Abstract LB-61: Targeting cancer cell metabolism in pancreatic cancer: p53, a key regulator of glycolysis and a major factor deciding the outcome of targeting the Warburg effect

Background and Aim: Tumor cells depend on metabolic alterations for their continued growth and survival, and such changes make cancer cells peculiarly addicted to the rapacious uptake of glucose. The Warburg effect is such a metabolic feature of cancers that helps to preferentially metabolize pyruvate via glycolytic pathway to lactate by lactate dehydrogenase A (LDHA). Our recent findings indicated that LDHA is required not only for tumor initiation but for tumor maintenance and progression (Le et al., PNAS, 2010). Here, we investigated the therapeutic potential of LDHA inhibition in pancreatic cancer, and attempt to delineate the factors responsible for tumor response. Methods: We evaluated the in vivo efficacy of FX11, a small molecule inhibitor of LDHA, in a panel of pancreatic cancer xenografts with annotated mutational status. Non-invasive quantitative assessment of lactate production was measured by real-time hyperpolarization experiments with 1-13C-labeled pyruvate using a DNP polarizer (HyperSense). [18F]-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET) combined with computed tomography (CT) imaging was conducted to evaluate the effect of FX11 treatment on glucose metabolism. Liquid chromatography - mass spectrometry (LC-MS) was used to quantify the tumor metabolites. Ki-67 and TUNEL staining were performed to determine the effect of FX11 treatment on apoptosis and tumor cell proliferation. Results: p53-deficient pancreatic cancer xenografts showed higher baseline metabolic activity and FX11 treatment down-regulated the tumor metabolic activity. Real-time imaging of pyruvate to lactate conversion using nuclear magnetic resonance (NMR) spectroscopy revealed that FX11 treatment inhibits pyruvate to lactate conversion in p53-deficient pancreatic cancer xenografts. Importantly, p53 promotes the expression of TP53-induced glycolysis regulator (TIGAR) and loss of p53 in tumors results in reduced TIGAR levels. The metabolic profiles of p53-deficient versus p53-proficient pancreatic cancer xenografts were remarkably different. FX11 treatment attenuates tumor progression, induces apoptosis and reduces tumor cell proliferation, preferentially in p53-deficient pancreatic cancer xenografts. Conclusions: Because the Warburg effect is characteristic of virtually all cancers and p53 is frequently mutated in vast majority of human cancers, our finding that p53, a key regulator of glycolysis and a major factor deciding the therapeutic outcome of targeting the Warburg effect may have broad clinical implications. Our findings may help to identify patient subsets that may be particularly responsive to LDHA targeted agents in clinical trials. Acknowledgement: Stand Up To Cancer-AACR Dream Team Translational Cancer Research Grant No. SU2C-AACR DT0509. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-61. doi:1538-7445.AM2012-LB-61