Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 16, Pages 4470-4475Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1525349113
Keywords
anti-angiogenic therapy; tumor microenvironment; tumor immunity; colony-stimulating factor 1; macrophage
Categories
Funding
- NIH [P01-CA080124, P50CA165962, R01CA126642, R35CA197743, R01-CA096915, S10-RR027070, R01-CA159258]
- National Cancer Institute/Federal Share Proton Beam Program Income
- Department of Defense Breast Cancer Research Innovator Award [W81XWH-10-1-0016]
- MedImmune
- National Foundation for Cancer Research
- Children's Tumor Foundation (CTF) Clinical Research Award
- American Cancer Society Research Scholar Award
- Ira Spiro Award
- CTF Drug Discovery Initiative
- German Research Foundation
- Solidar-Immun Foundation Fellowships
- Aid for Cancer Research Foundation Fellowship
- Susan G. Komen Postdoctoral Fellowship
- Tosteson Fund
- Affymetrix
- CTF Clinical Research Award
- American Cancer Society
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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.
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