Differential Effects of Ang-2/VEGF-A Inhibiting Antibodies in Combination with Radio- or Chemotherapy in Glioma.

Gergely Solecki,Wolfgang Wick,Yvonne Kienast,Oliver Krieter,Frank Winkler,Matthias Osswald,Daniel Weber,Malte Glock,Miriam Ratliff,Hans-Joachim Müller

doi:10.3390/cancers11030314

Abstract

Antiangiogenic strategies have not shown striking antitumor activities in the majority of glioma patients so far. It is unclear which antiangiogenic combination regimen with standard therapy is most effective. Therefore, we compared anti-VEGF-A, anti-Ang2, and bispecific anti-Ang-2/VEGF-A antibody treatments, alone and in combination with radio- or temozolomide (TMZ) chemotherapy, in a malignant glioma model using multiparameter two-photon in vivo microscopy in mice. We demonstrate that anti-Ang-2/VEGF-A lead to the strongest vascular changes, including vascular normalization, both as monotherapy and when combined with chemotherapy. The latter was accompanied by the most effective chemotherapy-induced death of cancer cells and diminished tumor growth. This was most probably due to a better tumor distribution of the drug, decreased tumor cell motility, and decreased formation of resistance-associated tumor microtubes. Remarkably, all these parameters where reverted when radiotherapy was chosen as combination partner for anti-Ang-2/VEGF-A. In contrast, the best combination partner for radiotherapy was anti-VEGF-A. In conclusion, while TMZ chemotherapy benefits most from combination with anti-Ang-2/VEGF-A, radiotherapy does from anti-VEGF-A. The findings imply that uninformed combination regimens of antiangiogenic and cytotoxic therapies should be avoided.

Highlights

Glioblastoma (GB) is the most common and most malignant adult primary brain tumor [1].It is associated with a poor prognosis and a high burden for the patient
To directly compare the effects of VEGF-A, Ang-2, and dual inhibition on glioma biology, we tested the effects of these three antibodies vs. control antibody in an identical, clinically relevant dose (5 mg/kg BW every third day)
When quantifying the occurrence of mitotic figures in glioma cells in vivo, we found that antiangiogenic treatments lead to a short‐time “burst” of glioma cell cells in vivo, we found that antiangiogenic treatments lead to a short-time “burst” of glioma cell proliferation that that ceased ceased at at later later time time points points and and was was not not present present when when antiangiogenic antiangiogenic agents agents where where proliferation combined with chemo‐

Summary

Introduction

Glioblastoma (GB) is the most common and most malignant adult primary brain tumor [1]. It is associated with a poor prognosis and a high burden for the patient. The standard treatment is maximum safe resection, followed by radiotherapy and concomitant and adjuvant temozolomide (TMZ) chemotherapy. Despite this intensive treatment, overall survival (OS) remains under two years [2], largely because of inherent tumor resistance mechanisms [3,4,5]. Cancers 2019, 11, 314 strategies are urgently needed, which includes those that make standard radio- and chemotherapy more efficient. GBs are characterized by dense but structurally and functionally abnormal blood vessels, which are driven by a high level of proangiogenic factors, VEGF-A [6,7,8] and Angiopoietin

Methods

Results

Discussion

Conclusion