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


ABSTRACT: 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.

SUBMITTER: Jue TR 

PROVIDER: S-EPMC5356284 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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

Jue Toni Rose TR   Nozue Kyoko K   Lester Ashleigh J AJ   Joshi Swapna S   Schroder Lisette B W LB   Whittaker Shane P SP   Nixdorf Sheri S   Rapkins Robert W RW   Khasraw Mustafa M   McDonald Kerrie L KL  

Journal of translational medicine 20170317 1


<h4>Background</h4>The O <sup>6</sup> -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.<h4>Methods</h4>The inhibition of PARP with veliparib (ABT-888), a potent and orally bioavailable in  ...[more]

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