Pancreatic ductal adenocarcinoma (PDAC) is a painful, deadly, and incurable disease for which effective treatments remain to be discovered and tested. The OVERALL OBJECTIVES of this study are to define mechanisms underlying the regulation of PDAC cell growth, by focusing on further characterizing a novel pathway for which individual components can be targeted pharmacologically. Previous studies along with our preliminary data indicate that mitotic aberrations and PDAC cell growth, two highly interrelated processes, rely on signaling from Aurora A (AurkA) to the HP1?-G9a pathway. Mutations or aberrant expression of either AurkA or the HP1? -G9a complex are implicated in the development of neoplasms of different origins, including PDAC. We will test the CENTRAL HYPOTHESIS that a novel AurkA-HP1?-G9a pathway regulates mitotic progression and PDAC cell growth in a manner amenable to pharmacological inhibition using combination therapy. Congruently, our SPECIFIC AIMS are: 1. To characterize the function of the HP1?-G9a complex as a downstream mediator of the effects of AurkA on mitotic progression in PDAC cells;2. To characterize cellular and molecular mechanisms that contribute to the inhibitory effects of the AurkA-HP1?-G9a pathway on PDAC growth;and 3. To characterize the effects of combined targeting of the AurkA-HP1?-G9a pathway on PDAC progression in orthotopic xenografts and genetically engineered mice models. Thus, our research will span from the level of molecules to cell populations to the whole organism. These studies are feasible for our laboratory, which has developed the appropriate conceptual framework, reagents, trained personnel and established collaborations to execute the proposed research. The design of this proposal is innovative as it seeks to maximize the yield of new mechanistic knowledge and pharmacological interventions, which impact on PDAC tumor growth. Since PDAC is a dismal disease, the discovery and proposed study of this novel AurkA-HP1?-G9a pathway bears significant biomedical relevance.
These investigations represent a defined strategy to discover novel therapeutic approaches for pancreatic ductal adenocarcinoma, a painful and deadly disease that ranks 4th in USA cancer deaths, for which no effective treatment currently exists. We propose to investigate a pathway that regulates pancreatic cancer cell division and growth in a manner that can be exploited by combined therapies for the ultimate goal of treating this dismal disease.
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|Mathison, Angela; Escande, Carlos; Calvo, Ezequiel et al. (2015) Phenotypic Characterization of Mice Carrying Homozygous Deletion of KLF11, a Gene in Which Mutations Cause Human Neonatal and MODY VII Diabetes. Endocrinology 156:3581-95|
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|Loncle, Celine; Bonjoch, Laia; Folch-Puy, Emma et al. (2015) IL17 Functions through the Novel REG3?-JAK2-STAT3 Inflammatory Pathway to Promote the Transition from Chronic Pancreatitis to Pancreatic Cancer. Cancer Res 75:4852-62|
|Leonard, Phoebe H; Grzenda, Adrienne; Mathison, Angela et al. (2015) The Aurora A-HP1? pathway regulates gene expression and mitosis in cells from the sperm lineage. BMC Dev Biol 15:23|
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