Veliparib in combination with radiotherapy for the treatment of MGMT unmethylated glioblastoma.
The O6-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.



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.



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.



Our results demonstrate preclinical efficacy of targeting PARP at multiple levels and provide a new approach for the treatment of MGMT unmethylated GBM.
Cure Brain Cancer Biomarkers and Translational Research Group, Prince of Wales Clinical School, Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Kensington, Australia.
Toni Rose
TR
Jue
Cure Brain Cancer Biomarkers and Translational Research Group, Prince of Wales Clinical School, Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Kensington, Australia.
Kyoko
K
Nozue
Cure Brain Cancer Biomarkers and Translational Research Group, Prince of Wales Clinical School, Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Kensington, Australia.
Ashleigh J
AJ
Lester
Cure Brain Cancer Biomarkers and Translational Research Group, Prince of Wales Clinical School, Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Kensington, Australia.
Swapna
S
Joshi
Cure Brain Cancer Biomarkers and Translational Research Group, Prince of Wales Clinical School, Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Kensington, Australia.
Lisette B W
LB
Schroder
Cure Brain Cancer Biomarkers and Translational Research Group, Prince of Wales Clinical School, Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Kensington, Australia.
Shane P
SP
Whittaker
Cure Brain Cancer Biomarkers and Translational Research Group, Prince of Wales Clinical School, Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Kensington, Australia.
Sheri
S
Nixdorf
Cure Brain Cancer Biomarkers and Translational Research Group, Prince of Wales Clinical School, Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Kensington, Australia.
Robert W
RW
Rapkins
Royal North Shore Hospital, St Leonards, NSW, Australia.
Mustafa
M
Khasraw
Cure Brain Cancer Biomarkers and Translational Research Group, Prince of Wales Clinical School, Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Kensington, Australia. k.mcdonald@unsw.edu.au.
Kerrie L
KL
McDonald
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D019175:DNA Methylation / Q000235:genetics*; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000532:radiotherapy*; D006801:Humans; D008819:Mice, Nude; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D001562:Benzimidazoles; D025521:Tumor Suppressor Proteins; C521013:veliparib; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes