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PMID: 27044097 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

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 of the United States of America ·Vol. 113 ·No. 16 ·2016-04-19 ·Pages 4470-5

Peterson TE, Kirkpatrick ND, Huang Y, Farrar CT, Marijt KA, Kloepper J, Datta M, Amoozgar Z, Seano G, Jung K, Kamoun WS, Vardam T, Snuderl M, Goveia J, Chatterjee S, Batista A, Muzikansky A, Leow CC, Xu L, Batchelor TT, Duda DG, Fukumura D, Jain RK

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.

Keywords

anti-angiogenic therapy colony-stimulating factor 1 macrophage tumor immunity tumor microenvironment

MeSH Terms

Animals Antibodies, Neoplasm/pharmacology Cell Line, Tumor Drug Screening Assays, Antitumor Glioblastoma/drug therapy,metabolism,pathology Macrophages/metabolism,pathology Mice Neoplasm Proteins/antagonists & inhibitors,metabolism Neoplasms, Experimental/drug therapy,metabolism,pathology Neovascularization, Pathologic/drug therapy,metabolism,pathology Quinazolines/pharmacology Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors,metabolism Ribonuclease, Pancreatic/antagonists & inhibitors,metabolism

Chemicals

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

Authors & Affiliations

23 authors, click to expand affiliations / ORCID

Peterson Teresa E

Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; Department of Biological Chemistry and Molecular Pharmacology, Harvard University, Boston, MA 02115;

Kirkpatrick Nathaniel D