Glioblastoma multiforme (GBM): An overview of current therapies and mechanisms of resistance

Wu, Wei; Klockow, Jessica; Zhang, Michael; Lafortune, Famyrah; Chang, Edwin; Jin, Linchun; Wu, Yang; Daldrup‐Link, Heike E.

doi:10.1016/j.phrs.2021.105780

Cited by 291 publications

(256 citation statements)

References 431 publications

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“…Even though their results seem promising, more experiments need to be done in PFA cells and tumor models, as their biology is crucially different from cancer cell lines like Daoy or U2OS. The limited penetration of the blood brain barrier (BBB) by PARP inhibitors is an additional concern that needs to be tackled by future research including PFA-specific pharmacokinetic and pharmacodynamic characterizations [ 27 , 51 , 72 , 86 , 87 ].…”

Section: Ezhip In Pfa Ependymomasmentioning

confidence: 99%

EZHIP: a new piece of the puzzle towards understanding pediatric posterior fossa ependymoma

et al. 2021

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Ependymomas (EPN) are tumors of the central nervous system (CNS) that can arise in the supratentorial brain (ST-EPN), hindbrain or posterior fossa (PF-EPN) or anywhere in the spinal cord (SP-EPN), both in children and adults. Molecular profiling studies have identified distinct groups and subtypes in each of these anatomical compartments. In this review, we give an overview on recent findings and new insights what is driving PFA ependymomas, which is the most common group. PFA ependymomas are characterized by a young median age at diagnosis, an overall balanced genome and a bad clinical outcome (56% 10-year overall survival). Sequencing studies revealed no fusion genes or other highly recurrently mutated genes, suggesting that the disease is epigenetically driven. Indeed, recent findings have shown that the characteristic global loss of the repressive histone 3 lysine 27 trimethylation (H3K27me3) mark in PFA ependymoma is caused by aberrant expression of the enhancer of zeste homolog inhibitory protein (EZHIP) or in rare cases by H3K27M mutations, which both inhibit EZH2 thereby preventing the polycomb repressive complex 2 (PRC2) from spreading H3K27me3. We present the current status of the ongoing work on EZHIP and its essential role in the epigenetic disturbance of PFA biology. Comparisons to the oncohistone H3K27M and its role in diffuse midline glioma (DMG) are drawn, highlighting similarities but also differences between the tumor entities and underlying mechanisms. A strong focus is to point out missing information and to present directions of further research that may result in new and improved therapies for PFA ependymoma patients.

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Section: Ezhip In Pfa Ependymomasmentioning

confidence: 99%

EZHIP: a new piece of the puzzle towards understanding pediatric posterior fossa ependymoma

et al. 2021

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“…GBM is the most frequent and the least treatable type of brain tumor, and the prognosis of GBM remains a challenge using the standard methods of treatment-TMZ, radiation, and surgical resection (Jiang et al, 2020b). TMZ is a novel methylating agent that demonstrated activity against recurrent GBM and is ineffective due to drug resistance (Wu et al, 2021). TCMs were considered anti-GBM auxiliary drugs, such as Solanum nigrum L. (Li et al, 2021), Panax ginseng, licorice, Lycium barbarum, Salvia miltiorrhiza bunge, Coptis rhizoma, and Sophora flavescens (Wang et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Network Pharmacology and Inflammatory Microenvironment Strategy Approach to Finding the Potential Target of Siraitia grosvenorii (Luo Han Guo) for Glioblastoma

Li¹,

Bi²,

Zhang³

et al. 2021

Front. Genet.

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Background: Glioblastoma (GBM) is the most common and aggressive primary intracranial tumor of the central nervous system, and the prognosis of GBM remains a challenge using the standard methods of treatment—TMZ, radiation, and surgical resection. Traditional Chinese medicine (TCM) is a helpful complementary and alternative medicine. However, there are relatively few studies on TCM for GBM.Purpose: We aimed to find the connection between TCM and anti-GBM.Study design: Network pharmacology and inflammatory microenvironment strategy were used to predict Siraitia grosvenorii (Luo Han Guo) target for treating glioblastoma.Methods: We mainly used network pharmacology and bioinformatics.Results: CCL5 was significantly highly expressed in GBM with poor prognostics. Uni-cox and randomForest were used to determine that CCL5 was especially a biomarker in GBM. CCL5 was also the target for SG and TMZ. The active ingredient of Luo Han Guo — squalene and CCL5 —showed high binding efficiency. CCL5, a chemotactic ligand, was enriched and positively correlated in eosinophils. CCL5 was also the target of Luo Han Guo, and its effective active integrate compound –— squalene — might act on CCL5.Conclusion: SG might be a new complementary therapy of the same medicine and food, working on the target CCL5 and playing an anti-GBM effect. CCL5 might affect the immune microenvironment of GBM.

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“…Moreover, so far, there is no standardized second-line treatment after tumor recurrence [ 5 ]. Multiple factors contribute to the treatment-refractory nature of glioblastoma including infiltration of normal brain, limited drug delivery into regions of tumor with an intact blood–brain barrier (BBB), inter- and intra-tumoral molecular heterogeneity, and inherent chemo- and radio-resistance [ 6 ]. A robust gene expression-based molecular classification of GBM identified proneural, neural, classical, and mesenchymal subtypes [ 7 ], and single-cell RNA sequencing revealed that multiple subtypes can reside within the same tumor [ 8 ], confirming cellular heterogeneity.…”

Section: Introductionmentioning

confidence: 99%

MV1035 Overcomes Temozolomide Resistance in Patient-Derived Glioblastoma Stem Cell Lines

Malacrida

Domizio²,

Bentivegna

et al. 2022

Biology

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Glioblastoma (GBM, grade IV glioma) represents the most aggressive brain tumor and patients with GBM have a poor prognosis. Until now surgical resection followed by radiotherapy and temozolomide (TMZ) treatment represents the standard strategy for GBM. We showed that the imidazobenzoxazin-5-thione MV1035 is able to significantly reduce GBM U87-MG cells migration and invasiveness through inhibition of the RNA demethylase ALKBH5. In this work, we focus on the DNA repair protein ALKBH2, a further MV1035 target resulting from SPILLO-PBSS proteome-wide scale in silico analysis. Our data demonstrate that MV1035 inhibits the activity of ALKBH2, known to be involved in GBM TMZ resistance. MV1035 was used on both U87-MG and two patient-derived (PD) glioma stem cells (GSCs): in combination with TMZ, it has a significant synergistic effect in reducing cell viability and sphere formation. Moreover, MV1035 induces a reduction in MGMT expression in PD-GSCs cell lines most likely through a mechanism that acts on MGMT promoter methylation. Taken together our data show that MV1035 could act as an inhibitor potentially helpful to overcome TMZ resistance and able to reduce GBM migration and invasiveness.

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Glioblastoma multiforme (GBM): An overview of current therapies and mechanisms of resistance

Cited by 291 publications

References 431 publications

EZHIP: a new piece of the puzzle towards understanding pediatric posterior fossa ependymoma

EZHIP: a new piece of the puzzle towards understanding pediatric posterior fossa ependymoma

Network Pharmacology and Inflammatory Microenvironment Strategy Approach to Finding the Potential Target of Siraitia grosvenorii (Luo Han Guo) for Glioblastoma

MV1035 Overcomes Temozolomide Resistance in Patient-Derived Glioblastoma Stem Cell Lines

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