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Biological Rationale and Current Clinical Experience With Anti-Insulin-Like Growth Factor 1 Receptor Monoclonal Antibodies in Treating Sarcoma: Twenty Years From the Bench to the Bedside

Olmos, David MD*†; Tan, Daniel S. W. MBBS†‡; Jones, Robin L. MBBS*†§; Judson, Ian R. MBBS*†

doi: 10.1097/PPO.0b013e3181dbebf9
Principles & Practice of Oncology: Recent Advances

Two decades have elapsed since insulin-like growth factor-1 receptor (IGF-1R) signaling was initially implicated in sarcoma biology to the first clinical experience of IGF-1R blockade in sarcoma. During these 21 years, the IGF pathway and its key mediator IGF-1R have been implicated in the genesis, growth, proliferation, metastasis, and resistance to conventional treatment in several sarcoma subtypes. In addition, IGF-1R has been validated, both in vitro and in vivo, as a target for the treatment of sarcoma. Several radiologic and clinical responses to IGF-1R monoclonal antibodies have been reported in Ewing sarcoma patients enrolled in early clinical studies. Furthermore, these therapies were well tolerated, and thus far severe toxicity has been rare. The early clinical evidence of antitumor activity has supported the initiation of various phase II clinical trials in Ewing and other sarcoma subtypes, the results of which are eagerly awaited, as well as studies assessing IGF-1R monoclonal antibodies in combination with traditional cytotoxics or other targeted therapies. Despite these encouraging results, not all patients benefit from IGF-1R inhibition and consequently there is an urgent need for the identification of predictive markers of response.

From the *Sarcoma Unit, The Royal Marsden NHS Foundation Trust, London; †Drug Development Unit, The Royal Marsden NHS Foundation Trust and The institute of Cancer Research, Sutton, United Kingdom; and ‡Department of Medical Oncology, National Cancer Centre Singapore, Singapore. §R.L.J. is currently at the Fred Hutchinson Cancer Research Center, Seattle, WA.

This work was supported by a translational research fellowship from the Spanish Society of Medical Oncology (SEOM) (to D.O.) and a Young Investigator Award from the American Society of Clinical Oncology (ASCO) Foundation (to D.S.W.T.). The Drug Development Unit of the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research is supported in part by a program grant from Cancer Research U.K. Support was also provided by the Experimental Cancer Medicine Centre (to the Institute of Cancer Research) and the National Institute for Health Research Biomedical Research Centre (jointly to the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research).

Reprints: David Olmos, The Royal Marsden Hospital, Downs Road, Sutton, SM2 5PT, United Kingdom. E-mail: david.olmos@icr.ac.uk.

© 2010 Lippincott Williams & Wilkins, Inc.