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Front Oncol. 2019 Jun 19;9:549. doi: 10.3389/fonc.2019.00549. eCollection 2019.

Combining the DNA Repair Inhibitor Dbait With Radiotherapy for the Treatment of High Grade Glioma: Efficacy and Protein Biomarkers of Resistance in Preclinical Models.

Biau J1,2,3,4,5,6, Chautard E5,7, Berthault N1,2,3,4, de Koning L8,9, Court F10, Pereira B11, Verrelle P1,6,12,13, Dutreix M1,2,3,4.

Author information

1
Centre de Recherche, Institut Curie, PSL Research University, Paris, France.
2
UMR3347, CNRS, Orsay, France.
3
U1021, INSERM, Orsay, France.
4
Research Department, Université Paris Sud, Orsay, France.
5
INSERM, U1240 IMoST, Université Clermont Auvergne, Clermont Ferrand, France.
6
Radiotherapy Department, Centre Jean Perrin, Université Clermont Auvergne, Clermont-Ferrand, France.
7
Pathology Department, Centre Jean Perrin, Université Clermont Auvergne, Clermont-Ferrand, France.
8
Laboratory of Proteomic Mass Spectrometry, Centre de Recherche, Institut Curie, Paris, France.
9
Department of Translational Research, Institut Curie, PSL Research University, Paris, France.
10
GReD Laboratory, CNRS UMR 6293, INSERM U1103, Université Clermont Auvergne, Clermont-Ferrand, France.
11
Biostatistics Department, DRCI, Clermont-Ferrand Hospital, Clermont-Ferrand, France.
12
U1196, INSERM, UMR9187, CNRS, Orsay, France.
13
Radiotherapy Department, Institut Curie Hospital, Paris, France.

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.

KEYWORDS:

Dbait; double-strand break; high grade glioma; preclinical study; radiation therapy; radioresistance; single-strand break

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