Triple Anti-Angiogenic Therapy for Brain Tumors

描述(申请人提供)：血管生成对胶质母细胞瘤的发展和维持至关重要，胶质母细胞瘤是最恶性和最常见的原发脑肿瘤形式。目前的证据表明，从正常周围组织中募集肿瘤血管，以及肿瘤血管生成的发展和维持，需要在两种主要血管生成因子：血管生成素-2(Ang-2)和血管内皮生长因子-A(VEGF-A)的表达时间和水平之间保持微妙的平衡。Ang-2和VEGF-A的联合表达导致内皮细胞周围支持的松弛，使新暴露的内皮细胞能够增殖。我们假设存在一个调节信号环，涉及到血管内皮生长因子和血管生成素-2的协调和顺序表达，阐明其潜在的机制可以为人脑胶质瘤中发生的血管生成过程开发一个更好的模型。重要的是，我们发现了Tie2在胶质瘤细胞中的表达。此外，利用血管内皮生长因子和血管生成素-2之间的相互依赖关系，可以开发出比现有的更有效、更合理的脑肿瘤抗血管生成治疗方法。因此，在这一应用中，我们将致力于揭示Ang-2与VEGF-A的相互作用机制，Ang-2表达在胶质瘤血管生成的动态肿瘤模型中的作用，并利用条件复制型腺病毒同时靶向Ang-2，利用反义策略指导VEGF的下调，从而开发有效的治疗方法。具体目的如下：特异性目的1：研究血管生成素-2对血管内皮生长因子-A的调控作用；特异性目的2：研究血管生成素-2对脑胶质瘤模型生长动力学和血管生成的影响；特异性目的3：检测基于血管生成素-2转移、溶瘤腺病毒和反义血管内皮生长因子联合治疗的抗胶质瘤作用。这项研究将为胶质瘤血管生成的异常调控提供重要的机制信息。此外，从我们的研究中获得的数据将有望成为开发1/11期临床试验的合理基础，以测试恶性胶质瘤的毒性和疗效，该三联疗法结合了Ang-2的过表达、VEGF的表达和肿瘤溶解。

DESCRIPTION (provided by applicant): Angiogenesis is critical for the development and maintenance of glioblastomas, the most malignant and most common form of primary brain tumors. Current evidence indicates that recruitment of tumor vessels from normal surrounding tissue, and development and maintenance of tumor angiogenesis require a delicate balance between the timing and level of expression of two major angiogenesis factors: Angiopoietin-2 (Ang-2) and the vascular endothelial growth factor-A (VEGF-A). The combination of Ang-2 and VEGF-A expressions results in loosening of peri-endothelial support rendering the newly exposed endothelial cells able to multiply. We hypothesize that there is a regulatory signaling loop involving the coordinated and sequential expression of VEGF and Ang-2, and that elucidating the underlying mechanisms can lead to developing a better model for the angiogenic process that occurs in human gliomas. Importantly, we have uncovered the expression of Tie2 in glioma cells. Moreover, exploiting the interdependence between VEGFand Ang-2 could be used to develop more effective and rational anti-angiogenesis therapies for brain tumors than currently exist. Therefore, in this application we shall aim to uncover the mechanisms of interaction between Ang-2 and VEGF-A, the role of Ang-2 expression in a dynamic tumor model of glioma angiogenesis, and to develop an effective treatment based on the simultaneous targeting of Ang-2, using conditionally-replicative adenoviruses, and direct down modulation of VEGF using antisense strategies. The specific aims are as follows: Specific Aim 1: To characterize the modulation of VEGF-A by Ang-2; Specific Aim 2: To determine the effects of Angiopoietin-2 on the growth kinetics and angiogenesis development in a glioma model; and Specific Aim 3: To examine the anti-glioma effect of combined therapies based on the transfer of Angiopoietin-2, using oncolytic adenoviruses, and anti-sense VEGF. This project should yield important mechanistic information about the abnormal regulation of angiogenesis in gliomas. Furthermore, data obtained from our studies will hopefully constitute a rational basis for the development of a Phase 1/11clinical trial to test the toxicity and efficacy of a triple treatment for malignant gliomas, which combines the overexpression of Ang-2, decreased VEGF expression, and oncolysis.