OS3.1 Differential impact of Ang-2, VEGF-A and dual Ang-2/VEGF-A blocking on the efficacy of radio- and chemotherapy in a glioblastoma model

High levels of pro-angiogenic factors like VEGF-A and angiopoietin-2 (Ang-2) in the microenvironment of brain tumors lead to an abnormal structure, organization and function of the tumor vasculature. It is of interest whether inhibition of Ang-2 or even dual inhibition of both major angiogenic factors is more efficient in glioma therapy, particularly with respect to vascular normalization. In this context, the ideal combination regimen with chemotherapy and/or radiotherapy is still unclear today. Here, we used an orthotopic glioblastoma model to compare dual blocking of Ang-2 and VEGF-A by a bispecific antibody vs. monospecific Ang-2 and VEGF-A blocking. In addition, we evaluated combinations of both antiangiogenic antibodies with either chemotherapy or radiation therapy. The best parameter to describe vascular normalization was the microvascular blood flow velocity: Both the control and the anti-Ang-2 antibody led to a strong reduction of this parameter in all treatment modalities. Anti-VEGF-A and anti-Ang-2/VEGF-A treatment schedules showed differential effects, depending on the combination cytotoxic therapy: while VEGF-A blockade led to an increased blood flow velocity only in combination with radiotherapy, anti-Ang-2/VEGF-A treatment was effective both in monotherapy and in combination with chemotherapy. To describe vascular changes longitudinally, different parameters (vascular diameter, total vessel length, vascular volume/ surface, number of branches, branch length/ tortuosity, lacunarity and the Hausdorff dimension which describes the degree of complexity) were determined. Anti-VEGF-A therapy as a monotherapy or in combination with temozolomide showed an impact on vascular volume in comparison to the control and anti-Ang-2 treatment schedules (p