Ewing tumor biology: perspectives for innovative treatment approaches

The Ewing's sarcoma family of tumors (EFT) is a group of malignancies affecting bone and soft tissue in adolescents. It is characterized by a unique gene rearrangement between the EWS gene and an ets transcription factor gene. EFT can be cured with conventional multi modal treatment, however, about 40% of patients still succumb to the disease. Relapses can be observed more than 5 years after the end of primary treatment suggesting persistence of minimal residual disease (MRD). Due to the still enigmatic nature of EFT histogenesis the phenotype of EFT stem cells and of dormant tumor cells remains unknown. The most frequent fusion product associated with EFT, EWS-FLI1, is the founding member of a whole class of similarly structured chimeric proteins associated with a variety of human sarcomas and also specific leukemias. The corresponding gene rearrangement constitutes a rate limiting step in oncogenesis as implied by the high association of EFT with EWS-ETS fusions, strong selective pressure for maintenance of a correct reading frame in the tumors, and by experimental data confirming the transforming and tumorigenic potential of EWS-FLI1. Understanding the biology of EWS-ETS gene fusions and its interplay with essential cellular pathways regulating cell growth, apoptosis, differentiation, genomic integrity, and treatment resistance may unravel specifically vulnerable sites for therapeutic targeting. This review summarizes the current knowledge about the EWS-FLI1 pathway in EFT and provides some ideas as to how this knowledge may be translated into innovative treatment approaches.