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Gene expression analysis of a subcutaneous MV4;11 tumor treated with curaxin CBL0137.

ABSTRACT: The aim of this experiment was to identify how CBL0137 decreased tumor growth in a subcutaneous MV4;11 xenograft model by investigating the gene expression changes induced upon treatment.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE126442 | GEO | 2019/02/13

REPOSITORIES: GEO

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Transcriptome analysis of xenograft tumors treated with vehicle control or CBL0137

Project description:RNAseq was used to identify host and viral transcriptome changes in xenograft tumors treated with DMSO or CBL0137. Mouse xenograft experiments were regulated by Institutional Animal Care & Use Committee (IACUC# 2017-0035) of Weill Cornell Medical Center(WCMC). Non-obese diabetic/severe combined immunodeficiency (NOD-SCID) mice were obtained from Jackson Laboratories. Six to eight-week-old male and female mice (10 male/18 female) were injected in the flank with 1 x 107 BL cells in PBS with Matrigel eleven days before the treatment. Once the mice developed tumors with the size greater than 300 mm^3, they were grouped randomly and injected with vehicle (5% dextrose), 10mg/kg, or 60mg/kg of CBL0137. One week later, mice were injected with second dose of vehicle or CBL0137. Mice were humanely sacrificed at set experimental timepoints or when tumors reached the institutional cutoff. Tumors were harvested and snap frozen in liquid nitrogen for RNA, DNA, and sectioning for immunohistochemistry. RNAseq experiments were performed with tumor samples from 3 control and 3 60mg/kg CBL0137 treated mice.

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Gene expression analysis of Th-MYCN neuroblastoma tumours treated with CBL0137 and panobinostat

Project description:The aim of this experiment is to identify the changes in gene expression induced by CBL0137, panobinostat and their combination

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Gene expression analysis of a subcutaneous MV4 11 tumor treated with curaxin CBL0137.

Project description:Gene expression analysis of a subcutaneous MV4 11 tumor treated with curaxin CBL0137.

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Transcriptome analysis of xenograft tumors treated with vehicle control or CBL0137

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Transcriptome of MV4;11 cells treated with ASH1L inhibitor AS-99

Project description:This study describes the transcriptome profiling of MV4;11 human leukemia cells treated for 6 days with: 1) DMSO; 2) 3 µM of AS-99 ASH1L inhibitor.

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Effect of CBL0137 on DIPG cells

Project description:Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumor for which new treatments are needed. A high throughput drug screen of 3600 pharmaceutical compounds found that anti-malarials, including quinacrine had potent activity against DIPG neurospheres. CBL0137 is a novel anti-cancer compound developed from quinacrine, which targets Facilitates Chromatin Transcription (FACT), a chromatin remodelling complex involved in transcription, replication, and DNA repair. We have found that CBL0137 displays profound cytotoxic activity against a panel of patient derived DIPG cultures, inhibiting cell proliferation and clonogenic potential, restoring tumor suppressor TP53 and Rb activity and inducing cell death through induction of apoptosis. Moreover, in an orthotopic model of DIPG, treatment with CBL0137 significantly extended animal survival. Histone mutations leading to the loss of histone trimethylation result in epigenetic dysregulation driving DIPG tumorigenesis. Treatment with CBL0137 targets this epigenetic defect, restoring both histone H3.3 acetylation and trimethylation and leading to tumor cell death. Combined epigenetic treatment with the histone deacetylase (HDAC) inhibitor panobinostat led to inhibition of the Rb/E2F1 pathway, and increased the enzymatic activity of enhancer of zeste homolog 2 (EZH2), leading to the restoration of H3K27 trimethylation. This combination therapy had synergistic activity against DIPG neurospheres with induction of apoptosis. Consistent with the in vitro results, the combination of CBL0137 and panobinostat significantly prolonged the survival of mice bearing DIPG orthografts suggesting a potential treatment strategy for DIPG.

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Combination of CBL0137 and Panobinostat in DIPG

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Effect of CBL0137 on gene expression in mouse cells and tissues

Project description:We analyzed changes in abundance of RNAs in mouse embryonic fibroblasts (MEF) from wild type and p53 knockout mice and in lungs of NIH Swiss mice upon treatment with 1microM (cells) or 60mg/kg IV (mice) of curaxin CBL0137 for 24 hours. CBL0137 is chromatin destabilizing agent.

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Effect of CBL0137 on gene expression in FACT positive and negative organs of mice

Project description:CBL0137 is chromatin destabilizing agent, which causing trapping of FACT histone chaperone in chromatin (Gasparian et all, Science TM, 2011, Safina et all, NAR, 2017). We compared effect of CBL0137 on gene expression in mouse organs, expressing FACT (testes, spleen ) or not (lung, liver) to figure out what effects of CBL0137 is due to the inhibition of FACT and which are independent of FACT.

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