Histone deacetylase inhibitors (HDACi) enhance oncolytic herpes simplex virus in malignant meningioma.
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ABSTRACT:
PROVIDER: PRJNA864618 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR20727803_1.fastq.gz | Fastqsanger.gz | |||
| SRR20727803_2.fastq.gz | Fastqsanger.gz | |||
| SRR20727804_1.fastq.gz | Fastqsanger.gz | |||
| SRR20727804_2.fastq.gz | Fastqsanger.gz | |||
| SRR20727805_1.fastq.gz | Fastqsanger.gz |
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Project description:The goal of the study was to determine whether low dose HDACi sensitizes human malignant meningioma cells to the cytotoxic capacity of oncolytic herpes simplex virus G47delta. RNA sequencing was used to examine transcriptomic changes mediated by HDACi preexposure before oncolytic virus infection.
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Project description:Approximately 20% of meningiomas are not benign (higher grade) and tend to relapse after surgery and radiation therapy. Malignant (anaplastic) meningioma (MM) is a minor subset of high-grade meningioma that is lethal with no effective treatment options currently. Oncolytic herpes simplex virus (oHSV) is a powerful anti-cancer modality that induces both direct cell death and anti-tumor immunity, and has shown activity in preclinical models of MM. However, clinically meaningful efficacy will likely entail rational mechanistic combination approaches. We here show that epigenome modulator histone deacetylase inhibitors (HDACi) increase anti-cancer effects of oHSV in human MM models, IOMM-Lee (NF2 wild-type) and CH157 (NF2 mutant). Minimally toxic, sub-micromolar concentrations of pan-HDACi, Trichostatin A and Panobinostat, substantively increased the infectability and spread of oHSV G47Δ within MM cells in vitro, resulting in enhanced oHSV-mediated killing of target cells when infected at low multiplicity of infection (MOI). Transcriptomics analysis identified selective alteration of mRNA processing and splicing modules that might underlie the potent anti-MM effects of combining HDACi and oHSV. In vivo, HDACi treatment increased intratumoral oHSV replication and boosted the capacity of oHSV to control the growth of human MM xenografts. Thus, our work supports further translational development of the combination approach employing HDACi and oHSV for the treatment of MM.
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Project description:Our single-cell transcriptomic dataset exceeds the scale of previous efforts to systematically characterize meningioma. We identified CLU is tumor suppresser, also promote the anti-tumor capability of macrophage, that why CLU decreased in meningioma malignancy. HDACi may inhibit meningioma by increasing CLU expression. Therefore, promoting CLU expression maybe a great strategy for meningioma therapeutics.
2024-05-13 | GSE206647 | 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:BackgroundHigher-grade meningiomas (HGMs; World Health Organization grades II and III) pose a clinical problem due to high recurrence rates and the absence of effective therapy. Preclinical development of novel therapeutics requires a disease model that recapitulates the genotype and phenotype of patient HGM. Oncolytic herpes simplex virus (oHSV) has shown efficacy and safety in cancers in preclinical and clinical studies, but its utility for HGM has not been well characterized.MethodsTumorsphere cultures and serial orthotopic xenografting in immunodeficient mice were used to establish a patient-derived HGM model. The model was pathologically and molecularly characterized by immunohistochemistry, western blot, and genomic DNA sequencing and compared with the patient tumor. Anti-HGM effects of oHSV G47Δ were assessed using cell viability and virus replication assays in vitro and animal survival analysis following intralesional injections of G47Δ.ResultsWe established a serially transplantable orthotopic malignant meningioma model, MN3, which was lethal within 3 months after tumorsphere implantation. MN3 xenografts exhibited the pathological hallmarks of malignant meningioma such as high Ki67 and vimentin expression. Both the patient tumor and xenografts were negative for neurofibromin 2 (merlin) and had the identical NF2 mutation. Oncolytic HSV G47Δ efficiently spread and killed MN3 cells, as well as other patient-derived HGM lines in vitro. Treatment with G47Δ significantly extended the survival of mice bearing subdural MN3 tumors.ConclusionsWe established a new patient-derived meningioma model that will enable the study of targeted therapeutic approaches for HGM. Based on these studies, it is reasonable to consider a clinical trial of G47Δ for HGM.
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Project description:We have previously developed the use of genetically engineered herpes simplex virus type 1 (G207) for the experimental treatment of malignant glioma (PMID: 18957964). We demonstrated that G207 propagates in and kills nervous system tumor cells with little to no evidence of viral encephalitis. Here, six adult patients with recurrent glioblastoma were recruited onto a phase 1b clinical trial to test safety and efficacy of G207 in anti-tumor response. We obtained resected tumor tissue before and after (within 2-5 days) inoculation with G207. RNA was extracted from all tissues and subject to gene expression profiling using NanoString Pancancer Immune panel. Our data indicate in the post-G207 samples that interferon immune response and the subsequent recruitment of an adaptive immune response strongly associated with overall survival after inoculation with oncolytic virus G207 in patients with recurrent malignant glioma.
