BRD9 Dictates Oncolytic Virus Resistance in Glioblastoma
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PROVIDER: PRJNA1083910 | ENA |
REPOSITORIES: ENA
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Project description:Glioblastoma multiforme (GBM) treatment is a persistent challenge for oncologists, and this challenge has motivated the exploration of novel therapeutic strategies such as oncolytic virus therapy. Despite recent advancements in oncolytic virus therapy clinical trials for glioblastoma, a substantial number of patients have shown limited responses to this treatment. Here, we performed CRISPR‒Cas9 knockout screening and identified non-canonical BRG1/BRM-associated factor (ncBAF) complex as a pivotal determinant of oncolytic virus resistance. Knockout of the ncBAF-specific subunit Bromodomain-containing protein 9 (BRD9) markedly augmented the antitumor efficacy of oncolytic herpes simplex virus type 1 (oHSV1), as evidenced by our in vitro and in vivo studies. Mechanistically, BRD9 bound to RELA, a key transcription factor in the nuclear factor-κB (NF-κB) signaling pathway, to potentiate the expression of downstream antiviral genes. The application of a small molecule inhibitor targeting BRD9 (IBRD9) significantly enhanced oHSV1 activity against GBM across various models, including cell lines, patient-derived organoids, ex vivo cultured primary tumor slices, and mouse models. Moreover, reduced BRD9 levels correlated with improved patient outcomes in oHSV1 clinical trials. These findings highlight BRD9 as a prospective target for augmenting the effectiveness of oncolytic virus therapy against glioblastoma, providing insights for the development of novel combination treatments.
2025-07-29 | GSE260886 | GEO
Project description:We explored the utility of oncolytic virus therapy against glioblastoma with Zika virus (ZIKV), a flavivirus that induces cell death and differentiation of neural precursor cells in the developing fetus. ZIKV preferentially infected and killed glioblastoma stem cells (GSCs) relative to differentiated tumor progeny or normal neuronal cells. The effects against GSCs were not a general property of neurotropic flaviviruses, as West Nile Virus (WNV) indiscriminately killed both tumor and normal neural cells. ZIKV potently depleted patient-derived GSCs grown in culture and in organoids. Moreover, mice with glioblastoma survived substantially longer and at greater rates when the tumor was inoculated with a murine adapted strain of ZIKV. Our results suggest that ZIKV is an oncolytic virus that can preferentially target GSCs, and thus, genetically modified strains that further optimize safety could have therapeutic efficacy for adult glioblastoma patients.
2017-08-23 | GSE102244 | GEO
Project description:The goal of the study was to determine whether photodynamic oncolytic virus therapy of glioblastoma and malignant meningioma xenografts in mice alters transciptomics associated with efficacy. RNA sequencing was used from tumors treated with PBS, laser, G47delta-KillerRed, and G47delta-KillerRed and laser, which is photodynamic oncolytic virus therapy.
2023-01-18 | GSE222895 | GEO
Project description:To further develop gene expression approach, we have employed whole genome microarray expression profiling as a discovery platform to identify genes with the potential to identify oncolytic virus (OV) infection effect in different subpopulations of glioblastoma stem-like cells (G cells). Cells were transfected with either control or OV. OV affects gene expression patterns in cell subtype specific pattern.
2020-07-29 | GSE155247 | GEO
Project description:Tumor-targeting oncolytic viruses engineered for glioblastoma immunotherapy
| PRJNA1021139 | ENA
Project description:A recent first-in-human clinical trial (clinicaltrials.gov NCT03152318) demonstrated that survival in glioblastoma (GBM) patients following rQNestin34.5v.2 oncolytic virus treatment was associated with immune activation signatures. Here we provide in situ evidence for ongoing T cell-mediated cytotoxicity against tumor cells at late timepoints following single treatment, with deep and persistent T cell infiltration into tumor regions. Shorter distances between cleaved caspase-3+ tumor cells and granzyme B+ T cells were associated with longer progression free survival following treatment. Pre-existing tumor-infiltrating T cells expanded locally upon treatment, correlating with longer overall patient survival. T cells with an early activation program closely interacted with tumor cells and were strongly enriched upon treatment. Viral remnants were restricted to necrotic regions, while T cells infiltrated deeply into live tumor regions. These data demonstrate that single oncolytic virus treatment can expand pre-existing T cell clones and trigger persistent T cell-mediated immunity against GBM.
