Gene expression-based screening of inhibitors of signal transduction

Advances in our understanding of cellular function and signal transduction have resulted in ever increasing number of therapeutical targets and, consequently, underscored a demand for simple and universally applicable markers to monitor activity of the biological system. Gene expression-based screening is based on the assumption that introduction of a compound into biological system would affect directly or indirectly the gene expression, initiating an elaborate expression response to the disturbance of the system. In my thesis work I investigated new strategies to create a limited expression signature accurately representing the activation state of a biological system and to decrease redundancy in the complex expression pattern. To test the validity of our approach, I generated an expression signature for PDGF activation of ERK pathway in human fibroblasts and used this signature to screen a chemical compound library for an inhibitor of PDGFR/ERK pathway. As a result of the screen, I identified aurintricarboxylic acid, ATA, as a new inhibitor of PDGF receptor. The success of this study suggests that endogenous mRNA expression signature is an effective tool to monitor activation state of a cell signaling pathway and can be broadly used to identify compounds modulating condition of a biological system. Thesis Supervisors: Eric S. Lander; Todd R. Golub Titles: Director of the Broad Institute; Director of Cancer Program, Broad Institute at MIT