Grant: CIHR Fellowship

Pancreatic cancer is the deadliest solid tumor cancer with a five-year survival rate of less than five percent. This is because it is very hard to detect in early stages and there are no curative treatments for late stage pancreatic cancer. Even though nearly all pancreatic cancers (>95%) have an oncogene KRAS mutation, how KRAS changes the cell surface proteins of early stage pancreatic cancer cells is not well understood. Using a simple cell model system, the Wells lab have identified a number of cell surface proteins that are found increased in cells with an oncogenic KRASG12V mutation, and a panel of antibodies was generated towards some of these targets. One particular antibody was able to identify a protein that's present in seven different established pancreatic cancer cell lines but not in cells derived from healthy pancreatic tissue. Encouraged by this result, this antibody was armed with a toxic compound and selectively killed tumor cells. This antibody was also engineered into a bispecific T-cell engager (BiTE) to successfully target T-cells to the tumor cells. When tagged with a radiolabeled isotope, this antibody readily detected tumors in mice using antibody-based positron emission tomography (immuno-PET) imaging techniques. Encouraged by these preliminary results, I hope to 1) expand our efforts to systematically investigate how different RAS mutations change cell surface protein expression in pancreatic cells, 2) generate and validate antibodies towards up to 48 early stage pancreatic cancer surface markers, and 3) further develop our existing antibodies to pre-clinical stage as immunotherapies and immuno-PET reagents. Collectively, these studies will result in a pool of new drug candidates with board implication in understanding pancreatic cancer, and high impact in developing novel immunotherapy/imaging agent towards pancreatic cancer.