GSTM4, a novel target for treating Ewing sarcoma.

Ewing sarcoma is a highly malignant bone cancer that occurs mostly in children and teenagers. Conventional treatment for Ewing sarcoma consists of multi-drug chemotherapy and surgery and/or radiation. These intensive treatments are toxic and have severe side effects and yet failed to improve the overall cure rate. New and effective therapies are needed.

Our hope lies in better understanding of the cause of Ewing sarcoma. A genetic locus translocation is responsible for a large percentage of Ewing sarcoma. This translocation produces a fusion protein called EWS/FLI. EWS/FLI then functions as the master regulator and controls expression of many cancer genes to develop Ewing sarcoma. By targeting these cancer genes, we may seek specific and tolerable treatments.

Unlike early work using unrelated models, we have innovatively developed a system to find out genes that are regulated by EWS/FLI in Ewing sarcoma itself. We found several interesting genes that are controlled by EWS/FLI and may be required for Ewing sarcoma development. In this proposal, we will focus on GSTM4, a gene that is important for eliminating toxic substances. Our exciting finding is that GSTM4 may be required for the cancerous character of Ewing sarcoma and it may be important for Ewing sarcoma cells to avoid the killing effect from therapeutic drugs. We plan to further study the importance of GSTM4 in Ewing sarcoma tumor formation and resistance to chemotherapy drugs in this proposal. We hope the results of these experiments will lead to better understanding and improved treatment for this severe childhood cancer.