VEGF-dependent and - Independent Anti-angiogenic Therapy

描述(申请人提供)：抗血管生成治疗代表一种 新出现的和有希望的治疗恶性肿瘤的方法，尽管 假定的血管生成抑制剂之间的对照比较已经被 缺乏。基因治疗方法非常适合于实验性的分娩。 不同的抗血管生成蛋白，鉴于载体构建的简便性 与重组蛋白相比，以及单次注射病毒的便利性 行政管理。我们已经使用腺病毒方法创造了一系列 表达抗血管生成蛋白的腺病毒，如可溶性的 血管内皮生长因子受体Flk-1、Flt-1和Flt-1 神经匹林，以及抗血管生成因子内皮抑素和血管抑素。 使用这些病毒，我们首次比较了基于血管内皮生长因子的 和非基于血管内皮生长因子的抗血管生成蛋白，并发现了优越的 可溶性Flk-1和Flt-1的抗血管生成和抗肿瘤活性 而不是肿瘤衍生蛋白，如内皮抑素和血管抑素。可溶的 FIK-1和Flt-1腺病毒对许多人的广谱抑制 以及皮下和原位模型中的小鼠肿瘤。 目前的提案在几个方面对这些调查结果进行了扩展。 首先，我们将探索一种假设，即血管内皮生长因子拮抗剂可以与 阻断不同的血管生成途径以实现协同增效 抑制血管生成和肿瘤生长。这将通过以下方式完成 几种新的腺病毒设计来拮抗Tie/Angiopoietin和 EphB4/eaffin-B2内皮受体酪氨酸激酶通路。第二，我们将 检验溶瘤病毒的局部和全身疗效的假设 可通过同时使用可溶性Flk-1和Flt-1来改善 腺病毒，或通过实际将溶瘤病毒修饰为自身 表达抗血管生成蛋白。最后，基于强大和 小鼠FIK-1和FIT-1可溶性血管内皮生长因子受体的广谱活性 将检验这样的假设：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。此外，这些 人源化受体将从受调控的腺病毒中表达，以赋予 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.