This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Scotlandi, K. Articles by Picci, P. Search for Related Content PubMed PubMed Citation Articles by Scotlandi, K. Articles by Picci, P.

Antitumor Activity of the Insulin-Like Growth Factor-I Receptor Kinase Inhibitor NVP-AEW541 in Musculoskeletal Tumors

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{at}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.

This article has been cited by other articles:

				P. Sabbatini, S. Korenchuk, J. L. Rowand, A. Groy, Q. Liu, D. Leperi, C. Atkins, M. Dumble, J. Yang, K. Anderson, et al. GSK1838705A inhibits the insulin-like growth factor-1 receptor and anaplastic lymphoma kinase and shows antitumor activity in experimental models of human cancers Mol. Cancer Ther., October 1, 2009; 8(10): 2811 - 2820. [Abstract] [Full Text] [PDF]

				P. Sabbatini, J. L. Rowand, A. Groy, S. Korenchuk, Q. Liu, C. Atkins, M. Dumble, J. Yang, K. Anderson, B. J. Wilson, et al. Antitumor Activity of GSK1904529A, a Small-molecule Inhibitor of the Insulin-like Growth Factor-I Receptor Tyrosine Kinase Clin. Cancer Res., May 1, 2009; 15(9): 3058 - 3067. [Abstract] [Full Text] [PDF]

				S. Avnet, L. Sciacca, M. Salerno, G. Gancitano, M. F. Cassarino, A. Longhi, M. Zakikhani, J. M. Carboni, M. Gottardis, A. Giunti, et al. Insulin Receptor Isoform A and Insulin-like Growth Factor II as Additional Treatment Targets in Human Osteosarcoma Cancer Res., March 15, 2009; 69(6): 2443 - 2452. [Abstract] [Full Text] [PDF]

				F. Huang, A. Greer, W. Hurlburt, X. Han, R. Hafezi, G. M. Wittenberg, K. Reeves, J. Chen, D. Robinson, A. Li, et al. The Mechanisms of Differential Sensitivity to an Insulin-like Growth Factor-1 Receptor Inhibitor (BMS-536924) and Rationale for Combining with EGFR/HER2 Inhibitors Cancer Res., January 1, 2009; 69(1): 161 - 170. [Abstract] [Full Text] [PDF]

				S. Y. Kim, J. A. Toretsky, D. Scher, and L. J. Helman The Role of IGF-1R in Pediatric Malignancies Oncologist, January 1, 2009; 14(1): 83 - 91. [Abstract] [Full Text] [PDF]

				A. Esparis-Ogando, A. Ocana, R. Rodriguez-Barrueco, L. Ferreira, J. Borges, and A. Pandiella Synergic antitumoral effect of an IGF-IR inhibitor and trastuzumab on HER2-overexpressing breast cancer cells Ann. Onc., November 1, 2008; 19(11): 1860 - 1869. [Abstract] [Full Text] [PDF]

				L. Cao, Y. Yu, I. Darko, D. Currier, L. H. Mayeenuddin, X. Wan, C. Khanna, and L. J. Helman Addiction to Elevated Insulin-like Growth Factor I Receptor and Initial Modulation of the AKT Pathway Define the Responsiveness of Rhabdomyosarcoma to the Targeting Antibody Cancer Res., October 1, 2008; 68(19): 8039 - 8048. [Abstract] [Full Text] [PDF]

				M. Q. Almeida, M. C. B. V. Fragoso, C. F. P. Lotfi, M. G. Santos, M. Y. Nishi, M. H. S. Costa, A. M. Lerario, C. C. Maciel, G. E. Mattos, A. A. L. Jorge, et al. Expression of Insulin-Like Growth Factor-II and Its Receptor in Pediatric and Adult Adrenocortical Tumors J. Clin. Endocrinol. Metab., September 1, 2008; 93(9): 3524 - 3531. [Abstract] [Full Text] [PDF]

				J. Rodon, V. DeSantos, R. J. Ferry Jr., and R. Kurzrock Early drug development of inhibitors of the insulin-like growth factor-I receptor pathway: Lessons from the first clinical trials Mol. Cancer Ther., September 1, 2008; 7(9): 2575 - 2588. [Abstract] [Full Text] [PDF]

				W. Liu, D. A. Bloom, W. G. Cance, E. V. Kurenova, V. M. Golubovskaya, and S. N. Hochwald FAK and IGF-IR interact to provide survival signals in human pancreatic adenocarcinoma cells Carcinogenesis, June 1, 2008; 29(6): 1096 - 1107. [Abstract] [Full Text] [PDF]

				P. E. Dube, K. J. Rowland, and P. L. Brubaker Glucagon-Like Peptide-2 Activates -Catenin Signaling in the Mouse Intestinal Crypt: Role of Insulin-Like Growth Factor-I Endocrinology, January 1, 2008; 149(1): 291 - 301. [Abstract] [Full Text] [PDF]

