Geoffrey Clark, PhD

Many lung cancers are driven by the abnormal activity of a cancer-promoting protein called RAS. This can be caused by mutations in the ras gene, or by defects that occur in the proteins that normally regulate RAS protein. Recently drugs have been developed that inhibit one subset of mutant RAS, but no drugs can address the remaining majority of RAS-driven lung tumors without this mutation. RAS works by binding to other proteins and activating them to drive cancer. One of these binding proteins is called RALGDS. It appears to be critical for RAS to induce tumor formation. We have developed the first targeted inhibitor for RALGDS and we have shown that we can use it to suppress RAS-mediated tumor formation in a test tube and mouse model. We will determine how it works and find the most effective strategy for its use against primary tumor models of RAS-driven lung cancer.

Update:
RALGDS is a member of the RALGEF protein family. We have begun testing our first-in-class RALGEF oncoprotein inhibitor in lung cancer models. We find it is effective against multiple lung tumor cell lines and we have and developed evidence that it is acting against cancer stem cells. In year two we will determine the activity of our inhibitor on a transgenic mouse model of RAS-driven lung cancer.