GRANTEE: Lynn McGregor, PhD
Institution: University of California, San Francisco
Research Project: Development of an Oncogene-Specific Inhibitor of K-Ras G12D
Award: Pancreatic Cancer Action Network – NCI, Frederick National Laboratory for Cancer Research KRAS Fellowship
Award Period: January 1, 2015 – December 31, 2015
Dr. McGregor is a postdoctoral fellow at the University of California, San Francisco (UCSF). Dr. McGregor was an undergraduate at Yale University where she studied cell-penetrating peptides in the laboratory of Dr. Alanna Schepartz. She then earned a PhD in Chemical Biology at Harvard University. Dr. McGregor’s graduate work in the laboratory of Dr. David R. Liu focused on the development of novel methods for identifying protein-small molecule interactions and has potential applications in early stage drug discovery. Under the mentorship of Dr. Kevan Shokat at UCSF, Dr. McGregor is currently pursuing the development of a small molecule inhibitor of K-Ras G12D, which is found in half of all pancreatic cancers.
In healthy cells and tissues, a protein called K-Ras helps regulate growth and division by switching between an “on” state and an “off” state. Nearly all pancreatic tumors contain mutated versions of K-Ras that remain in the “on” state and send signals that result in uncontrolled cancer cell growth and division. Because of the frequency of mutation and dependency of pancreatic cancer cells on mutant K-Ras activity, blocking K-Ras has been considered an attractive therapeutic strategy. However, for over thirty years, academic and industrial groups have attempted to develop small molecules that block K-Ras function, but the first direct inhibitors were not identified until 2012. The most potent new K-Ras inhibitors only recognize the K-Ras G12C mutant, which is most common in lung cancers. During the Pancreatic Cancer Action Network – NCI, Frederick National Laboratory for Cancer Research KRAS Fellowship, Dr. McGregor will pursue a strategy to develop a small molecule that irreversibly blocks the K-Ras G12D mutant, found in half of pancreatic cancers. Making use of the unique chemical properties of the K-Ras G12D mutant protein, Dr. McGregor will make revised versions of previous successful K-Ras inhibitors and test their ability to selectively and irreversibly interact with K-Ras G12D. Dr. McGregor will then ask whether molecules that interact with K-Ras G12D can prevent the growth and division of human pancreatic cancer cells that contain K-Ras G12D. A successful molecule should not affect normal, non-mutated K-Ras found in healthy cells and tissues, thereby reducing side effects. Small molecules developed during this Fellowship will have use both as chemical starting points for potential therapeutics and as tools to study the role of the K-Ras G12D mutation in the progression of pancreatic cancer.