Mouse models of glioblastoma for the evaluation of novel therapeutic strategies

Haddad, Alexander F; Young, Jacob S; Amara, Dominic; Berger, Mitchell S.; Raleigh, David R.; Aghi, Manish K.; Butowski, Nicholas

doi:10.1093/noajnl/vdab100

Cited by 97 publications

(117 citation statements)

References 156 publications

(205 reference statements)

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“…Moreover, considering the key role played by the COX-2/PGE2/EP signal pathway not only in GBM-chemoresistance but also in immunotherapy-resistance, the study of inhibition of this pathway in preclinical models could be of particular interest [57,58]. An innovative preclinical model particularly appealing in this context could be represented by GBM patient-derived xenografts (PDX) implanted in a humanized mouse model, immunodeficient mice with peripheral blood mononuclear cells derived from the same patient, recapitulating the patient's immune-GBM interface [59,60].…”

Section: Discussionmentioning

confidence: 99%

Up-Regulation of Cyclooxygenase-2 (COX-2) Expression by Temozolomide (TMZ) in Human Glioblastoma (GBM) Cell Lines

Lombardi

Augello

Artone

et al. 2022

IJMS

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TMZ-resistance remains a main limitation in glioblastoma (GBM) treatment. TMZ is an alkylating agent whose cytotoxicity is modulated by O6-methylguanine-DNA methyltransferase (MGMT), whose expression is determined by MGMT gene promoter methylation status. The inflammatory marker COX-2 has been implicated in GBM tumorigenesis, progression, and stemness. COX-2 inhibitors are considered a GBM add-on treatment due to their ability to increase TMZ-sensitivity. We investigated the effect of TMZ on COX-2 expression in GBM cell lines showing different COX-2 levels and TMZ sensitivity (T98G and U251MG). β-catenin, MGMT, and SOX-2 expression was analyzed. The effects of NS398, COX-2 inhibitor, alone or TMZ-combined, were studied evaluating cell proliferation by the IncuCyte® system, cell cycle/apoptosis, and clonogenic potential. COX-2, β-catenin, MGMT, and SOX-2 expression was evaluated by RT-PCR, Western blotting, and immunofluorescence and PGE2 by ELISA. Our findings, sustaining the role of COX-2/PGE2 system in TMZ-resistance of GBM, show, for the first time, a relevant, dose-dependent up-regulation of COX-2 expression and activity in TMZ-treated T98G that, in turn, correlated with chemoresistance. Similarly, all the COX-2-dependent signaling pathways involved in TMZ-resistance also resulted in being up-modulated after treatment with TMZ. NS398+TMZ was able to reduce cell proliferation and induce cell cycle arrest and apoptosis. Moreover, NS398+TMZ counteracted the resistance in T98G preventing the TMZ-induced COX-2, β-catenin, MGMT, and SOX-2 up-regulation.

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Section: Discussionmentioning

confidence: 99%

Up-Regulation of Cyclooxygenase-2 (COX-2) Expression by Temozolomide (TMZ) in Human Glioblastoma (GBM) Cell Lines

Lombardi

Augello

Artone

et al. 2022

IJMS

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“…Development of new diagnostic and therapeutic strategies requires animal models that would accurately mimic human GBMs ( 3 , 4 ). An ideal human GBM model should possess the following characteristics: 1) be highly reproducible with predictable growth in mice; 2) be orthotopic to provide the appropriate microenvironment; 3) histologically resemble human GBM and recapitulate cellular intratumoral heterogeneity; 4) have diffuse invasive growth into brain parenchyma without encapsulation; 5) be genetically similar to the original tumor, particularly preserving the expression profile of main tumor markers.…”

Section: Introductionmentioning

confidence: 99%

“…A number of different approaches have been utilized for establishing GBM models in animals, which include syngeneic rodent models, genetically engineered mouse models, human cell-line xenografts, and PDXs ( 3 , 4 ). Among these models, PDXs are the most “close-to-patient” by definition and represent an important preclinical system.…”

