Pancreatic ductal adenocarcinoma (PDA) is a deadly human cancer with a overall 5-year survival rate of less than 5%. Better preventive and treatment strategies are desperately needed for this disease. Unlike most other solid malignancies, PDA is surprisingly homogeneous genetically. The great majority (>90%) of human PDA contain a unique genetic signature: they have activating mutations of the Kras proto-oncogene. The critical role of Kras activation in the development of this malignancy is supported by studies showing that mice expressing an activated Kras mutant in pancreatic cells develop the full spectrum of premalignant and malignant tumors commonly found in pancreatic cancer patients. This proposal addresses an important research question with high translational value: does downregulation of phosphatidylinositol 3-kinase (PI3K) p110? prevent the development or block the progression of pancreatic cancer induced by oncogenic Kras? Aim 1 uses molecular and cellular studies to gain mechanistic insight into how PI3K p110? regulates and is regulated by Kras. Results from these experiments will increase our knowledge regarding how to treat all Kras-induced cancers.
Aim 2 uses genetic ablation of PI3K p110? in a mouse model of PDA induced by Kras and p53 mutations to test if p110a is a viable therapeutic target in pancreatic cancer.
Aim 3 uses a pharmacological approach to investigate if chemical inhibition of PI3K prevents is a safe approach to prevent the development of PDA in the Kras induced tumors. Results from this study have obvious clinical implications for the testing of existing PI3K inhibitors and for the development of novel compounds in this class. Successful completion of our animal studies should lead to investigation of natural and synthetic PI3K inhibitors as a chemopreventive intervention for pancreatic cancer in humans.
Pancreatic ductal adenocarcinoma is a deadly human cancer with an overall 5-year survival rate of less than 5%. Better preventive and treatment strategies are desperately needed for this disease that kills ~33,000 Americans a year, making it the fourth leading cause of cancer death. This project is directed at understanding the importance of the phosphatidylinositol 3-kinase (PI3K) biochemical pathway in mediating pancreatic tumor formation. Successful completion of our studies should lead to investigation of PI3K inhibitors as preventive interventions for pancreatic cancer in humans.
|Liou, Geou-Yarh; DÃ¶ppler, Heike; Braun, Ursula B et al. (2015) Protein kinase D1 drives pancreatic acinar cell reprogramming and progression to intraepithelial neoplasia. Nat Commun 6:6200|
|Mehner, Christine; Miller, Erin; Khauv, Davitte et al. (2014) Tumor cell-derived MMP3 orchestrates Rac1b and tissue alterations that promote pancreatic adenocarcinoma. Mol Cancer Res 12:1430-9|
|Nelson, Victoria L B; Jiang, Ya-Ping; Dickman, Kathleen G et al. (2014) Adipose tissue insulin resistance due to loss of PI3K p110Î± leads to decreased energy expenditure and obesity. Am J Physiol Endocrinol Metab 306:E1205-16|
|Bailey, Jennifer M; DelGiorno, Kathleen E; Crawford, Howard C (2014) The secret origins and surprising fates of pancreas tumors. Carcinogenesis 35:1436-40|
|Wu, Chia-Yen C; Carpenter, Eileen S; Takeuchi, Kenneth K et al. (2014) PI3K regulation of RAC1 is required for KRAS-induced pancreatic tumorigenesis in mice. Gastroenterology 147:1405-16.e7|
|DelGiorno, Kathleen E; Tam, Jason W; Hall, Jason C et al. (2014) Persistent salmonellosis causes pancreatitis in a murine model of infection. PLoS One 9:e92807|
|Delgiorno, Kathleen E; Hall, Jason C; Takeuchi, Kenneth K et al. (2014) Identification and manipulation of biliary metaplasia in pancreatic tumors. Gastroenterology 146:233-44.e5|
|Hall, Jason C; Crawford, Howard C (2014) The conspiracy of autophagy, stress and inflammation in acute pancreatitis. Curr Opin Gastroenterol 30:495-9|
|Ray, K C; Moss, M E; Franklin, J L et al. (2014) Heparin-binding epidermal growth factor-like growth factor eliminates constraints on activated Kras to promote rapid onset of pancreatic neoplasia. Oncogene 33:823-31|
|Dou, Zhixun; Pan, Ji-An; Dbouk, Hashem A et al. (2013) Class IA PI3K p110Î² subunit promotes autophagy through Rab5 small GTPase in response to growth factor limitation. Mol Cell 50:29-42|
Showing the most recent 10 out of 18 publications