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

胰岛素样生长因子结合蛋白 2 的高亲和力蛋白酶抗性类似物：潜在的癌症联合治疗

• 批准号: nhmrc : 104924
• 负责人: A/Pr Briony Forbes
• 金额: $ 19.63万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2000
• 资助国家: 澳大利亚
• 起止时间: 2000-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/high-affinity-protease-co-therapeutic/94556
• 关键词: affinity; protease; resistant; analog; Insulin

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.

在许多人类癌症中，包括前列腺癌和乳腺癌，血清胰岛素样生长因子(IGF)-II水平升高，这种生长因子被强烈地与促进这些肿瘤的进展有关。IGF-II刺激肿瘤生长的作用是通过细胞表面的1型IGF受体介导的。IGF结合蛋白IGFBP-2已被证明在体外可以增强IGF-II在一些癌细胞中的作用。通过以IGF-II-IGFBP-2复合体的形式与细胞外部结合，然后通过持续释放的过程将IGF-II呈现给受体。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(OOptimizedIGFBP-2O)，它将隔离IGF-II，并有效地阻止它与受体或天然IGFBP-2结合。我们还将设计优化的IGFBP-2O，使其不能与细胞外部结合。有了这种新的多肽，OOptimizedIGFBP-2O，我们将测试这一假设，即可以通过阻止IGF-II的定位和IGF受体的呈现来阻止依赖胰岛素样生长因子(IGF)的肿瘤的生长。我们期望IGF-II的这种封闭剂的可用性将增加目前癌症化疗药物的有效性，因为众所周知，IGF-II可以帮助挽救癌细胞，使其免于化疗诱导的死亡。