Molecular understanding of Ewing sarcomas and potential targets for treatment

Bone and soft tissue sarcomas are an infrequent and heterogeneous group of mesenchymal tumors, including more than a hundred different entities. Sarcomas are quite resistant to conventional chemotherapy (anthracyclines and ifosfamide), with the exception of some subtypes such as Ewing sarcoma (ES). New drugs with proved efficacy against sarcomas include taxanes, gemcitabine, and ET-743. Preclinical studies have also identified key molecular events leading to the progression and development of ES which are good candidates to targeted therapy. Inhibitors of tyrosine kinase receptors, such as IGF-1R, c-kit, PDGFR, VEGFR, or the mTOR signaling pathway, proteasome, angiogenesis, and stress response proteins are under clinical evaluation against ES. This particular neoplasm, characterized by chromosomal translocations that originate gene fusions (EWS-FLI1, EWS-ERG), is an example of a good chemotherapy responder tumor whose survival rate shows a plateau in recent years, especially in metastatic disease. Preclinical studies have identified that new targets such as HSP90 are of relevance to ES. On the other hand, recent studies showed the role of cancer stem cells (CSCs) in sarcomas and the relevance of the identification of reliable molecular markers and possible therapeutic targets. New therapeutic approaches could be directed against CSCs. This talk describes more recent targeted therapy in sarcomas, with special emphasis on ES and the role of CSCs. We also emphasize the role of high-throughput genomics/proteomics techniques in identifying new therapeutic targets.Research at Enrique de Alava’s lab is supported by the European Commission (Network of excellence on sarcomas EuroBoNet), the Ministry of Science of Spain, and the Maria Garcia-Estrada Foundation.Peer Reviewe