Therapeutic Targeting of the Warburg Effect in Pancreatic Cancer Relies on an Absence of p53 Function.

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. [18F]-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 13C 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 13C MRS as well as therapeutic response.

• Authors: N V Rajeshkumar, Prasanta Dutta, Shinichi Yabuuchi, Roeland F de Wilde, Gary V Martinez, Anne Le, Jurre J Kamphorst, Joshua D Rabinowitz, Sanjay K Jain, Manuel Hidalgo, Chi V Dang, Robert J Gillies, Anirban Maitra
• Journal: Cancer research (Cancer Res) Vol. 75 Issue 16 Pg. 3355-64 (Aug 15 2015) ISSN: 1538-7445 [Electronic] United States
• PMID: 26113084 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• 3-dihydroxy-6-methyl-7-(phenylmethyl)-4-propylnaphthalene-1-carboxylic acid
• Apoptosis Regulatory Proteins
• Intracellular Signaling Peptides and Proteins
• Isoenzymes
• Lactates
• Naphthalenes
• Tumor Suppressor Protein p53
• Fluorodeoxyglucose F18
• Pyruvic Acid
• L-Lactate Dehydrogenase
• Lactate Dehydrogenase 5
• Phosphoric Monoester Hydrolases
• TIGAR protein, human

Topics

• Animals
• Apoptosis (drug effects, genetics)
• Apoptosis Regulatory Proteins
• Carbon-13 Magnetic Resonance Spectroscopy
• Cell Proliferation (drug effects, genetics)
• Fluorodeoxyglucose F18
• Gene Expression Regulation, Neoplastic
• Glycolysis (drug effects)
• Humans
• Immunohistochemistry
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Isoenzymes (antagonists & inhibitors, metabolism)
• L-Lactate Dehydrogenase (antagonists & inhibitors, metabolism)
• Lactate Dehydrogenase 5
• Lactates (metabolism)
• Male
• Mice, Nude
• Mutation
• Naphthalenes (pharmacology)
• Pancreatic Neoplasms (drug therapy, genetics, metabolism)
• Phosphoric Monoester Hydrolases
• Positron-Emission Tomography (methods)
• Pyruvic Acid (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Burden (drug effects, genetics)
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Xenograft Model Antitumor Assays