Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract, with an estimated annual occurrence of 3,300-6,000 in the United States. GISTs are believed to arise from the Interstitial Cells of Cajal, the pacemaker cells of the gut, or from interstitial mesenchymal precursor stem cells. GISTs express and are clinically diagnosed by immunohistochemical staining of CD117, the 145 kDa transmembrane glycoprotein KIT. The most common primary sites for these neoplasms are the stomach (60-70%), followed by the small intestine (25-35%). The majority (~80%) of GISTs possess gain-of-function mutations in KIT in either exons 9, 11, 13 or 17, causing constitutive activation of the kinase receptor, whereas smaller subsets of GISTs possess either gain-of-function mutations in PDGFRA (~5-8%), BRAF (<2%) or no mutations in either KIT or PDGFRA (~12-15%). The majority of the GISTs lacking these mutations have recently been shown to have defects (i.e. mutations, hypermethylation) in the succinate dehydrogenase (SDH) pathway. Imatinib mesylate, an oral drug that inhibits the KIT/PDGFRA, is very effective at controlling metastatic disease and preventing recurrence after initial surgery. Unfortunately, in patients with advanced disease, imatinib stops working after approximately two years. 

Our group is studying what happens to GIST cells when they are treated with imatinib and what leads to clinical resistance. Our initial studies identified genetic markers that could predict the response of patients with metastatic/recurrent GIST to imatinib, and current studies focus on genomic and proteomic changes associated with the pathogenesis of GIST and response to molecular targeted therapies. We have also shown an important role for IGF signaling in adult and pediatric GISTs that lack activating kinase mutations. Based on these studies, clinical trials have been developed (by Dr. Margaret von Mehren, Director of the Sarcoma Program at  Fox Chase) with the goal of ultimately eradicating this disease.