Role of atypical PKCs in Pancreatic Tumor Growth and Metastasis

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DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer deaths in the United States with an overall 5-year survival rate of <5%. The American Cancer Society estimated that, in 2007, approximately 37,170 people in the United States would be diagnosed with pancreatic cancer and about 33,370 would die of the disease. The poor prognosis of pancreatic cancer is attributable to its tendency for late presentation, aggressive local invasion, early metastases, and poor response to chemotherapy. Oncogenic K-ras mutations are detected in >90% of invasive pancreatic ductal adenocarcinoma (PDAC). Oncogenic K-ras and its downstream effector pathways are required for initiation and maintenance of PDAC. Our lab and others have identified a requisite role for atypical protein kinase Cs (aPKCs), PKC iota (PKC?) and PKC zeta (PKC?) in oncogenic K-ras signaling in vitro and in vivo. Our preliminary results demonstrate that pancreatic cancer, and multiple human pancreatic cancer cells express PKC? and PKC?. Genetic or pharmacological inhibition of PKC? and PKC? blocks transformed growth of human pancreatic cancer cells in vitro. Genetic inhibition of aPKCs blocks tumor cell proliferation in vivo, and blocks Hedgehog (HH-GLI) signaling pathway activity. Based on this preliminary data, we hypothesize that aPKCs play an essential role in pancreatic tumor growth and metastasis in vivo, and are therefore a potential target for pancreatic cancer therapy. Three specific aims are proposed to test this hypothesis. In Aim 1 we will determine whether pharmacological inhibition of aPKCs blocks tumor growth and metastasis in an orthotopic model of PDAC, in Aim 2 we will determine whether aPKCs are required for growth and metastasis in an orthotopic model of PDAC and in Aim 3 we will evaluate the effect of inhibition of aPKC signaling on oncogenic cellular signaling in pancreatic tumors in an orthotopic model of PDAC. Completion of the proposed studies will generate important in vivo data regarding the requirement for aPKCs in pancreatic cancer growth and metastasis, and will provide a characterization of the ability of a molecularly-targeted aPKC inhibitor to inhibit pancreatic tumor growth and metastasis. In addition, we will begin to dissect the oncogenic signaling pathways regulated by aPKCs, allowing us to make rational decisions about potential combination therapy in the future. The proposed studies will generate significant preliminary data to support a comprehensive grant application to evaluate aPKCs as a potential target for PDAC chemotherapy in a clinical setting. PUBLIC HEALTH RELEVANCE: Pancreatic cancer has the worst survival rate of any solid tumor due to its late detection, early metastasis and resistance to conventional chemotherapy. This project will characterize the requirement for atypical protein kinase Cs (aPKC) in pancreatic cancer growth and metastasis in a pre-clinical model. The results of these studies will likely provide support for future clinical trials utilizing a molecularly targeted inhibitor of aPKCs to treat pancreatic cancer. We will also evaluate the role of aPKCs in oncogenic signaling with an eye toward rational design of combination therapy studies for treatment of pancreatic cancer.