The disappointingly low survival rate observed in Ewing's sarcoma (ES)/peripheral neuroectodermal tumor (PNET) despite the adoption of aggressive multimodal treatments prompted us to study the existence of autocrine circuits to be used as innovative therapeutic targets. Of the several circuits analyzed, only the insulin-like growth factor receptor (IGF-IR)-mediated loop was found to be constantly present both in cell lines and clinical samples, suggesting a role for this autocrine circuit in the pathogenesis of ES/PNET. The in vitro inhibition of the IGF-IR-mediated circuit by the specific IGF-IR binding antibody αIR3 suppressed the growth of ES/PNET cells by decreasing the proliferative rate and increasing apoptosis. αIR3 also significantly inhibited the ability of ES/PNET cells to grow in soft agar and to migrate following a chemotactic stimulus. Inactivation of the IGF-IR signaling pathway may therefore be considered as an effective therapeutic modality for patients with ES/PNET.

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This work was supported by the Consiglio Nazionale delle Ricerche, the Progetto Finalizzato Applicazioni Cliniche della Ricerca Oncologica; by the Istituti Ortopedici Rizzoli, Ricerca Corrente; and by the Ministero della Sanità, Ricerca Finalizzata. S. B. is a recipient of a fellowship from Associazione Italiana per la Ricerca sul Cancro. M. C. M. is a recipient of a fellowship from Federazione Italiana per la Ricerca sul Cancro.

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