Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Effects of the Combination Therapy of a CDK4/6 and a MEK inhibitor in a Mouse Model of Diffuse Midline Glioma

ABSTRACT: Diffuse intrinsic pontine glioma (DIPG) arises in the brainstem of children, leading tumor-related death among children. A heterozygous histone H3.3K27M mutation has been shown to occur in ~80% of DIPGs, and results in brainstem gliomagenesis. There is no clinical trial for the patients with DIPG that proved to prolong survival time so far. Recently, CDK4/6 inhibitor showed feasibility and early therapeutic effect against DIPG. Also, recent research with human DIPG specimens have detected the MAPK pathway highly activated. Here, we evaluated a novel combination therapy with CDK4/6 inhibitor and MEK inhibitor to the mouse DIPG model. In order to generate DIPG‐bearing mice, we are using the RCAS/Tv‐a system, with which we are able to target specific genetic alterations in RCAS viruses (avian retroviruses) to specific cells‐of‐origin using transgenic Tv‐a‐expressing mice (Tv‐a being the receptor for RCAS viruses). We injected P3‐P5 Nestin-Tv-a;p53fl/fl mice (C56Bl/6 background) with RCAS‐PDGF‐A + RCAS‐H3.3K27M, and RCAS-Cre. The mice are treated with vehicle (methylcellurose), ribociclib as monotherapy, trametinib as monotherapy, and ribociclib and combination as combination. For short-term use, tumor tissues treated with ribociclib showed cytostatic effect, and those treated with trametinib showed cytotoxic effect, and those with combination showed both. Long-term use showed that combination therapy modestly prolonged mice survival compared with vehicle. Therefore, we need to find how DIPG showed registence to the long-term chemotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE184786 | GEO | 2021/09/28

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

RNAseq analysis of murine brainstem gliomas with and without H3.3K27M

Project description:Using the RCAS/tv-a system, we induced murine brainstem gliomas (PDGF-B; p53 loss using RCAS-Cre with and without H3.3K27M) in Nestin tv-a; p53 floxed mice

2017-05-11 | GSE98765 | GEO

A Novel Mouse Model of Diffuse Midline Glioma Initiated in Neonatal Oligodendrocyte Progenitor Cells Highlights Cell- of-origin Dependent Effects of H3K27M III

Project description:Diffuse midline glioma (DMG) is a type of lethal brain tumor that develops mainly in children. The majority of DMG harbor the K27M mutation in histone H3. Oligodendrocyte progenitor cells (OPCs) in the brainstem are candidate cells-of-origin for DMG, yet there is no genetically engineered mouse model of DMG initiated in OPCs. Here, we used the RCAS/Tv-a avian retroviral system to generate DMG in Olig2-expressing progenitors and Nestin-expressing progenitors in the neonatal mouse brainstem. PDGF-B overexpression, along with p53 deletion, resulted in gliomas. Exogenous overexpression of H3.3K27M had a significant effect on tumor latency and tumor cell proliferation when compared with H3.3WT in Nestin+ cells but not in Olig2+ cells. Further, the fraction of H3.3K27M-positive cells was significantly lower in DMGs initiated in Olig2+ cells relative to Nestin+ cells, suggesting that the requirement for H3.3K27M is reduced when tumorigenesis is initiated in Olig2+ cells. Interestingly, H3K27 trimethylation was decreased with H3.3K27M induction even in Olig2+ cells. Therefore, we need to find if there is transcriptional changes for the tumorigenesis with H3.3K27M in Olig2+ cells.

2021-10-05 | GSE184936 | GEO

A Novel Mouse Model of Diffuse Midline Glioma Initiated in Neonatal Oligodendrocyte Progenitor Cells Highlights Cell- of-origin Dependent Effects of H3K27M II

Project description:Diffuse midline glioma (DMG) is a type of lethal brain tumor that develops mainly in children. The majority of DMG harbor the K27M mutation in histone H3. Oligodendrocyte progenitor cells (OPCs) in the brainstem are candidate cells-of-origin for DMG, yet there is no genetically engineered mouse model of DMG initiated in OPCs. Here, we used the RCAS/Tv-a avian retroviral system to generate DMG in Olig2-expressing progenitors and Nestin-expressing progenitors in the neonatal mouse brainstem. PDGF-A overexpression, along with p53 deletion, resulted in gliomas. Exogenous overexpression of H3.3K27M had a significant effect on tumor latency and tumor cell proliferation when compared with H3.3WT in Nestin+ cells but not in Olig2+ cells. Further, the fraction of H3.3K27M-positive cells was significantly lower in DMGs initiated in Olig2+ cells relative to Nestin+ cells, suggesting that the requirement for H3.3K27M is reduced when tumorigenesis is initiated in Olig2+ cells. Interestingly, H3K27 trimethylation was decreased with H3.3K27M induction even in Olig2+ cells. Therefore, we need to find if there is transcriptional changes for the tumorigenesis with H3.3K27M in Olig2+ cells.

