Therapeutic targeting of the warburg effect in pancreatic cancer relies on an absence of p53 function

N. V. Rajeshkumar, Prasanta Dutta, Shinichi Yabuuchi, Roeland F. De Wilde, Gary V. Martinez, Quy Hoa Le Thi, Jurre J. Kamphorst, Joshua D. Rabinowitz, Sanjay Jain, Manuel Hidalgo, Chi V. Dang, Robert J. Gillies, Anirban Maitra

Research output: Contribution to journalArticle

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 atten-uated tumor growth when exposed to FX11. [18F]-FDG PET-CT scans revealed a relative increase in glucose uptake in mutant TP53 versus WTTP53 tumors, with FX11 administration down-regulating 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.

Original languageEnglish (US)
Pages (from-to)3355-3364
Number of pages10
JournalCancer Research
Volume75
Issue number16
DOIs
StatePublished - Aug 15 2015

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Pancreatic Neoplasms
Neoplasms
Pyruvic Acid
Therapeutics
Lactic Acid
Glycolysis
Heterografts
Magnetic Resonance Spectroscopy
Glucose
p53 Genes
Fluorodeoxyglucose F18
Biomarkers
Apoptosis
Enzymes
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Rajeshkumar, N. V., Dutta, P., Yabuuchi, S., De Wilde, R. F., Martinez, G. V., Le Thi, Q. H., ... Maitra, A. (2015). Therapeutic targeting of the warburg effect in pancreatic cancer relies on an absence of p53 function. Cancer Research, 75(16), 3355-3364. https://doi.org/10.1158/0008-5472.CAN-15-0108

Therapeutic targeting of the warburg effect in pancreatic cancer relies on an absence of p53 function. / Rajeshkumar, N. V.; Dutta, Prasanta; Yabuuchi, Shinichi; De Wilde, Roeland F.; Martinez, Gary V.; Le Thi, Quy Hoa; Kamphorst, Jurre J.; Rabinowitz, Joshua D.; Jain, Sanjay; Hidalgo, Manuel; Dang, Chi V.; Gillies, Robert J.; Maitra, Anirban.

In: Cancer Research, Vol. 75, No. 16, 15.08.2015, p. 3355-3364.

Research output: Contribution to journalArticle

Rajeshkumar, NV, Dutta, P, Yabuuchi, S, De Wilde, RF, Martinez, GV, Le Thi, QH, Kamphorst, JJ, Rabinowitz, JD, Jain, S, Hidalgo, M, Dang, CV, Gillies, RJ & Maitra, A 2015, 'Therapeutic targeting of the warburg effect in pancreatic cancer relies on an absence of p53 function', Cancer Research, vol. 75, no. 16, pp. 3355-3364. https://doi.org/10.1158/0008-5472.CAN-15-0108
Rajeshkumar, N. V. ; Dutta, Prasanta ; Yabuuchi, Shinichi ; De Wilde, Roeland F. ; Martinez, Gary V. ; Le Thi, Quy Hoa ; Kamphorst, Jurre J. ; Rabinowitz, Joshua D. ; Jain, Sanjay ; Hidalgo, Manuel ; Dang, Chi V. ; Gillies, Robert J. ; Maitra, Anirban. / Therapeutic targeting of the warburg effect in pancreatic cancer relies on an absence of p53 function. In: Cancer Research. 2015 ; Vol. 75, No. 16. pp. 3355-3364.
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AU - Dutta, Prasanta

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AU - De Wilde, Roeland F.

AU - Martinez, Gary V.

AU - Le Thi, Quy Hoa

AU - Kamphorst, Jurre J.

AU - Rabinowitz, Joshua D.

AU - Jain, Sanjay

AU - Hidalgo, Manuel

AU - Dang, Chi V.

AU - Gillies, Robert J.

AU - Maitra, Anirban

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N2 - 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 atten-uated tumor growth when exposed to FX11. [18F]-FDG PET-CT scans revealed a relative increase in glucose uptake in mutant TP53 versus WTTP53 tumors, with FX11 administration down-regulating 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.

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