Treatment of pancreatic cancer patient–derived xenograft panel with metabolic inhibitors reveals efficacy of phenformin

N. V. Rajeshkumar, Shinichi Yabuuchi, Shweta G. Pai, Elizabeth De Oliveira, Jurre J. Kamphorst, Joshua D. Rabinowitz, Hector Tejero, Fatima Al-Shahrour, Manuel Hidalgo, Anirban Maitra, Chi V. Dang

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Purpose: To identify effective metabolic inhibitors to suppress the aggressive growth of pancreatic ductal adenocarcinoma (PDAC), we explored the in vivo antitumor efficacy of metabolic inhibitors, as single agents, in a panel of patient-derived PDAC xenograft models (PDX) and investigated whether genomic alterations of tumors correlate with the sensitivity to metabolic inhibitors. Experimental Design: Mice with established PDAC tumors from 6 to 13 individual PDXs were randomized and treated, once daily for 4 weeks, with either sterile PBS (vehicle) or the glutaminase inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES), transaminase inhibitor aminooxyacetate (AOA), pyruvate dehydrogenase kinase inhibitor dichloroacetate (DCA), autophagy inhibitor chloroquine (CQ), and mitochondrial complex I inhibitor phenformin/metformin. Results: Among the agents tested, phenformin showed significant tumor growth inhibition (>30% compared with vehicle) in 5 of 12 individual PDXs. Metformin, at a fivefold higher dose, displayed significant tumor growth inhibition in 3 of 12 PDXs similar to BPTES (2/8 PDXs) and DCA (2/6 PDXs). AOA and CQ had the lowest response rates. Gene set enrichment analysis conducted using the baseline gene expression profile of pancreatic tumors identified a gene expression signature that inversely correlated with phenformin sensitivity, which is in agreement with the phenformin gene expression signature of NIH Library of Integrated Network-based Cellular Signatures (LINCS). The PDXs that were more sensitive to phenformin showed a baseline reduction in amino acids and elevation in oxidized glutathione. There was no correlation between phenformin response and genetic alterations in KRAS, TP53, SMAD4, or PTEN. Conclusions: Phenformin treatment showed relatively higher antitumor efficacy against established PDAC tumors, compared with the efficacy of other metabolic inhibitors and metformin. Phenformin treatment significantly diminished PDAC tumor progression and prolonged tumor doubling time. Overall, our results serve as a foundation for further evaluation of phenformin as a therapeutic agent in pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)5639-5647
Number of pages9
JournalClinical Cancer Research
Volume23
Issue number18
DOIs
StatePublished - Sep 15 2017

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Treatment of pancreatic cancer patient–derived xenograft panel with metabolic inhibitors reveals efficacy of phenformin'. Together they form a unique fingerprint.

  • Cite this

    Rajeshkumar, N. V., Yabuuchi, S., Pai, S. G., De Oliveira, E., Kamphorst, J. J., Rabinowitz, J. D., Tejero, H., Al-Shahrour, F., Hidalgo, M., Maitra, A., & Dang, C. V. (2017). Treatment of pancreatic cancer patient–derived xenograft panel with metabolic inhibitors reveals efficacy of phenformin. Clinical Cancer Research, 23(18), 5639-5647. https://doi.org/10.1158/1078-0432.CCR-17-1115