Research
The broad goals of our research are to elucidate the genetic and molecular basis of cancer and to develop targeted therapies for cancer treatment. Our research is focused on two main areas. First, the RAS oncogenes comprise the most frequently mutated oncogenes in human cancers (33%), in particular cancers where current therapeutic optio ns are limited or ineffective (e.g., lung, pancreatic, colon cancers). However, despite considerable effort over almost three decades, currently, no effective anti-Ras therapies have reached clinical application. Since Ras is not a classically “druggable” target, it is believed that further molecular understanding of Ras oncoprotein function and how it causes aberrant signal transduction will provide critical clues for development of the elusive anti-Ras drug(s). Second, the three Ras proteins are founding members of a large (>150) superfamily of Ras-related proteins. Much of our current investigation centers on members of the Rho family of Ras-related proteins (e.g., RhoA, Rac1 and Cdc42). Rho family proteins function as regulators of diverse spectrum of cellular processes that include actin cytoskeletal organization, gene expression and cell cycle progression. Rho family proteins serve as key players in promoting the invasive and malignant properties of tumor cells. Unlike Ras proteins, mutational activation of Rho proteins has not been identified in human cancers. Instead, indirect mechanisms have been discovered. We have focused on elucidating the molecular mechanisms of Rho activation in cancer and have identified diverse mechanisms that include aberrant gene transcription, protein phosphorylation, and abnormal protein ubiquitination and protein degradation. Our research is focused on colorectal, lung and pancreatic cancer, and melanoma, and involves the use of human cell culture and mouse models of cancer, gene profiling, protein crystallography and C. elegans genetics.
