- Protein phosphorylation and protein kinase-mediated signaling pathways; application of proteomics to elucidate mechanisms of drug action
- Protein kinase inhibitors as therapeutics
- Regulation of metabolic enzymes by phosphorylation and interacting proteins
- Pharmacology of mitochondrial ClpP activators in cancer and other diseases
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. To accomplish our goal, we are using methods of affinity capture and proteomics-based 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.
A second major emphasis has to do with a recent discovery from our lab. We discovered that the mitochondrial protease ClpP was a target for a new class of anti-cancer drugs known as imipridones. Working in collaboration with Madera Therapeutics and others, we are examining the pharmacology of select ClpP activators with an emphasis on how ClpP activation affects mitochondrial properties in normal and cancer cells. Our current research is focused on how ClpP activators specifically impact the cancer cell proteome and metabolome. Overall our 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 or other diseases.
Project #1 Kinome Adaptations in Disease
The human kinome is a collection of ~500 kinases that define phosphorylation-dependent cell signaling pathways. The kinome is dynamically regulated in disease and in response to targeted therapies or traditional chemotherapies. Understanding kinome adaptations may provide insight into improved approaches to prevent cancer cell growth or metastasis. Moreover, these studies may provide fundamental information on why drugs fail. We have been working closely with the labs of Der and Cox (UNC-Pharmacology) to understand kinome adaptations in pancreatic cancer. We are also applying kinome proteomics to examine kinome responses to viral infection with the Moorman lab (UNC-Microbiology/Immunology) and others at UNC.
Project #2 Examining the Pharmacology of ClpP Activators
Our recent discovery of ClpP as an unexpected target for ONC201 and the much more potent TR compounds (Madera Therapeutics), has initiated a comprehensive investigation into the biochemical/pharmacological basis of these promising new drugs. We are completing the analysis of new and even more potent TR analogues in multiple models of cancer cells and normal cells. This includes proteomics analysis (UNC-Proteomics), metabolomics analysis (Sumner Lab- UNC Metabolomics (Kannapolis)), and testing on mouse models of breast cancer (UNC-Mouse Phase One Unit). We are also examining how perturbation of this mitochondrial protease (ClpP), specifically initiates communication with nuclear and other cell signaling events. For more details-please visit the individual student projects listed in our lab website.