Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages
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Author
Peterson, Teresa
Kirkpatrick, Nathaniel
Huang, Yuhui
Farrar, Christian
Marijt, Koen
Kloepper, Jonas
Datta, Meenal
Amoozgar, Zohreh
Seano, Giorgio
Jung, Keehoon
Kamoun, Walid
Vardam, Trupti
Snuderl, Matija
Goveia, Jermaine
Chatterjee, Sampurna
Batista, Ana
Muzikansky, Alona
Leow, Ching Ching
Xu, Lei
Batchelor, Tracy
Duda, Dan
Fukumura, Dai
Jain, Rakesh
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https://doi.org/10.1073/pnas.1525349113Metadata
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Peterson, 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.Abstract
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.Terms of Use
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