Despite significant progress in understanding the nature and development of pancreatic cancer (PanCA), it still remains a disease of near uniform lethality. Innovative strategies to prevent the development and progression of PanCA are urgently needed for its management. The goal of this exploratory application submitted in response to PA-08-185 is to test whether Nexrutine, an herbal extract from the bark of Phellodendron amurense can inhibit pancreatic cancer development in vivo and determine whether Nexrutine-mediated inhibition of Akt signaling is sufficient to inhibit pancreatic cancer growth. This goal is based on supporting data from our laboratory showing (i) inhibition of proliferation;(ii) induction of apoptosis and (iii) reduction in the levels of pAkt following treatment of multiple pancreatic cancer cell lines that differ in the status of K-Ras with Nexrutine. A review of the literature reveals that no known studies have been undertaken to assess the effect of Nexrutine in pancreatic cancer in vitro or in vivo. We have proposed two specific aims. Aim 1: Establish the preventive efficacy and bioavailability of Nexrutine in the pre clinical LSL K-ras G12D/Pdx-1Cre transgenic model. 4-5 week old LSL K-ras G12D/Pdx-1Cre transgenic mice will be administered 0, 150, 300, 600 and 900 mg/kg Nexrutine through diet for 6 months. Prevention of tumor development will be monitored by (i) non-invasive fluorine-18 fluorodeoxyglucose positron-emission tomography (FDG-PET) sequentially during progression at 8-weeks, 16-weeks and at the time of termination of the study and (ii) histological evaluation of the mPanIN lesions at the termination of the experiment. Levels of Nexrutine and expression of Akt signaling molecules will be analyzed in the pancreas using HPLC and immunohistochemistry respectively. Aim 2: Demonstrate the role of Akt and its upstream and downstream signaling pathways in Nexrutine-induced inhibition of proliferation. A variety of biochemical (cell proliferation, apoptosis), molecular and genetic approaches (knock-in and knock-out) will be used to explore the role of PI3K/Akt signaling in mediating the antiproliferative activity of Nexrutine in pancreatic cancer cells. Successful completion of this exploratory project with high translational potential will (i) identify a non-toxic compound for use in PanCA prevention;and (ii) identify Akt and down-stream signaling components as markers of Nexrutine action. Furthermore these studies will provide enough preliminary data to determine whether the efficacy of Nexrutine is specific to any particular stage of PanCA, to reverse chemotherapy induced drug resistance in preclinical models and to delineate the precise mechanism of action of Nexrutine. The LSL K-ras G12D/Pdx-1Cre transgenic model is highly appropriate murine model in which the development and progression of pancreatic cancer (PanCA) recapitulates human PanCA development and progression. Moreover since Nexrutine is already in human use the results obtained from this study may be extended to explore its use as a prevention agent for human pancreatic cancer. PUBLIC HEALTH RELEVANCE: Pancreatic cancer (PanCA) is a major health problem with incidence and mortality rates being equal. The goal of this application is to test a cost-effective and non toxic dietary supplement as an anti-PanCA agent using a preclinical model that recapitulates human pancreatic cancer. This is therefore very timely and highly significant.