				F. U. Garcia, K. Urbanska, L. Koltowski, K. Reiss, and C. Sell Insulin-Like Growth Factor-I Produced by Seminal Vesicles: Relationship to Intraepithelial Basal Cell Hyperplasia in the Prostate Clin. Cancer Res., June 1, 2007; 13(11): 3140 - 3146. [Abstract] [Full Text] [PDF]

				J. Carrillo, E. Garcia-Aragoncillo, D. Azorin, N. Agra, A. Sastre, I. Gonzalez-Mediero, P. Garcia-Miguel, A. Pestana, S. Gallego, D. Segura, et al. Cholecystokinin Down-Regulation by RNA Interference Impairs Ewing Tumor Growth Clin. Cancer Res., April 15, 2007; 13(8): 2429 - 2440. [Abstract] [Full Text] [PDF]

				M. C. Manara, L. Landuzzi, P. Nanni, G. Nicoletti, D. Zambelli, P. L. Lollini, C. Nanni, F. Hofmann, C. Garcia-Echeverria, P. Picci, et al. Preclinical In vivo Study of New Insulin-Like Growth Factor-I Receptor-Specific Inhibitor in Ewing's Sarcoma Clin. Cancer Res., February 15, 2007; 13(4): 1322 - 1330. [Abstract] [Full Text] [PDF]

				A. A. Samani, S. Yakar, D. LeRoith, and P. Brodt The Role of the IGF System in Cancer Growth and Metastasis: Overview and Recent Insights Endocr. Rev., February 1, 2007; 28(1): 20 - 47. [Abstract] [Full Text] [PDF]

				J Riedemann and V M Macaulay IGF1R signalling and its inhibition Endocr. Relat. Cancer, December 1, 2006; 13(Supplement_1): S33 - S43. [Abstract] [Full Text] [PDF]

				B. Tanno, C. Mancini, R. Vitali, M. Mancuso, H. P. McDowell, C. Dominici, and G. Raschella Down-Regulation of Insulin-Like Growth Factor I Receptor Activity by NVP-AEW541 Has an Antitumor Effect on Neuroblastoma Cells In vitro and In vivo. Clin. Cancer Res., November 15, 2006; 12(22): 6772 - 6780. [Abstract] [Full Text] [PDF]

				B. A. Whitson, B. A. Jacobson, S. Frizelle, M. R. Patel, D. Yee, M. A. Maddaus, and R. A. Kratzke Effects of insulin-like growth factor-1 receptor inhibition in mesothelioma. Ann. Thorac. Surg., September 1, 2006; 82(3): 996 - 1001. [Abstract] [Full Text] [PDF]

				Z. Wang, G. Chakravarty, S. Kim, Y. D. Yazici, M. N. Younes, S. A. Jasser, A. A. Santillan, C. D. Bucana, A. K. El-Naggar, and J. N. Myers Growth-Inhibitory Effects of Human Anti-Insulin-Like Growth Factor-I Receptor Antibody (A12) in an Orthotopic Nude Mouse Model of Anaplastic Thyroid Carcinoma Clin. Cancer Res., August 1, 2006; 12(15): 4755 - 4765. [Abstract] [Full Text] [PDF]

				C. M. van Golen, T. S. Schwab, B. Kim, M. E. Soules, S. Su Oh, K. Fung, K. L. van Golen, and E. L. Feldman Insulin-Like Growth Factor-I Receptor Expression Regulates Neuroblastoma Metastasis to Bone. Cancer Res., July 1, 2006; 66(13): 6570 - 6578. [Abstract] [Full Text] [PDF]

				A. S. Martins, C. Mackintosh, D. H. Martin, M. Campos, T. Hernandez, J.-L. Ordonez, and E. de Alava Insulin-Like Growth Factor I Receptor Pathway Inhibition by ADW742, Alone or in Combination with Imatinib, Doxorubicin, or Vincristine, Is a Novel Therapeutic Approach in Ewing Tumor. Clin. Cancer Res., June 1, 2006; 12(11): 3532 - 3540. [Abstract] [Full Text] [PDF]

				R. Taulli, C. Scuoppo, F. Bersani, P. Accornero, P. E. Forni, S. Miretti, A. Grinza, P. Allegra, M. Schmitt-Ney, T. Crepaldi, et al. Validation of Met as a Therapeutic Target in Alveolar and Embryonal Rhabdomyosarcoma. Cancer Res., May 1, 2006; 66(9): 4742 - 4749. [Abstract] [Full Text] [PDF]

				M. Hopfner, V. Baradari, A. Huether, C. Schofl, and H. Scherubl The insulin-like growth factor receptor 1 is a promising target for novel treatment approaches in neuroendocrine gastrointestinal tumours. Endocr. Relat. Cancer, March 1, 2006; 13(1): 135 - 149. [Abstract] [Full Text] [PDF]