Sharon Gorski, PhD
British Columbia Cancer Agency Branch (BC Cancer)
Co-PI: Robert Young, PhD, MC, FRSC, Simon Fraser University
Research Project: ATG4 Family Members as Therapeutic Targets for Pancreatic Cancer
Award: 2018 Pancreatic Cancer Action Network Translational Research Grant
Award Period: July 1, 2018 – June 30, 2021
Dr. Gorski was awarded her PhD in developmental biology / biomedical sciences from Washington University, St. Louis in 1999; previously she had completed her BSc (honours) in biology (Simon Fraser University [SFU]) and MSc in human genetics (University of British Columbia), in Vancouver, British Columbia. She is a professor in the molecular biology and biochemistry department at SFU. Her research team is active in the study of two types of pancreatic cancer: pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumors (PNET). Dr. Gorski has been a leader in the field of autophagy, a strategy for cells to adapt to challenging environments. Her research efforts are focused on the study of autophagy in both normal development and in cancer.
Dr. Young is a professor of chemistry at SFU. He received his PhD in organic chemistry from the University of British Columbia and then a DIC (Diploma of the Imperial College) in chemistry from the Imperial College of Science and Technology in London. He has worked for 29 years in the pharmaceutical industry, including his significant research and leadership role in the discovery and bringing five novel drugs to market. Since joining SFU in 2007 he has worked on several projects looking at new ways to inhibit autophagy and other potential new therapies for cancers.
Recent studies show that pancreatic adenocarcinoma tumors are dependent on a cell survival and stress adaptation process called autophagy. Studies using pancreatic cancer cells grown in a dish and animal models have shown that inhibiting autophagy can slow tumor growth and enhance the effects of chemotherapy.
An autophagy-related protease (protein that can cleave, or cut, other proteins) called ATG4B is of interest as a potential therapeutic target (an aspect of cancer cells that can be targeted and treated by drugs), due to its important roles in the autophagy process. Several groups, including Dr. Gorski’s and Dr. Young’s, have developed small molecule ATG4B (and ATG4A) inhibitors, but the effects of ATG4 inhibition in pancreatic cancer have not yet been explored.
While inhibiting ATG4B alone in other cancers can make it harder for cancer cells to survive, the research team’s preliminary investigations revealed that selective ATG4B inhibition did not have a similar effect in pancreatic cancer cells. Instead, they found that other ATG4 family members in human cells likely compensate for loss of ATG4B.
The overall objective of this study is to investigate the biological roles and therapeutic target potential of all four ATG4 family proteins (ATG4A, ATG4B, ATG4C and ATG4D) in pancreatic cancer. To achieve this objective, Drs. Gorski and Young and their colleagues will study the effects of inhibiting single and multiple ATG4 family members in normal pancreas cells and in pancreatic cancer cells. This research will help them to determine how best to manipulate these proteins for therapeutic benefit. They will also use experimental pancreatic cancer animal model systems to test the effects of ATG4 inhibition-related therapeutic strategies on tumor growth and progression. In addition, they will examine how ATG4 inhibition affects proteins and processes within the tumor and in surrounding cells, and work to identify potential new markers indicative of response to ATG4 inhibition. Together, these studies will provide new knowledge on the biological roles and therapeutic potential of ATG4 family proteins in pancreatic cancer and may lead to the development of an urgently needed new treatment option for patients with pancreatic cancer.