Abstract
High grade glioma relapses occur often within the irradiated volume mostly due to a high resistance to radiation therapy (RT). Dbait (which stands for DNA strand break bait) molecules mimic DSBs and trap DNA repair proteins, thereby inhibiting repair of DNA damage induced by RT. Here we evaluate the potential of Dbait to sensitize high grade glioma to RT. First, we demonstrated the radiosensitizer properties of Dbait in 6/9 tested cell lines. Then, we performed animal studies using six cell derived xenograft and five patient derived xenograft models, to show the clinical potential and applicability of combined Dbait+RT treatment for human high grade glioma. Using a RPPA approach, we showed that Phospho-H2AX/H2AX and Phospho-NBS1/NBS1 were predictive of Dbait efficacy in xenograft models. Our results provide the preclinical proof of concept that combining RT with Dbait inhibition of DNA repair could be of benefit to patients with high grade glioma.
Highlights
High grade gliomas are the most frequent primary brain tumors in adults [1, 2]
We tested the potential of Dbait to induce DNA-PK activation in human glioblastoma cell lines by assaying phosphorylated H2AX proteins by Western blot in the 9 high grade glioma cell lines
As we had access to samples from a dog that spontaneously developed a glioblastoma (Figure 2B), we confirmed that Dbait induced phosphorylation of both H2AX and HSP90 in dissociated cells from the brain tumor (Figure 2C)
Summary
High grade gliomas are the most frequent primary brain tumors in adults [1, 2]. They represent an important source of morbidity and mortality and are a public health care challenge [3, 4]. Recurrence often occurs in the irradiated volume due to a high radioresistance of glioblastoma cells [7,8,9,10].
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