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Clin Cancer Res. 2017 Sep 15;23(18):5639-5647. doi: 10.1158/1078-0432.CCR-17-1115. Epub 2017 Jun 13.

Treatment of Pancreatic Cancer Patient-Derived Xenograft Panel with Metabolic Inhibitors Reveals Efficacy of Phenformin.

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Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, United Kingdom.
Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, United Kingdom.
Lewis-Sigler Institute for Integrative Genomics and Department of Chemistry, Princeton University, Princeton, New Jersey.
Spanish National Cancer Research Center (CNIO), Madrid, Spain.
Division of Hematology-Oncology, Rosenberg Clinical Cancer Center, Beth Israel Deaconess Medical Center (BIDMC), Boston, Massachusetts.
Department of Pathology and Translational Molecular Pathology, Sheikh Ahmad Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Abramson Cancer Center, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.


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 PTENConclusions: 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. Clin Cancer Res; 23(18); 5639-47. ©2017 AACR.

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