GRANTEE: John Hunter, PhD
Institution: UT Southwestern Medical Center
Research Project: Structural Studies on Mutant K-Ras
Award: Samuel Stroum – Pancreatic Cancer Action Network – NCI, Frederick National Laboratory for Cancer Research KRAS Fellowship
Award Period: January 1, 2015 – December 31, 2015
Dr. Hunter is a postdoctoral fellow in the radiation oncology department at the UT Southwestern Medical Center in the laboratory of Dr. Kenneth Westover. Dr. Hunter’s postdoctoral research has focused on KRAS, an important signaling protein that becomes mutated in nearly all cases of pancreatic cancer, leading to uncontrolled disease progression. In collaboration with Dr. Nathanael Gray’s laboratory at the Dana Farber Cancer Institute, Dr. Hunter has been working to develop inhibitors that interfere with the protein structure of mutated forms of KRAS.
Dr. Hunter completed his BS in chemistry at the University of Utah and his PhD in biochemistry at Brigham Young University in the laboratory of Dr. Daniel Simmons. During his graduate work, Dr. Hunter studied variants of cyclooxygenase, a primary driver of inflammation, with the goal of understanding their role in the body’s immune response, chronic inflammation and cancer.
KRAS is the most frequently mutated cancer-causing gene in pancreatic cancer. The protein that results from the gene is normally involved in regulating cell growth and division. Because KRAS activity is essential for normal cell function, effective therapies must be carefully designed to alter or block the activity of the mutant version of the protein without impacting the normal protein in other cells throughout the body. Due to this challenge, and despite decades of effort by multiple academic and industrial research groups, no effective therapies directly targeting KRAS are available to patients.
KRAS activity is controlled by a small, abundant molecule called GTP. When GTP binds (touches) KRAS, KRAS becomes activated and “turns on” cellular growth signals. Normally, the signal is temporary and can be turned off by molecularly changing GTP into a similar molecule, GDP, in a process mediated by a group of enzymes (proteins that facilitate chemical reactions) called “GTPase-activating proteins,” or GAPs. Mutated forms of KRAS, such as the ones found in the cells that form many tumors, are structurally incapable of being controlled in this way. This inability to be turned off causes KRAS to be constantly active, leading to uncontrolled growth signaling and, ultimately, to cancer progression.
Dr. Hunter aims to determine the three-dimensional structure of a GAP enzyme bound to the mutated forms of KRAS. To achieve his goal, he is using a method called x-ray crystallography that is used to define, or solve, the structure of molecules. Solving the structure of these two proteins bound together is expected to enhance our understanding of the structural effects the KRAS mutations have on the GAP enzyme that render it ineffective in changing GTP and regulating KRAS activity. Dr. Hunter’s results will be further used to guide efforts to find drugs that would restore GAP’s ability to shut down KRAS signaling, creating an exciting path to novel therapies for pancreatic cancer.