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

Abstract

BackgroundThe 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.MethodsThe 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.ResultsThe 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.ConclusionsOur results demonstrate preclinical efficacy of targeting PARP at multiple levels and provide a new approach for the treatment of MGMT unmethylated GBM.

Poly-(ADP-ribose)-polymerase inhibitors as radiosensitizers: a systematic review of pre-clinical and clinical human studies

“…Thanks to inhibition of BER, PARPi prevent repair of N7-guanine and N3-adenine methylation induced by TMZ, increase DNA strand breaks and is responsible of a TMZ chemosensitization [ 53 , 54 ] even on glioblastoma stem cell [ 55 ]. Data concerning the role of PARPi as TMZ chemosensitizer depending on MGMT status stay debated [ 40 , 56 – 58 ]even if some phase II-III clinical trials recruits only patients with methylated MGMT (NCT0215298). Moreover, PARPi could induce synthetic lethality in PTEN deleted glioblastoma (36% of Glioblastoma) suggesting that it might be logical to treat PTEN-deficient glioblastomas with PARP inhibitors in the future [ 59 ].…”

DNA repair genes in astrocytoma tumorigenesis, progression and therapy resistance

“…Indeed, using MGMT non-methylated GBM models, a recent study showed that the association of veliparib, a PARP1 inhibitor, with IR inhibited colony formation, reduced the levels of MRE11 (HR pathway) and increased apoptosis. Furthermore, the oral administration of veliparib plus concomitant RT induced apoptosis and diminished cell proliferation in mice (Jue et al, 2017).…”

Glioma through the looking GLASS: molecular evolution of diffuse gliomas and the Glioma Longitudinal Analysis Consortium

“… 36 These hypermutated tumors may be sensitive to immune checkpoint inhibitors, 22 including programmed death 1 (PD-1) inhibitors 65 and poly-adenosine diphosphate ribose polymerase inhibitors. 66 However, clinical trial data supporting these hypotheses have yet to emerge. Another study used whole-genome and multisector exome sequencing of 23 predominantly IDH -wildtype GBM and matched recurrent tumors.…”