Understanding and Targeting Alkylator Resistance in Glioblastoma

Abstract

Summary:Alkylating chemotherapy is the mainstay in the treatment of pediatric and adult glioblastoma despite primary and acquired resistance and scientifi c efforts to precisely defi ne therapies for individual patients. A focus on non-MGMT-mediated temozolomide resistance for pediatric glioblastoma suggests options for new drug combinations. Cancer Discov; 4(10); 1120-2. ©2014 AACR.See related article by Agnihotri et al., p. 1198 (9).In 2014, noncomplex, unspecifi c genotoxic therapies, specifi cally radiochemotherapy with the alkylating agent temozolomide, remain the therapeutic mainstay for most patients with a newly diagnosed glioblastoma. This is in sharp contrast to the rapid characterization of the cancer (epi)genome, paralleled by the development of drugs targeting oncogenically activated proteins that drive tumor growth. Apart from O 6 -methylguanine DNA methyltransferase ( MGMT ) promoter methylation, there are no predictive biomarkers allowing tailoring of primary therapies in adult glioblastoma. With the current tests, MGMT promoter hypermethylation signifying sensitivity toward alkylating agents occurs in one third of patients ( 1 ). Whether this rate is overestimated for pediatric glioblastoma or other mechanisms of chemoresistance are acting in this molecularly distinct disease is not well understood. Although data demonstrating a wide range of MGMT methylation stem from uncontrolled series, controlled trials with adequate MGMT analyses are not yet available.Only recently has it become evident that MGMT activity is regulated by not only cell-intrinsic but also cell-extrinsic cues. In addition to promoter methylation, histone modifi cations, aberrant expression or function of transcriptional activators or repressors, and posttranscriptional regulation by various miRNA species can regulate MGMT expression. Increased methylation of histone H3 lysine 9 (H3K9) and concomitant binding of methyl-CpG-binding protein 2 (MeCP2), a methylated DNA-binding protein whose dysfunction leads to various neurodevelopmental disorders, to the MGMT promoter region were associated with promoter methylation and transcriptional downregulation, whereas histone H3 and H4 acetylation and methylation of H3 lysine 4 were detected in MGMT-expressing cells ( 2, 3 ). Increased acetylation of H3K9 and decreased dimethylation of this residue have been linked to MGMT upregulation and acquired temozolomide resistance in glioblastoma cell lines. Treatment with histone deacetylase inhibitors potentiated the evolution of acquired temozolomide resistance ( 4 ). Induction of resistance may also be conferred by the hypoxia-, radiation-, and steroidinducible mTOR downstream target N-myc downstreamregulated gene 1 ( NDRG1 ), the protein product of which binds to and thus probably sustains action of MGMT ( 5 ).Patients with no apparent expression of MGMT may also be resistant to temozolomide, but the mechanism underlying this resistance is incompletely understood. There is both clinical and experimental evidence that pediatric and adult gliob...

Long Non-Coding RNA MALAT1 Decreases the Sensitivity of Resistant Glioblastoma Cell Lines to Temozolomide

“…Although oral chemotherapy with TMZ contributes to an overall increase in the survival of glioblastoma patients, the cancer cells eventually develop resistance to TMZ at pharmacotherapeutic concentrations. Its therapeutic efficiency gradually worsens, as with many anti-tumor drugs [3], which leads to the failure of chemotherapy in a large number of patients. Therefore, TMZ resistance is a major obstacle for the treatment of glioblastoma.…”

High frequency of mismatch repair deficiency among pediatric high grade gliomas in Jordan

“…Recent work suggest that they do not respond to chemotherapies currently used for HGG such as temozolomide and these agents may, much to the contrary, lead to further mutation accumulation and resistance. 17 Second, recognition of bMMRD can allow for early detection of other cancers in these patients resulting in improved survival with use of less toxic therapies. Indeed, the two survivors of glioblastoma developed an additional four tumors in the combined 13 years of follow up.…”

Metformin as Potential Therapy for High-Grade Glioma

“…The cytotoxic effect of its action is based on the methylation of the guanine bases in DNA to O-6-methylguanine forms. This causes mispairing and disruption in the process of DNA replication leading to tumor cell apoptosis [158]. However, the mechanism of action of the drug on tumor cells is very complex and involves many signaling pathways.…”

“…The enzyme O6-methylguanine methyltransferase (MGMT) removes the alkyl groups made by TMZ, causing the repair of its damage and reversing the effect of the drug. This results in low sensitivity of some GBM patients to this type of therapy [158]. Sesen et al, conducted a study on GBM cell lines examining the effect of the combination of TMZ and metformin on proliferation intensity.…”