GRANTEE: Perry Kennedy, PhD
H. Lee Moffitt Cancer Center & Research Institute
Research Project: Discovery of Small Molecules that Bind to and Inhibit Mutant K-Ras
Award: 2016 Pancreatic Cancer Action Network – NCI Frederick National Laboratory for Cancer Research KRAS Fellowship
Award Period: April 1, 2016 – March 31, 2017
Following an undergraduate degree in chemistry from Randolph-Macon College in Ashland, Va., Dr. Kennedy pursued graduate studies at the University of Virginia. After earning a PhD in pharmacology from the University of Virginia, Dr. Kennedy completed initial postdoctoral work at the Mayo Clinic Cancer Center in Jacksonville, Fla. In both his graduate and subsequent postdoctoral work, he discovered and utilized novel chemical compounds, called small molecule inhibitors, to shut down certain protein activity and specific cellular signaling pathways in order to stop cancer cells from surviving and growing. He has also been involved in preclinical efforts to advance promising drug candidates through progressive stages of testing toward the patient. Currently, Dr. Kennedy is a postdoctoral research fellow in the department of drug discovery at the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Fla. In his position in Dr. Said Sebti’s group, he will screen many candidate small molecules to discover specific inhibitors of mutant KRAS, which is a protein that contributes to the initiation and progression of almost every pancreatic cancer case.
Normal cells receive cues from their environment that help them know when to maintain their survival, make copies of themselves and move around. Once these cues are sensed by the cell, they trigger a switch inside the cell that activates a protein called KRAS. When KRAS switches “on,” it binds to other proteins in the cell to turn on cell survival, proliferation and motility (cellular movement). Normally, KRAS is able to switch itself “off” at an appropriate time to help regulate these processes. Mutant KRAS, however, is unable to turn itself “off,” and thus the switch remains “on” constantly, contributing to cancer. KRAS is mutated in 95 percent of pancreatic cancer cases and is known to play a critical role in early-stage pancreatic cancer development as well as disease progression.
Small molecule inhibitors function to selectively block protein signaling pathways that are abnormally active in cancer cells, sparing normal cells. A small molecule inhibitor that effectively blocks mutant KRAS activity could stop or slow pancreatic cancer cell growth and significantly improve patient outcomes. Dr. Kennedy aims to screen large chemical libraries (collections) of small molecules to determine which ones are capable of binding to mutant KRAS to change its protein structure and turn it “off.” He will also separately evaluate which ones can prevent mutant KRAS (in its “on” state) from binding to and activating other signaling proteins in the context of pancreatic cancer. Finally, Dr. Kennedy will further investigate any lead small molecule inhibitor(s) that show activity against mutant KRAS by determining the three-dimensional structure of the inhibitor attached to the KRAS protein. The knowledge gained from this structure would allow scientists to develop better, more effective inhibitors of KRAS to shut down tumor formation. This project aligns very closely with and complements the National Cancer Institute’s RAS Initiative, which is also using small molecule libraries to screen for inhibitors of KRAS. If successful, Dr. Kennedy’s project would represent an important first step toward developing mutant KRAS inhibitors for the benefit of pancreatic cancer patients.