Novel Nematode-Based Screen for Anticancer Agents

Genetic damage that increases activity of the ras pathway of man is frequently associated withoncogenic transformations. Compounds that inhibit the action of activated ras pathway might be usedas anticancer agents. Another well-studied ras pathway controls cell determination in development ofthe hermaphrodite vulva of the nematode Caenorhabditis elegans. Recent analyses show that thecomponents of the C. elegans ras pathway are close homologues of those of the mammalian raspathway that controls mitogenesis. Furthermore, several compounds, which can block ras-inducedtransformation of mammalian cells, appear to suppress the activated ras pathway of C. elegans. Ouraim is to develop and test C. elegans-based screens for compounds that decrease activity of the C.elegans ras pathway. During Phase I, we will develop a primary high-throughput screen and test itssensitivity to compounds known to be active on the mammalian ras pathway. In addition, we willinvestigate secondary screens for establishing the site of drug action within the ras pathway. DuringPhase II we will expand the capabilities of secondary screens and apply the technologies in partnershipwith major pharmaceutical companies.