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

Proc Natl Acad Sci U S A. 2016 Apr 19;113(16):4470-5. doi: 10.1073/pnas.1525349113. Epub 2016 Apr 4.


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.

Keywords: anti-angiogenic therapy; colony-stimulating factor 1; macrophage; tumor immunity; tumor microenvironment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antibodies, Neoplasm / pharmacology*
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Glioblastoma* / drug therapy
  • Glioblastoma* / metabolism
  • Glioblastoma* / pathology
  • Macrophages* / metabolism
  • Macrophages* / pathology
  • 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


  • Antibodies, Neoplasm
  • Neoplasm Proteins
  • Quinazolines
  • Receptors, Vascular Endothelial Growth Factor
  • Ang2 protein, mouse
  • Ribonuclease, Pancreatic
  • cediranib