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

Purpose: To identify effective metabolic inhibitors to suppress the aggressive growth of pancreatic ductal adenocarcinoma (PDAC), we explored the in vivo anti-tumor efficacy of metabolic inhibitors in a panel of patient-derived PDAC xenograft models (PDXs), and investigated whether genomic alterations of tumors correlate with the sensitivity to metabolic inhibitors. <p>Experimental Design: Mice with PDAC tumors from six to thirteen individual PDXs were randomized and treated, once daily for 4 weeks, with either PBS (vehicle) or the glutaminase inhibitor BPTES, transaminase inhibitor aminooxyacetate (AOA), pyruvate dehydrogenase kinase inhibitor dichloroacetate (DCA), autophagy inhibitor chloroquine (CQ), mitochondrial complex I inhibitor phenformin/metformin.</p> <p>Results: Among the single agents tested, phenformin showed significant tumor growth inhibition (>30% compared to vehicle) in 5 out of 12 individual PDXs. Metformin displayed significant growth inhibition in 3 out of 12 PDXs similar to BPTES (2/8 PDXs) and DCA (2/6 PDXs). AOA and CQ had the lowest response rates. Intriguingly, tumor growth inhibition of PDXs by phenformin inversely correlates with the tumors showing a phenformin gene expression signature prior to therapy. The PDXs 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.</p> <p>Conclusions: Phenformin treatment showed relatively higher anti-tumor efficacy against established PDAC tumors, compared to the efficacy of other metabolic inhibitors and metformin. Phenformin treatment significantly diminished PDAC tumor progression and prolonged tumor doubling time, which provides rationale for further clinical evaluation of phenformin as a therapeutic agent in pancreatic cancer.

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