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Sarcomas are a heterogeneous group of malignant tumors that are derived from mesenchymal tissues, including bone, muscle, and cartilage. Unlike carcinomas, which affect the elderly and are the final result of a long history of progressively accumulating preneoplastic lesions that allowed the molecular definition of multiple carcinogenic events, mostly sarcomas arise abruptly in infants, and their natural history of sarcomas is still mostly unknown. However, in the last decade, we have gained significant new insights into the genetic abnormalities that underlie the pathogenesis of these tumors. Specific molecular alterations have been associated with specific histological subtypes of sarcomas, leading to a new classification of many sarcomas. Conventionally grouped in either soft tissue or bone sarcomas according to the site of their origin, these tumors can now be genetically distinguished in two main groups: those carrying a tumor-specific recurrent chromosome aberrations that appear to be central to the pathogenesis of the tumor and are therefore included among diagnostic criteria and those with complex karyotypes and variable genetic alterations (Helman and Meltzer 2003; Wunder et al. 2007). Sarcomas with recurrent molecular changes include, among others, Ewing sarcoma family tumors, synovial sarcoma, alveolar rhabdomyosarcoma, myxoid liposarcoma, and myxoid chondrosarcoma. These tumors typically carry disease-specific chromosome translocations that frequently result in the expression of an oncogenic chimeric transcription factor, such as EWS-FLI1 in Ewing sarcoma. EWS-FLI1, which is present in around 85 % of Ewing sarcoma, derives specifically from a chromosomal translocation between chromosomes 11 and 22 and is referred to as t(11;22). While other translocations have also been described in Ewing sarcoma, including t(21;22) and t(7;22), all of the translocations involve the fusion of the EWS gene with an ETS family gene. Survival rates of patients with the different translocations appear to be the same (Le Deley et al. 2010; van Doorninck et al. 2010). Forced expression of EWS-FLI1 in normal cells can induce tumorigenesis. However, the effects of EWS-FLI1 expression are strongly dependent on cellular background (Kovar 2005). For example, EWS-FLI1 transforms immortalized murine NIH3T3 fibroblasts or mesenchymal stem cells and is required for the oncogenic phenotype of patient-derived EWS cells, but its introduction into primary human or murine fibroblasts leads to growth arrest or cell death, respectively. These data suggest that oncogenic transformation by EWS-FLI requires a permissive cellular background. The critical factors in the permissive background are largely unknown, but may include disruption of the p53 and RB pathways and the presence of an intact IGF pathway as well as of CD99, a 32 kD integral membrane glycoprotein that is highly expressed in most cases of Ewing sarcoma. Recently it was clearly shown how EWS-FLI1 can induce upregulation of IGF1, inducing autocrine activation of IGF-1R and/or of CD99, thus sustaining its transforming activity in mesenchymal stem cells (Cironi et al. 2008; Riggi et al. 2005; Herrero-Martín et al. 2009; McKinsey et al. 2011).

The presence of specific chimeric product is very attractive from a therapeutic point of view. Unfortunately the chimeric transcription factors that give rise to Ewing sarcoma are not druggable at the best of our current knowledge. Thus, the most interesting therapeutic options are druggable pathways regulated by EWS-FLI1, such as the IGF-1R-mediated signaling pathway. Antibodies or tyrosine-kinase inhibitors directed against the IGF-1 receptor protein have also been studied as a potential treatment for advanced Ewing sarcoma (Manara et al. 2007) and have implications for therapy. However, phase I–III clinical studies with anti-IGF-IR drugs have clearly indicated modest toxic effects, with mild and reversible hyperglycemia as the most common toxicity, but limited effectiveness. Particularly in Ewing’s sarcoma (EWS), despite the presence of the target in all tumors and ample preclinical evidence supporting the potential value of anti-IGF-IR agents, less than 10 % of cases extraordinarily responded to this therapy (Olmos et al. 2010; Pappo et al. 2011). Evidences for a compensatory role of IR-A when IGF-1R is disrupted (Garofalo et al. 2011, 2012) have been provided, indicating the relationship between these two receptors as one mechanism responsible for acquired and intrinsic resistance to selective anti-IGF-IR therapy. However, further studies are clearly necessary to better define patients that may really benefit from an anti-IGF-IR therapy as well as to rationalize the use of this targeted therapy in combination treatments.

CD99 is another molecule being studied as a potential immunotherapy target for the treatment of Ewing sarcoma. Engagement by anti-CD99 monoclonal antibodies induces massive apoptosis and reduces malignant potential of Ewing sarcoma cells (Scotlandi et al. 2000; Cerisano et al. 2004). An increased antitumor effectiveness of the anti-CD99 monoclonal antibody has recently been demonstrated both in vitro and in vivo when combined with doxorubicin (Scotlandi et al. 2006). In addition recent research suggests that CD99 plays a role in preventing the normal neural differentiation of Ewing cells (Rocchi et al. 2010). Apoptosis also occurs following activation of cell surface receptors by the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and the use of agonistic monoclonal antibodies activating the TRAIL receptors is one of the emerging targeted strategies in cancer management, either as monotherapy or in association with other treatment modalities. There is evidence that Ewing’s sarcoma cells are exquisitely sensitive to TRAIL-mediated apoptosis. A preclinical study showing efficacy of TRAIL in animals was recently reported (Picarda et al. 2010). These drugs are still purely investigational at this point.

Finally EWS-FLI1 fusion genes were recently found to act in a positive feedback loop to maintain the expression of PARP1, which was required for EWS-FLI-mediated transcription, thereby enforcing oncogene-dependent sensitivity to PARP-1 inhibition (Brenner et al. 2012). Ewing sarcoma cells, primary tumor xenografts, and tumor metastases were all highly sensitive to PARP1 inhibition. Addition of a PARP1 inhibitor to the second-line chemotherapeutic agent temozolomide resulted in complete responses of all treated tumors in an EWS-FLI1-driven mouse xenograft model of Ewing sarcoma. These findings offer a strong preclinical rationale to target the EWS-FLI1:PARP1 intersection as a therapeutic strategy to improve the treatment of Ewing sarcoma.