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

TitleTreatment of Pancreatic Cancer Patient-Derived Xenograft Panel with Metabolic Inhibitors Reveals Efficacy of Phenformin.
Publication TypeJournal Article
Year of Publication2017
AuthorsRajeshkumar, NV, Yabuuchi, S, Pai, SG, De Oliveira, E, Kamphorst, JJ, Rabinowitz, JD, Tejero, H, Al-Shahrour, F, Hidalgo, M, Maitra, A, Dang, CV
JournalClin Cancer Res
Volume23
Issue18
Pagination5639-5647
Date Published2017 Sep 15
ISSN1078-0432
KeywordsAnimals, Antineoplastic Agents, Autophagy, Biomarkers, Tumor, Cell Line, Tumor, Chloroquine, Disease Models, Animal, DNA Copy Number Variations, Energy Metabolism, Female, Genetic Variation, Glutamine, Humans, Hypoglycemic Agents, Metabolic Networks and Pathways, Metabolomics, Metformin, Mice, Mutation, Pancreatic Neoplasms, Phenformin, Xenograft Model Antitumor Assays
Abstract

<p> To identify effective metabolic inhibitors to suppress the aggressive growth of pancreatic ductal adenocarcinoma (PDAC), we explored the 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. 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. 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 , or 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. .</p>

DOI10.1158/1078-0432.CCR-17-1115
Alternate JournalClin. Cancer Res.
PubMed ID28611197
PubMed Central IDPMC6540110
Grant ListR01 CA057341 / CA / NCI NIH HHS / United States
R01 CA163591 / CA / NCI NIH HHS / United States
R01 CA051497 / CA / NCI NIH HHS / United States
P30 CA016520 / CA / NCI NIH HHS / United States
R01 CA113669 / CA / NCI NIH HHS / United States