Triple Anti-Angiogenic Therapy for Brain Tumors

描述（由申请人提供）：血管生成对于胶质母细胞瘤的发展和维持至关重要，胶质母细胞瘤是原发性脑肿瘤中最恶性和最常见的形式。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））表达的时间和水平之间的微妙平衡。Ang-2和VEGF-A表达的组合导致内皮周围支持的松动，使得新暴露的内皮细胞能够增殖。我们假设，有一个调节信号循环涉及协调和顺序表达的VEGF和Ang-2，阐明潜在的机制可以导致开发一个更好的模型，发生在人类胶质瘤的血管生成过程。重要的是，我们已经发现了Tie 2在胶质瘤细胞中的表达。此外，利用VEGF和Ang-2之间的相互依赖性，可用于开发比目前存在的更有效和合理的脑肿瘤抗血管生成疗法。因此，在本申请中，我们的目标是揭示Ang-2和VEGF-A之间的相互作用机制，Ang-2表达在胶质瘤血管生成的动态肿瘤模型中的作用，并开发基于同时靶向Ang-2的有效治疗，使用条件复制腺病毒，并使用反义策略直接下调VEGF。具体目的如下：具体目的1：表征Ang-2对VEGF-A的调节;具体目的2：确定血管生成素-2对神经胶质瘤模型中生长动力学和血管生成发展的作用;以及具体目的3：检查基于使用溶瘤腺病毒转移血管生成素-2和反义VEGF的联合疗法的抗神经胶质瘤作用。这个项目应该产生重要的神经胶质瘤血管生成的异常调节机制的信息。此外，从我们的研究中获得的数据将有望为1/11期临床试验的发展提供合理的基础，以测试恶性胶质瘤三联治疗的毒性和疗效，该三联治疗结合了Ang-2的过表达、VEGF表达降低和肿瘤溶解。

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.