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Combination of CBL0137 and Panobinostat in DIPG

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE153441 | GEO | 2021/02/12

REPOSITORIES: GEO

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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.

2021-03-07 | GSE153883 | GEO

Combination of CBL0137 and Panobinostat in DIPG

Project description:Combination of CBL0137 and Panobinostat in DIPG

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Functionally-defined Therapeutic Targets in DIPG

Project description:<p>Diffuse Intrinsic Pontine Glioma (DIPG) is a universally fatal childhood cancer. Here, we performed a chemical screen in patient-derived DIPG cell cultures along with RNAseq expression analysis and integrated computational modeling to identify potentially effective therapeutic strategies. Panobinostat, among the more promising agents identified, demonstrated efficacy in pontine orthotopic xenograft models of both H3K27M and histone WT DIPG. These data suggest the potential utility of specific drug combinations and provides evidence of in vivo treatment efficacy of the multi-histone deacetylase inhibitor panobinostat. We are depositing to dbGaP deep sequencing whole exome data for 22 patient tumor samples and 13 matched normals, along with RNAseq data for 12 patient tumor samples and 6 normal pediatric brain tissue samples. In addition, we are depositing 22 RNAseq samples from DIPG cell lines before and after panobinostat treatment.</p>

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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

2021-09-21 | GSE151689 | GEO

HDAC inhibition suppresses telomerase activity in neuroblastoma cells harboring TERT rearrangements [ChIP-Seq]

Project description:We report the application of single-molecule-based sequencing technology for high-throughput profiling of histone modifications in mammalian cells. The three histone marks acetylation of histone 3 at lysine residue 27 (H3K27ac), trimethylation of histone 3 at lysine residue 4 (H3K4me3) and trimethylation of histone 3 at lysine residue 36 (H3K36me3) were selected, representing marks for an open chromatin structure and enable gene transcription. The two histone marks standing for a condensed chromatin state and disabled gene transcription trimethylation of histone 3 at lysine residue 27 (H3K27me3) and trimethylation of histone 3 at lysine residue 9 (H3K9me3) were chosen. ChIP sequencing of the five histone marks was investigated in high-risk TERT-rearranged neuroblastoma GI-ME-N cells treated with solvent or HDAC inhibitor panobinostat. Exemplary samples include solvent-treated and panobinostat-treated samples after 18 h of treatment.

2022-08-04 | GSE155705 | GEO

Effect of CBL0137 on DIPG cells

Project description:Effect of CBL0137 on DIPG cells

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Differential gene expression in neuroblastoma cells after treatment with vehicle control, JQ1, panobinostat, or combination of JQ1 and panobinostat

Project description:The bromodomain inhibitor JQ1 and the histone deacetylase inhibitor panobinostat induce synergistic anticancer effects We analyzed whether JQ1 and panobinostat synergistically modulate gene expression Neuroblastoma SK-N-BE(2) cells were treated with vehicle control, 1 microM JQ1, 10 nM panobinostat, or combination of JQ1 and panobinostat for 6 hours, and subjected to differential gene expression studies with Affymetrix microarrays.

2015-12-31 | E-GEOD-68690 | biostudies-arrayexpress

Proteomic analysis of chemical and genetic EZH2 inhibition in diffuse intrinsic pontine glioma cell lines

Project description:Diffuse Intrinsic Pontine Glioma (DIPG) is a rare and highly aggressive pediatric tumor. The average survival time after diagnosis is less than one year. Currently, there are no effective treatments. Characteristic of DIPG is a mutation in histone H3 which leads to a substitution of Lysine 27 to Methionine (H3K27M) which deregulates Polycomb Repressive Complex 2 (PRC2), including enzymatic activity of EZH2. Previous studies have shown that inhibition of EZH2 by chemical agents decreases DIPG cell proliferation and inhibits tumor growth in vivo. My thesis project aims to confirm that EZH2 could be a therapeutic target using chemical EZH2 inhibitors, small interfering RNAs and a CRISPR/Cas9 approach in a series of DIPG tumor cell lines and to determine underlying molecular mechanisms of action.

