title: Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages.
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.
authors.affiliation: 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;
authors.forename: Teresa E
authors.initials: TE
authors.lastname: Peterson
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Nathaniel D
authors.initials: ND
authors.lastname: Kirkpatrick
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129;
authors.forename: Christian T
authors.initials: CT
authors.lastname: Farrar
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Koen A
authors.initials: KA
authors.lastname: Marijt
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Jonas
authors.initials: J
authors.lastname: Kloepper
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; Department of Chemical and Biological Engineering, Tufts University, Medford, MA 02155;
authors.forename: Meenal
authors.initials: M
authors.lastname: Datta
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Zohreh
authors.initials: Z
authors.lastname: Amoozgar
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Giorgio
authors.initials: G
authors.lastname: Seano
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Keehoon
authors.initials: K
authors.lastname: Jung
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Walid S
authors.initials: WS
authors.lastname: Kamoun
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Trupti
authors.initials: T
authors.lastname: Vardam
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Matija
authors.initials: M
authors.lastname: Snuderl
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Jermaine
authors.initials: J
authors.lastname: Goveia
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Sampurna
authors.initials: S
authors.lastname: Chatterjee
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Ana
authors.initials: A
authors.lastname: Batista
authors.affiliation: Biostatistics Center, Massachusetts General Hospital and Harvard Medical School, Boston; MA 02114;
authors.forename: Alona
authors.initials: A
authors.lastname: Muzikansky
authors.affiliation: Department of Translational Medicine Oncology, MedImmune, Gaithersburg, MD 20878;
authors.forename: Ching Ching
authors.initials: CC
authors.lastname: Leow
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Stephen E. and Catherine Pappas Center for Neuro-Oncology, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
authors.forename: Tracy T
authors.initials: TT
authors.lastname: Batchelor
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; dai@steele.mgh.harvard.edu jain@steele.mgh.harvard.edu.
authors.forename: Dai
authors.initials: D
authors.lastname: Fukumura
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; dai@steele.mgh.harvard.edu jain@steele.mgh.harvard.edu.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011799:Quinazolines / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D012259:Ribonuclease, Pancreatic / Q000037:antagonists & inhibitors / Q000378:metabolism; D007211:Indoles
chemical_list: D000912:Antibodies, Neoplasm; D009363:Neoplasm Proteins; D011799:Quinazolines; D040262:Receptors, Vascular Endothelial Growth Factor; D012259:Ribonuclease, Pancreatic; C099439:Ang2 protein, mouse; C500926:cediranib; D007211:Indoles
keywords: anti-angiogenic therapy; colony-stimulating factor 1; macrophage; tumor immunity; tumor microenvironment