2026-02-12 | GSE296577 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE15350: Resistance of primary ovarian cancer cells to oncolytic adenoviruses part1 of 2 GSE15351: Resistance of primary ovarian cancer cells to oncolytic adenoviruses part2 of 2 Refer to individual Series
2009-04-01 | E-GEOD-15473 | biostudies-arrayexpress
Project description:Oncolytic viruses are complex biological agents that interact at multiple levels with both tumor and normal tissues. Anti-viral pathways induced by interferon are known to play a critical role in determining tumor cell sensitivity and normal cell resistance to infection with oncolytic viruses. Here we pursue a synthetic biology approach to identify methods that enhance anti-tumor activity of oncolytic viruses through suppression of IFN signaling. Based on the mathematical analysis of multiple strategies, we hypothesize that a positive feedback loop, established by virus-mediated expression of a soluble interferon-binding decoy receptor, increases tumor cytotoxicity without compromising normal cells. Oncolytic rhabodviruses engineered to express a secreted interferon antagonist have improved oncolytic potential in cellular cancer models, and display improved therapeutic potential in tumor-bearing mice. Our results demonstrate the potential of this methodology in evaluating potential caveats of viral immune evasion strategies and improving the design of oncolytic viruses. The following series of microarray experiments was utilized to assess the impact of cloning an IFN decoy receptor isolated from vaccinia virus termed B19R on the transcriptional response against an IFN sensitive maraba virus strain termed MG1. RNA extraction was performed 24h post infection in 786-0 cells. Duplicate samples were pooled, and hybridized on Affymetrix human gene 1.0 ST arrays according to manufacturer instructions. Data analysis was performed using AltAnalyze. Briefly, probeset filtering implemented a DABG threshold of 70 & pV<0.05 and utilized exclusively constitutively expressed exons to assess levels of gene expression.
2013-06-01 | E-MTAB-1636 | biostudies-arrayexpress
Project description:Glioblastoma (GBM) is the most malignant primary brain tumor with no cure. While chimeric antigen receptor (CAR)-T cell therapy has exhibited considerable success for hematopoietic malignancies, CAR-T therapy for GBM is limited by heterogeneous tumor antigen expression, antigen loss after treatment with CAR-T targeting single antigens, and an immunosuppressive tumor microenvironment (TME). To address these challenges, we developed a multimodal immunotherapy platform for effective GBM treatment by combining bispecific CAR-T (BiCAR-T) cells with oncolytic virus carrying dual antigens and membrane-bound cytokines. Specifically, we developed a dual-antigen-encoding oncolytic virus (OVDual) that delivers truncated CD19 (CD19t) and EGFRvIII (EGFRvIIIt) antigens to GBM cells and BiCAR-T cells that are equipped with both CD19 CAR and EGFRvIII CAR. We demonstrated that OVDual effectively delivers CD19t and EGFRvIIIt to GBM cells and that BiCAR-T cells exhibited superior tumor-killing efficacy when combined with OVDual. To improve immune cell expansion/persistence and cytotoxicity, we engineered an OV expressing membrane-bound IL-15 and IL-21 (OVmIL15/21) and showed that OVmIL15/21 enhanced the expansion and killing activity of BiCAR-T and BiCAR-NK cells against GBM cells in vitro and boosted the anti-tumor effect in vivo. The combination of OVDual with BiCAR-T or BiCAR-NK cells allowed us to address the main challenges associated with inefficient CAR-T therapy for GBM, including heterogeneous antigen expression, antigen escape, and the immunologically ‘cold’ TME, and cytokine-armed OV further boosted the expansion/persistence and cytotoxicity of CAR immune cells. The multimodal platform developed in this study offers promising potential for effective GBM therapeutic development.
2026-02-05 | GSE310003 | GEO
Project description:Development of gene expression signatures for glioblastoma stem-like cells infected with oncolytic virus
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