Identification of novel therapeutic targets in Ewing’s Sarcoma by modeling tumorigenesis in differentiating human embryonic stem cells

Ewing’s Sarcoma (ES) is a bone and soft tissue malignancy that occurs in children, adolescents and adults.  This cancer is defined by a recurrent chromosomal translocation between the EWSR1 gene and different ETS genes, such as FLI1, that generates a tumorigenic fusion protein (EWS/FLI1).  While the overall cure for patients with non-metastatic disease is approximately 70%, the five-year survival of patients with metastatic disease is less than 20%.  Consequently, there is a significant need for improved therapies for this cancer.  One roadblock in developing new therapies in ES has been the lack of a genetically-defined tumor model in human cells.  To address this problem, we have developed a novel approach to transform human cells and model ES that uses differentiating human embryonic cells.  This has allowed us to study the effects of EWS/FLI1 on gene expression in isogenic cell lines and compile a list of genes regulated, directly and indirectly, by EWS/FLI1.  The next step, and goal of this proposal, is to use a focused shRNA screen to define which of these genes might function as novel, therapeutic targets in ES.