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Differential impact of VEGF-A vs. dual Angiopoietin-2/VEGF-A blocking on the efficacy of radio- and chemotherapy in a glioblastoma model

Solecki G, Department of Neurooncology, University Hospital Heidelberg, Germany and Clinical Cooperation Unit Neurooncology, DKFZ, Heidelberg, Germany; Osswald M, Department of Neurooncology, University Hospital Heidelberg, Germany and Clinical Cooperation Unit Neurooncology, DKFZ, Heidelberg, Germany; Glock M, Clinical Cooperation Unit Neurooncology, DKFZ, Heidelberg, Germany; Gömmel MDepartment of Neurooncology, University Hospital Heidelberg, Germany and Clinical Cooperation Unit Neurooncology, DKFZ, Heidelberg, Germany; Mueller HJ, Pharmaceutical Research and Early Development (pRED), Innovation Center Penzberg; Krieter O, Pharmaceutical Research and Early Development (pRED), Innovation Center Penzberg; Wick W, Department of Neurooncology, University Hospital Heidelberg, Germany and Clinical Cooperation Unit Neurooncology, DKFZ, Heidelberg, Germany; Winkler F, Department of Neurooncology, University Hospital Heidelberg, Germany and Clinical Cooperation Unit Neurooncology, DKFZ, Heidelberg, Germany


Introduction: Angiogenesis is a hallmark of malignant gliomas, but two phase III clinical trials of anti-VEGF-A therapy in combination with radiotherapy plus chemotherapy demonstrated only increased progression free, but not overall survival. Therefore, to explore future avenues of development of these agents in glioma, differential effects of antiangiogenic agents on radiation- vs. chemotherapy need to be better characterized. Here, we used an orthotopic glioblastoma model to compare dual blocking of two key angiogenic factors Angiopoietin-2 (Ang2) and VEGF-A by a bispecific antibody vs. monospecific VEGF-A blocking. In addition, we evaluated combinations of both antiangiogenic antibodies with either chemotherapy or radiation therapy.
Methods: We grew highly angiogenic glioblastomas under a cranial window in the nude mouse brain, and tracked them by in vivo multiphoton microscopy to record multiple anatomical and functional tumor parameters. Monospecific anti-VEGF-A vs. bispecific anti-Ang2/VEGF-A vs. control antibodies (10 mg/kg, qw) were administered in monotherapy or in combination with radiotherapy (3x7 Gy) or chemotherapy (3x 20 mg/kg TMZ).
Results: Increased blood flow velocity, an established integrating parameter for vascular normalization, and decreased tumor growth were strongly associated in all treatment schedules. We were able to demonstrate that radio- and chemotherapy alone induced vascular normalization, i.e. without concurrent use of antiangiogenics. However, combining monospecific and bispecific antiangiogenic antibodies with radio- or chemotherapy led to strikingly differential antitumor effects. The best combination partner for anti-VEGF-A treatment was concomitant radiotherapy, while combined with chemotherapy anti-Ang2/VEGF-A treatment resulted in significantly enhanced antitumor efficacy.
Conclusions: Vascular normalization is most effectively achieved with dual targeting of Ang2 and VEGF-A, which results in improved response to chemotherapy, but attenuated effectiveness of radiotherapy. This is of potential relevance for the future development of antiangiogenic agents in glioblastoma.

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