DNA repair mechanisms and their clinical impact in glioblastoma

Erasimus, Hélène; Gobin, Matthieu; Niclou, Simone P.; Dyck, Eric Van

doi:10.1016/j.mrrev.2016.05.005

Cited by 146 publications

(119 citation statements)

References 195 publications

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“…GBs respond to DNA injuries induced by ionizing radiation (IR) and genotoxic drugs by activating the DNA repair machinery [8,9,10]. Furthermore, tumors are able to eliminate chemotherapeutic compounds from cells through the increased expression and activity of efflux ATP-binding cassette (ABC) transporters, specifically P-glycoprotein (P-gp)/MDR1, MRP1 and BCRP1/ABCG2 [11,12].…”

Section: Introductionmentioning

confidence: 99%

Chemotherapeutic Drugs: DNA Damage and Repair in Glioblastoma

Annovazzi

Mellai

Schiffer

2017

Cancers

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Despite improvements in therapeutic strategies, glioblastoma (GB) remains one of the most lethal cancers. The presence of the blood–brain barrier, the infiltrative nature of the tumor and several resistance mechanisms account for the failure of current treatments. Distinct DNA repair pathways can neutralize the cytotoxicity of chemo- and radio-therapeutic agents, driving resistance and tumor relapse. It seems that a subpopulation of stem-like cells, indicated as glioma stem cells (GSCs), is responsible for tumor initiation, maintenance and recurrence and they appear to be more resistant owing to their enhanced DNA repair capacity. Recently, attention has been focused on the pivotal role of the DNA damage response (DDR) in tumorigenesis and in the modulation of therapeutic treatment effects. In this review, we try to summarize the knowledge concerning the main molecular mechanisms involved in the removal of genotoxic lesions caused by alkylating agents, emphasizing the role of GSCs. Beside their increased DNA repair capacity in comparison with non-stem tumor cells, GSCs show a constitutive checkpoint expression that enables them to survive to treatments in a quiescent, non-proliferative state. The targeted inhibition of checkpoint/repair factors of DDR can contribute to eradicate the GSC population and can have a great potential therapeutic impact aiming at sensitizing malignant gliomas to treatments, improving the overall survival of patients.

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Section: Introductionmentioning

confidence: 99%

Chemotherapeutic Drugs: DNA Damage and Repair in Glioblastoma

Annovazzi

Mellai

Schiffer

2017

Cancers

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“…TMZ creates a number of DNA lesions including N 3 -methyladenine, O 6 -methylguanine, and N 7 -methylguanine, the most commonly formed DNA adduct (7). In addition, methylation at the N7 position of guanine produces a more toxic DNA lesion, termed an abasic site, which forms by the spontaneous depurination of the methylated base (8). Although each type of DNA lesion stimulates DNA repair pathways to induce apoptosis, resistance to TMZ can unfortunately develop through the inactivation of DNA repair pathways such as DNA mismatch repair (MMR).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Translesion DNA Synthesis as a Novel Therapeutic Strategy to Treat Brain Cancer

2018

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Temozolomide is a DNA-alkylating agent used to treat brain tumors, but resistance to this drug is common. In this study, we provide evidence that efficacious responses to this drug can be heightened significantly by coadministration of an artificial nucleoside (5-nitroindolyl-2 0 -deoxyriboside, 5-NIdR) that efficiently and selectively inhibits the replication of DNA lesions generated by temozolomide. Conversion of this compound to the corresponding nucleoside triphosphate, 5-nitroindolyl-2 0 -deoxyriboside triphosphate, in vivo creates a potent inhibitor of several human DNA polymerases that can replicate damaged DNA. Accordingly, 5-NIdR synergized with temozolomide to increase apoptosis of tumor cells. In a murine xenograft model of glioblastoma, whereas temozolomide only delayed tumor growth, its coadministration with 5-NIdR caused complete tumor regression. Exploratory toxicology investigations showed that high doses of 5-NIdR did not produce the side effects commonly seen with conventional nucleoside analogs. Collectively, our results offer a preclinical pharmacologic proof of concept for the coordinate inhibition of translesion DNA synthesis as a strategy to improve chemotherapeutic responses in aggressive brain tumors.Significance: Combinatorial treatment of glioblastoma with temozolomide and a novel artificial nucleoside that inhibits replication of damaged DNA can safely enhance therapeutic responses. Cancer Res; 78(4); 1-14. Ó2018 AACR.

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“…Such DNA adducts induce nicks in the DNA leading to cell cycle arrest and apoptosis [7,8]. Over-activation of the DNA repair enzyme, O 6 -methylguanine-DNA methyltransferase (MGMT) can lead to resistance to TMZ in GBM patients [7,9]. In fact, one great disadvantage of TMZ-chemotherapy is that about 90% of GBM patients acquire resistance and do not respond to a second round of TMZ treatment [7].…”

Section: Introductionmentioning

confidence: 99%

RNA interference for glioblastoma therapy: Innovation ladder from the bench to clinical trials

2017

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Glioblastoma multiforme (GBM) is the most common and deadliest type of primary brain tumor with a prognosis of 14 months after diagnosis. Current treatment for GBM patients includes “total” tumor resection, temozolomide-based chemotherapy, radiotherapy or a combination of these options. Although, several targeted therapies, gene therapy, and immunotherapy are currently in the clinic and/or in clinical trials, the overall survival of GBM patients has hardly improved over the last two decades. Therefore, novel multitarget modalities are urgently needed. Recently, RNA interference (RNAi) has emerged as a novel strategy for the treatment of most cancers, including GBM. RNAi-based therapies consist of using small RNA oligonucleotides to regulate protein expression at the post-transcriptional level. Despite the therapeutic potential of RNAi molecules, systemic limitations including short circulatory stability and low release into the tumor tissue have halted their progress to the clinic. The effective delivery of RNAi molecules through the blood-brain barrier (BBB) represents an additional challenge. This review focuses on connecting the translational process of RNAi-based therapies from in vitro evidence to pre-clinical studies. We delineate the effect of RNAi in GBM cell lines, describe their effectiveness in glioma mouse models, and compare the proposed drug carriers for the effective transport of RNAi molecules through the BBB to reach the tumor in the brain. Furthermore, we summarize the most important obstacles to overcome before RNAi-based therapy becomes a reality for GBM treatment.

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DNA repair mechanisms and their clinical impact in glioblastoma

Cited by 146 publications

References 195 publications

Chemotherapeutic Drugs: DNA Damage and Repair in Glioblastoma

Chemotherapeutic Drugs: DNA Damage and Repair in Glioblastoma

Inhibition of Translesion DNA Synthesis as a Novel Therapeutic Strategy to Treat Brain Cancer

RNA interference for glioblastoma therapy: Innovation ladder from the bench to clinical trials

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