Ewing's sarcoma family tumors (ESFT) are characterized by specific chromosomal translocations, which give rise to EWS-ETS chimeric proteins. These aberrant transcription factors are the main pathogenic drivers of ESFT. Elucidation of the factors influencing EWS-ETS expression and/or activity will guide the development of novel therapeutic agents against this fatal disease.

The European Network for Cancer Research in Children and Adolescents (ENCCA) provides an interaction platform for stakeholders in research and care of children with cancer. Among ENCCA objectives is the establishment of biology-based prioritization mechanisms for the selection of innovative targets, drugs, and prognostic markers for validation in clinical trials. Specifically for sarcomas, there is a burning need for novel treatment options, since current chemotherapeutic treatment protocols have met their limits. This is most obvious for metastatic Ewing sarcoma (ES), where long term survival rates are still below 20%. Despite significant progress in our understanding of ES biology, clinical translation of promising laboratory results has not yet taken place due to fragmentation of research and lack of an institutionalized discussion forum. To fill this gap, ENCCA assembled 30 European expert scientists and five North American opinion leaders in December 2011 to exchange thoughts and discuss the state of the art in ES research and latest results from the bench, and to propose biological studies and novel promising therapeutics for the upcoming European EWING2008 and EWING2012 clinical trials.

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Ewing's sarcoma family tumors (ESFT) are characterized in 85% of cases by the oncogenic fusion protein EWS-FLI1 resulting from a chromosomal translocation. While FLI1 is an ETS transcription factor, EWS belongs to the evolutionarily conserved FET family of RNA-binding proteins. So far, functional studies of oncogenic EWS fusion proteins have concentrated on their presumed role as transcriptional regulators. However, chimeric FET proteins are usually co-expressed with their intact counterparts and previous protein interaction studies have shown that EWS and EWS-FLI1 interact with each other. Therefore, it is possible that functional interference with normal EWS function accounts for part of the oncogenic activities of EWS-FLI1. However, the role of EWS in post-transcriptional and transcriptional gene regulation is poorly defined. Since FET proteins associate with a number of RNA processing factors, we investigated the influence of modulated EWS expression on genome wide splicing using Affymetrix HuEx-1.0stv2 arrays. For that purpose, we used two model systems: a unique ESFT cell line lacking endogenous EWS was studied upon stable restoration of EWS expression, and an ESFT cell line allowing for inducible RNAi-mediated EWS-FLI1 suppression was analyzed upon transient EWS knockdown. As a result, we found significant differences between cells with and without EWS expression in splicing patterns as well as alternative promoter usage for more than 50 genes. GO analysis of the top ranking genes is consistent with previously suggested functions of the FET protein family such as DNA repair, chromatin structure and RNA transcription. The alternative splicing patterns were verified by RT-qPCR of candidate genes which are currently tested for their functional relevance to ESFT. One of these candidate genes is structural maintainance of chromosome 5 (SMC5). As a core component of the SMC5-SMC6 complex it is involved in sister chromatid homologous recombination by recruiting the SMC1-SMC3 cohesin complex to DNA double-strand breaks during anaphase. Ongoing studies concentrate on the influence of EWS-FLI1 on EWS-dependent alternative RNA processing patterns in these model systems. This study is supported by grant P20665-B12 of the Austrian Science Fund FWF Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3158.