Notch Decoy Targeting the Notch Signaling Pathway in Pancreatic Cancer

"Notch receptors are involved in regulating the balance between cell differentiation and stem cell proliferation during organogenesis of the pancreas, and their expressions are absent in adult pancreas. However, upregulation of Notch1, Notch2, Notch3, and Notch4 receptors and their ligands are frequently observed in human pancreatic cancer and PanIN (pancreatic intraepithelial neoplasia). This notion that the Notch pathway is dysregulated in pancreatic cancer is further supported by a genomic analysis revealing that at least one of the genes in the Wnt/Notch signaling pathway is mutated in 100 percent human pancreatic ductal adenocarcinoma (PDA). The upregualtion of the Notch genes are also observed in a genetically engineered mouse model, LSL-KrasG12D; PDX1-Cre, which has been validated to simulate human pancreatic cancer. Recent reports show that the development of PanINs in this mouse model is aided by activated Notch signaling and the synergy between Notch and Kras. All of these evidences suggest that the reactivation of the Notch signaling in adult human pancreas is not a mere bystander effect, but an active contributor to pancreatic tumorigenesis. This leads us to hypothesize that inhibition of Notch pathway activation may diminish the growth or progression of pancreatic tumor and serves as an effective therapeutic option. In this proposal, we will explore if blocking the Notch signaling in genetically engineered mouse models will mitigate the growth or progression of PanIN to invasive cancer and metastasis. This will be accomplished by either deleting the Notch1 gene or blocking the Notch signaling using a novel Notch1 decoy. These two complimentary approaches will allow us to evaluate the impacts of Notch1 inactivation on the tumor and/or its microenvironment. This proposal will be the first step to investigate the utility of the Notch1 decoy in treating pancreatic cancer. This AACR/PanCAN grant will provide the vital support for our team of research scientists with diverse expertise in pancreatic cancer, the Notch signaling pathway, and angiogenesis to advance a novel therapeutic agent for pancreatic cancer."