Dual Targeting of Angiopoietin-2 and VEGF Signaling for the Treatment of Glioblastoma

Abstract

Glioblastoma (GBM) is the most common and aggressive brain tumor in humans. Because GBM is highly angiogenic, the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab has now become the standard of care for treatment of recurrent GBM. However, GBMs rapidly become refractory to standard anti-VEGF therapy. It was previously demonstrated that vessel normalization and subsequent reduction of intracranial vasogenic edema accounts for a majority of the benefit from inhibiting VEGF-signaling in GBM. Also, ectopic over-expression of Ang-2 compromises the benefits of anti-VEGF receptor (VEGFR) treatment in mice and showed that circulating levels of Ang-2 rebound after an initial decrease in GBM patients treated with anti-VEGFR agents. This thesis examines the hypothesis that combined inhibition of VEGF and Ang-2 signaling can improve survival in murine models of GBM, and investigates potential underlying mechanisms. The efficacy of cediranib, a pan-VEGFR tyrosine kinase inhibitor, combined with MEDI3617, an anti-Ang-2 neutralizing antibody, was tested in two orthotopic models of GBM (U87 and Gl261). Combination therapy improved survival in both models beyond that of the monotherapy arms and of control IgG by delaying Gl261 growth and increasing U87 necrosis. Combination therapy increased perivascular cell coverage in both tumor models and led to a more mature, normalized tumor vasculature than that in the tumors treated with cediranib alone. Importantly, combination therapy was as effective at controlling edema as cediranib. Vascular normalization with VEGF-blockade has been shown to convert an immunoinhibitory tumor microenvironment to an immunostimulatory one. Improved vessel normalization resulting from combined Ang-2 and VEGFR inhibition was associated with an increase in the number of M1-like (anti-tumor) tumor associated macrophages (TAMs) compared to the cediranib-treated tumors. Inhibition of TAM recruitment with an anti-colony stimulating factor-1 (CSF1) neutralizing antibody compromised the survival benefit of anti-Ang-2/VEGFR combination therapy. The work described here provides new insight into a potential therapeutic strategy for the treatment of GBM and should inform of the design of clinical trials on this therapeutic combination.