PARP inhibition sensitizes childhood high grade glioma, medulloblastoma and ependymoma to radiation

Dannis G Van Vuurden,Jacqueline Cloos,W Peter Vandertop,Olga L.M Meijer,Laurine E Wedekind,Hendrik Witt,David P Noske,Marcel Kool,Esther Hulleman,Thomas Würdinger,Gertjan J.L Kaspers

doi:10.18632/oncotarget.362

Abstract

Poly ADP-ribose polymerase (PARP) is a protein involved in single strand break repair. Recently, PARP inhibitors have shown considerable promise in the treatment of several cancers, both in monotherapy and in combination with cytotoxic agents. Synthetic lethal action of PARP inhibitors has been observed in tumors with mutations in double strand break repair pathways. In addition, PARP inhibition potentially enhances sensitivity of tumor cells to DNA damaging agents, including radiotherapy. Aim of this study is to determine the radiosensitizing properties of the PARP inhibitor Olaparib in childhood medulloblastoma, ependymoma and high grade glioma (HGG). Increased PARP1 expression was observed in medulloblastoma, ependymoma and HGG, as compared to non-neoplastic brain tissue. Pediatric high grade glioma, medulloblastoma and ependymoma gene expression profiling revealed that high PARP1 expression is associated with poor prognosis. Cell growth inhibition assays with Olaparib resulted in differential sensitivity, with IC50 values ranging from 1.4 to 8.4 µM, irrespective of tumor type and PARP1 protein expression. Sensitization to radiation was observed in medulloblastoma, ependymoma and HGG cell lines with subcytotoxic concentrations of Olaparib, which coincided with persistence of double strand breaks. Combining PARP inhibitors with radiotherapy in clinical studies in childhood high grade brain tumors may improve therapeutic outcome.

Highlights

Tumors of the central nervous system (CNS) are the second most common type of pediatric cancer after hematologic malignancies
The PARP1 expression was significantly higher in pediatric ependymoma and medulloblastoma, compared to cortex and cerebellum, while PARP1 expression in high grade glioma (HGG) was significantly higher compared to normal cortex. (Figure 1)
We show that PARP1 is expressed in high grade pediatric brain tumors, thereby indicating the rationale of PARP1 as a potential therapeutic target in these cancers

Summary

Introduction

Tumors of the central nervous system (CNS) are the second most common type of pediatric cancer after hematologic malignancies. Malignant childhood brain tumors have an incidence of 3.2 per 100,000 persons, with a large heterogeneity of classifying diagnoses. Treatment of children diagnosed with a high grade malignant CNS tumor consists of a multimodal approach based on surgery, radiotherapy and chemotherapy. Radiosensitizers may offer the opportunity to ameliorate the therapeutic index by increasing the efficacy of radiotherapy, while reducing the toxicity and damage to the developing brain. The therapeutic index can for instance be improved by targeting specific characteristics of the tumors cells such as their replication dependency and DNA repair defects. Inhibitors of DNA repair are potential treatment options in highly proliferative high grade childhood brain tumors, arising in largely non-replicative normal tissues with proficient DNA repair

Methods

Results

Conclusion