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Therapeutic Targeting of the Warburg Effect in Pancreatic Cancer Relies on an Absence of p53 Function
Open accessPublished version of a preprint
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. Cancer Res; 75(16); 3355–64. ©2015 AACR.
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“altered p53 function has a multitude of tumor-promoting effects on neoplastic cells, including increased genomic instability30, reprogrammed cellular metabolism57,58, and enhanced metastatic propensity59.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [58]
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“Directly targeting glycolysis through lactate dehydrogenase inhibition has shown mixed results depending on p53 status58”
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Metadata
- Authors
- Rajeshkumar, N. V., Dutta, P., Yabuuchi, S., de Wilde, R. F., Martinez, G. V., Le, A., Kamphorst, J. J., Rabinowitz, J. D., Jain, S. K., Hidalgo, M., Dang, C. V., Gillies, R. J., & Maitra, A.
- Affiliations
- Johns Hopkins University (US)
- Moffitt Cancer Center (US)
- 1Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
- Princeton University (US)
- Spanish National Cancer Research Centre (ES)
- Abramson Cancer Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Maitra, Anirban
- ORCID
- Venue
- Cancer Research
- Published
- 2015-08-13
- Volume
- 75
- Issue
- 16
- Pages
- 3355-3364
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC4537812
- OpenAlex
- W2164355096
- Cited by
- 158
- References
- 48
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 12 · 2023: 12 · 2022: 14 · 2021: 29 · 2020: 16 · 2019: 14 · 2018: 15 · 2017: 12 · 2016: 15 · 2015: 4
- FWCI
- 5.07
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Cancer Research UK (22311)
- National Cancer Institute (R01CA113669, R01CA057341, R01CA077575, R01CA051497, R01CA163591, P30CA016520)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- Warburg effect, pancreatic cancer, p53 status, TP53 mutation, aerobic glycolysis, lactic acid production, TIGAR, glucose metabolism, patient-derived xenografts, predictive biomarkers, 13C NMR, hyperpolarized pyruvate, 18F-FDG PET/CT
- MeSH terms
- Lactate Dehydrogenase 5, Animals, Glycolysis, Humans, Immunohistochemistry, Isoenzymes, L-Lactate Dehydrogenase, Lactates, Male, Mice, Nude, Mutation, Naphthalenes, Pancreatic Neoplasms, Phosphoric Monoester Hydrolases, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Apoptosis, Pyruvic Acid, Fluorodeoxyglucose F18, Reverse Transcriptase Polymerase Chain Reaction, Xenograft Model Antitumor Assays, Tumor Burden, Intracellular Signaling Peptides and Proteins, Cell Proliferation, Positron-Emission Tomography, Apoptosis Regulatory Proteins, Carbon-13 Magnetic Resonance Spectroscopy
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