Investigators

Summary

The majority of gastrointestinal stromal tumors (GISTs) are caused by oncogenic mutations in the KIT or PDGFRA protein kinases. GISTs are the prototypical example of a solid tumor entity that was fatal in the past but that can now be successfully treated with a novel class of drugs, small molecule kinase inhibitors. Imatinib mesylate (Gleevec') is the first and most prominent inhibitor belonging to this group. Although imatinib has revolutionized the treatment of GIST, the occurrence of imatinib-resistant tumors is a problem for a large number of patients. It is therefore imperative to find novel treatment options for these patients. Although an FDA-approved second-line therapy (Sutent') and an array of potential third-line therapeutic options are in clinical and preclinical trials, most of these compounds also target the activated KIT or PDGFRA kinase. This "kinase-centric" approach to novel therapies is difficult, however, because the most prominent imatinib-resistance mechanisms involve secondary mutations in KIT/PDGFRA genes themselves. Our laboratory therefore uses a different approach to identify novel treatments. We are focusing on two major strategies: 1. Over the past several years, we have successfully applied a candidate approach to find new therapeutic targets. Using this strategy, we are dissecting the molecular mechanisms of action of imatinib in the induction of apoptosis and tumor cell quiescence. Having identified the molecular players that are involved in these processes allows us to target these molecules for therapeutic purposes. 2. The second major line of research employs medium- to large-scale screening strategies. We are currently using siRNA-based screens to identify survival genes that could be targeted for therapy in GIST. Furthermore, we are screening drug compound libraries to rapidly identify novel therapeutic agents. We are also applying the above-mentioned strategies to other soft-tissue sarcomas, such as leiomyosarcomas.