Gastrointestinal Stromal Tumor is the most common mesenchymal tumor of the GI tract. The current standard of care for metastatic or inoperable GIST, therapy with small molecule inhibitors targeting the receptor tyrosine kinase KIT, has vastly improved the outcome for patients with this disease. However, many patients who initially respond to therapy exhibit refractory disease within a few years. In these cases, options are still limited, and patients face therapy choices with more severe side effects. GIST is also a paradigm for targeted treatment in solid tumors, and findings in this disease may well be extrapolated to other types of cancer. The goal of the project described in this application is t investigate how Fibroblast Growth Factor 2 (FGF2) contributes to the development of imatinib resistance in Gatrointestinal Stromal Tumor (GIST). Under this goal, aims drawing from preliminary data will be to 1) Characterize a potential direct interaction between the receptor tyrosine kinases KIT and Fibroblast Growth Factor Receptor 3 using Bimolecular Fluorescence Complementation (BiFC) microscopy, 2) Determine the mechanism of FGF2 upregulation in a novel imatinib-resistant GIST cell line, and evaluate the clinical relevance of this mechanism in GIST patient samples, and 3) Determine whether there is a statistically significant correlation and a functional link between tumor-intrinsic expression of FGF2 and resistance to targeted therapy in GIST. The thesis research will contribute to the mechanistic understanding of GIST cell signaling and resistance. Findings have the potential to provide new markers for the stratification of GIST patients, and/or rationale for the use of new targeted therapeutics or combination therapies, with the ultimate aim of anticipating or overcoming resistance to targeted therapy in this disease. Thus, this project addresses the most pressing question in the GIST field, which has a large impact on patients' quality of life and overall survival.

Public Health Relevance

Gastrointestinal Stromal Tumor (GIST) is the most common mesenchymal cancer of the GI tract. Although we have a thorough understanding of the genetic aberrations driving GIST, and drugs targeting these mutations are initially very successful, there is still a high risk of recurrence for patients receiving these therapies. I am proposing research o characterize a new pathway of resistance, with the ultimate goal of laying the groundwork for improved therapy options and better outcomes for patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1)
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Damico, Mark W
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Oregon Health and Science University
Schools of Medicine
United States
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Yoda, Akinori; Adelmant, Guillaume; Tamburini, Jerome et al. (2015) Mutations in G protein ? subunits promote transformation and kinase inhibitor resistance. Nat Med 21:71-5
Javidi-Sharifi, Nathalie; Traer, Elie; Martinez, Jacqueline et al. (2015) Crosstalk between KIT and FGFR3 Promotes Gastrointestinal Stromal Tumor Cell Growth and Drug Resistance. Cancer Res 75:880-91
Traer, Elie; Javidi-Sharifi, Nathalie; Agarwal, Anupriya et al. (2014) Ponatinib overcomes FGF2-mediated resistance in CML patients without kinase domain mutations. Blood 123:1516-24