Despite aggressive therapeutic treatment, pancreatic ductal adenocarcinoma (PDA) remains the fourth leading cause of cancer-related death worldwide, with a dismal five-year survival rate. There is a great urgency to understand the molecular mechanisms of PDA formation and progression and to identify new therapeutic targets. Oncogenic Kras has been demonstrated to be the key initiator of PDA and its continued presence is required for PDA progression. However, pharmacological targeting of Kras has thus far been unsuccessful. Oncogenic Kras has several downstream effectors that can be more easily targeted with small molecule inhibitors, including phosphoinositide 3-kinase (PI3K). Our laboratory has previously demonstrated that the PI3K p110? isoform is absolutely required for oncogenic Kras to induce pancreatic tumors in mice. We have now produced a new mouse model to test whether PI3K p110? is also required for maintenance of pancreatic tumors once they are established. Preliminary studies using this novel animal model showed that turning off p110? expression results in complete regression of pancreatic tumors caused by oncogenic Kras. Based on these results, the driving hypothesis of this proposal is that ablation of p110? induces tumor regression through changes in the Kras oncogenic program required to sustain pancreatic tumors.
Two Specific Aims will address this hypothesis.
Aim 1 will determine the kinetics of tumor regression and identify the earliest timepoint following p110? deletion when the organ is still replete with pancreatic tumors. These p110?-null pancreatic tumors will be characterized in detail by histological and immunohistochemical techniques to investigate mechanisms contributing to tumor regression.
Aim 2 will utilize pancreatic tissue extracts prepared at the timepoint identified in Aim 1 to further investigate underlying mechanisms of tumor regression. Biochemical and molecular analyses to examine the activation status and expression of key signaling pathways will be performed. In addition, RNA sequencing will be performed on these pancreatic samples to examine the whole transcriptome in an unbiased manner. Our novel animal model mimics the clinical situation in which patients that have already been diagnosed are treated with a selective PI3K inhibitor. Multiple drugs targeting all or individual PI3K catalytic isoforms, including p110?, are in clinical trials. Positive results fromour study will strongly suggest that p110? is an important drug target in PDA and warrants further clinical investigation.
Pancreatic cancer is one of the most difficult forms of cancer to effectively treat due to its minimal symptoms in the early stages, ability to quickly metastasize, and its resistance to available therapies. The goal of this proposal is to validate th enzyme phosphoinositide 3-kinase p110a as a potential new drug target for pancreatic cancer treatment. Positive results from this study will strongly suggest that p110a inhibition will be an effective treatment for pancreatic cancer and warrant further clinical studies.