Activating mutations of KIT are found in a number of human malignancies, including Gastrointestinal stromal tumors ( GIST, 80%), mast cell neoplasms (95-100%), melanoma (rare overall, but up to 25% of certain subtypes), seminoma (10-25%), and acute myeloid leukemia (<5% overall, but 20-40% of certain subtypes). Although KIT inhibitory drugs such as imatinib (Gleevec) have been effective for treating some of these cancers, the efficacy of these drugs is limited by primary as well as acquired drug resistance. Dr. Heinrich and his team have been leaders in the development of these targeted molecular treatments for KIT-mutant cancers. This proposal seeks to further improve treatment of GIST and other KIT-mutant cancers (e.g. melanoma), using combination therapy to simultaneously target KIT and other critical signaling pathways. Dr. Heinrich’s project will provide critical data that can be readily translated into the design and conduct of future clinical studies of the treatment of advanced KIT-mutant cancers. These studies will be conducted by a multidisciplinary team that includes: Dr. Michael Heinrich (Cancer Biology, Medical Oncology), Dr. Christopher Corless (Cancer Biology, Pathology, Animal Models), Dr. Jeffrey Tyner (Cancer Biology, Animal Models), Dr. Marc Loriaux (Cancer Biology, Pathology), and Dr. Harv Fleming (Animal Models of Cancer, Medical Oncology).
