Project 2: Chemoprevention of pancreatic cancer with lipid-lowering and antidiabetic agents

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PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human diseases. The focus of research, which had been placed mostly on development of therapeutic agents, has shifted gradually towards its prevention. In this context, many studies have linked obesity and long-standing type-2 diabetes mellitus with PDAC development. These metabolic diseases are characterized by peripheral insulin resistance, hyperinsulinemia, increased IGF-1 and chronic inflammation. Previously, crosstalk mechanisms between insulin/IGF-1 receptors, G protein-coupled receptor (GPCR) and EGF receptor (EGFR) signaling systems have been identified that potently stimulate proliferation of PDAC cells harboring a KRAS mutations. Mitogenic crosstalk depended on the function of mTORC1, ERK and PKD and opposed by AMPK, a target for the antidiabetic agent metformin. The identification of the key downstream targets of this signaling network is of fundamental significance and major translational interest. The YAP/TAZ transcriptional co-activators are emerging as points of integration in the action of KRAS, GPCRs and AMPK, all signaling pathways highly relevant in PDAC. New preliminary studies demonstrate that YAP/TAZ activation is a crucial point of convergence in the crosstalk between GPCR and insulin signaling in PDAC cells. Importantly, lipid-lowering drugs of the statin family potently blocked YAP/TAZ activity, including YAP/TAZ/TEAD-regulated genes, such as CTGF, Cyr61 and NUAK2. Lipophilic statins, including cerivastatin, simvastatin and atorvastatin, strikingly inhibited colony formation of human and mouse PDAC cells. Statins inhibited PDAC colony formation acting synergistically with metformin. Further preliminary results in vivo show that oral administration of simvastatin attenuated the loss of intact acini and the development of pre-neoplastic lesions in the pancreas promoted by an obesogenic diet in conditional KrasG12D (KC) mice. Accordingly, the central hypothesis to be explored in Project 2 of this P01 is that the well tolerated cholesterol-lowering drugs of the statin family inhibit obesity-induced promotion of PDAC via inhibition of PKD/YAP/TAZ. The Specific Aims of Project 2 have been designed to investigate important gaps in current knowledge: 1) Characterize the chemopreventive effects of statins on the progression of PanINs and development of PDAC using the conditional KrasG12D model (KC mice) subjected to control or diet-induced obesity (DIO) and in KC mice carrying a homozygous deletion of the ob gene. 2) Identify a novel molecular mechanism by which statins inhibit YAP/TEAD signaling in mouse and human pancreatic cells. 3) Characterize the inhibitory effect of a low-dose combination of statin and metformin on the development of PDAC: a novel chemopreventive strategy. The studies proposed in Project 2 of this P01 will provide mechanisms and rationale for novel chemo-preventive strategies in obesity-related PDAC. Since statins and metformin are widely used Food and Drug Administration (FDA)-approved drugs, the mechanistic and preclinical studies proposed have the potential for rapid translation to PDAC and other obesity-associated cancers.