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[Abstract]

The "Warburg effect" describes a peculiar metabolic feature of many solid tumors, namely their increased glucose uptake and high glycolytic rates, which allow cancer cells to accumulate building blocks for the biosynthesis of macromolecules. During aerobic glycolysis, pyruvate is preferentially metabolized to lactate by the enzyme lactate dehydrogenase-A (LDH-A), suggesting a possible vulnerability at this target for small-molecule inhibition in cancer cells. In this study, we used FX11, a small-molecule inhibitor of LDH-A, to investigate this possible vulnerability in a panel of 15 patient-derived mouse xenograft (PDX) models of pancreatic cancer. Unexpectedly, the p53 status of the PDX tumor determined the response to FX11. Tumors harboring wild-type (WT) TP53 were resistant to FX11. In contrast, tumors harboring mutant TP53 exhibited increased apoptosis, reduced proliferation indices, and attenuated tumor growth when exposed to FX11. [(18)F]-FDG PET-CT scans revealed a relative increase in glucose uptake in mutant TP53 versus WT TP53 tumors, with FX11 administration downregulating metabolic activity only in mutant TP53 tumors. Through a noninvasive quantitative assessment of lactate production, as determined by (13)C magnetic resonance spectroscopy (MRS) of hyperpolarized pyruvate, we confirmed that FX11 administration inhibited pyruvate-to-lactate conversion only in mutant TP53 tumors, a feature associated with reduced expression of the TP53 target gene TIGAR, which is known to regulate glycolysis. Taken together, our findings highlight p53 status in pancreatic cancer as a biomarker to predict sensitivity to LDH-A inhibition, with regard to both real-time noninvasive imaging by (13)C MRS as well as therapeutic response. Cancer Res; 75(16); 3355-64. ©2015 AACR.

©2015 American Association for Cancer Research.

[Author information]

Rajeshkumar NV1, Dutta P2, Yabuuchi S1, de Wilde RF1, Martinez GV2, Le A1, Kamphorst JJ3, Rabinowitz JD3, Jain SK4, Hidalgo M5, Dang CV6, Gillies RJ2, Maitra A7.

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1Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.

2Department of Cancer Imaging and Metabolism, Moffitt Cancer Center and Research Institute, Tampa, Florida.

3Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey.

4Center for Infection and Inflammation Imaging Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland.

5Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, Madrid, Spain.

6Abramson Cancer Center, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania. AMaitra@mdanderson.org dangvchi@exchange.upenn.edu.

7Department of Pathology and Translational Molecular Pathology, Sheikh Ahmad Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas. AMaitra@mdanderson.org dangvchi@exchange.upenn.edu.