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.
We propose a comprehensive approach to dissect the mechanisms of GBM escape from anti-VEGF therapy. We will examine two distinct pathways of evasion that emerged from our preclinical and clinical studies in GBM. Our research will generate important and translatable results for new combination therapy paradigms that are desperately needed for this dreadful disease.
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