- Ras oncogenes
- Rho family small GTPases
- protein kinases
- signal transduction
- target-based anti-cancer drug discovery
The broad goal of our research is to delineate the molecular basis of cancer to identify novel approaches for cancer treatment. One major focus of our studies is the study of the Ras oncoproteins, which are key regulators of signal transduction pathways that control normal cell growth and differentiation. Mutationally activated Ras proteins are found in 30% of all human cancers and are validated drivers of cancer cell growth, invasion, and metastasis. Our studies focus on neoplasms with high frequency RAS mutations – cancers of the pancreas, colon, lung and skin. We are evaluating how aberrant Ras proteins alter the regulation of metabolism, protein kinases and the phosphoproteome, and gene expression to promote oncogenesis. One facet of these studies involves a dissection of the complex signaling mechanisms that are deregulated by Ras in cancer cells, including the Raf-MEK-ERK mitogen-activated protein kinase and the PI3K-AKT-mTOR signaling cascades. Another major aspect of our studies involves the study of Ras-related proteins. The human Ras proteins are but a small branch of a larger superfamily of Ras-related GTPases. We focus on the Ras homologous (Rho) small GTPases (Rac1, RhoA), recently found mutated in human cancers. Our studies utilize patient tumor-derived xenografts (PDX) and PDX-derived cell lines, organoid cultures and mouse models of cancer. Finally, we apply chemical and genetic functional screens, gene expression, protein kinase activation and phosphoprotein profiling, to identify novel therapeutic strategies to block mutant RAS for cancer treatment.