Research: Ewing sarcoma is the second most common bone malignancy of childhood. Treatment regimens are highly toxic and patients with metastatic disease are rarely cured. Efforts to utilize targeted therapies for patients with Ewing sarcoma have been limited due to an insufficient number of validated clinical targets. To this end, I performed a kinome profiling screen of Ewing sarcoma cell lines that identified focal adhesion kinase (FAK) as highly active. I demonstrated that activated FAK is expressed in tumors and downregulation of this target impairs growth, survival, and tumor proliferation in this disease. However, it is currently unknown how FAK is activated in Ewing sarcoma, whether FAK is necessary for the development of metastasis as seen in other cancers, and how to best utilize FAK inhibitors in the clinic for patients with Ewing sarcoma. In a recent screening effort to identify non-kinase molecular vulnerabilities in Ewing sarcoma, I found that Ewing sarcoma cell lines are dependent on a number of integrins, a class of transmembrane receptors known to activate FAK and play a role in cancer metastasis. Based on additional preliminary data, I now propose to demonstrate that Ewing sarcoma is dependent on one of these integrins, ITGB2, for growth, survival, tumor progression, and FAK activation. I also propose to show that ITGB2 and FAK are necessary for the development of metastasis in this disease. Finally, in a large-scale screening effort to identify therapeutic combinations for use with FAK inhibitors, I found that Aurora kinase inhibitors synergized with FAK inhibition in a Ewing sarcoma cell line. Therefore, I propose to validate the preliminary finding that Aurora B kinase inhibitors in combination with FAK inhibition is an efficacious combination and a candidate for testing in second-generation clinical trials for patients with Ewing sarcoma. Candidate Career Goals: The time period encompassed by this career development award will be the final critical training phase of my career prior to transition to independence. During this time I will gain the knowledge, laboratory skills, writing experience, and maturity necessary to apply for a tenure-track physician-scientist position in academic pediatric oncology. In the long- term, my goal is to be a leading expert in the identification of new therapeutic strategies for pediatric sarcomas through the use of innovative approaches in the lab. The research proposed in this application will be performed under the mentorship of Dr. Kimberly Stegmaier at Dana- Farber Cancer Institute and Dr. Todd Golub at the Broad Institute with guidance of a scientific advisory committee composed of leading experts in cancer biology. Environment: The Dana-Farber Cancer Institute houses internationally recognized research programs in cancer biology and translational discovery. The Division of Pediatric Oncology has a distinguished record of training young physician-scientists for leadership roles in pediatric cancer research. Graduates from this training have gone on to make transformative discoveries that continue to shape the future of clinical care for pediatric cancer patients.
Despite an accelerated pace of cancer discovery over the last decade, little has changed in our approach to treating high-grade pediatric solid tumors. Focal adhesion kinase (FAK) is a newly validated therapeutic target in Ewing sarcoma, a devastating bone malignancy of adolescence and young adulthood. The work proposed in this application aims to determine the role of another adhesion molecule, ITGB2, determine its potential role in FAK activation in Ewing sarcoma, validate the importance of ITGB2 and FAK in poor-prognosis metastatic disease, and identify highly effective combinations of drugs with FAK inhibitors for testing in clinical trials.
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