High-affinity protease-resistant analog of Insulin-like Growth Factor binding protein-2: Potential Cancer Co-Therapeutic

在包括前列腺癌和乳腺癌在内的许多人类癌症中，血清中胰岛素样生长因子(IGF)-II的水平升高，而这种生长因子在促进这些肿瘤的进展中有很强的作用。IGF- ii刺激肿瘤生长的作用是通过细胞表面1型IGF受体介导的。IGF结合蛋白，IGFBP-2，已经被证明可以在体外增加一些癌细胞中IGF- ii的作用。通过与细胞外部结合形成IGF-II- igfbp -2复合物，然后通过持续释放的过程将IGF-II呈递给受体。我们建议生产一种非常高亲和力的胰岛素样生长因子结合蛋白-2 (OOptimised igfbp - 20)，它将隔离IGF-II并有效地阻止其与受体或天然IGFBP-2结合。我们还将设计优化后的igfbp - 20，使其不能与细胞外部结合。利用这种新型肽OOptimised igfbp - 20，我们将验证胰岛素样生长因子（IGF）依赖性肿瘤的生长可以通过阻止IGF- ii向IGF受体的定位和呈递来阻止的假设。我们期望这种IGF-II隔离剂的可用性将提高当前癌症化疗药物的有效性，因为已知IGF-II可以帮助拯救化疗诱导的癌细胞死亡。

In many human cancers, including prostate and breast cancer, serum levels of insulin-like growth factor (IGF)-II are elevated, and this growth factor has been strongly implicated in promoting the progression of these tumours. The action of IGF-II in stimulating tumour growth is mediated through Type 1 IGF receptors on the surface of the cells. The IGF binding protein, IGFBP-2, has been shown to increase the action of IGF-II in some cancer cells in vitro. by binding to the outside of the cells as an IGF-II-IGFBP-2 complex and then presenting the IGF-II to the receptor by a process of sustained release. We propose to produce a very high affinity form of insulin-like growth factor binding protein-2 (OOptimised IGFBP-2O) which will sequester the IGF-II and effectively prevent it from binding to the receptor or the native IGFBP-2. We shall also engineer the OOptimised IGFBP-2O so that it is unable to bind to the outside of the cells. With this novel peptide, OOptimised IGFBP-2O, we will test the hypothesis that the growth of insulin-like growth factor (IGF)-dependent tumours can be arrested by preventing the localisation and presentation of IGF-II to IGF receptors. We expect that the availability of such a sequestering agent for IGF-II will increase the effectiveness of current cancer chemotherapy agents since it is known that IGF-II can help save cancer cells from chemotherapy-induced death.