Ang-2 and VEGF Inhibition alters tumor associated macrophages and normalizes tumor vasculature in glioblastoma

Tejaswini Reddy

 Introduction: Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults and the current standard of treatment of care is surgical resection of tumor(s) followed by external beam irradiation and taking cytotoxic agent temozolomide orally [1-6]. However, many tumors develop resistance to temozolomide, which is why targeted therapies such as a monoclonal antibody against vascular endothelial growth factor (VEGF), known as bevacizumab,  have been incorporated into combination therapy regimens [7-10].  Unfortunately, bevacizumab in combination with radiotherapy and temozolomide did not improve overall survival in newly diagnosed GBM patients and patients developed resistance to bevacizumab [2, 7]. Preclinical studies have suggested that the angiopoietin-2 (Ang-2)/TEK receptor kinase 2 (Tie2) pathway plays a role in the developed resistance to VEGF inhibition[7, 8, 10-14]. Clinical studies found that in GBM patients treated with bevacizumab, there were increased levels of Ang-2 in circulation[11]. In murine glioblastoma models, ectopic expression of Ang-2 in combination with bevacizumab treatment destabilized blood vessels and compromised the survival benefit of VEGF inhibition, leading to increased vascular permeability and cerebral edema [11, 15]. Hypothesis: The hypothesis is that dual inhibition of Ang-2 and VEGF could induce vessel normalization, improve survival, and promote antitumor activity in murine models of glioblastoma [7, 16, 17].  Methods: Two orthotopic murine GBM models, G1261 and U87 were utilized. The mice were treated with control IgG, anti-Ang2 neutralizing monoclonal (MEDI3617), pan-VEGF receptor inhibitor (Cediranib), or MEDI3617+Cediranib dual therapy. The effects of the dual therapy on survival, tumor growth, vascular normalization, and tumor associated macrophage (TAM) phenotype were studied [7, 8]. Results: Murine glioblastoma models treated with dual Anti-Ang2/Anti-VEGF treatment had extended survival, decreased tumor growth and decreased tumor volume in comparison to Anti-VEGF or Anti-Ang2 monotherapy alone [7]. Dual Anti-Ang2/Anti-VEGF therapy also promoted increased microvascular density, increased perivascular cell coverage, and significantly higher basement membrane coverage, which are all indicators of improved   vascular structure and normalization [7, 15]. Dual inhibition of Ang2 and VEGF also resulted in increased M1 macrophages (anti-tumor phenotype) than M2 macrophages (pro-tumor phenotype)[7, 8, 18-22].  Conclusions: Dual inhibition of Ang2 and VEGF may be an effective combination therapy for GBM due to this synergistic ability to improve survival, vascular normalization, and reprogram GBM-associated TAMs from a M2, protumor phenotype to a M1, antitumor phenotype.

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