The insulin receptor: a new target for cancer therapy.
The insulin receptor: a new target for cancer therapy.
复制标题
DOI：
10.3389/fendo.2011.00093
复制
发表时间：
2011
影响因子：
5.2
通讯作者：
Belfiore A
中科院分区：
文献类型：
--
作者：
Malaguarnera R;Belfiore A
大量证据表明，IGF-I受体（IGF-IR）和胰岛素受体（IR）在癌症的发生和发展中都起着重要作用。特别是，IGF-II过度激活IR在癌细胞中很常见，特别是在去分化/干细胞样细胞中。尽管有这些发现，直到最近，只有IGF-IR而不是IR被认为是癌症治疗的靶点。尽管一些临床前研究表明选择性抗igf - ir药物具有良好的抗癌活性，但临床首次试验的结果令人失望。事实上，只有一小部分恶性肿瘤对这些疗法表现出客观的反应。对抗igf -IR药物的耐药性可能包括癌细胞中IR异构体A （IR-A）的上调及其通过增加自分泌IGF-II分泌而过度激活。这些发现导致了这样一个概念，即IR与IGF-IR共同靶向可能会提高治疗效果，并防止对选择性抗IGF-IR药物的适应性耐药。对于高IR- a:IGF-IR比值和高自分泌IGF-II水平的肿瘤，应特别考虑IR阻断。相反，胰岛素增敏剂可以改善与代谢紊乱和癌症治疗相关的胰岛素抵抗，可能对癌症的预防和管理具有重要意义。目前只有少数药物可以同时靶向IR和IGF-IR。理想情况下，未来的IR靶向策略应该能够选择性地抑制IR的促肿瘤作用，而不损害其代谢作用。
A large body of evidences have shown that both the IGF-I receptor (IGF-IR) and the insulin receptor (IR) play a role in cancer development and progression. In particular, IR overactivation by IGF-II is common in cancer cells, especially in dedifferentiated/stem-like cells. In spite of these findings, until very recently, only IGF-IR but not IR has been considered a target in cancer therapy. Although several preclinical studies have showed a good anti-cancer activity of selective anti-IGF-IR drugs, the results of the clinical first trials have been disappointing. In fact, only a small subset of malignant tumors has shown an objective response to these therapies. Development of resistance to anti-IGF-IR drugs may include upregulation of IR isoform A (IR-A) in cancer cells and its overactivation by increased secretion of autocrine IGF-II. These findings have led to the concept that co-targeting IR together with IGF-IR may increase therapy efficacy and prevent adaptive resistance to selective anti-IGF-IR drugs. IR blockade should be especially considered in tumors with high IR-A:IGF-IR ratio and high levels of autocrine IGF-II. Conversely, insulin sensitizers, which ameliorate insulin resistance associated with metabolic disorders and cancer treatments, may have important implications for cancer prevention and management. Only few drugs co-targeting the IR and IGF-IR are currently available. Ideally, future IR targeting strategies should be able to selectively inhibit the tumor promoting effects of IR without impairing its metabolic effects.