Overcoming Resistance to Anti-VEGF Treatment of Glioblastoma

克服胶质母细胞瘤抗 VEGF 治疗的耐药性

• 批准号: 8463131
• 负责人: Rakesh K. Jain
• 金额: $ 23.82万
• 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: 2013-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8463131
• 关键词: Accounting; Angiopoietin-2; Antibodies; Brain Edema; Brain Neoplasms; CXCR4 gene; Clinical Research; Clinical Trials; Combined Modality Therapy; Data; Disease; Edema; Functional disorder; Genetic; Glioblastoma; Human; Infiltration; Instruction; Molecular; Mus; Outcome; Pathway interactions; Patients; Phenotype; Physiological; Recurrence; Research; Resistance; Role; Solid Neoplasm; Testing; Vascular Endothelial Growth Factors; Work; base; bevacizumab; improved; macrophage; preclinical study; response; standard care; standard of care; tumor

Glioblastoma (GBM) is the most common and most aggressive brain tumor in humans. Because it is highly angiogenic, the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab has now^ become the standard of care for treatment of recurrent GBM. We have found that vessel normalization and subsequent reduction of brain edema accounts for a major part of anti-VEGF treatment's benefit in GBM. However, this resulting benefit is modest and tumors inevitably progress and may even develop an increased invasive phenotype. To overcome this resistance, we aim to target two pathways that increase during escape from vessel normalization: ANG2 (Aims 1 & 2) and SDFla/CXCR4 (Aim 3). Based on our prelinrdnary data, we hypothesize that anti-ANG2 therapy will increase the efficacy of anti-VEGF therapy by increasing the window of normalization and thereby sustainably decreasing edema (Aim 1). We also hypothesize that anti-VEGF and ANG2 combined therapy will polarize pro-tumor tumor-associated macrophages (TAMs) to anti-tumor TAMs and thus increase tumor response and mouse survival (Aim 2). Lastly, CXCR4-blockade can reduce infiltration and activation of immtmosuppressive (Gr-1+) BMDCs in non-CNS tumors, and preliminary evidence shows that SDFIa can reduce GBM invasion caused by anti-VEGF treatment. Thus, we now propose to use both genetic and pharmacologic approaches to test the role SDFla/CXCR4-blockade in improving the outcome of anti-VEGF therapy (Aim 3). TTie proposed work will reveal the molecular, cellular and physiological mechanisms of action of anti-Ang-2 and anti-SDFla/CXCR4 agents in GBM - alone and with anti-VEGF agents, and inform the planned clinical trials with these agents in GBM patients.

胶质母细胞瘤(GBM)是人类最常见和最具侵袭性的脑肿瘤。抗血管内皮细胞生长因子(VEGF)抗体贝伐单抗因其高度的血管生成作用，现已成为治疗复发性GBM的标准药物。我们发现，血管正常化和随后脑水肿的减少是抗血管内皮生长因子治疗在GBM中受益的主要部分。然而，由此产生的好处是温和的，肿瘤不可避免地进展，甚至可能发展为更多的侵袭性表型。为了克服这种阻力，我们的目标是针对两条在逃避血管正常化过程中增加的通路：ANG2(目标1和2)和SDFla/CXCR4(目标3)。根据我们的前期临床数据，我们假设抗血管紧张素转换酶2治疗将通过增加正常化窗口从而可持续地减轻水肿来增加抗血管内皮生长因子治疗的疗效(目标1)。我们还假设抗血管内皮生长因子和血管生成素2联合治疗将使亲肿瘤的肿瘤相关巨噬细胞(TAM)极化为抗肿瘤的TAM，从而提高肿瘤反应和小鼠的存活率(目标2)。最后，CXCR4阻断可以减少免疫抑制(Gr-1+)BMDCs在非中枢神经系统肿瘤中的渗透和激活，初步证据表明SDFIa可以减少抗VEGF治疗引起的GBM侵袭。因此，我们现在建议使用遗传学和药理学方法来测试SDF1a/CXCR4阻断在改善抗血管内皮生长因子治疗结果中的作用(目标3)。TTie建议的工作将揭示抗Ang-2和抗SDFla/CXCR4药物单独作用于GBM以及与抗VEGF药物联合作用的分子、细胞和生理机制，并为这些药物在GBM患者中的临床试验计划提供信息。