5/1/2005 Antitumor Activity of the Insulin-Like Growth Factor-I Receptor Kinase Inhibitor NVP-AEW541 in Musculoskeletal Tumors Experimental Therapeutics, Molecular Targets, and Chemical Biology Antitumor Activity of the Insulin-Like Growth Factor-I Receptor Kinase Inhibitor NVP-AEW541 in Musculoskeletal Tumors Katia Scotlandi1, Maria Cristina Manara1, Giordano Nicoletti1, Pier-Luigi Lollini2, Stella Lukas1, Stefania Benini1, Stefania Croci2, Stefania Perdichizzi1, Diana Zambelli1, Massimo Serra1, Carlos García-Echeverría3, Francesco Hofmann3 and Piero Picci1 1 Laboratory of Oncologic Research, Orthopaedic Rizzoli Institute; 2 Cancer Research Section, Department of Experimental Pathology, University of Bologna, Bologna, Italy and 3 Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland Requests for reprints: Katia Scotlandi, Laboratory of Oncologic Research, Orthopaedic Rizzoli Institute, Via Di Barbiano 1/10, 40136 Bologna, Italy. Phone: 39-51-6366760; Fax: 39-51-6366761; E-mail: katia.scotlandi@ior.it . Identification of new drugs is strongly needed for sarcomas. Insulin-like growth factor-I receptor (IGF-IR) was found to provide a major contribution to the malignant behavior of these tumors, therefore representing a very promising therapeutic target. In this study, we analyzed the therapeutic potential of a novel kinase inhibitor of IGF-IR, NVP-AEW541, in Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma, the three most frequent solid tumors in children and adolescents. NVP-AEW541 inhibits IGF-I-mediated receptor activation and downstream signaling. Ewing's sarcoma cells were generally found to be more sensitive to the effects of this drug compared with rhabdomyosarcoma and osteosarcoma, in agreement with the high dependency of this neoplasm to IGF-IR signaling. NVP-AEW541 induced a G1 cell cycle block in all cells tested, whereas apoptosis was observed only in those cells that show a high level of sensitivity. Concurrent exposure of cells to NVP-AEW541 and other chemotherapeutic agents resulted in positive interactions with vincristine, actinomycin D, and ifosfamide and subadditive effects with doxorubicin and cisplatin. Accordingly, combined treatment with NVP-AEW541 and vincristine significantly inhibited tumor growth of Ewing's sarcoma xenografts in nude mice. Therefore, results encourage inclusion of this drug especially in the treatment of patients with Ewing's sarcoma. For the broadest applicability and best efficacy in sarcomas, NVP-AEW541 may be combined with vincristine, actinomycin D, and ifosfamide, three major drugs in the treatment of sarcomas. Cancer Research 65, 3868-3876, May 1, 2005] © 2005 American Association for Cancer Research To read entire article: http://cancerres.aacrjournals.org/cgi/content/abstract/65/9/3868?ct