title: IGF-1R as an anti-cancer target--trials and tribulations.
abstract: Type I insulin-like growth factor receptor (IGF-1R) has long been recognized for its role in tumorigenesis and growth, but only recently have the tools for targeting the IGF pathway become available. More than 10 IGF/IGF-1R inhibitors have entered clinical trials, and these belong to three main classes: (1) monoclonal antibodies against IGF-1R, (2) monoclonal antibodies against IGF-1R ligands (IGF-1 and IGF-2), and (3) IGF-1R tyrosine kinase inhibitors. These IGF-1R-targeting agents share common effects on IGF-1R signaling but differ in mechanisms of action, spectrum of target inhibition, and pharmacological features. Clinical activity of IGF-1R inhibitors has been demonstrated with sustained responses in a small number of patients with select tumor types, such as Ewing sarcoma and thymoma. However, many large clinical trials involving patients with adult tumors, including non-small cell lung cancer, breast cancer, and pancreatic cancer, failed to show clinical benefit in the overall patient population. Possible reasons for failure include the complexity of the IGF-1R/insulin receptor system and parallel growth and survival pathways, as well as a lack of patient selection markers. While IGF-1R remains a valid target for selected tumor types, identification of predictive markers and rational combinations will be critical to success in future development.
authors.affiliation: National Cancer Institute, Bethesda, MD 20892, USA. helen.chen@nih.gov
authors.forename: Helen X
authors.initials: HX
authors.lastname: Chen
authors.forename: Elad
authors.initials: E
authors.lastname: Sharon
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D004338:Drug Combinations; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors; D007335:Insulin-Like Growth Factor II / Q000037:antagonists & inhibitors; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000628:therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000276:immunology; D012512:Sarcoma, Ewing / Q000628:therapy; D015398:Signal Transduction
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D004338:Drug Combinations; D047428:Protein Kinase Inhibitors; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1