Prognosis of patients with
glioblastoma (GBM) remains dismal despite maximal surgical resection followed by aggressive chemo-
radiation therapy. Almost every GBM, regardless of genotype, relapses as aggressive recurrent disease. Sensitization of GBM cells to chemo-radiation is expected to extend survival of patients with GBM by enhancing treatment efficacy. The PARP family of
enzymes has a pleiotropic role in DNA repair and metabolism and has emerged as an attractive target for sensitization of
cancer cells to genotoxic
therapies. However, despite promising results from a number of preclinical studies, progress of clinical trials involving
PARP inhibitors (PARPI) has been slower in GBM as compared to other
malignancies. Preclinical in vivo studies have uncovered limitations of PARPI-mediated targeting of base excision repair, considered to be the likely mechanism of sensitization for
temozolomide (TMZ)-resistant GBM. Nevertheless, PARPI remain a promising sensitizing approach for at least a subset of GBM
tumors that are inherently sensitive to TMZ. Our PDX preclinical trial has helped delineate MGMT promoter hyper-methylation as a
biomarker of the PARPI
veliparib-mediated sensitization. In clinical trials, MGMT promoter hyper-methylation now is being studied as a potential predictive
biomarker not only for response to TMZ
therapy alone, but also PARPI-mediated sensitization of TMZ
therapy. Besides the combination approach being investigated, IDH1/2 mutant
gliomas associated with 2-hydroxygluterate (2HG)-mediated homologous recombination (HR) defect may potentially benefit from PARPI monotherapy. In this article, we discuss existing results and provide additional data in support of potential alternative mechanisms of sensitization that would help identify potential
biomarkers for PARPI-based therapeutic approaches to GBM.