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

J Transl Med. 2017 Mar 17;15(1):61. doi: 10.1186/s12967-017-1164-1.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Benzimidazoles / pharmacology
  • Benzimidazoles / therapeutic use*
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / radiotherapy*
  • Cell Line, Tumor
  • Combined Modality Therapy
  • DNA Methylation / genetics*
  • DNA Modification Methylases / genetics*
  • DNA Repair Enzymes / genetics*
  • Disease Models, Animal
  • Female
  • Glioblastoma / drug therapy*
  • Glioblastoma / radiotherapy*
  • Humans
  • Mice, Nude
  • Survival Analysis
  • Tumor Suppressor Proteins / genetics*


  • Benzimidazoles
  • Tumor Suppressor Proteins
  • veliparib
  • DNA Modification Methylases
  • MGMT protein, human
  • DNA Repair Enzymes