Journal Article

Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages

Goveia, Jermaine, Farrar, Christian T., Seano, Giorgio, Huang, Yuhui, Amoozgar, Zohreh, Kamoun, Walid S., Marijt, Koen A., Fukumura, Dai, Peterson, Teresa E., Kloepper, Jonas, Chatterjee, Sampurna, Kirkpatrick, Nathaniel D., Jung, Keehoon, Jain, Rakesh K., Vardam, Trupti, Leow, Ching Ching, Datta, Meenal, Snuderl, Matija, Xu, Lei, Duda, Dan G., Batista, Ana, Batchelor, Tracy T., Muzikansky, Alona

2016

Overview

Glioblastomas (GBMs) rapidly become refractory to anti-VEGF therapies. We previously demonstrated that ectopic overexpression of angiopoietin-2 (Ang-2) compromises the benefits of anti-VEGF receptor (VEGFR) treatment in murine GBM models and that circulating Ang-2 levels in GBM patients rebound after an initial decrease following cediranib (a pan-VEGFR tyrosine kinase inhibitor) administration. Here we tested whether dual inhibition of VEGFR/Ang-2 could improve survival in two orthotopic models of GBM, Gl261 and U87. Dual therapy using cediranib and MEDI3617 (an anti–Ang-2–neutralizing antibody) improved survival over each therapy alone by delaying Gl261 growth and increasing U87 necrosis, effectively reducing viable tumor burden. Consistent with their vascular-modulating function, the dual therapies enhanced morphological normalization of vessels. Dual therapy also led to changes in tumor-associated macrophages (TAMs). Inhibition of TAM recruitment using an anti–colony-stimulating factor-1 antibody compromised the survival benefit of dual therapy. Thus, dual inhibition of VEGFR/Ang-2 prolongs survival in preclinical GBM models by reducing tumor burden, improving normalization, and altering TAMs. This approach may represent a potential therapeutic strategy to overcome the limitations of anti-VEGFR monotherapy in GBM patients by integrating the complementary effects of anti-Ang2 treatment on vessels and immune cells.

• Publisher: National Academy of Sciences
• Subject: Animals / Antibodies, Neoplasm - pharmacology / Biological Sciences / Cancer / Cell Line, Tumor / Cells / Drug Screening Assays, Antitumor / Gene expression / Glioblastoma - drug therapy / Glioblastoma - metabolism / Glioblastoma - pathology / Kinases / Macrophages - metabolism / Macrophages - pathology / Medical Sciences / Mice / Neoplasm Proteins - antagonists & inhibitors / Neoplasm Proteins - metabolism / Neoplasms, Experimental - drug therapy / Neoplasms, Experimental - metabolism / Neoplasms, Experimental - pathology / Neovascularization, Pathologic - drug therapy / Neovascularization, Pathologic - metabolism / Neovascularization, Pathologic - pathology / Quinazolines - pharmacology / Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors / Receptors, Vascular Endothelial Growth Factor - metabolism / Ribonuclease, Pancreatic - antagonists & inhibitors / Ribonuclease, Pancreatic - metabolism / Survival / Survival analysis / Tumors