IGF1R signalling and its inhibition
IGF1R signalling and its inhibition
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DOI：
10.1677/erc.1.01280
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发表时间：
2006-12-01
影响因子：
3.9
通讯作者：
Macaulay, V. M.
中科院分区：
文献类型：
--
作者：
Riedemann, J.;Macaulay, V. M.
I型胰岛素样生长因子受体(IGF1R)是一种跨膜酪氨酸激酶，经常在肿瘤中过度表达，并介导增殖和细胞凋亡保护。IGF信号还影响低氧信号、蛋白酶分泌、肿瘤细胞的运动和黏附，从而影响侵袭和转移的倾向。因此，IGF1R现在是一个有吸引力的抗癌治疗靶点。这篇综述概述了IGF1R在肿瘤细胞中的激活作用，并将描述可用于阻断IGF信号转导的策略，作为研究工具和新型抗癌疗法。由于与胰岛素受体的同源性很高，设计特异性的IGF1R抑制剂一直存在问题，但最近已经证明有可能设计选择性的IGF1R抑制剂。这些化合物和IGF1R抗体在人类癌症的临床前模型中表现出了希望，几种药物现在处于早期临床试验阶段。这两类药物都通过直接抑制或抗体诱导的胰岛素受体下调来影响胰岛素受体信号转导。这种作用可能会导致临床毒性，但在治疗上可能有益于通过能够对IGF-II产生丝裂原反应的不同胰岛素受体来阻断信号。IGF1R靶向的特异性可以通过反义和siRNA介导的IGF1R下调来实现；这些方法作为研究工具无疑具有实用价值，并可能在未来产生基于核酸的治疗方法。重要的是使用临床前和早期临床试验的数据来建立IGF1R阻断敏感性的分子相关性，以及将这一新方法与标准治疗模式相结合的最佳方法。
The type 1 IGF receptor (IGF1R) is a transmembrane tyrosine kinase that is frequently overexpressed by tumours, and mediates proliferation and apoptosis protection. IGF signalling also influences hypoxia signalling, protease secretion, tumour cell motility and adhesion, and thus can affect the propensity for invasion and metastasis. Therefore, the IGF1R is now an attractive anticancer treatment target. This review outlines the effects of IGF1R activation in tumour cells, and will describe the strategies that are available to block IGF signalling, both as investigational tools and as novel anti-cancer therapeutics. Design of specific IGF1R inhibitors has been problematic due to close homology with the insulin receptor, but recently it has proved possible to design selective IGF1R inhibitors. These compounds and IGF1R antibodies are showing promise in preclinical models of human cancer, and several agents are now in early phase clinical trials. Both classes of agents affect insulin receptor signalling, either by direct kinase inhibition or antibody-induced insulin receptor downregulation. This effect may lead to clinical toxicity, but could be therapeutically beneficial in blocking signalling via variant insulin receptors capable of a mitogenic response to IGF-II. Specificity for IGF1R targeting can be achieved by antisense and siRNA-mediated IGF1R downregulation; these approaches have undoubted utility as research tools, and may in future generate nucleic-acid-based therapeutics. It will be important to use data from preclinical and early clinical trials to establish the molecular correlates of sensitivity to IGF1R blockade, and the optimum means of combining this new approach with standard treatment modalities.