Studies in Mice to Improve Efficacy/Safety of Paclitaxel/Docetaxel with an Anti-I

描述（由申请人提供）：分化抑制剂（Id）基因和蛋白质在肿瘤生物学中发挥重要作用，并且假设抗Id疗法与紫杉烷类（一种广泛处方的细胞毒性（紫杉醇/多西他赛、多西他赛或蛋白结合紫杉醇））组合治疗癌症，可显著改善紫杉烷类的疗效，而不影响安全性，同时还提供额外的抗癌活性。有效的Id 1抑制剂将通过三种不同的机制潜在地改善紫杉烷类的功效：（i）防止内皮修复，从而促进紫杉醇/多西他赛的内在抗血管生成作用，（ii）降低肿瘤的抗凋亡环境，使其更容易受到紫杉醇/多西他赛的细胞毒性的影响，以及（iii）通过直接抗癌作用增强紫杉醇/多西他赛的细胞毒性。本提案的目的是提供数据，以证明这种抗Id 1小分子治疗方法的正式临床前开发和初步临床评价的合理性。该基金资助的实验包括小鼠异种移植研究，以建立抗Id药物和紫杉烷类药物的最佳给药方案。 公共卫生相关性：抗微管紫杉烷类药物如紫杉醇和多西他赛是广泛用于治疗癌症的细胞毒性药物。有效的Id 1抑制剂将通过三种不同的机制潜在地改善紫杉烷类的功效：（i）防止内皮修复，从而促进紫杉烷类的内在抗血管生成作用，（ii）降低肿瘤的抗凋亡环境，使其对紫杉烷类的细胞毒性更敏感，和（iii）通过直接抗癌作用增强紫杉烷类的细胞毒性。本提案的目的是提供数据，以证明使用抗Id 1小分子的这种治疗方法的正式临床前开发和初步临床评价的合理性。

DESCRIPTION (provided by applicant): Inhibitor of differentiation (Id) genes and proteins play a significant role in tumor biology, and an anti-Id therapy in combination with a taxanes, a widely prescribed class of cytotoxic (paclitaxel/docetaxel, docetaxel or protein-bound paclitaxel) to treat cancer, is hypothesized to significantly improve the efficacy of the taxane without compromising safety while also providing additional anti-cancer activity. An effective Id1 inhibitor would potentially improve the efficacy of the taxanes by three distinct mechanisms: (i) preventing endothelial repair and thereby promoting the intrinsic anti-angiogenic effect of paclitaxel/docetaxel, (ii) lowering the anti-apoptotic environment of the tumor making it more susceptible to the cytotoxicity of paclitaxel/docetaxel and (iii) augmenting the cytotoxicity of paclitaxel/docetaxel by a direct anti-cancer effect. The goal of this proposal is to provide data to justify formal preclinical development and initial clinical evaluation of this therapeutic approach with an anti-Id1 small molecule. Experiments to be funded by the grant include xenograft studies in mice to establish the optimum dosing regimen for both the anti-Id agent and the taxanes. PUBLIC HEALTH RELEVANCE: Anti-microtubule taxanes like paclitaxel and docetaxel are widely prescribed cytotoxics to treat cancer. An effective Id1 inhibitor would potentially improve the efficacy of taxanes by three distinct mechanisms: (i) preventing endothelial repair and thereby promoting the intrinsic anti-angiogenic effect of taxanes, (ii) lowering the anti-apoptotic environment of the tumor making it more susceptible to the cytotoxicity of the taxanes, and (iii) augmenting the cytotoxicity of the taxanes by a direct anti-cancer effect. The goal of this proposal is to provide data to justify formal preclinical development and initial clinical evaluation of this therapeutic approach using an anti-Id1 small molecule.