Radiosensitizing the Vasculature of Primary Brainstem Gliomas Fails to Improve Tumor Response to Radiation Therapy

Abstract

Diffuse intrinsic pontine gliomas (DIPGs) arise in the pons and are the leading cause of death from brain tumors in children. DIPGs are routinely treated with radiation therapy, which temporarily improves neurological symptoms but generally fails to achieve local control. Because numerous clinical trials have not improved survival from DIPG over standard radiation therapy alone, there is a pressing need to evaluate new therapeutic strategies for this devastating disease. Vascular damage caused by radiation therapy can increase the permeability of tumor blood vessels and promote tumor cell death. To investigate the impact of endothelial cell death on tumor response to radiation therapy in DIPG, we used dual recombinase (Cre+FlpO) technology to generate primary brainstem gliomas which lack ataxia telangiectasia mutated (Atm) in the vasculature. Here, we show that Atm-deficient tumor endothelial cells are sensitized to radiation therapy. Furthermore, radiosensitization of the vasculature in primary gliomas triggered an increase in total tumor cell death. Despite the observed increase in cell killing, in mice with autochthonous DIPGs treated with radiation therapy, deletion of Atm specifically in tumor endothelial cells failed to improve survival. These results suggest that targeting the tumor cells, rather than endothelial cells, during radiation therapy will be necessary to improve survival among children with DIPG.