UNC Chapel Hill
Department of Pharmacology
Area of Interest
My lab is interested in exploring mechanisms of cancer drug resistance. Part of my lab studies the role of kinome remodeling in response to targeted therapeutics using affinity chromatography, phosphoproteomics and mass spectrometry. The other half of my lab studies a novel class of therapeutics (the imipridones, represented by ONC201), that are in clinical studies for a number of different cancers. We have novel chemical analogs from Madera Therapeutics that are ~100 times more potent than ONC201. Using an affinity chromatography approach, we recently discovered that the mitochondrial peptidase ClpP is a major target for this class of molecules. We further showed that these compounds are highly potent activators of the ClpP protease activity. Our goals are to now investigate how activation of this mitochondrial protease impacts cell metabolism, cell signaling and potential immune recruitment to tumors. We are applying a series of proteomics and metabolomics studies to better understand the mechanism of drug action. We are studying this in breast, pancreatic and other cancer cells. A further goal is to determine if combinatorial therapies can be discovered utilizing clinically approved kinase inhibitors, anti-apoptotic compounds or immune regulators to improve the efficacy of the imipridone class of anti-cancer agents.
The Graves Lab is investigating cellular mechanisms of drug resistance in cancer. Protein kinases are key mediators of extracellular and intracellular signaling and are frequently mutated or dysregulated in cancer. We are focusing on global changes in protein kinases or the “kinome” in response to highly targeted therapeutics. In this regard we are collaborating with Dr. Gary Johnson, Dr. Ben Major and others here at UNC. To accomplish our goals we are using new methods of affinity capture and proteomics mass spectrometry to gain insight into changes in kinase expression or activity. We are specifically interested in identifying these kinome adaptations and connecting them to changes in intracellular signaling and metabolic pathways that are disrupted in cancers. We are particularly interested in studying unique kinases that are part of the “untargeted” kinome. These studies have the potential to identify new and unexpected cellular responses to drugs and to provide an experimental rationale for alternative treatments for drug resistant cancers.