Peterson, TeresaKirkpatrick, NathanielHuang, YuhuiFarrar, ChristianMarijt, KoenKloepper, JonasDatta, MeenalAmoozgar, ZohrehSeano, GiorgioJung, KeehoonKamoun, WalidVardam, TruptiSnuderl, MatijaGoveia, JermaineChatterjee, SampurnaBatista, AnaMuzikansky, AlonaLeow, Ching ChingXu, LeiBatchelor, TracyDuda, DanFukumura, DaiJain, Rakesh2019-10-052016Peterson, Teresa E., Nathaniel D. Kirkpatrick, Yuhui Huang, Christian T. Farrar, Koen A. Marijt, Jonas Kloepper, Meenal Datta, et al. 2016. “Dual Inhibition of Ang-2 and VEGF Receptors Normalizes Tumor Vasculature and Prolongs Survival in Glioblastoma by Altering Macrophages.” Proceedings of the National Academy of Sciences 113 (16): 4470–75. https://doi.org/10.1073/pnas.1525349113.0027-84240744-28311091-6490http://nrs.harvard.edu/urn-3:HUL.InstRepos:41482925Glioblastomas (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.en-USJournal Article2019-10-0510.1073/pnas.1525349113