Limitations of current in vitro models for testing the clinical potential of epigenetic inhibitors for treatment of pediatric ependymoma
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PROVIDER: PRJNA439220 | ENA |
REPOSITORIES: ENA
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Project description:Background: Epigenetic modifications have been shown to play an important role in the classification and pathogenesis of the pediatric brain tumor ependymoma, suggesting they are a potential therapeutic target. Methods: The effects of agents targeting epigenetic modifications on the growth and death of a panel of ependymoma cell lines was investigated, as well as toxicity to normal fetal neural stem cells. The ependymoma cell lines were characterized using DNA methylation profiling. Results: Agents targeting epigenetic modifications inhibited the growth and induced the death of ependymoma cells with variable efficiency. However, this was often not at clinically achievable doses. Additionally, DNA methylation profiling revealed a lack of similarity to primary ependymomas suggesting alterations were induced during culture. Toxicity to fetal neural stem cells was also seen at similar drug concentrations Conclusions: Agents targeting epigenetic modifications were able to inhibit the growth and induced the death of ependymoma cells grown in vitro. However, many agents were only active at high doses, outside clinical ranges, and also resulted in toxicity to normal brain cells. The lack of similarity in DNA methylation profiles between cultured cells and primary ependymomas questions the validity of using in vitro cultured cells for pre-clinical analysis of agents targeting epigenetic mechanisms and suggests further investigation using models that are more appropriate should be undertaken before agents are taken forward for clinical testing.
2018-12-26 | GSE112067 | GEO
Project description:Pediatric ependymoma has relatively low frequencies of DNA mutations, which suggest that epigenetics may drive tumors. However, the epigenetic mechanisms for recurrent ependymoma are still poorly understood. Here, we performed longitudinal and comprehensive DNA methylation and gene expression analysis for recurrent pediatric ependymoma tumors from 10 patients, total 46 DNA methylomes (including primary tumors and matched recurrent tumors; normal pediatric brain tissues and PDOX tumors). Both RELA and PFA tumors maintained the subtype DNA methylation signatures during repeated relapses. We further identified the potential DNA methylation predictors, drivers and boosters and their potential regulated genes for recurrent ependymoma tumors. Increased DNA methylation levels within H3K4me1 enriched regions indicates disturbed functions of LSD1 gene in recurrent ependymoma tumors. Combining novel LSD1 inhibitor SYC-836 with radiation (XRT) significantly prolonged animal survival times in PDOX models of recurrent PFA ependymoma. Our PDOX models provide a unique platform for preclinical testing drugs and development of new therapy for pediatric recurrent ependymoma.
2022-07-12 | GSE156619 | GEO
Project description:BackgroundEpigenetic modifications have been shown to play an important role in the classification and pathogenesis of the pediatric brain tumor ependymoma, suggesting they are a potential therapeutic target.ResultsAgents targeting epigenetic modifications inhibited the growth and induced the death of ependymoma cells with variable efficiency. However, this was often not at clinically achievable doses. Additionally, DNA methylation profiling revealed a lack of similarity to primary ependymomas suggesting alterations were induced during culture. Toxicity to fetal neural stem cells was also seen at similar drug concentrations.ConclusionsAgents targeting epigenetic modifications were able to inhibit the growth and induced the death of ependymoma cells grown in vitro. However, many agents were only active at high doses, outside clinical ranges, and also resulted in toxicity to normal brain cells. The lack of similarity in DNA methylation profiles between cultured cells and primary ependymomas questions the validity of using in vitro cultured cells for pre-clinical analysis of agents targeting epigenetic mechanisms and suggests further investigation using models that are more appropriate should be undertaken before agents are taken forward for clinical testing.Materials and methodsThe effects of agents targeting epigenetic modifications on the growth and death of a panel of ependymoma cell lines was investigated, as well as toxicity to normal fetal neural stem cells. The ependymoma cell lines were characterized using DNA methylation profiling.
| S-EPMC6284855 | biostudies-literature
Project description:Despite extensively growing knowledge on the molecular biology of ependymoma, effective treatments are still lacking for about half patients with high-risk tumors. By applying single cell RNA-sequencing, we comprehensively identify a cellular hierarchy within ependymoma spanning undifferentiated and differentiated tumor cell states across all major molecular groups. This not only refines the concept of these established molecular groups but moreover provides a biological context for the well-known capacity of aggressive ependymomas for late recurrence and treatment resistance. Our newly defined transcriptomic signatures also prove to be of prognostic relevance within established high-risk ependymoma groups. Consequently, the newly characterized cell states could serve as promising future therapeutic targets and biomarkers for clinical trials.
2020-07-13 | GSE141460 | GEO
Project description:We compared genomic characteristics of primary and first recurrent pediatric ependymoma to identify sub-group specific differences.
2016-09-11 | GSE50876 | GEO
Project description:Epigenetic Landscape of Pediatric Ependymoma Recurrence
| PRJNA658524 | ENA
Project description:Ependymoma (EPN) is the third most common central nervous system (CNS) tumor in childhood and, recently, has been classified in nine robust molecular subgroups (Pajtler et al., 2015). However, molecular and clinical features of pediatric EPNs from Brazilian cohorts remain unexplored. Herein, we aimed to analyze the gene expression profile among three different molecular subgroups: ST-EPN-RELA, ST-EPN-YAP1 and PF-EPN-A.
2023-03-03 | GSE181162 | GEO
Project description:We compared molecular characteristics of primary and recurrent pediatric ependymoma to identify sub-group specific differences. Gene expression profiles were used to identify unique immunobiologic sub-types of posterior fossa pediatric ependymoma. Gene expression profiles were generated from surgical tumor (ependymoma) (n=65) using Affymetrix HG-U133plus2 chips (Platform GPL570). Normalization was performed on our entire cohort of ependymoma. Of the 65 samples, a sub-set of 58 were used in the corresponding manuscript. Excluded samples are noted. Gene expression profiles were filtered to obtain gene expression of key immune cell markers. Comparative analyses between tumor samples were used to identifiy unique immunobiology between posterior fossa sub-groups.
2013-08-30 | E-GEOD-50385 | biostudies-arrayexpress
Project description:Pediatric ependymoma is a devastating brain cancer marked by its relapsing pattern and lack of effective chemotherapies. This shortage of treatments is due to limited knowledge about ependymoma tumorigenic mechanisms. By means of single-nucleus chromatin accessibility and gene expression profiling of posterior fossa primary tumors and distal metastases, we reveal key transcription factors and enhancers associated with the differentiation of ependymoma tumor cells into tumor-derived cell lineages and their transition into a mesenchymal-like state. We identify NFkB, AP-1, and MYC as mediators of this transition, and show that the gene expression profiles of tumor cells and infiltrating microglia are consistent with abundant pro-inflammatory signaling between these populations. In line with these results, both TGF-b1 and TNF-a induce the expression of mesenchymal genes on a patient-derived cell model, and TGF-b1 leads to an invasive phenotype. Altogether, these data suggest that tumor gliosis induced by inflammatory cytokines and oxidative stress underlies the mesenchymal phenotype of posterior fossa ependymoma. This SuperSeries is composed of the SubSeries listed below.
2022-06-24 | GSE206580 | GEO
Project description:Temporal and Clonal Progression in Pediatric Ependymoma
| PRJNA408011 | ENA