Endocrinology Unit, Department of Clinical and Experimental Medicine, University Magna Graecia of Catanzaro Catanzaro, Italy.
Front Endocrinol (Lausanne). 2011 Dec 6;2:93. doi: 10.3389/fendo.2011.00093. eCollection 2011.
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.
大量证据表明，胰岛素样生长因子-1 受体（IGF-IR）和胰岛素受体（IR）都在癌症的发生和发展中发挥作用。特别是 IGF-II 对 IR 的过度激活在癌细胞中很常见，尤其是在去分化/干细胞样细胞中。尽管有这些发现，但直到最近，只有 IGF-IR 而不是 IR 才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 药物具有很好的抗癌活性，但临床试验的结果却令人失望。事实上，只有一小部分恶性肿瘤对这些治疗有客观反应。对抗 IGF-IR 药物的耐药性发展可能包括癌细胞中 IR 同工型 A（IR-A）的上调及其通过自分泌 IGF-II 的增加分泌而过激活。这些发现导致了这样一种概念，即同时靶向 IR 和 IGF-IR 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。在具有高 IR-A:IGF-IR 比值和高水平自分泌 IGF-II 的肿瘤中，应特别考虑 IR 阻断。相反，改善与代谢紊乱和癌症治疗相关的胰岛素抵抗的胰岛素增敏剂可能对癌症预防和管理具有重要意义。目前只有少数同时靶向 IR 和 IGF-IR 的药物。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。
