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Cancers 2019, 11(3), 314; https://doi.org/10.3390/cancers11030314

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

1
Neurology Clinic and Neurooncology Program at the National Center for Tumor Disease, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany
2
German Cancer Consortium (DKTK), Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
3
Business Unit Service and Customer Care, Carl Zeiss Microscopy GmbH, 07745 Jena, Germany
4
Neurosurgery Department, University Medical Center Mannheim, 68167 Mannheim, Germany
5
Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Munich, 82377 Munich, Germany
*
Author to whom correspondence should be addressed.
Received: 31 December 2018 / Revised: 28 February 2019 / Accepted: 28 February 2019 / Published: 6 March 2019
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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. View Full-Text
Keywords: Ang-2; antiangiogenic therapy; in vivo imaging; radio- and chemotherapy; VEGF-A Ang-2; antiangiogenic therapy; in vivo imaging; radio- and chemotherapy; VEGF-A
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Solecki, G.; Osswald, M.; Weber, D.; Glock, M.; Ratliff, M.; Müller, H.-J.; Krieter, O.; Kienast, Y.; Wick, W.; Winkler, F. Differential Effects of Ang-2/VEGF-A Inhibiting Antibodies in Combination with Radio- or Chemotherapy in Glioma. Cancers 2019, 11, 314.

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