文章：

肿瘤中的胰岛素和胰岛素样生长因子受体家族：最新进展

The insulin and insulin-like growth factor receptor family in neoplasia: an update

原文发布日期：2012-02-16

DOI: 10.1038/nrc3215

类型: Review Article

开放获取: 否

要点：

1. Preclinical evidence for a role of insulin and insulin-like growth factor (IGF) signalling in promoting neoplastic growth is impressive.
2. Several different targeting strategies for the insulin and IGFI receptor family exist, and dozens of drug candidates have shown activity in model systems.
3. Phase III clinical trials have so far been undertaken only with IGFI receptor-specific antibodies. Although the final results have not yet been published, disappointing reports have been presented for some of these trials. Future trials may differ by incorporating predictive biomarkers, by using rational combination therapy approaches and by using other pharmacological approaches to targeting, such as anti-ligand antibodies or tyrosine kinase inhibitors.
4. The insulin and IGFI receptor family may be involved in resistance mechanisms to therapies that target other signalling nodes in cancer cells, suggesting that there may be situations in which co-targeting will confer benefit.
5. The insulin and IGFI receptor family is now known to have a role in the important relationships between macronutrient intake and cancer, diabetes and cancer, and obesity and cancer.
6. Biguanides, such as metformin, which is widely used in diabetes treatment, have been reported in hypothesis-generating retrospective population studies of subjects with diabetes to be associated with reduced cancer burden. These agents lower insulin levels if they are increased, and have a variety of effects on cellular signalling and cellular metabolism. However, there are gaps in knowledge related to their pharmacokinetics and mechanisms of action that require elucidation.

要点翻译：

1. 胰岛素及胰岛素样生长因子（IGF）信号通路在促进肿瘤生长方面的临床前证据令人瞩目。
2. 目前针对胰岛素和IGF-I受体家族已开发出多种靶向策略，数十种候选药物在模型系统中显示出活性。
3. 迄今仅IGF-I受体特异性抗体进入了III期临床试验。虽然最终结果尚未正式发表，但部分试验已传来令人失望的报告。未来的试验可通过整合预测性生物标志物、采用合理联合治疗方案、以及运用其他药理学靶向方法（如抗配体抗体或酪氨酸激酶抑制剂）来实现创新。
4. 胰岛素和IGF-I受体家族可能参与癌细胞中其他信号节点靶向治疗的耐药机制，这表明在某些情况下联合靶向治疗可能带来获益。
5. 目前已知，胰岛素和IGF-I受体家族在宏量营养素摄入与癌症、糖尿病与癌症、肥胖与癌症等重要关联中发挥着作用。
6. 根据糖尿病受试者假设生成性回顾性人群研究报道，二甲双胍等双胍类药物与癌症负担减轻相关。这类药物能在胰岛素水平升高时予以降低，并对细胞信号传导和细胞代谢产生多重效应。然而，关于其药代动力学和作用机制仍存在需要阐明的认知空白。

英文摘要：

Although several early phase clinical trials raised enthusiasm for the use of insulin-like growth factor I receptor (IGF1R)-specific antibodies for cancer treatment, initial Phase III results in unselected patients have been disappointing. Further clinical studies may benefit from the use of predictive biomarkers to identify probable responders, the use of rational combination therapies and the consideration of alternative targeting strategies, such as ligand-specific antibodies and receptor-specific tyrosine kinase inhibitors. Targeting insulin and IGF signalling also needs to be considered in the broader context of the pathophysiology that relates obesity and diabetes to neoplasia, and the effects of anti-diabetic drugs, including metformin, on cancer risk and prognosis. The insulin and IGFI receptor family is also relevant to the development of PI3K–AKT pathway inhibitors.

摘要翻译： 

尽管多项早期临床试验激起了人们对使用胰岛素样生长因子I受体（IGF1R）特异性抗体治疗癌症的热情，但在未经筛选患者中进行的首次III期研究结果令人失望。进一步的临床研究可能受益于使用预测性生物标志物来识别潜在应答者、使用合理的联合疗法以及考虑替代靶向策略，如配体特异性抗体和受体特异性酪氨酸激酶抑制剂。在更广泛的病理生理背景下，靶向胰岛素和IGF信号还需考虑肥胖和糖尿病与新生物形成之间的关系，以及包括二甲双胍在内的抗糖尿病药物对癌症风险和预后的影响。胰岛素和IGFI受体家族也与PI3K-AKT通路抑制剂的开发相关。

原文链接：

The insulin and insulin-like growth factor receptor family in neoplasia: an update