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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 :
- Academic Search Index
- Journal :
- Journal of Translational Medicine
- Publication Type :
- Academic Journal
- Accession number :
- 121933446
- Full Text :
- https://doi.org/10.1186/s12967-017-1164-1