Targeting the Vasular System

针对血管系统

• 批准号: 8588485
• 负责人: Tracy T Batchelor
• 金额: $ 27.62万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-19 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8588485
• 关键词: Angiogenic Factor; Angiopoietin-2; Angiopoietins; Animal Model; Antibodies; Biological Markers; Biometry; Blood Vessels; Brain; Brain Edema; CCL4 gene; Cell Survival; Cells; Clinical; Clinical Data; Clinical Trials; DC101 Monoclonal Antibody; Data; Endothelial Cells; Family; Foundations; Future; Glioblastoma; Glioma; Grant; Growth Factor; Growth Factor Inhibition; Hyperplasia; Image; Immune; Immunity; Immunohistochemistry; Infiltration; Lead; Magnetic Resonance Imaging; Malignant Neoplasms; Measurement; Messenger RNA; Modeling; Monoclonal Antibodies; Mus; Neoplasms in Vascular Tissue; Outcome; Pathology; Pathway interactions; Patients; Pattern; Phase II Clinical Trials; Plasma; Pre-Clinical Model; Process; Progression-Free Survivals; Receptor Protein-Tyrosine Kinases; Recurrence; Role; Safety; Schedule; Signal Transduction; Signal Transduction Pathway; Simulate; System; Techniques; Testing; Tumor Angiogenesis; Tumor Cell Invasion; Tyrosine Kinase Inhibitor; United States Food and Drug Administration; Up-Regulation; Vascular Endothelial Growth Factors; Weight; angiogenesis; base; bevacizumab; cytokine; design; drug action; improved; inhibitor/antagonist; innovation; insight; interest; intravital microscopy; member; mouse model; neoplastic cell; novel; overexpression; pre-clinical; programs; research study; response; standard care; success; therapeutic target; tumor; tumor growth; tumor microenvironment; tumor progression

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.

项目1旨在改善胶质母细胞瘤抗血管生成疗法的结果。食物 药物管理局批准了抗VEGF单克隆抗体的贝伐单抗作为单一疗法 但是，2009年的复发性胶质母细胞瘤。然而，该药物在胶质母细胞瘤中作用的确切机制是 不完全理解。以前，我们表明用鼠抗VEGF阻止VEGF信号dc101 抗体或AZD2171，一种泛VEGF酪氨酸激酶抑制剂，使胶质母细胞瘤血管和 在动物模型中增加了总体生存。但是，抗VEGF疗法对总体生存的影响 在胶质母细胞瘤患者中显得适度 调节其他促血管生成信号转导途径。一个特定的促血管生成分子 对这方面的兴趣是Angiopoietin-2（ANG2）。我们已经证明了Ang2的过表达 DC101治疗损害了生存益处。此外，Ang2表达在 血管归一化窗口，但随着肿瘤血管开始变得异常而增加。这个模式 在经过治疗的复发性胶质母细胞瘤患者的血浆中也观察到了动态ANG2表达 与AZD2171。基于这些临床前和临床数据，我们假设抑制Ang2可能 延长标准化窗口，从而改善VEGF-Blockade引起的临床益处。我们要 测试在不同时间表中阻止ANG2和VEGF信号传导是否会抑制肿瘤成长和 在不同的鼠胶质母细胞瘤模型中增加了总体存活率（AIM ONE）。随后，我们将测试 阻止这两种途径是否可以通过延长标准化窗口来增加生存 仅通过VEGF抑制（目标两个）而pbs。最后，我们将进行临床试验（瞄准三） 将评估选择性ANG2抑制对复发中血管归一化窗口的影响 胶质母细胞瘤患者以及抗ANG2治疗的安全性和潜在功效。该临床试验将 为ANG2和VEGF抑制剂的未来组合试验提供了基础，后者由 目标的结果一和两个。