Cancers in children are frequently caused by the joining of two genes that are not normally together. These genes are called fusions genes. Ewing sarcoma and related tumors are one example of this type of cancer: Ewing sarcoma tumors nearly always appear to be cause by a family of fusion genes called EWSR1-FLI1 that controls whether other genes are turned on or off. By turning some genes on, and others off, EWSR1-FLI1 causes Ewing sarcoma. The EWSR1-FLI1 fusion gene represents a major challenge to discovering new treatments for Ewing sarcoma. There is not a straightforward way to generate drugs that block the action of EWSR1-FLI1. Therefore, understanding how EWSR1-FLI1 re-wires cel...

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Cancers in children are frequently caused by the joining of two genes that are not normally together. These genes are called fusions genes. Ewing sarcoma and related tumors are one example of this type of cancer: Ewing sarcoma tumors nearly always appear to be cause by a family of fusion genes called EWSR1-FLI1 that controls whether other genes are turned on or off. By turning some genes on, and others off, EWSR1-FLI1 causes Ewing sarcoma. The EWSR1-FLI1 fusion gene represents a major challenge to discovering new treatments for Ewing sarcoma. There is not a straightforward way to generate drugs that block the action of EWSR1-FLI1. Therefore, understanding how EWSR1-FLI1 re-wires cells to become cancer is critically important. Once these details are understood, we can then begin to consider new ways to block the action of this cancer gene. The focus of this proposal is to identify 1) the proteins that EWSR1-FLI1 works with, and 2) the genes that it controls to cause cancer cells to grow and divide. The McFadden laboratory has used advanced genetic engineering methods to modify the EWSR1-FLI1 gene in patient-derived Ewing sarcoma cells to include a "self-destruct" switch (called a degron) and a molecular handle (called an epitope tag). Using this system, the McFadden lab has shown that Ewing sarcoma cells stop growing when the EWSR1-FLI1 protein is turned off. Although this system cannot be applied to patient tumors, it represents a valuable new laboratory tool identify exactly how EWSR1-FLI1 drives Ewing sarcoma cell growth. The goals of this project are to use the molecular handle to identify other proteins that work with EWSR1-FLI1 to cause cancer cells to divide, and to use the “self-destruct” switch combined with new genetic screening methods to identify the genes that EWSR1-FLI1 controls to cause cancer cells to grow. These insights are expected to identify new ways to impair EWSR1-FLI1 and form the basis of new treatment approaches.

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