Current trends in mouse models of glioblastoma

Miyai, Masafumi; Tomita, Hiroyuki; Soeda, Akio; Yano, Hirohito; Iwama, Toru; Hara, Akira

doi:10.1007/s11060-017-2626-2

Cited by 96 publications

(91 citation statements)

References 63 publications

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“…Some of the current and state-of-the-art strategies for developing animal models of GBM will be summarized here. [This subject has been reviewed extensively by Huszthy et al (2012) , Miyai et al (2017) , and Schuhmacher and Squatrito (2017) ].…”

Section: Emerging Targets In Glioblastomamentioning

confidence: 99%

Current Challenges and Opportunities in Treating Glioblastoma

et al. 2018

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Glioblastoma multiforme (GBM), the most common and aggressive primary brain tumor, has a high mortality rate despite extensive efforts to develop new treatments. GBM exhibits both intra- and intertumor heterogeneity, lending to resistance and eventual tumor recurrence. Large-scale genomic and proteomic analysis of GBM tumors has uncovered potential drug targets. Effective and “druggable” targets must be validated to embark on a robust medicinal chemistry campaign culminating in the discovery of clinical candidates. Here, we review recent developments in GBM drug discovery and delivery. To identify GBM drug targets, we performed extensive bioinformatics analysis using data from The Cancer Genome Atlas project. We discovered 20 genes, BOC, CLEC4GP1, ELOVL6, EREG, ESR2, FDCSP, FURIN, FUT8-AS1, GZMB, IRX3, LITAF, NDEL1, NKX3-1, PODNL1, PTPRN, QSOX1, SEMA4F, TH, VEGFC, and C20orf166AS1 that are overexpressed in a subpopulation of GBM patients and correlate with poor survival outcomes. Importantly, nine of these genes exhibit higher expression in GBM versus low-grade glioma and may be involved in disease progression. In this review, we discuss these proteins in the context of GBM disease progression. We also conducted computational multi-parameter optimization to assess the blood-brain barrier (BBB) permeability of small molecules in clinical trials for GBM treatment. Drug delivery in the context of GBM is particularly challenging because the BBB hinders small molecule transport. Therefore, we discuss novel drug delivery methods, including nanoparticles and prodrugs. Given the aggressive nature of GBM and the complexity of targeting the central nervous system, effective treatment options are a major unmet medical need. Identification and validation of biomarkers and drug targets associated with GBM disease progression present an exciting opportunity to improve treatment of this devastating disease.

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Section: Emerging Targets In Glioblastomamentioning

confidence: 99%

Current Challenges and Opportunities in Treating Glioblastoma

et al. 2018

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“…The development of genome editing technologies such as viral vectors or CRISPR tools in combination with conditional gene expression technologies (time and/or tissue specific, i.e., CreLoxP strategy) promoted the development of GEMs [1]. In most GEMs key signalling molecules known to be deregulated in GB such as PI3K, EGFR, TP53, Rb, Ras, CDKN2A are modulated [85,170]. While GEMs are closer to human GBs in terms of histopathology, they cannot per se recapitulate the great genomic and phenotypic heterogeneity characteristic of GB.…”

Section: Robert Burnsmentioning

confidence: 99%

Considering the Experimental Use of Temozolomide in Glioblastoma Research

Herbener¹,

Burster

Goreth³

et al. 2020

Biomedicines

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Temozolomide (TMZ) currently remains the only chemotherapeutic component in the approved treatment scheme for Glioblastoma (GB), the most common primary brain tumour with a dismal patient’s survival prognosis of only ~15 months. While frequently described as an alkylating agent that causes DNA damage and thus—ultimately—cell death, a recent debate has been initiated to re-evaluate the therapeutic role of TMZ in GB. Here, we discuss the experimental use of TMZ and highlight how it differs from its clinical role. Four areas could be identified in which the experimental data is particularly limited in its translational potential: 1. transferring clinical dosing and scheduling to an experimental system and vice versa; 2. the different use of (non-inert) solvent in clinic and laboratory; 3. the limitations of established GB cell lines which only poorly mimic GB tumours; and 4. the limitations of animal models lacking an immune response. Discussing these limitations in a broader biomedical context, we offer suggestions as to how to improve transferability of data. Finally, we highlight an underexplored function of TMZ in modulating the immune system, as an example of where the aforementioned limitations impede the progression of our knowledge.

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“…Genetically engineered mouse models (GEMMs) have been, so far, the method of choice for identifying the molecular events underlying glioblastoma pathology. Their use has deepened the molecular understanding of glioblastoma initiation and progression and been demonstrated as valuable tools to test new therapies 6 . However, these conventional transgenic approaches are rather time- and cost-intensive.…”

Section: Introductionmentioning

confidence: 99%

A novel neural stem cell-derived immunocompetent mouse model of glioblastoma for preclinical studies

Costa

Fletcher

Ivanova

et al. 2020

Preprint

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Glioblastomas are the most lethal tumors affecting the central nervous system in adults. Simple and inexpensive syngeneic in vivo models that closely mirror human glioblastoma, including interactions between tumor and immune cells, are urgently needed for deciphering glioma biology and developing more effective treatments. Here, we generated glioblastoma cell lines by repeated in-vivo passaging of cells isolated from a neural stem cell-specific Pten/p53 double-knockout genetic mouse brain tumor model. Transcriptome and genome analyses of the cell lines revealed molecular heterogeneity comparable to that observed in human glioblastoma. Upon orthotopic transplantation into syngeneic hosts they formed high-grade gliomas that faithfully recapitulated the histopathological features, invasiveness and myeloid cell infiltration characteristic of human glioblastoma. These features make our cell lines unique and useful tools to study multiple aspects of glioblastoma pathomechanism and test novel treatments, especially immunotherapies in syngeneic preclinical models.

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Current trends in mouse models of glioblastoma

Cited by 96 publications

References 63 publications

Current Challenges and Opportunities in Treating Glioblastoma

Current Challenges and Opportunities in Treating Glioblastoma

Considering the Experimental Use of Temozolomide in Glioblastoma Research

A novel neural stem cell-derived immunocompetent mouse model of glioblastoma for preclinical studies

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