PARP Inhibitors for Sensitization of Alkylation Chemotherapy in Glioblastoma: Impact of Blood-Brain Barrier and Molecular Heterogeneity

Abstract

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.

DNA repair genes in astrocytoma tumorigenesis, progression and therapy resistance

“…Although mutations in BRCA genes are rare in GBM, PTEN mutations similarly impair HR and are found in one-third of cases, enabling the exploration of PARPi synthetic lethality also for GBM (McEllin et al, 2010). However, the literature is still not conclusive about the benefits of the use of PARPi for GBM patients (Gupta et al, 2018). There are in vivo/in vitro conflicting data (Gupta et al, 2014) and PARPi have limited permeability and an efflux liability through the blood-brain barrier, showing heterogeneous response .…”

Rapid and temporary improvement of depression and anxiety observed following niraparib administration: a case report

“…Also, each time the niraparib was begun, her improvement in mood was temporary with the recurrence of some of her symptoms after 10 days to 2 weeks. Brain penetration and retention for many PARP inhibitors is poor and is a deterrent to treating brain cancers [22]. In contrast, niraparib crosses the blood brain barrier and accumulates in brain tissue [23].…”

Advances in the Knowledge of the Molecular Biology of Glioblastoma and Its Impact in Patient Diagnosis, Stratification, and Treatment

“…[ 127 ] Poly (ADP ribose) polymerase (PARP) family of enzymes has a pleiotropic role in DNA repair and has emerged as an attractive target for sensitization of GBM cells to TMZ. [ 128 ] Clinical trials are ongoing to prove efficacy of PARP inhibitors in treating glioma/GBM patients, alone or in combination with TMZ/radiation therapy. Some of these molecules are veliparib (NCT03581292, NCT02152982, NCT01514201), olaparib (NCT03233204, NCT01390571, PARADIGM‐2, NCT03212742), and pamiparib (NCT03150862, NCT03333915, NCT02361723).…”