title: PARP inhibition sensitizes childhood high grade glioma, medulloblastoma and ependymoma to radiation.
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.
authors.affiliation: Department of Pediatric Oncology / Hematology, Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands. dg.vanvuurden@vumc.nl
authors.forename: Dannis G
authors.initials: DG
authors.lastname: van Vuurden
authors.forename: Esther
authors.initials: E
authors.lastname: Hulleman
authors.forename: Olga L M
authors.initials: OL
authors.lastname: Meijer
authors.forename: Laurine E
authors.initials: LE
authors.lastname: Wedekind
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.forename: Hendrik
authors.initials: H
authors.lastname: Witt
authors.forename: Peter W
authors.initials: PW
authors.lastname: Vandertop
authors.forename: Thomas
authors.initials: T
authors.lastname: Würdinger
authors.forename: David P
authors.initials: DP
authors.lastname: Noske
authors.forename: Gertjan J L
authors.initials: GJ
authors.lastname: Kaspers
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Cloos
mesh_terms: D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D002490:Central Nervous System / Q000473:pathology; D002648:Child; D004806:Ependymoma / Q000188:drug therapy* / Q000532:radiotherapy; D020869:Gene Expression Profiling; D005910:Glioma / Q000188:drug therapy* / Q000532:radiotherapy; D006657:Histones / Q000378:metabolism; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy* / Q000532:radiotherapy; D010793:Phthalazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology
chemical_list: C468783:H2AX protein, human; D006657:Histones; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012333:RNA, Messenger; D011838:Radiation-Sensitizing Agents; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C531550:olaparib