Abstract LB-184: Hyperpolarized 13C-pyruvate magnetic resonance spectroscopic imaging of prostate cancer tumor xenografts

Abstract

Abstract Purpose: Non-invasive magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized 13C-labeled pyruvate and its metabolite lactate is being used to profile the metabolism of solid tumors. During this imaging, the metabolism of a bolus of 13C-labeled pyruvate to lactate is observed in the imaged tumor. Thus, the concentrations of pyruvate may not represent the physiological steady state of the tumor. We hypothesize that in our model system hyperpolarized 13C-pyruvate/lactate MRSI detects the glycolytic potential of prostate tumor xenografts not the metabolic steady state and may be used to predict response of tumors to metabolic inhibitors. Materials/Methods: Two non-androgen responsive prostate cancer cell lines, PC3 and DU145, were characterized for steady state metabolic differences by in vitro cell culture. Metabolic profiling in vitro was conducted by analysis of the extracellular acidification rate (glycolysis) and the oxygen consumption rate (oxidative phosphorylation). MCT1 and LDHA expression was monitored by immunoblotting. Pyruvate uptake and lactate production were also assayed to compare common glycolytic markers between cell lines. In vivo analysis of PC3 and DU145 tumor xenografts was conducted by MRSI of hyperpolarized 13C-labeled pyruvate/lactate. The effects of LDHA inhibition (FX11) on tumor growth were monitored for both types of tumor xenografts. Results: In vitro metabolic analysis showed that PC3 and DU145 cells have similar extracellular acidification rates (109and 116 mpH/min, respectively, p>0.05) and oxygen consumption rates (233 and 203 pmol O2/min, respectively, p>0.05) suggesting that their metabolic profile is similar with regards to glycolysis and oxidative phosphorylation. In addition, MCT1 and LDHA expression was similar, pyruvate uptake was about twice as high in PC3 cells than in DU145 cells (p<0.05) and lactate production was similar under aerobic conditions (494 nmoles/mg and 506 nmoles/mg, respectively, p>0.05). In vivo analysis by hyperpolarized 13C-pyruvate MRSI revealed that the lactate/pyruvate ratio was 21% (p<0.05) higher in DU145 tumor xenografts than in PC3 tumors suggesting that in vivo DU145 tumors have higher glycolytic potential. Finally LDHA inhibition with FX11 delayed growth of DU145 tumor xenografts by 7 days compared to no growth delay seen in FX11 treated PC3 tumor xenografts (p<0.05) suggesting that DU145 tumors are dependent on glycolysis for growth. Conclusions: In vitro analysis of PC3 and DU145 cells suggests that there is little difference at steady state in many of the markers of glycolysis between these cell lines. However hyperpolarized MRSI data indicates that DU145 tumors have a higher glycolytic potential than PC3 tumors. Our data suggest that hyperpolarized 13C-pyruvate MRSI could be more useful in predicting the response of tumors to metabolic inhibitors of glycolysis than steady state analysis. Citation Format: Bradley T. Scroggins, Masayuki Matsuo, Jeeva P. Munasinghe, Ayla O. White, Carole Sourbier, Shingo Matsumoto, W. Marston Linehan, James B. Mitchell, Murali C. Krishna, Deborah E. Citrin. Hyperpolarized 13C-pyruvate magnetic resonance spectroscopic imaging of prostate cancer tumor xenografts. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-184.