Ewing sarcoma is the second most common cancer of bone and soft tissues in children and young adults and is characterized by the chromosomal translocation generating a fusion oncogene between EWS and an Ets family transcription factor, most commonly FLI-1. EWS-FLI-1 fusion accounts for 85% of Ewing sarcoma cases. Ewing sarcoma is an aggressive cancer with relatively poor long-term outcome. Overall survival is approximately 50% and the five-year survival of recurrent cases is less than 10%. Considering that current cytotoxic chemotherapies used for Ewing sarcoma are not improving the survival of metastatic or recurrent disease, a new approach for targeted therapy needs to be developed. The g...

Read More

Ewing sarcoma is the second most common cancer of bone and soft tissues in children and young adults and is characterized by the chromosomal translocation generating a fusion oncogene between EWS and an Ets family transcription factor, most commonly FLI-1. EWS-FLI-1 fusion accounts for 85% of Ewing sarcoma cases. Ewing sarcoma is an aggressive cancer with relatively poor long-term outcome. Overall survival is approximately 50% and the five-year survival of recurrent cases is less than 10%. Considering that current cytotoxic chemotherapies used for Ewing sarcoma are not improving the survival of metastatic or recurrent disease, a new approach for targeted therapy needs to be developed. The growth and survival of Ewing sarcoma cells critically depend on the EWS-FLI-1 fusion oncoprotein. Therefore targeting EWS-FLI-1 is a promising approach to treat Ewing sarcoma. Despite many attempts, however, EWS-FLI-1-targeted therapy has not materialized to date and EWS-FLI-1 continues to be “the perfect target without a therapeutic agent.” Previous efforts to target EWS-FLI-1 were focused on inhibiting the gene regulatory activity of EWS-FLI-1. In this project, we will pursue an entirely different approach to target EWS-FLI-1: proteolytic degradation of the EWS-FLI-1 protein. We have discovered that EWS-FLI-1 is selectively degraded by the lysosome (unlike most cellular proteins that are degraded by the proteasome) and demonstrated that EWS-FLI-1 can be targeted for degradation by a compound that stimulates lysosome biogenesis. In this application, we propose to delineate the mechanism of EWS-FLI-1 lysosomal degradation and identify the compounds that efficiently degrade EWS-FLI-1. The successful completion of this project will provide a basis for a novel therapeutic approach to Ewing sarcoma and develop new drugs to treat this cancer.

Read Less