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Project description:Since the genome of herpes simplex virus 1 (HSV-1) was first sequenced more than 30 years ago, the 84 genes it was thought to encode have been intensively studied. Here, we unravel the full complement of viral transcription and translation during lytic infection with base-pair resolution by computational integration of multi-omics data. This includes a total of 201 viral transcripts and 296 open reading frames (ORFs), comprising all known large ORFs, 55 large novel ORFs including a novel spliced ORF in the ICP0 locus that initiates from a non-AUG start codon and a novel strongly translated ORF in the ICP34.5 locus as well as multiple short ORFs. By defining viral gene modules, we link translation of ORFs to the expression of transcript isoforms. This explained translation of the vast majority of viral ORFs as well as N-terminal extensions and truncations thereof. We show that N-terminal extensions initiating from non-AUG start codons govern subcellular protein localization and packaging of key viral regulators and structural proteins. This work has great implications for future functional studies, vaccine design and novel oncolytic therapies.
2020-05-22 | PXD013407 | Pride
Project description:New therapies are needed for metastatic breast cancer patients. Oncolytic herpes simplex virus (oHSV) is an exciting therapy being developed for use against aggressive tumors and established metastases. Although oHSV have been demonstrated safe in clinical trials, a lack of sufficient potency has slowed the clinical application of this approach. We utilized histone deacetylase (HDAC) inhibitors, which have been noted to impair the innate antiviral response and improve gene transcription from viral vectors, to enhance the replication of oHSV in breast cancer cells. A panel of chemically diverse HDAC inhibitors were tested at three different doses (<, ?=?, and >LD50) for their ability to modulate the replication of oHSV in breast cancer cells. Several of the tested HDAC inhibitors enhanced oHSV replication at low multiplicity of infection (MOI) following pre-treatment of the metastatic breast cancer cell line MDA-MB-231 and the oHSV-resistant cell line 4T1, but not in the normal breast epithelial cell line MCF10A. Inhibitors of class I HDACs, including pan-selective compounds, were more effective for increasing oHSV replication compared to inhibitors that selectively target class II HDACs. These studies demonstrate that select HDAC inhibitors increase oHSV replication in breast cancer cells and provides support for pre-clinical evaluation of this combination strategy.
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Project description:Transcriptomic signatures, or biomarkers, of toxicity can facilitate rapid mechanistic analysis of chemicals using high-content transcriptomic data and identification of potential hazards to human health. We developed an 81-gene transcriptomic biomarker, named TGx-HDACi, to detect histone deacetylase inhibitors (HDACi) in TK6 human lymphoblastoid cells after 4 hours of chemical exposure. This work leveraged an established transcriptomic biomarker of DNA damage, TGx-DDI, which was developed by Heng Hong Li et al. (2015); TGx-DDI contains 63 genes and can distinguish between DNA damage-inducing (DDI) and non-DDI agents after 4 hours of exposure in TK6 cells. TGx-HDACi was derived from Templated Oligo-Sequencing (TempO-Seq) whole transcriptome gene expression profiles of 20 reference compounds, consisting of 10 HDACi and 10 non-HDACi compounds. Fourteen of the TGx-HDACi reference compounds are also part of the 28-compound reference set for TGx-DDI. The nearest shrunken centroid (NSC) method was applied to the gene expression profiles and 81 genes were identified that accurately identified HDACi compounds in the NSC probability analysis. The classification performance of TGx-HDACi was validated using an additional set of 11 test compounds (4 HDACi and 7 non-HDACi). Thus far, TGx-HDACi has demonstrated 100% accuracy. The availability of TGx-HDACi increases the diversity of tools that can facilitate mode of action analysis of toxicants using gene expression profiling.
2021-04-14 | GSE164478 | GEO
Project description:Herpes simplex virus mutants lacking the vhs gene are severely attenuated in animal models of pathogenesis and exhibit reduced growth in primary cell culture. As a result of these properties vhs-deleted virus have been proposed as live-attenuated viruses. Despite these findings and their implications for vacccines, the mechanisms by which vhs promotes infection in cell culture and in vivo are not understood. In this study we demonstrate that vhs-deficent viruses replicate to reduced levels in interferon(IFN)- primed cells. Furthermore, vhs-defective viruses induce increased levels of IFN? and IFN?-stimulated genes, and increased levels of eIF2? phosphorylation in infected cells. In addition, we demonstrate a generalized over-expression of viral RNAs following infection with a vhs-deficient virus. This suggests increased expression of IFN pathway inducing double stranded RNA, a potent pathogen-associated molecular pattern (PAMP). Together these data show that vhs likely functions to reduce innate immune responses and thereby acts as critical determinant of viral pathogenesis. Keywords: time course, genetic modification Time course (1,3,6,9 & 12h) of HSV infected mouse embryo fibroblasts. Wild type (KOS) virus is co-hybridized with vhs null virus (NHB). Each time-point is hybridized in quadruplicate.
2008-04-03 | E-GEOD-10962 | biostudies-arrayexpress