Section: Introductionmentioning

confidence: 99%

Highly Invasive Fluorescent/Bioluminescent Patient-Derived Orthotopic Model of Glioblastoma in Mice

et al. 2022

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Development of the novel diagnostic and therapeutic approaches in neuro-oncology requires tumor models that closely reproduce the biological features of patients’ tumors. Patient-derived xenografts (PDXs) are recognized as a valuable and the most “close-to-patient” tool for preclinical studies. However, their establishment is complicated by the factors related to both the surgical material and technique of the orthotopic implantation. The aim of this work was to develop a patient-derived glioblastoma multiform (GBM) model that stably co-expresses luciferase and a far-red fluorescent protein for monitoring of tumor progression in the brain and, using this model, to validate new diagnostic methods—macroscopic fluorescence lifetime imaging (macro-FLIM) and cross-polarization optical coherence tomography (CP OCT). The established model was similar to the original patient’s GBM in terms of histological and immunohistochemical features and possessed reproducible growth in nude mice, which could be observed by both fluorescence and bioluminescence imaging. Our results demonstrated the high potential of macro-FLIM and CP OCT for intraoperative differentiation of GBM from the white matter. Thus, the dual-labeled PDX model of GBM proved to be an excellent approach for observation of tumor development by optical methods.

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“…These results can be explained by (i) the higher MDSC frequency observed in the combination group that could inhibit the effector T cell activity, or (ii) the high efficacy of ICBs due to the immunogenicity of GL261. Indeed, the murine GL261 model is highly immunogenic while human GBM is not [ 38 , 39 ]. Therefore, mice bearing GL261 could respond better to ICBs than humans, as clinical trials did not demonstrate the efficacy of using ICBs for patients facing GBM [ 9 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

Combination of DNA Vaccine and Immune Checkpoint Blockades Improves the Immune Response in an Orthotopic Unresectable Glioblastoma Model

et al. 2022

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Combination immunotherapy has emerged as a promising strategy to increase the immune response in glioblastoma (GBM) and overcome the complex immunosuppression occurring in its microenvironment. In this study, we hypothesized that combining DNA vaccines—to stimulate a specific immune response—and dual immune checkpoint blockade (ICB)—to decrease the immunosuppression exerted on T cells—will improve the immune response and the survival in an orthotopic unresectable GL261 model. We first highlighted the influence of the insertion position of a GBM epitope sequence in a plasmid DNA vaccine encoding a vesicular stomatitis virus glycoprotein (VSV-G) (here referred to as pTOP) in the generation of a specific and significant IFN-γ response against the GBM antigen TRP2 by inserting a CD8 epitope sequence in specific permissive sites. Then, we combined the pTOP vaccine with anti-PD-1 and anti-CTLA-4 ICBs. Immune cell analysis revealed an increase in effector T cell to Treg ratios in the spleens and an increase in infiltrated IFN-γ-secreting CD8 T cell frequency in the brains following combination therapy. Even if the survival was not significantly different between dual ICB and combination therapy, we offer a new immunotherapeutic perspective by improving the immune landscape in an orthotopic unresectable GBM model.

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Mouse models of glioblastoma for the evaluation of novel therapeutic strategies

Cited by 97 publications

References 156 publications

Up-Regulation of Cyclooxygenase-2 (COX-2) Expression by Temozolomide (TMZ) in Human Glioblastoma (GBM) Cell Lines

Up-Regulation of Cyclooxygenase-2 (COX-2) Expression by Temozolomide (TMZ) in Human Glioblastoma (GBM) Cell Lines

Highly Invasive Fluorescent/Bioluminescent Patient-Derived Orthotopic Model of Glioblastoma in Mice

Combination of DNA Vaccine and Immune Checkpoint Blockades Improves the Immune Response in an Orthotopic Unresectable Glioblastoma Model

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