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Veliparib in combination with radiotherapy for the treatment of MGMT unmethylated glioblastoma.
- Source :
- Journal of Translational Medicine; 3/17/2017, Vol. 15, p1-8, 8p
- Publication Year :
- 2017
-
Abstract
- <bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>Our results demonstrate preclinical efficacy of targeting PARP at multiple levels and provide a new approach for the treatment of MGMT unmethylated GBM. [ABSTRACT FROM AUTHOR]
- Subjects :
- O6-Methylguanine-DNA Methyltransferase
GLIOBLASTOMA multiforme
GLIOBLASTOMA multiforme treatment
METHYLTRANSFERASES
RADIOTHERAPY
PATIENTS
ANIMALS
APOPTOSIS
BIOLOGICAL models
BRAIN tumors
CELL lines
COMBINED modality therapy
DNA
ENZYMES
GLIOMAS
HETEROCYCLIC compounds
MICE
PROTEINS
SURVIVAL analysis (Biometry)
DNA methylation
Subjects
Details
- Language :
- English
- ISSN :
- 14795876
- Volume :
- 15
- Database :
- Complementary Index
- Journal :
- Journal of Translational Medicine
- Publication Type :
- Academic Journal
- Accession number :
- 121933446
- Full Text :
- https://doi.org/10.1186/s12967-017-1164-1