (42 µg/mouse/day for 5 days x 2 weekly cycles). Lactate production, pyruvate uptake, extracellular acidification rates and oxygen consumption of the prostate cancer cell lines was analyzed in vitro. Protein levels of glycolysis regulators were assessed with immunoblotting. Results: DU145 tumors demonstrated an enhanced conversion of pyruvate to lactate with HP [1-13C] MRSI relative to PC3 tumors (21% higher 13C-lactate/pyruvate p&amp;lt;0.05). In addition, DU145 xenografts have a 42% (p&amp;lt;0.05) reduction in 13C-lactate/pyruvate after FX-11 treatment while PC3 xenografts demonstrate no sensitivity to FX-11 treatment. In correlation FX-11 significantly delayed DU145 tumor volume doubling time by 3.4 days (p&amp;lt;0.05). By comparison no difference was observed between DU145 and PC3 xenografts in steady state measures of lactate, oxygenation, or perfusion. The two cell lines also exhibited similar pyruvate uptake, lactate production, extracellular acidification and oxygen consumption rates and sensitivity to FX-11 in vitro. Difference in the expression of glycolysis regulators such as Hif-1α, LDHA, MCT1, MCT4, HK2 and PFKP were observed in vitro but did not correlate with HP [13C]-lactate/pyruvate MRSI results or FX-11 sensitivity. Conclusions: Hyperpolarized [1-13C]-pyruvate MRSI of prostate cancer xenografts predicted the efficacy of targeting LDH when steady state markers of glycolysis, in vivo and in vitro, did not. Citation Format: Bradley T. Scroggins, Masayuki Matsuo, Ayla O. White, Keita Saito, Jeeva P. Munasinghe, Carole Sourbier, Kazutoshi Yamamoto, Vivian Diaz, James B. Mitchell, Murali C. Krishna, Deborah E. Citrin. Hyperpolarized [1-13C]-pyruvate/lactate magnetic resonance spectroscopic imaging of prostate cancer in vivo predicts response to lactate dehydrogenase inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4106.