This proposal seeks to make therapeutic advances by characterizing targeted therapy resistancemechanisms in gastrointestinal stromal tumors (GISTs). Most GISTs express mutant, constitutivelyactivated, KIT or PDGFRA oncoproteins. We have shown that these formerly untreatable cancers can bepalliated in 80% of patients by oral single-agent therapy with the KIT/PDGFRA inhibitor, imatinib. Patientswho develop resistance to imatinib can benefit from second-line therapy with sunitinib, which is an alternateKIT/PDGFRA inhibitor. Ultimately, however, most GIST patients will progress on both of these FDA-approved kinase inhibitors. Therefore, the aims of the research proposed here are to characterizeimatinib/sunitinib resistance mechanisms in GISTs, and then identify therapeutic strategies that cancircumvent the resistance mechanisms. Notably, our preliminary studies show that GIST imatinib resistancemechanisms vary from patient to patient, and also between metastatic lesions in a given patient. We haveshown that even a single progressing GIST metastasis contains subsets of cells whose imatinib resistancemechanism differs from those in other cells from the same tumor focus. In the present effort, by revealingthe scope - and particularly the heterogeneity - of the imatinib/sunitinib resistance problem in GIST, we willprovide the understanding needed to design more effective clinical strategies. At the same time, thesestudies will enable the development of biomarkers,assays and cell lines to enable preclinical validation ofnovel therapeutic strategies to circumvent imatinib/sunitinib resistance. The goal in these studies is totranslate the understanding of imatinib/sunitinib resistance into improved medical therapy for GIST patientswho are progressing on imatinib or sunitinib. Initially, we will evaluate HSP90 inhibition as a strategy toinhibit the varied gain-of-function KIT mutations that manifest, in each patient, at the point of clinicalprogression on imatinib and sunitinib. This will be accomplished through a phase l/ll clinical trial of theHSP90 inhibitor, IPI-504, combined with imatinib, in patients showing progression of metastatic GIST onimatinib or sunitinib. Through these studies, we will translate the basic science proposed in this SPOREthrough to clinical application.
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