The significance of this project is to develop an efficient agent for the prevention of highly lethal pancreatic cancer through targeting both c-Raf and sEH. Early detection and prevention is of great importance to reduce the mortality of pancreatic cancer. Mutant Kras is the most common and earliest molecular event involved in human pancreatic carcinogenesis;and using mutant Kras-initiated tumorigenesis in mice, it has been demonstrated that c-Raf is required for Kras-initiated tumorigenesis and knockout c-Raf blocks Kras- initiated cancer development. Chronic pancreatitis is a well-recognized risk factor of pancreatic cancer. In mutant Kras-initiated pancreatic tumorigenesis in Pdx1-Cre/LSL-KrasG12D mice (called PanKras), caerulein- induced pancreatitis enhances malignant progression. In addition to pancreatitis, mutant Kras cooperates with mutant p53 (the second most common genetic alteration) leading to pancreatic cancer development in mice, mainly via synergistically regulating ERK-MAPK and NF-kB. Anti-inflammatory EETs are quickly inactivated by pro-inflammatory soluble epoxide hydrolase (sEH). Our preliminary data showed that 1) 96% (27/28) and 90% (27/30) of human pancreatic adenocarcinoma samples displayed a distinct over-expression of sEH and p-c-Raf, respectively, and 2) our novel dual c-Raf/sEH inhibitor t-CUPM exhibited strong inhibitory effect on pancreatitis and mPanIN formation in PanKras mice. Our hypothesis is that c-Raf and sEH play key roles in pancreatic carcinogenesis initiated by mutant Kras and enhanced by pancreatitis or mutant p53;and targeting these two enzymes together is a novel and relevant preventive strategy for pancreatic cancer.
Three specific aims are proposed to test this hypothesis: 1) to determine the effects of c-Raf/sEH dual inhibitor t-CUPM, sEH inhibitor t- AUCB and Raf inhibitor Raf265/sorafenib on mutant Kras-initiated and pancreatitis-enhanced carcinogenesis in PanKras mice;2) to determine whether blocking mutant Kras-activated c-Raf using inhibitors or gene knockout suppresses mutant Kras-p53 interaction and malignant progression in Pdx1-KrasG12D-p53R172 mice;and 3) to determine the role of sEH in pancreatitis and carcinogenesis using the approach of sEH gene knockout in PanKras mice. Successfulness of the proposed study will not only lead us to demonstrate the role of c-Raf and sEH in pancreatic carcinogenesis, but also to establish a significance of t-CUPM as a novel agent for inhibiting the pancreatic cancer development.
In humans, the most common and well recognized risk factor/s and key molecular event for the development of pancreatic cancer are chronic pancreatitis and Kras gene mutation. Inflammation-activated aberrant arachidonic acid metabolites and pro-inflammatory enzyme soluble epoxide hydrolase (sEH) as well as mutant Kras-activated c-Raf are believed to be the key mediators contributing to pancreatic carcinogenesis. Therefore, targeting sEH and mutant Kras-activated c-Raf would constitute a highly significant strategy for the prevention of pancreatic cancer.
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