Chen Helen X, Sharon Elad
National Cancer Institute, Bethesda, MD 20892, USA.
Chin J Cancer. 2013 May;32(5):242-52. doi: 10.5732/cjc.012.10263. Epub 2013 Apr 19.
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.
I型胰岛素样生长因子受体（IGF-1R）长期以来因其在肿瘤发生和生长中的作用而被认可，但直到最近，靶向IGF途径的工具才得以应用。超过10种IGF/IGF-1R抑制剂已进入临床试验，它们主要分为三类：（1）抗IGF-1R单克隆抗体，（2）抗IGF-1R配体（IGF-1和IGF-2）单克隆抗体，以及（3）IGF-1R酪氨酸激酶抑制剂。这些靶向IGF-1R的药物对IGF-1R信号传导具有共同作用，但在作用机制、靶标抑制谱和药理学特性方面存在差异。在少数特定肿瘤类型（如尤因肉瘤和胸腺瘤）患者中，IGF-1R抑制剂已显示出持续反应的临床活性。然而，许多涉及成年肿瘤患者（包括非小细胞肺癌、乳腺癌和胰腺癌）的大型临床试验未能在总体患者人群中显示出临床获益。失败的可能原因包括IGF-1R/胰岛素受体系统的复杂性和平行的生长与生存途径，以及缺乏患者选择标志物。虽然IGF-1R仍然是某些特定肿瘤类型的有效靶点，但识别预测标志物和合理联合用药对于未来开发的成功至关重要。
