Bevacizumab Targeting Diffuse Intrinsic Pontine Glioma: Results of 89Zr-Bevacizumab PET Imaging in Brain Tumor Models.
The role of the VEGF inhibitor bevacizumab in the treatment of diffuse intrinsic pontine glioma (DIPG) is unclear. We aim to study the biodistribution and uptake of zirconium-89 ((89)Zr)-labeled bevacizumab in DIPG mouse models. Human E98-FM, U251-FM glioma cells, and HSJD-DIPG-007-FLUC primary DIPG cells were injected into the subcutis, pons, or striatum of nude mice. Tumor growth was monitored by bioluminescence imaging (BLI) and visualized by MRI. Seventy-two to 96 hours after (89)Zr-bevacizumab injections, mice were imaged by positron emission tomography (PET), and biodistribution was analyzed ex vivo High VEGF expression in human DIPG was confirmed in a publically available mRNA database, but no significant (89)Zr-bevacizumab uptake could be detected in xenografts located in the pons and striatum at an early or late stage of the disease. E98-FM, and to a lesser extent the U251-FM and HSJD-DIPG-007 subcutaneous tumors, showed high accumulation of (89)Zr-bevacizumab. VEGF expression could not be demonstrated in the intracranial tumors by in situ hybridization (ISH) but was clearly present in the perinecrotic regions of subcutaneous E98-FM tumors. The poor uptake of (89)Zr-bevacizumab in xenografts located in the brain suggests that VEGF targeting with bevacizumab has limited efficacy for diffuse infiltrative parts of glial brain tumors in mice. Translating these results to the clinic would imply that treatment with bevacizumab in patients with DIPG is only justified after targeting of VEGF has been demonstrated by (89)Zr-bevacizumab immuno-PET. We aim to confirm this observation in a clinical PET study with patients with DIPG. Mol Cancer Ther; 15(9); 2166-74. ©2016 AACR.
Department of Pediatrics, Pediatric Hematology and Oncology, Cancer Center, Amsterdam, the Netherlands.
Marc H A
MH
Jansen
Neuro-oncology Research Group Cancer Center, Amsterdam, the Netherlands. Department of Neurosurgery VU University Medical Center and Academic Medical Center, Amsterdam, the Netherlands.
Tonny
T
Lagerweij
Department of Pediatrics, Pediatric Hematology and Oncology, Cancer Center, Amsterdam, the Netherlands. Neuro-oncology Research Group Cancer Center, Amsterdam, the Netherlands.
A Charlotte P
AC
Sewing
Department of Radiology & Nuclear Medicine VU University Medical Center, Amsterdam, the Netherlands.
Danielle J
DJ
Vugts
Department of Pediatrics, Pediatric Hematology and Oncology, Cancer Center, Amsterdam, the Netherlands. Neuro-oncology Research Group Cancer Center, Amsterdam, the Netherlands.
Dannis G
DG
van Vuurden
Department of Radiology & Nuclear Medicine VU University Medical Center, Amsterdam, the Netherlands.
Carla F M
CF
Molthoff
Department of Pediatrics, Pediatric Hematology and Oncology, Cancer Center, Amsterdam, the Netherlands. Neuro-oncology Research Group Cancer Center, Amsterdam, the Netherlands. Departments of Neurology, Pediatrics and Neurosurgery, Stanford University School of Medicine, Stanford, California.
Viola
V
Caretti
Department of Pediatrics, Pediatric Hematology and Oncology, Cancer Center, Amsterdam, the Netherlands. Neuro-oncology Research Group Cancer Center, Amsterdam, the Netherlands.
Susanna J E
SJ
Veringa
Neuro-oncology Research Group Cancer Center, Amsterdam, the Netherlands.
Naomi
N
Petersen
Preclinical Therapeutics and Drug Delivery Research Program, Department of Oncology, Hospital Sant Joan de Déu, Barcelona, Spain.
Angel M
AM
Carcaboso
Neuro-oncology Research Group Cancer Center, Amsterdam, the Netherlands. Department of Neurosurgery VU University Medical Center and Academic Medical Center, Amsterdam, the Netherlands.
David P
DP
Noske
Department of Neurosurgery VU University Medical Center and Academic Medical Center, Amsterdam, the Netherlands.
W Peter
WP
Vandertop
Neuro-oncology Research Group Cancer Center, Amsterdam, the Netherlands. Department of Pathology VU University Medical Center. Amsterdam, the Netherlands. Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.
Pieter
P
Wesseling
Department of Radiology & Nuclear Medicine VU University Medical Center, Amsterdam, the Netherlands.
Guus A M S
GA
van Dongen
Department of Pediatrics, Pediatric Hematology and Oncology, Cancer Center, Amsterdam, the Netherlands.
Gertjan J L
GJ
Kaspers
Department of Pediatrics, Pediatric Hematology and Oncology, Cancer Center, Amsterdam, the Netherlands. Neuro-oncology Research Group Cancer Center, Amsterdam, the Netherlands. e.hulleman@vumc.nl.
Esther
E
Hulleman
D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics; D000068258:Bevacizumab; D020295:Brain Stem Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015870:Gene Expression; D005910:Glioma / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging / Q000379:methods; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011868:Radioisotopes; D014018:Tissue Distribution; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D015040:Zirconium
D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D012333:RNA, Messenger; D011868:Radioisotopes; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; C580636:89Zr-bevacizumab; D015040:Zirconium; D040301:Vascular Endothelial Growth Factor Receptor-2