The Role of Pim Kinases as a Novel Molecular Target in Pancreatic Cancer

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DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth most common cause of cancer deaths in the United States. Due to the aggressive nature of this cancer and the lack of biomarkers for early detection, the incidence and mortality rates for pancreatic cancer are nearly equivalent. The presence of oncogenically mutated K-Ras in 90% of human pancreatic ductal adenocarcinomas (PDAC) strongly suggests a critical role for this genetic mutation in the development of this disease. However, despite many years of research, there are no anti-Ras therapies that have successfully reached the clinic. Microarray studies have revealed hundreds of genes that are differentially expressed in pancreatic cancer tissues/cells compared with the normal pancreas. One of the genes that have been found to be over-expressed after oncogenic K-Ras activation in immortalized human pancreatic ductal epithelial cells is the Pim-1 kinase. Most recently, another member of the Pim family, Pim-3 kinase, was shown to be aberrantly expressed and to block apoptosis in PDAC cell lines and patient tumors. With these and other observations implicating Pim kinases as oncogenes and inhibitors of apoptosis, the overall goal of our research is to determine the functional significance of the Pim kinase family in PDAC growth. We hypothesize that inhibition of Pim function will be an effective approach for antagonizing the aberrant growth of pancreatic carcinoma. Initially, we will determine the contribution of up- regulated Pim kinase genes in K-Ras mediated transformation of pancreatic cancer cell lines (specific aim 1). In order to understand the mechanism(s) by which Pim kinases promote PDAC growth, it will be instrumental to identify novel molecular targets downstream of the Pims. Recently, one of the RUNX transcription factors was found to be a substrate for Pim-1. We plan to determine whether the RUNX transcription factors are important downstream targets of Pim kinases in pancreatic cancer (specific aim 2). Results from the proposed study will help to define the role of K-Ras activation in Pim up-regulation and determine the consequences of Pim inhibition on PDAC growth. Furthermore, these findings will allow us to critically validate these kinases as novel therapeutic targets for PDAC treatment.