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。由于抗血管内皮生长因子（VEGF）抗体贝伐单抗具有高度的血管生成性，目前已成为治疗复发性GBM的标准治疗方法。我们发现血管正常化和随后脑水肿的减少是抗vegf治疗在GBM中获益的主要部分。然而，由此产生的益处是有限的，肿瘤不可避免地会进展，甚至可能发展出增加的侵袭性表型。为了克服这种阻力，我们的目标是在血管正常化逃逸过程中增加的两个途径：ANG2 （Aims 1 & 2）和SDFla/CXCR4 （aim 3）。根据我们的前期数据，我们假设抗ang2治疗将通过增加正常化窗口来提高抗vegf治疗的疗效，从而持续减少水肿（Aim 1）。我们还假设抗vegf和ANG2联合治疗将使促肿瘤肿瘤相关巨噬细胞（tam）极化为抗肿瘤的tam，从而提高肿瘤反应和小鼠存活率（Aim 2）。最后，cxcr4阻断可以减少非中枢神经系统肿瘤中免疫抑制（Gr-1+） bmdc的浸润和活化，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SDFla/ cxcr4阻断在改善抗vegf治疗结果中的作用（目的3）。这项工作将揭示抗ang2和抗sdfla /CXCR4药物在GBM中单独或与抗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.