INSULIN-LIKE GROWTH-FACTOR-I RECEPTOR-MEDIATED CIRCUIT IN EWINGS-SARCOMA PERIPHERAL NEUROECTODERMAL TUMOR - A POSSIBLE THERAPEUTIC TARGET

The disappointingly low survival rate observed in Ewing's sarcoma (ES) /peripheral neuroectodermal tumor (PNET) despite the adoption of aggre ssive multimodal treatments prompted us to study the existence of auto crine circuits to be used as innovative therapeutic targets. Of the se veral 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 circ uit in the pathogenesis of ES/PNET. The in vitro inhibition of the IGF -IR-mediated circuit by the specific IGF-IR binding antibody alpha IR3 suppressed the growth of ES/PNET cells by decreasing the proliferativ e rate and increasing apoptosis, alpha IR3 also significantly inhibite d the ability of ES/PNET cells to grow in soft agar and to migrate fol lowing a chemotactic stimulus. Inactivation of the IGF-IR signaling pa thway may therefore be considered as an effective therapeutic modality for patients with ES/PNET.