@article{3042, keywords = {Animals, Disease Models, Animal, Mice, Humans, Mutation, Female, Genetic Variation, Energy Metabolism, Cell Line, Tumor, DNA Copy Number Variations, Biomarkers, Tumor, Antineoplastic Agents, Metabolomics, Metabolic Networks and Pathways, Autophagy, Xenograft Model Antitumor Assays, Pancreatic Neoplasms, Glutamine, Chloroquine, Hypoglycemic Agents, Metformin, Phenformin}, author = {N Rajeshkumar and Shinichi Yabuuchi and Shweta Pai and Elizabeth De Oliveira and Jurre Kamphorst and Joshua Rabinowitz and H{\'e}ctor Tejero and Fatima Al-Shahrour and Manuel Hidalgo and Anirban Maitra and Chi Dang}, title = {Treatment of Pancreatic Cancer Patient-Derived Xenograft Panel with Metabolic Inhibitors Reveals Efficacy of Phenformin.}, abstract = {
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. .
}, year = {2017}, journal = {Clin Cancer Res}, volume = {23}, pages = {5639-5647}, month = {2017 Sep 15}, issn = {1557-3265}, doi = {10.1158/1078-0432.CCR-17-1115}, language = {eng}, }