2022-04-01 | PXD017525 | Pride

Next Generation Sequencing Facilitates Quantitative Analysis of Wild Type and CANT1 Overexpression Retinoblastoma Transcriptomes

Project description:PURPOSE: Retinoblastoma (RB) is the most common malignant intraocular tumor of childhood. Recent studies have shown that long non-coding RNAs (lncRNAs), which are longer than 200 bp and without protein-coding ability, are key regulators of tumorigenesis. However, the role of lncRNAs in retinoblastoma remains to be elucidated. METHODS: LncRNA CASC15-New-Transcript 1 (CANT1) expression was determined by real-time PCR in RB cells. Tumor characteristics in CANT1-overexpressing RB cells were determined through CCK8 cell viability assay, soft agar assay and mouse xenograft experiment. RNA transcriptome-sequencing was performed to find downstream target genes of CANT1. CANT1's interactions with phosphoinositide 3-kinase gamma (PI3Kγ) were studied through chromatin oligonucleotide precipitation (ChOP) and chromatin immunoprecipitation (ChIP) assays. RESULTS: In this study, we found that the expression of lncRNA CANT1 was significantly downregulated in RB. Notably, CANT1 overexpression significantly inhibited RB growth both in vitro and in vivo. Furthermore, lncRNA CANT1, which was mainly located in the nucleus, occupied the promoter of PI3Kγ and blocked histone methyltransferase hSET1 from binding to the PI3Kγ promoter, thus abolishing hSET1-mediated histone H3K4 trimethylation of the PI3Kγ promoter and inhibiting PI3Kγ expression. Furthermore, we found that silencing PI3Kγ either by CANT1 overexpression or by PI3Kγ siRNA, reduced the activity of PI3K/Akt signaling and suppressed RB tumorigenesis. CONCLUSIONS: LncRNA CANT1 acts as a suppressor of RB progression by blocking gene-specific histone methyltransferase recruitment. These findings outline a new CANT1 modulation mechanism and provide an alternative option for RB treatment.

2020-02-05 | GSE141327 | GEO

Therapeutic opportunities for diffuse midline glioma identified from high-throughput combination drug screening

Project description:Diffuse midline gliomas (DMG) are a group of molecularly related malignancies occurring in midline structures of the childhood central nervous system, including thalamus, pons, and spinal cord. These cancers are characterized by high prevalence of the histone-3K27M mutation and are universally lethal, with median survival of only 9-11 months for pontine DMG (a.k.a. DIPG). In search of novel therapeutic options, we examined multiple cell models in sequential, quantitative high-throughput screens of approved and investigational drugs. This effort generated a total of 17,456 single-agent dose responses that inspired a subsequent series of HTS-enabled drug combination assessments encompassing a total of 8883 drug-drug examinations. Top combinations were validated across a panel of patient-derived cell lines representing the major DMG genotypes. In vivo testing in patient-derived xenograft models validated the combination of the multi-HDAC inhibitor panobinostat and the proteasome inhibitor marizomib as a promising therapeutic approach. Transcriptional and metabolomic surveys revealed substantial alterations to the cellular unfolded protein response and key metabolic processes following treatment with panobinostat and marizomib. Rescue of drug induced cytotoxicity and basal mitochondrial respiration with exogenous application of nicotinamide mononucleotide (NMN) or exacerbation of these phenotypes when blocking NAD+ production via NAMPT inhibition demonstrated that metabolic catastrophe drives the combination-induced cytotoxicity. This study represents the most comprehensive single-agent and combinatorial drug screen for DIPG reported to date and identifies concomitant HDAC and proteasome inhibition as a promising therapeutic strategy that underscores under-recognized metabolic vulnerabilities in DIPG. The combined screening outcomes represent a public resource for the DMG community.

2019-11-29 | GSE123278 | GEO

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