Therapeutic modulation with thrombospondin-1

说明(申请人提供)：凝血酶敏感蛋白-1(TSP-1)是一种内源性血管生成抑制因子，通常由多种细胞分泌。各种来源的肿瘤，包括胶质母细胞瘤，已被发现下调血栓反应蛋白-1(TSP-1)的表达。我们之前已经证明，TSP-1在人胶质母细胞瘤细胞中的过表达降低了免疫低下小鼠的致瘤性，显然是由于抑制了血管生成。我们建议通过确定在先前存在的脑瘤中诱导TSP-1的表达是否会导致皮下和颅内胶质瘤模型中的肿瘤生长停止或逆转，来扩大我们的致瘤性研究。此外，我们计划研究仅含有1型重复序列的迷你TSP-1蛋白是否具有与全长TSP-1类似的抗血管生成活性。我们最终将使用神经前体细胞作为治疗工具，在脑胶质瘤模型中传递TSP-1或迷你TSP-1。通过这种方法，TSP-1或迷你TSP-1在肿瘤部位的稳定和有效水平将是理想的。这种治疗方式的实验成功将很容易适应临床情况，并可能导致新的高效治疗胶质母细胞瘤和其他类型的癌症。

DESCRIPTION (provided by applicant): Thrombospondin-1 (TSP-1), an endogenous angiogenisis inhibitor, is normally secreted by many cell types. Tumors of various origins, including glioblastomas, have been found to down-regulate thrombospondin-1 (TSP-1) expression. We have previously shown that overexpression of TSP-1 in human glioblastoma cells reduces their tumorigenicity in immunocompromised mice, apparently due to inhibition of angiogenesis. We propose to extend our tumorigenicity studies by determining whether induced expression of TSP-1 in a pre-existing brain tumor will result in arrest or reversal of tumor growth in subcutaneous and intracranial glioma models. Additionally, we plan to investigate if mini-TSP-1 proteins containing solely type 1 repeats will have anti-angiogenic activities comparable to full length TSP-1. We will ultimately use neural progenitor cells as a therapeutic tool to deliver TSP-1 or mini-TSP-1 in an intracranial glioma model. With this approach steady and efficacious levels of TSP-1 or mini-TSP-1 will be ideally achievable at the tumor sites. Experimental success in this treatment modality will be readily adaptable to a clinical situation, and could lead to new and highly effective treatment for glioblastomas and other types of cancer.