0f50cd35-b2e6-4548-8118-a023893b5511 - samples
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ABSTRACT:
PROVIDER: EGAD00001011079 | EGA |
REPOSITORIES: EGA
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Project description:In this study, we used RNA-sequencing gene expression profiling in order to characterize specific phenotypic traits in DIPG-derived glioma stem cell (GSC) models. Twenty-two primary GSC models derived from biopsies collected at diagnosis were cultured in an ECM-mimicking compound before for RNA extraction and subsequent rRNA-depletion and sequencing .
| EGAS00001007182 | EGA
Project description: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
2020-08-31 | E-MTAB-9282 | biostudies-arrayexpress
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
Project description:In patient-derived DIPG models from multiple patients, with both H3K27M mutation and EZHIP overexpression, were generated CRISPR/Cas9-engineered and subclonal isogenic cells with KMT5B and/or KMT5C deficiency.
2021-07-20 | PXD026670 | Pride
Project description:As metabolic rewiring is crucial for cancer cell proliferation, metabolic phenotyping of patient-derived organoids is desirable to identify drug-induced changes and trace metabolic vulnerabilities of tumor subtypes. We established a novel protocol for metabolomic and lipidomic profiling of colorectal cancer organoids by LC-QTOF-MS facing the challenge of capturing metabolic information from minimal sample amount (< 500 cells/injection) in the presence of extracellular matrix (ECM). The best procedure of the tested protocols included ultrasonic metabolite extraction with acetonitrile/methanol/water (2:2:1, v/v/v) without ECM removal. To eliminate ECM-derived background signals, we implemented a data filtering procedure based on p-value and fold change cut-offs which retained features with signal intensities >120% compared to matrix-derived signals present in blank samples. As a proof-of-concept, the method was applied to examine the early metabolic response of colorectal cancer organoids to 5-fluorouracil treatment. Statistical analysis revealed dose-dependent changes in the metabolic profiles of treated organoids including elevated levels of 2'-deoxyuridine, 2'-O-methylcytidin, inosine and 1-methyladenosine and depletion of 2'-deoxyadenosine and specific phospholipids. In accordance with the mechanism of action of 5-fluorouracil, changed metabolites are mainly involved in purine and pyrimidine metabolism. The novel protocol provides a first basis for the assessment of metabolic drug response phenotypes in 3D organoid models.
2021-10-12 | MTBLS2130 | MetaboLights
Project description:Tumor targeted therapies have been largely inefficient due to lack of concomitant effects on the tumor microenvironment (TME). We investigated the MAtrix REgulating MOtif (MAREMO) mimicking peptide MP5, that inhibits the pro-tumorigenic extracellular matrix (ECM) molecule tenascin-C, using immunocompetent autologous breast cancer bearing mice. MP5 treatment led to tumor regression and reduced tumor cell dissemination. Several cancer hallmarks were abolished such as tumor cell promoting growth suppression and inhibition of plasticity enhancing responsiveness to death inducers. MP5 acts on other TME players leading to blood vessel normalization and depletion of fibroblasts diminishing the ECM as an orchestrator of immune suppression, causing immune cell infiltration and reactivation of anti-tumor immunity involving IFNgamma. Thus, targeting the tumor matrix using MAREMO in tenascin-C represents a powerful novel anti-cancer strategy.
2024-01-20 | E-MTAB-13677 | biostudies-arrayexpress
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.
2021-02-12 | GSE153441 | GEO
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
Project description:Diffuse intrinsic pontine glioma (DIPG) is a rare and fatal pediatric brain cancer without cure. DIPG has high percentage histone mutation at K27M on histone H3 locus, which is believed to be one of the drivers of the tumorigenesis. Dysregulation of G1/S cell cycle checkpoint is more enriched in the H3.3K27M mutant subgroup. In this study, we reported that palbociclib (PD0332991), a specific and cytostatic inhibitor of CDK4/6, effectively suppresses the growth of DIPG cells in vitro and in vivo. We established patient derived cell lines from treatment-naïve specimens, which all have H3.3K27M mutation. And our DIPG cell lines with H3.3K27M mutation have high CDK4/6 expression. Then, we showed that depletion of CDK4 or CDK6 inhibits DIPG cells growth and blocks G1/S transition. Furthermore, palbociclib effectively repressed all 8 cell lines self-renewal, proliferation and cell cycle progression from G1 to S phase in vitro. Transcriptome analysis showed that palbociclib not only blocks G1/S transition, it also blocks other oncogenic targets such as Myc. Finally, palbociclib activity was assayed in vivo against DIPG orthotropic xenografts to demonstrate the high efficiency of blocking tumor growth. Our findings revealed that palbociclib could be the therapy strategy for DIPG.
2019-06-20 | GSE115976 | GEO
Project description:Diffuse intrinsic pontine glioma (DIPG) is one of the devastating childhood cancers. Radiation therapy remains the only effective treatment yet provides a 5-year survival rate of only1%. Several clinical trials have attempted to enhance radiation anti-tumor activity using radiosensitizing agents, though none have been successful in doing so. Given this, there is a critical need for identifying effective therapeutics to enhance radiation sensitivity for the treatment of DIPG. Using high-throughput radiosensitivity screening, we identified bromo- and extra-terminal domain (BET) protein inhibitors as potent radiosensitizers in DIPG. Genetic and pharmacologic inhibition of BET bromodomain activity reduced DIPG cell proliferation and enhanced radiation-induced DNA damage by inhibiting DNA repair pathways. RNA- and CUT-RUN-sequencing showed that BET bromodomain inhibitors regulate the expression of DNA repair genes mediated by H3K27acetylation at enhancers. BET bromodomain inhibitors enhanced DIPG radiation-response in patient-derived xenografts as well as genetically engineered mouse models. Together, our results highlight BET bromodomain inhibitor as a novel radiosensitizer and provide a rationale for developing combination therapy with radiation for the treatment DIPG.
2023-12-01 | GSE236598 | GEO