Browse
Submit Data
Databases
API
Help

Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

7 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Methylation array profiling of DIPG tumours, patient-derived cell culture, and patient-derived xenografts from the BIOMEDE phase II prospective trial

ABSTRACT: BIOMEDE (NCT02233049) was a phase II, biopsy-driven clinical trial in DIPG patients with randomisation of stratification between dasatinib, erlotinib and everolimus. Methylation array profiling was carried out alongside drug screening in newly-established patient-derived models of DIPG in vitro and in vivo. Alongside exome, RNAseq, phospho-proteomics, these data highlight the MAPK pathway as a therapeutic target in DIPG, and show the importance of parallel resistance modelling and rational combinatorial treatment

ORGANISM(S): Homo sapiens

SUBMITTER: Alan Mackay

PROVIDER: E-MTAB-9282 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

ACCESS DATA

Json Xml

Similar Datasets

Patient-derived primary cultures of paediatric high grade glioma and DIPG - molecular profiling by methylation array (Infinium HumanMethylationEPIC)

Project description:Molecular profiling by methylation array (Illumina Infinium HumanMethylationEPIC) in a panel of models generated under 2D (laminin matrix) and/or 3D (neurospheres) conditions fully credentialed by phenotypic and molecular comparison to the original tumour sample. Patient-derived in vitro primary cell cultures represent potentially useful tools for mechanistic and preclinical investigation based upon their retention of key features of tumour subgroups under experimental conditions amenable to high-throughput approaches.

2020-08-31 | E-MTAB-9297 | biostudies-arrayexpress

Patient-derived primary cultures of paediatric high grade glioma and DIPG - molecular profiling by methylation array (Infinium HumanMethylation450)

Project description:Molecular profiling by methylation array (Illumina Infinium HumanMethylation450K) in a panel of models generated under 2D (laminin matrix) and/or 3D (neurospheres) conditions fully credentialed by phenotypic and molecular comparison to the original tumour sample. Patient-derived in vitro primary cell cultures represent potentially useful tools for mechanistic and preclinical investigation based upon their retention of key features of tumour subgroups under experimental conditions amenable to high-throughput approaches.

2020-08-31 | E-MTAB-9298 | biostudies-arrayexpress

DIPG harbour alterations targetable by MEK inhibitors, with acquired resistance mechanisms overcome by combinatorial inhibition

Project description:The survival of children with DIPG remains dismal, with new treatments desperately needed. In the era of precision medicine, targeted therapies represent an exciting treatment opportunity, yet resistance can rapidly emerge, playing an important role in treatment failure. In a prospective biopsy-stratified clinical trial, we combined detailed molecular profiling (methylation BeadArray, exome, RNAseq, phospho-proteomics) linked to drug screening in newly-established patient-derived models of DIPG in vitro and in vivo. We identified a high degree of in vitro sensitivity to the MEK inhibitor trametinib in samples which harboured genetic alterations targeting the MAPK pathway, including the non-canonical BRAFG469V mutation, and those affecting PIK3R1 and NF1. However, treatment of PDX models and the patient with trametinib at relapse failed to elicit a significant response. We generated trametinib-resistant clones in the BRAF_G469V model through continuous drug exposure, and identified acquired mutations in MEK1/2 (MEK1_K57N, MEK1_I141S and MEK2_I115N) with sustained pathway up-regulation. These cells showed the hallmarks of mesenchymal transition, and expression signatures overlapping with inherently trametinib-insensitive primary patient-derived cells that predicted a confirmed sensitivity to dasatinib. Combinations of trametinib with dasatinib and the downstream ERK inhibitor ulixertinib showed highly synergistic effects in vitro. These data highlight the MAPK pathway as a therapeutic target in DIPG, and show the importance of parallel resistance modelling and rational combinatorial treatments likely to be required for meaningful clinical translation.

2021-07-20 | PXD019701 | Pride

The immunopeptidome and proteome of DIPG

Project description:DIPG is a devastating paediatric and young adult brainstem tumour with no cure and a median overall survival of 9 months. Cellular immunotherapy approaches require specific targeting of unique and tumour specific cell surface antigens, however, there is a paucity of known targets for DIPG. Here we used a proteomics platform approach to interrogate an array of patient derived DIPG cell lines to facilitate a multi-omics based approach to identify cell surface protein candidates enriched or unique to DIPG.

2023-09-25 | PXD038271 | Pride

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

2021-02-12 | GSE153441 | GEO

Genome-wide chromatin accessibility profile of human DIPG cell lines

Project description:To study the chromatin accessibility across the genome of DIPG-VII, DIPG-IV, and DIPG-XIII cell lines, we performed ATACseq (Assay for Transposase-Accessible Chromatin with high-throughput sequencing).

2023-12-31 | GSE239938 | GEO

ChIP-seq of H3K27ac and H3K27me3 in HSJD-DIPG-007 cell line

Project description:Identification of super enhancer regions in the HSJD-DIPG-007 cell line and the associated genes with these regions. This study aims to evaluate the efficacy of combined use of BET and CBP inhibition in DIPG.

2020-08-01 | E-MTAB-8242 | biostudies-arrayexpress

Genome-wide gene expression profile of human DIPG cell lines (ONC201 treatment)

Project description:To study the effect of ONC201 treatment on DIPG-VII, DIPG-IV, and DIPG-XIII cell lines, we treated cell lines and performed RNA-Seq analysis.

2023-12-31 | GSE239939 | GEO

Non-inflammatory tumor microenvironment of Diffuse Intrinsic Pontine Glioma (DIPG)

Project description:Diffuse intrinsic pontine glioma (DIPG) is a universally fatal malignancy of the childhood central nervous system, with a median overall survival of 9-11 months. We have previously shown that primary DIPG tissue contains numerous tumor-associated macrophages, and substantial work has demonstrated a significant pathological role for adult glioma-associated macrophages. However, work over the past decade has highlighted many molecular and genomic differences between pediatric and adult glioblastomas (GBM). Thus, we directly compared inflammatory characteristics of DIPG and adult GBM. We found that the leukocyte (CD45+) compartment in primary DIPG tissue samples is predominantly composed of CD11b+ macrophages, with very few CD3+ T-lymphocytes. In contrast, T-lymphocytes are more abundant in adult GBM tissue samples. RNA sequencing of macrophages isolated from primary tumor samples revealed that DIPG- and adult GBM-associated macrophages both express gene programs related to ECM remodeling and angiogenesis, but DIPG-associated macrophages express substantially fewer inflammatory factors than their adult GBM counterparts. Examining the secretome of glioma cells, we found that patient-derived DIPG cell cultures secrete markedly fewer cytokines and chemokines than patient-derived adult GBM cultures. Concordantly, bulk and single-cell RNA sequencing data indicates low to absent expression of chemokines and cytokines in DIPG. Together, these observations suggest that the inflammatory milieu of the DIPG tumor microenvironment is fundamentally different than adult GBM. The low intrinsic inflammatory signature of DIPG cells may contribute to the lack of lymphocytes and non-inflammatory phenotype of DIPG-associated microglia/macrophages. Understanding the glioma subtype-specific inflammatory milieu may inform the design and application of immunotherapy-based treatments.

2018-08-23 | GSE115397 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data