PARP Inhibitors for Sensitization of Alkylation Chemotherapy in Glioblastoma: Impact of Blood-Brain Barrier and Molecular Heterogeneity
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 surv...
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doaj-aadda5d7499241cebbf1b673ba724aab2020-11-25T02:12:26ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2019-01-01810.3389/fonc.2018.00670437872PARP Inhibitors for Sensitization of Alkylation Chemotherapy in Glioblastoma: Impact of Blood-Brain Barrier and Molecular HeterogeneityShiv K. Gupta0Emily J. Smith1Ann C. Mladek2Shulan Tian3Paul A. Decker4Sani H. Kizilbash5Gaspar J. Kitange6Jann N. Sarkaria7Departments of Radiation Oncology, Mayo Clinic, Rochester, MN, United StatesDepartments of Radiation Oncology, Mayo Clinic, Rochester, MN, United StatesDepartments of Radiation Oncology, Mayo Clinic, Rochester, MN, United StatesDivision of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United StatesDivision of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United StatesDepartments of Oncology, Mayo Clinic, Rochester, MN, United StatesDepartments of Radiation Oncology, Mayo Clinic, Rochester, MN, United StatesDepartments of Radiation Oncology, Mayo Clinic, Rochester, MN, United StatesPrognosis 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.https://www.frontiersin.org/article/10.3389/fonc.2018.00670/fullPARP (poly(ADP-ribose) polymerasechemo-radiation sensitivityDNA Damagereplication stressDNA repair activity |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Shiv K. Gupta Emily J. Smith Ann C. Mladek Shulan Tian Paul A. Decker Sani H. Kizilbash Gaspar J. Kitange Jann N. Sarkaria |
spellingShingle |
Shiv K. Gupta Emily J. Smith Ann C. Mladek Shulan Tian Paul A. Decker Sani H. Kizilbash Gaspar J. Kitange Jann N. Sarkaria PARP Inhibitors for Sensitization of Alkylation Chemotherapy in Glioblastoma: Impact of Blood-Brain Barrier and Molecular Heterogeneity Frontiers in Oncology PARP (poly(ADP-ribose) polymerase chemo-radiation sensitivity DNA Damage replication stress DNA repair activity |
author_facet |
Shiv K. Gupta Emily J. Smith Ann C. Mladek Shulan Tian Paul A. Decker Sani H. Kizilbash Gaspar J. Kitange Jann N. Sarkaria |
author_sort |
Shiv K. Gupta |
title |
PARP Inhibitors for Sensitization of Alkylation Chemotherapy in Glioblastoma: Impact of Blood-Brain Barrier and Molecular Heterogeneity |
title_short |
PARP Inhibitors for Sensitization of Alkylation Chemotherapy in Glioblastoma: Impact of Blood-Brain Barrier and Molecular Heterogeneity |
title_full |
PARP Inhibitors for Sensitization of Alkylation Chemotherapy in Glioblastoma: Impact of Blood-Brain Barrier and Molecular Heterogeneity |
title_fullStr |
PARP Inhibitors for Sensitization of Alkylation Chemotherapy in Glioblastoma: Impact of Blood-Brain Barrier and Molecular Heterogeneity |
title_full_unstemmed |
PARP Inhibitors for Sensitization of Alkylation Chemotherapy in Glioblastoma: Impact of Blood-Brain Barrier and Molecular Heterogeneity |
title_sort |
parp inhibitors for sensitization of alkylation chemotherapy in glioblastoma: impact of blood-brain barrier and molecular heterogeneity |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Oncology |
issn |
2234-943X |
publishDate |
2019-01-01 |
description |
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. |
topic |
PARP (poly(ADP-ribose) polymerase chemo-radiation sensitivity DNA Damage replication stress DNA repair activity |
url |
https://www.frontiersin.org/article/10.3389/fonc.2018.00670/full |
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