BRD9 Dictates Oncolytic Virus Resistance in Glioblastoma
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ABSTRACT:
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.
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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.
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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.
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Project description:Our study shows that acute myeloid leukemia (AML) cells require the BRD9 subunit of the SWI/SNF chromatin remodeling complex to sustain MYC transcription, rapid cell proliferation, and a block in differentiation. Based on these observations, we derived small-molecule inhibitors of the BRD9 bromodomain, which selectively suppressed the proliferation of mouse and human AML cell lines. To establish these effects as on-target, we engineered a bromodomain-swap allele of BRD9, which retains functionality despite a radically altered bromodomain pocket. Expression of this allele in AML cells conferred resistance to the anti-proliferative effects of our compound series, thus establishing BRD9 as the relevant cellular target. Furthermore, we used an analogous domain-swap strategy to generate an inhibitor-resistant allele of EZH2. Our study provides the first evidence for a role of BRD9 in cancer and reveals a simple genetic strategy for constructing resistance alleles to demonstrate on-target activity of chemical probes in cells.
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