Bevacizumab targeting diffuse intrinsic pontine glioma: results of 89Zr-bevacizumab PET imaging in brain tumor models

Abstract

The role of the vascular endothelial growth factor (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 (89Zr)-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 Magnetic Resonance Imaging (MRI). Seventy-two to 96 hours after 89Zr-bevacizumab injections, mice were imaged by Positron Emitting 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 89Zr-bevacizumab uptake could be detected in xenografts located in the pons and striatum at an early or late stage of the disease. The E98-FM, and to a lesser extent the U251-FM and HSJD-DIPG-007 subcutaneous tumors, showed high accumulation of 89Zr-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 89Zr-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 DIPG patients is only justified after targeting of VEGF has been demonstrated by 89Zr-bevacizumab immuno-PET. We aim to confirm this observation in a clinical PET study with DIPG patients.