Can we unlock the potential of IGF-1R inhibition in cancer therapy?
Can we unlock the potential of IGF-1R inhibition in cancer therapy?
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DOI：
10.1016/j.ctrv.2014.07.004
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发表时间：
2014-10
影响因子：
11.8
通讯作者：
Macaulay, Valentine M.
中科院分区：
文献类型：
--
作者：
King, Helen;Aleksic, Tamara;Haluska, Paul;Macaulay, Valentine M.
关键词：
IGF- 1r抑制剂进入临床是伴随着基于IGF- 1r靶向的临床前活性的乐观情绪，以及对低IGF生物活性可以预防癌症的认识。由于担心对正常组织IGF-1R的毒性以及与胰岛素受体（InsR）的交叉反应性，这一研究结果有所缓和。事实上，毒性并不是表演的拦路石；关键问题是疗效。虽然IGF-1R抑制可诱导肉瘤单药治疗和普通癌症化疗或靶向药物治疗的反应，但在未选择的患者中进行的2/3期试验阴性促使一些制药项目停止。在这里，我们回顾了已完成和正在进行的IGF-1R抗体、激酶抑制剂和配体抗体的试验。我们评估了用于患者选择的候选生物标志物，强调了循环igf / igfbp的潜在预测价值，对IGF-1R标准化检测的需求，以及变异InsRs介导对IGF-1R抗体耐药的临床前证据。我们回顾了假设导向和无偏倚的方法来评估IGF-1R抑制剂与其他药物的结合，并强调需要考虑化疗的测序。过去几年是IGF- 1r治疗的艰难时期，但也带来了对IGF生物学的理解的进展。即使失败的研究也包括获益的患者；应该对它们进行调查，以确定反应者与非反应者的肿瘤和宿主环境的特征。我们强调将生物标本收集纳入试验设计的重要性，并强调在获得新数据时允许对试验材料进行事后分析的患者同意。这些信息是释放这种方法潜力的关键，为下一代IGF信号抑制剂的试验提供信息。
IGF-1R inhibitors arrived in the clinic accompanied by optimism based on preclinical activity of IGF-1R targeting, and recognition that low IGF bioactivity protects from cancer. This was tempered by concerns about toxicity to normal tissue IGF-1R and cross-reactivity with insulin receptor (InsR). In fact, toxicity is not a show-stopper; the key issue is efficacy. While IGF-1R inhibition induces responses as monotherapy in sarcomas and with chemotherapy or targeted agents in common cancers, negative Phase 2/3 trials in unselected patients prompted the cessation of several Pharma programs. Here, we review completed and on-going trials of IGF-1R antibodies, kinase inhibitors and ligand antibodies. We assess candidate biomarkers for patient selection, highlighting the potential predictive value of circulating IGFs/IGFBPs, the need for standardized assays for IGF-1R, and preclinical evidence that variant InsRs mediate resistance to IGF-1R antibodies. We review hypothesis-led and unbiased approaches to evaluate IGF-1R inhibitors with other agents, and stress the need to consider sequencing with chemotherapy. The last few years were a tough time for IGF-1R therapeutics, but also brought progress in understanding IGF biology. Even failed studies include patients who derived benefit; they should be investigated to identify features distinguishing the tumors and host environment of responders from non-responders. We emphasize the importance of incorporating biospecimen collection into trial design, and wording patient consents to allow post hoc analysis of trial material as new data become available. Such information represents the key to unlocking the potential of this approach, to inform the next generation of trials of IGF signalling inhibitors.
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影响因子：
11.5
作者：
Chitnis, Meenali M.;Yuen, John S. P.;Macaulay, Valentine M.
通讯作者：
Macaulay, Valentine M.
影响因子：
11.5
作者：
Atzori, Francesco;Tabernero, Josep;Baselga, Jose
通讯作者：
Baselga, Jose
影响因子：
1.4
作者：
Ayalon, D.;Glaser, T.;Werner, H.
通讯作者：
Werner, H.
影响因子：
5.6
作者：
Bodzin, Adam S.;Wei, Zhengyu;Doria, Cataldo
通讯作者：
Doria, Cataldo
影响因子：
11.2
作者：
Buck, Elizabeth;Eyzaguirre, Alexandra;Ji, Qun-Sheng
通讯作者：
Ji, Qun-Sheng