PPARα: A Novel Target in Pancreatic Cancer

Abstract

BackgroundThe tumor stroma is increasingly implicated in pancreatic cancer. Pancreatic cancer is characterized by a highly fibrotic tumor microenvironment resulting in stromal resistance to chemotherapy. Peroxisome proliferator activated receptor alpha (PPARα), a ligand‐activated nuclear receptor/transcription factor, is a key negative regulator of inflammation. In PPARα deficient mice, stromal processes inhibited tumor growth resulting in dormant tumors. We hypothesized that blocking the PPARα pathway with a small molecule PPARα antagonist (NXT00120) may inhibit pancreatic cancer by targeting inflammation and cell signaling pathways that regulate cell cycle progression.ResultsSystemic administration of the PPARα antagonist, NXT00120, inhibited primary human pancreatic cancer cancer (HPAF‐II) and ascites formation in an aggressive orthotopic pancreatic cancer model. Combination of NXT00120 with gemcitabine induced sustained tumor regression in an orthotopic model of pancreatic cancer (PancOH7). NXT00120 reduced levels of phospho‐AKT, AKT, PCNA, Cyclin‐D1, RB protein levels.ConclusionWe demonstrated NXT00120 induced proliferation arrest by negatively modulating cell cycle regulatory proteins. Targeting pancreatic cancer with a PPARα antagonist is an entirely novel approach to complement chemotherapy to combat pancreatic cancer.Research Support: ROCA148633