Veliparib in combination with radiotherapy for the treatment of MGMT unmethylated glioblastoma.

Published online

Journal Article

BACKGROUND: The O 6 -methylguanine methyltransferase (MGMT) gene is frequently unmethylated in patients with glioblastoma (GBM), rendering them non-responsive to the standard treatment regime of surgery followed by concurrent radiotherapy (RT) and temozolomide. Here, we investigate the efficacy of adding a PARP inhibitor, veliparib, to radiotherapy to treat MGMT unmethylated GBM. METHODS: The inhibition of PARP with veliparib (ABT-888), a potent and orally bioavailable inhibitor in combination with RT was tested on a panel of patient derived cell lines (PDCLs) and patient-derived xenografts (PDX) models generated from GBM patients with MGMT unmethylated tumors. RESULTS: The combination of veliparib and RT inhibited colony formation in the majority of PDCLs tested. The PDCL, RN1 showed significantly reduced levels of the homologous repair protein, Mre11 and a heightened response to PARP inhibition measured by increased apoptosis and decreased colony formation. The oral administration of veliparib (12.5 mg/kg, twice daily for 5 days in a 28-day treatment cycle) in combination with whole brain RT (4 Gy) induced apoptosis (Tunel staining) and decreased cell proliferation (Ki67 staining) in a PDX of MGMT unmethylated GBM. Significantly longer survival times of the PDX treated with the combination treatment were recorded compared to RT only or veliparib only. CONCLUSIONS: Our results demonstrate preclinical efficacy of targeting PARP at multiple levels and provide a new approach for the treatment of MGMT unmethylated GBM.

Full Text

Duke Authors

Cited Authors

  • Jue, TR; Nozue, K; Lester, AJ; Joshi, S; Schroder, LBW; Whittaker, SP; Nixdorf, S; Rapkins, RW; Khasraw, M; McDonald, KL

Published Date

  • March 17, 2017

Published In

Volume / Issue

  • 15 / 1

Start / End Page

  • 61 -

PubMed ID

  • 28314386

Pubmed Central ID

  • 28314386

Electronic International Standard Serial Number (EISSN)

  • 1479-5876

Digital Object Identifier (DOI)

  • 10.1186/s12967-017-1164-1

Language

  • eng

Conference Location

  • England