Ewing sarcoma is a cancer of bone and soft tissue in children and young adults. Because currently used cytotoxic chemotherapies are not improving the survival of metastatic or recurrent Ewing sarcoma cases, there is an obvious need for a novel molecularly targeted therapy. Ewing sarcoma is primarily driven by a fusion oncoprotein called EWS-FLI1. Therefore, targeting EWS-FLI1 is a rational approach to treat this cancer. Despite many attempts, however, EWS-FLI1-targted therapy has not been developed to date and EWS-FLI1 continues to be “the perfect target without a therapeutic agent.” One way to resolve this conundrum is to find and target the “Achilles’ heel” created by EWS-FLI1. We disc...

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Ewing sarcoma is a cancer of bone and soft tissue in children and young adults. Because currently used cytotoxic chemotherapies are not improving the survival of metastatic or recurrent Ewing sarcoma cases, there is an obvious need for a novel molecularly targeted therapy. Ewing sarcoma is primarily driven by a fusion oncoprotein called EWS-FLI1. Therefore, targeting EWS-FLI1 is a rational approach to treat this cancer. Despite many attempts, however, EWS-FLI1-targted therapy has not been developed to date and EWS-FLI1 continues to be “the perfect target without a therapeutic agent.” One way to resolve this conundrum is to find and target the “Achilles’ heel” created by EWS-FLI1. We discovered a novel signaling pathway activated by EWS-FLI1. Inhibiting this pathway profoundly impairs proliferation and tumorigenicity of Ewing sarcoma. The goal of the proposed work is to understand the biological role and molecular mechanism of this novel signaling pathway in Ewing sarcoma and evaluate the feasibility of targeting this pathway. When the project is completed, we will understand how the growth of Ewing sarcoma is controlled by this signaling pathway and generate new insights to inform the therapeutic targeting of this pathway. Furthermore, the proposed research will provide a model of finding and targeting the vulnerability created by a cancer driver that itself is refractory to therapeutic targeting, a common theme in cancer research.

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