The focus of my research is concentrated on detection and molecular characterization of prognostic markers in soft tissue sarcomas. More specifically, a significant effort in my lab is dedicated to the characterization of molecular mechanisms of pathogenesis and drug resistance in gastrointestinal stromal tumors (GIST). Near all GISTs are KIT expressing and KIT-signaling driven mesenchymal tumors. The principal genetic event responsible for the GIST pathogenesis has been identified to be a gain-of-function mutation in the KIT proto-oncogene or occasionally in PDGFRA gene. As these two receptor tyrosine kinases are highly sensitive targets to specific kinase inhibition (such as imatinib mesylate) when constitutively activated, GIST has become the prototype disease for the molecular therapy of cancer. We are presently following the following projects: (1) the impact of KIT genotype on outcome and response to selective tyrosine kinase inhibitors, such as imatinib; (2) relationship of gene expression profiling to KIT mutation status and clinical outcome in GIST patients; and (3) the role of these events in triggering mechanisms of tumor progression and resistance to therapeutic intervention, such as imatinib, using our recently developed KITV558del GIST mouse model; (4) in-vitro screening of second generation kinase inhibitors on a library of genetically engineered cell lines harboring imatinib sensitive single KIT mutations, as well as imatinib-resistant double KIT mutations; (5) to identify alternative signaling pathways in wild-type GIST, including pediatric GIST by gene expression and proteome array analysis.
Using a genomic scale approach, our lab is also investigating candidate genes involved in tumor progression and also suitable for targeted intervention in other sarcoma types, such as liposarcoma, malignant fibrous histiocytoma, clear cell sarcoma, etc. Recently, in collaboration with Dr Ladanyi's lab we have identified a novel EWS-CREB1 fusion transcript in gastrointestinal clear cell sarcoma and angiomatoid fibrous histiocytoma.
