Targeting the Vasular System

项目1旨在改善胶质母细胞瘤抗血管生成治疗的结局。食品 和药物管理局批准贝伐单抗，一种抗VEGF的单克隆抗体，作为单药治疗， 2009年复发的胶质母细胞瘤然而，这种药物在胶质母细胞瘤中的确切作用机制是 没有完全理解。以前，我们发现用DC 101阻断VEGF信号传导，DC 101是一种鼠抗VEGF抗体， 抗体或泛VEGF酪氨酸激酶抑制剂AZD 2171，使胶质母细胞瘤血管正常化， 增加动物模型的总体存活率。然而，抗VEGF治疗对总生存期的影响 在胶质母细胞瘤患者中，由于肿瘤最终从正常化中逃脱， 调节其他促血管生成信号转导途径。一种促血管生成分子 在这方面感兴趣是血管生成素-2（Ang 2）。我们已经证明过表达Ang 2 损害了DC 101治疗的生存益处。此外，Ang 2表达在 血管正常化窗口，但随着肿瘤血管开始变得异常而增加。这种模式 在接受治疗的复发性胶质母细胞瘤患者的血浆中也观察到动态Ang 2表达 AZD2171基于这些临床前和临床数据，我们假设Ang 2的抑制可能 延长正常化窗口，从而改善VEGF阻断诱导的临床益处。我们会的 测试在不同的时间表中阻断Ang 2和VEGF信号传导是否抑制肿瘤生长， 增加不同鼠胶质母细胞瘤模型的总存活率（Aim One）。随后，我们将测试 阻断这两种途径是否可以通过延长正常化窗口来增加生存率， 仅用VEGF抑制剂观察（目的二）。最后，我们将进行一项临床试验（目标三）， 将评估选择性Ang 2抑制对复发性高血压患者血管正常化窗口的影响。 胶质母细胞瘤患者以及抗Ang 2疗法的安全性和潜在功效。本临床试验将 为Ang 2和VEGF抑制剂的未来联合试验提供基础，后者由 目标一和目标二的结果。

Project 1 is designed to improve upon the outcome of anti-angiogenic therapy in glioblastoma. The Food and Drug Administration approved bevacizumab, an anti-VEGF monoclonal antibody, as monotherapy for recurrent glioblastoma in 2009. However, the precise mechanism(s) of action of this drug in glioblastoma is not fully understood. Previously, we showed that blocking VEGF-signaling with DC101, a murine anti-VEGF antibody, or AZD2171, a pan-VEGF tyrosine kinase inhibitor, normalizes glioblastoma blood vessels and increases overall survival in animal models. However, the effects of anti-VEGF therapies on overall survival appear modest in glioblastoma patients as the tumor eventually escapes from normalization by the up regulation of other pro-angiogenic signal transduction pathways. One pro-angiogenic molecule of particular interest in this regard is angiopoietin-2 (Ang2). We have demonstrated that overexpression of Ang2 compromises the survival benefit from DC101 treatment. Moreover, Ang2 expression decreased during the vascular normalization window but increased as the tumor vessels began to become abnormal. This pattern of dynamic Ang2 expression has also been observed in the plasma of recurrent glioblastoma patients treated with AZD2171. Based on these pre-clinical and clinical data, we hypothesize that the inhibition of Ang2 may prolong the normalization window, thereby improving the clinical benefit induced by VEGF-blockade. We wiil test whether blocking both Ang2 and VEGF signaling in different schedules inhibits tumor growrth and increases overall survival in different murine glioblastoma models (Aim One). Subsequently, we will test whether blocking both of these pathways can increase survival by prolonging the normalization window over that pbserved with VEGF inhibition alone (Aim Two). Finally, we will conduct a clinical trial (Aim Three) that will assess the impact of selective Ang2 inhibition on the vascular normalization window in recurrent glioblastoma patients as well as the safety and potential efficacy of anti-Ang2 therapy. This clinical trial will provide the foundation for future combination trials of Ang2 and VEGF inhibitors, the latter informed by the results of Aims One and Two.