VEGF-dependent and - Independent Anti-angiogenic Therapy

描述（由申请人提供）：抗血管生成治疗代表了 新兴的和有前途的方式治疗恶性肿瘤，虽然 假定的血管生成抑制剂之间的对照比较已经 缺乏基因治疗方法非常适合于实验性递送 不同的抗血管生成蛋白，考虑到载体构建的容易性， 与重组蛋白相比， 局我们已经利用腺病毒的方法来创建一个阵列， 表达抗血管生成蛋白的腺病毒， 血管内皮生长因子（VEGF）受体Flk 1、Flt 1和 neuropilin，以及抗血管生成因子内皮抑制素和血管抑制素。 使用这些病毒，我们已经进行了第一次比较基于VEGF的 和非基于VEGF的抗血管生成蛋白质，并且已经发现了上级 用可溶性Flk 1和Flt 1处理的抗血管生成和抗肿瘤活性 而不是肿瘤衍生的蛋白质，如内皮抑素和血管抑素。可溶性 FIk 1和Flt 1腺病毒表现出广谱抑制许多人类 和小鼠肿瘤的皮下和原位模型。 目前的建议在几个方面扩展了这些调查结果。 首先，我们将探讨VEGF阻断可以与 阻断不同的血管生成途径，以实现相加到协同 抑制血管生成和肿瘤生长。这将通过使用 几种新的腺病毒设计拮抗TIE/血管生成素， EphB 4/ephrin-B2内皮受体酪氨酸激酶途径。二是 检验溶瘤病毒的局部和全身效力 可以通过同时用可溶性Flk 1和Flt 1处理来改善 腺病毒，或者通过实际上将溶瘤病毒改造成自身， 表达抗血管生成蛋白。最后，基于强大的 小鼠FIk 1和FIt 1可溶性VEGF受体的广谱活性，我们 将检验这些蛋白质的人源化版本将 有效抑制肿瘤生长和肿瘤血管生成。而且这些 人源化受体将从受调节的腺病毒表达， 作为最终临床使用的前奏的额外安全程度。

DESCRIPTION (provided by applicant): Anti-angiogenic therapy represents an emerging and promising modality for the treatment of malignancies, although controlled comparisons between putative angiogenesis inhibitors has been lacking. Gene therapy approaches are well suited for the experimental delivery of diverse anti-angiogenic proteins, given the ease of vector construction versus recombinant protein, and the convenience of single injection viral administration. We have exploited an adenoviral approach to create an array of adenoviruses expressing anti-angiogenic proteins such as soluble ectodomains of the Vascular Endothelial Growth Factor (VEGF) receptors Flk 1, Flt 1 and neuropilin, as well as the anti-angiogenic factors endostatin and angiostatin. Using these viruses, we have performed the first comparison between VEGF-based and non-VEGF-based anti-angiogenic proteins, and have found superior antiangiogenic and anti-tumor activity with soluble Flk 1 and Flt 1 treatment over tumor-derived proteins such as endostatin and angiostatin. The soluble FIk 1 and Flt 1 adenoviruses exhibit broad-spectrum suppression of numerous human and murine tumors in both subcutaneous and orthotopic models. The current proposal extends upon these findings in several respects. First, we will explore the hypothesis that VEGF blockade can be combined with blockade of distinct angiogenic pathways to achieve additive to synergistic inhibition of angiogenesis and tumor growth. This will be accomplished using several new adenoviruses designed to antagonize the TIE/angiopoietin and EphB4/ephrin-B2 endothelial receptor tyrosine kinase pathways. Second, we will test the hypothesis that the local and systemic efficacy of oncolytic viruses can be improved by simultaneous treatment with soluble Flk 1 and Flt 1 adenoviruses, or by actually modifying the oncolytic viruses to themselves express anti-angiogenic proteins. Finally, based upon the strong and broad-spectrum activity of the murine FIk 1 and FIt 1 soluble VEGF receptors, we will examine the hypothesis that humanized versions of these proteins will effectively suppress tumor growth and tumor angiogenesis. Moreover, these humanized receptors will be expressed from regulated adenoviruses to confer an additional degree of safety as a prelude to eventual clinical use.