Regulation of Apoptosis in Ewing Sarcoma

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Ewing sarcoma is the second most frequently encountered bone and soft tissue solid tumor in children and adolescents. Current therapeutic regimens cure only 50% to 70% of patients with localized Ewing sarcoma and less than 30% of patients with metastatic disease. Intensified chemotherapy has not improved the patients survival. Also, due to absence of biologic indicators of aggressiveness, stratification of patients for more aggressive treatments is difficult. We have generated experimental evidence that supports a role for survivin in the resistance of Ewing sarcoma cells to chemotherapy and have found association of survivin expression in non metastatic Ewing sarcoma tissues with overall patient survival (manuscript in preparation). Our data support that survivin is a prognostic marker and a therapeutic target in Ewing sarcoma. A small molecule inhibitor of survivin is considered for a clinical trial by Dr. Widemann at the NCI and we will be involved in the evaluation of the tissues for expression of survivin. We have also explored the possibility of engaging alternative pathways to kill ESFT cells, such the receptor-mediated apoptotic pathway, using TRAIL as a ligand. Our previous data and those of others have shown that Ewing sarcoma cells are generally sensitive to TRAIL in vitro (Mitsiades, N., et al, Cancer Res. 2001). Because TRAIL kills only tumor and not normal cells, it is a desirable alternative agent for drug-resistant tumors and a clinical phase I study at the NCI in which we participated has now been completed (presented at ASCO 2010) and showed that TRAIL is tolerated well without major toxicities by children and young adults. However as we and our collaborators have shown (Lissat, A., et al Am. J. Pathol. 2007), Ewing sarcoma cells with low caspase 8 expression are TRAIL resistant and we have since shown that this is primarily due to their high levels of survivin. Our recent experiments support that the mechanism by which survivin inhibits TRAIL-induced apoptosis is by binding and inhibiting the proapoptotic protein SMAC and by binding and protecting the antiapoptotic protein XIAP from cleavage by caspase 3. We showed that combined treatment with Smac mimetics and survivin RNA interference reverses TRAIL resistance (manuscript in preparation). Our data indicate that combined treatment with small molecule inhibitors of survivin and Smac mimetics can improve the outcome of Ewing sarcoma patients treated with TRAIL. More recently, we found that survivin is transcriptionally upregulated by EWS/FLI-1, a Ewing-specific aberrant transcription factor which is necessary for the maintenance of the tumor, and that this regulation involves the NF-kB pathway. Pharmacological inhibition of the NF-kB pathway or downregulation of the EWS/FLI-1 transcript with siRNA results in downregulation of survivin and sensitization of Ewing sarcoma cells to TRAIL. These data suggest that NF-kB inhibitors may have a role in the treatment of Ewing sarcoma in combination with TRAIL or chemotherapuetic agents.