Overcoming Resistance to Anti-VEGF Treatment of Glioblastoma

胶质母细胞瘤（GBM）是人类最常见和最具侵袭性的脑肿瘤。因为它是高度血管生成的，抗血管内皮生长因子（VEGF）抗体贝伐单抗现在已经成为治疗复发性GBM的护理标准。我们发现血管正常化和随后脑水肿的减少是抗VEGF治疗GBM的主要益处。然而，这种产生的益处是适度的，并且肿瘤不可避免地进展，甚至可能发展出增加的侵袭性表型。为了克服这种阻力，我们的目标是靶向在逃避血管正常化期间增加的两种途径：ANG 2（目的1和2）和SDFla/CXCR 4（目的3）。基于我们的初步数据，我们假设抗ANG 2治疗将通过增加正常化窗口从而可持续地减少水肿来增加抗VEGF治疗的功效（目的1）。我们还假设抗VEGF和ANG 2联合治疗将使促肿瘤肿瘤相关巨噬细胞（TAM）转化为抗肿瘤TAM，从而增加肿瘤应答和小鼠存活（目的2）。最后，CXCR 4阻断可以减少非CNS肿瘤中免疫抑制性（Gr-1+）BMDC的浸润和活化，并且初步证据显示SDFIa可以减少由抗VEGF治疗引起的GBM侵袭。因此，我们现在提出使用遗传学和药理学方法来测试SDFla/CXCR 4阻断在改善抗VEGF治疗的结果中的作用（目的3）。TTie提出的工作将揭示抗Ang-2和抗SDFla/CXCR 4药物在GBM中单独和与抗VEGF药物作用的分子、细胞和生理机制，并为计划在GBM患者中使用这些药物的临床试验提供信息。

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.