Targeting the insulin-like growth factor receptor pathway in lung cancer: problems and pitfalls
Targeting the insulin-like growth factor receptor pathway in lung cancer: problems and pitfalls
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DOI：
10.1177/1758834011427576
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发表时间：
2012-03-01
影响因子：
4.9
通讯作者：
Bonomi, Philip
中科院分区：
文献类型：
--
作者：
Fidler, Mary Jo;Shersher, David D.;Bonomi, Philip
胰岛素样生长因子 (IGF) 途径是一条复杂的途径，涉及膜结合受体、配体、结合蛋白、下游效应器和其他受体酪氨酸激酶信号级联之间的相互作用。基于以下激发因素，IGF 通路已被确定为非小细胞肺癌 (NSCLC) 的潜在治疗靶点。 NSCLC 的临床前观察表明，该途径涉及肿瘤细胞的增殖、存活和侵袭。此外，在大量非小细胞肿瘤标本中发现 IGF-1R 蛋白表达。最初的治疗工作涉及开发针对 IGF-1R（一种跨膜受体酪氨酸激酶）的单克隆抗体和酪氨酸激酶抑制剂。当一项随机 II 期研究表明，将抗 IGF-1R 单克隆抗体（figitumumab）与铂双联药物相结合可带来更高的缓解率以及优越的无进展生存期和总生存期的趋势时，针对这一途径的热情增加了。随后，一项 III 期研究未能证实 II 期试验中观察到的有希望的结果。目前，研究人员正在研究针对 IGF-1R 的不同单克隆抗体和酪氨酸激酶。在未经选择的患者中，迄今为止提供的结果并未表明该药物的疗效。然而，回顾性亚组分析表明，循环 IGF-1 水平可能会识别出哪些患者可以从 IGF-1R 单克隆抗体治疗中受益，并且可能需要对预测性分子标志物进行进一步的探索性研究。本文的目的是简要讨论 IGF 通路及其与肺癌中其他信号通路的关系，并回顾正在进行的 IGF 临床试验和识别预测分子标志物的努力。
The insulin-like growth factor (IGF) pathway is a complex pathway involving interactions between membrane-bound receptors, ligands, binding proteins, downstream effectors, and other receptor tyrosine kinase signaling cascades. The IGF pathway has been identified as a potential therapeutic target in non-small cell lung cancer (NSCLC) based on the following provocative factors. Preclinical observations in NSCLC have shown that this pathway is involved in tumor cell proliferation, survival, and invasiveness. In addition, IGF-1R protein expression is found in a significant number of non-small cell tumor specimens. Initial therapeutic efforts involved the development of monoclonal antibodies and tyrosine kinase inhibitors that target IGF-1R, a transmembrane receptor tyrosine kinase. Enthusiasm for targeting this pathway increased when a randomized phase II study showed that combining an anti-IGF-1R monoclonal antibody (figitumumab) with a platinum doublet resulted in a higher response rate and trends for superior progression-free survival and overall survival. Subsequently, a phase III study failed to confirm the promising results observed in the phase II trial. Currently, investigators are studying different monoclonal antibodies and tyrosine kinases targeting IGF-1R. In unselected patients, results presented thus far do not suggest efficacy of this agent. However, retrospective subgroup analyses suggest that circulating IGF-1 levels might identify patients who could benefit from treatment with an IGF-1R monoclonal antibody and may warrant further exploratory studies for predictive molecular markers. The purpose of this paper is to briefly discuss the IGF pathway and its relationship with other signaling pathways in lung cancer and to review the ongoing IGF clinical trials and efforts to identify predictive molecular markers.