Our research centers on understanding the molecular basis of human carcinogenesis. Specifically, our research studies have dealt with three distinct aspects of Ras family oncogene proteins and on the discovery of novel oncogenes involved in specific human cancers. First, we are interested in complex nature of signal transduction pathways that mediate the oncogenic actions of Ras. Ras is mutationally activated in 30% of all human cancers, with high frequencies seen in lung, colon, and pancreatic cancers. It has become apparent that Ras regulates a multitude of signaling pathways via its interaction with a surprisingly diverse spectrum of downstream effector targets, which include the Raf serine/threonine kinase and the Tiam1 activator of Rac. To date, at least a dozen distinct Ras effector targets have been identified and we are interested in how each contributes to oncogenic Ras deregulation of gene expression and promotion of tumor cell invasion and metastasis.

Second, we now know that the three Ras proteins represent only a mere subset of a large superfamily of Ras-related proteins. Mammalian members of this family number more than 100, with more likely to be discovered. Since Ras-related proteins share strong sequence and biochemical similarities with Ras proteins, a logical question is whether the aberrant function of any other members of this superfamily are also oncogene proteins involved in cancer development. Much of our current interest has centered on members of the Rho family of Ras-related proteins, which function as regulators of a wide spectrum of cellular processes that include actin cytoskeletal organization, gene expression and cell cycle progression. How Rho proteins contribute to Ras transformation, and what signaling pathways connect Ras with Rho, are questions that we are pursuing in our studies. Another class of Ras superfamily proteins appears to function as tumor suppressors, rather than oncogenes. Understanding why these proteins share significant biochemical properties with Ras, yet inhibit tumor progression, is a goal of our studies.

Third, we are involved in drug discovery efforts to target Ras for cancer treatment. For example, our studies involve evaluating the ability of inhibitors of Ras signaling (e.g., Raf and MEK kinase inhibitors) to block the growth of Ras mutation positive human cancers. Finally, we have developed biological screens to search for novel oncogenes that are activated in a variety of human cancers, including carcinomas of the breast, colon, prostate and pancreas. In summary, our studies span the broad range from gene discovery to drug discovery, with the long range goal of identifying better diagnostic and therapeutic approaches for cancer treatment.