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

Jue, Toni Rose, Nozue, Kyoko, Lester, Ashleigh J., Joshi, Swapna, Schroder, Lisette B. W., Whittaker, Shane P., Nixdorf, Sheri, Rapkins, Robert W., Khasraw, Mustafa and McDonald, Kerrie L. 2017, Veliparib in combination with radiotherapy for the treatment of MGMT unmethylated glioblastoma, Journal of translational medicine, vol. 15, no. 61, pp. 1-8, doi: 10.1186/s12967-017-1164-1.

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Title Veliparib in combination with radiotherapy for the treatment of MGMT unmethylated glioblastoma
Author(s) Jue, Toni Rose
Nozue, Kyoko
Lester, Ashleigh J.
Joshi, Swapna
Schroder, Lisette B. W.
Whittaker, Shane P.
Nixdorf, Sheri
Rapkins, Robert W.
Khasraw, MustafaORCID iD for Khasraw, Mustafa orcid.org/0000-0003-3249-9849
McDonald, Kerrie L.
Journal name Journal of translational medicine
Volume number 15
Issue number 61
Start page 1
End page 8
Total pages 8
Publisher BMC
Place of publication London, Eng.
Publication date 2017-03
ISSN 1479-5876
Keyword(s) Animals
Apoptosis
Benzimidazoles
Brain Neoplasms
Cell Line, Tumor
Combined Modality Therapy
DNA Methylation
DNA Modification Methylases
DNA Repair Enzymes
Disease Models, Animal
Female
Glioblastoma
Humans
Mice, Nude
Survival Analysis
Tumor Suppressor Proteins
Science & Technology
Life Sciences & Biomedicine
Medicine, Research & Experimental
Research & Experimental Medicine
POLY(ADP-RIBOSE) POLYMERASE INHIBITION
HUMAN GLIOMA-CELLS
OVARIAN-CANCER
BREAST-CANCER
IN-VITRO
HOMOLOGOUS RECOMBINATION
PARP INHIBITORS
TEMOZOLOMIDE
RADIOSENSITIZATION
ABT-888
Summary 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.
Language eng
DOI 10.1186/s12967-017-1164-1
Field of Research 11 Medical And Health Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2017, The Authors
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30109294

Document type: Journal Article
Collections: School of Medicine
Open Access Collection
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.