Abstract 3462: PARP inhibition sensitizes high grade childhood brain tumors to radiation

Abstract

Abstract Background: Poly ADP-ribose polymerases (PARPs) are proteins involved in single strand break repair. Recently, PARP inhibitors have shown considerable promise in the treatment of several cancers, both in monotherapy as in combination with cytotoxic agents. Synthetic lethal action of PARP inhibitors has been observed in tumors with mutations in genes in double strand break repair pathways. Besides this, PARP inhibition enhances sensitivity of tumor cells to DNA damaging agents, such as chemo- and radiotherapy. Aim of this study is to investigate the expression of PARP1 in normal brain tissues and high grade childhood brain tumors, medulloblastoma, ependymoma and high grade glioma (HGG), and to analyse sensitivity and radiosensitizing properties of PARP inhibitor Olaparib in cell lines of these tumors. Methods: Expression of PARP1 has been determined in medulloblastoma, ependymoma and HGG patient material and normal brain tissues by in silico analysis of PARP1 mRNA expression arrays, Western blot and immunohistochemistry. In addition, we performed clonogenic and viability assays, combining radiation with PARP inhibition in medulloblastoma, ependymoma and HGG cell lines. Results: Increased PARP1 expression was observed in medulloblastoma, ependymoma and HGG, as compared to non-neoplastic brain tissue. Moreover, medulloblastoma gene expression analysis revealed high PARP1 expression to be associated with poor prognosis. Growth inhibition with PARP inhibitor Olaparib resulted in differential sensitivity, with IC50 values ranging from 1.8 to 30 µM in cell lines, irrespective of PARP1 protein expression. HGG cell line SF-188, which harbors a focal deletion of NF1 gene, showed a 15-fold higher sensitivity to Olaparib compared to other HGG cell lines. This high sensitivity may be due to synthetic lethality and warrants further investigation. The combination of subcytotoxic concentrations of Olaparib and radiation showed increased cytotoxicity and reduced clonogenic capacity in medulloblastoma, ependymoma and HGG cell lines. Conclusion: PARP1 is overexpressed in high grade childhood brain tumors. In medulloblastoma, high PARP expression is correlated with poor prognosis. PARP inhibition sensitizes ependymoma, medulloblastoma and HGG cells to radiation. These results provide a basis for clinical translation, combining PARP inhibitors with radiotherapy in clinical studies in childhood high grade brain tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3462. doi:10.1158/1538-7445.AM2011-3462