2021-10-05 | GSE184935 | GEO

A Novel Mouse Model of Diffuse Midline Glioma Initiated in Neonatal Oligodendrocyte Progenitor Cells Highlights Cell- of-origin Dependent Effects of H3K27M I

Project description:Diffuse midline glioma (DMG) is a type of lethal brain tumor that develops mainly in children. The majority of DMG harbor the K27M mutation in histone H3. Oligodendrocyte progenitor cells (OPCs) in the brainstem are candidate cells-of-origin for DMG, yet there is no genetically engineered mouse model of DMG initiated in OPCs. Here, we used the RCAS/Tv-a avian retroviral system to generate DMG in Olig2-expressing progenitors and Nestin-expressing progenitors in the neonatal mouse brainstem. PDGF-A or PDGF-B overexpression, along with p53 deletion, resulted in gliomas in both models. Exogenous overexpression of H3.3K27M had a significant effect on tumor latency and tumor cell proliferation when compared with H3.3WT in Nestin+ cells but not in Olig2+ cells. Further, the fraction of H3.3K27M-positive cells was significantly lower in DMGs initiated in Olig2+ cells relative to Nestin+ cells, both in PDGF-A and PDGF-B-driven models, suggesting that the requirement for H3.3K27M is increased when tumorigenesis is initiated in Nestin+ cells. Therefore, we need to find how the tumorigenic effects of H3.3K27M are more oncogenic in Nestin+ cells than Olig2+ cells.

2021-10-05 | GSE184934 | GEO

Generation of diffuse intrinsic pontine glioma mouse models by brainstem targeted in utero electroporation

Project description:Diffuse intrinsic pontine gliomas (DIPGs) are highly lethal childhood brain tumors. Their unique genetic makeup, pathological heterogeneity, and brainstem location all present challenges to treatment. Developing mouse models that accurately reflect each of these distinct features will be critical to advance our understanding of DIPG development, progression, and therapeutic resistance. The aim of this study was to generate new mouse models of DIPG, and characterize the role of specific oncogenic combinations in DIPG pathogenesis. We used in utero electroporation (IUE) to transfect neural stem cells in the developing brainstem with PiggyBac DNA transposon plasmids. Combinations of PDGFB or PdgfraD842V, dominant negative Trp53 (DNp53), and H3.3K27M expression induced fully penetrant brainstem gliomas. IUE enabled the targeted transfection of brainstem neural stem cells. PDGFB + DNp53 induced the rapid development of grade-IV gliomas. PdgfraD842V + DNp53 produced slower forming grade-III gliomas. Addition of H3.3K27M only significantly accelerated PdgfraD842V DIPG development. Glioma subgroup molecular signatures were associated with differences in bulk PDGFB and PdgfraD842V tumor composition. H3.3K27M induced both overlapping and unique gene expression changes in PDGFB and PdgfraD842V tumors. Paracrine effects of PDGFB promote disruption of pericyte-endothelial interactions and angiogenesis in PDGFB DIPG mouse models. Brainstem targeted in utero electroporation provides a rapid and flexible system to generate diverse DIPG mouse models. Using IUE to investigate mutation and pathohistological heterogeneity of DIPG will provide a valuable tool for future genetic and preclinical studies.

2019-11-14 | GSE128807 | GEO

Genome-wide Analyses of Diffuse Intrinsic Pontine Gliomas

Project description:Purpose: More than 90% of children with diffuse intrinsic pontine glioma (DIPG) die within 2 years of diagnosis. There is a dire need to identify therapeutic targets, however lack of patient material for research has limited progress. We evaluated a large cohort of diffuse intrinsic pontine gliomas (DIPGs) to identify recurrent genomic abnormalities and gene expression signatures underlying DIPG. Patients and Methods: We used single nucleotide polymorphism arrays to evaluate genomic copy number imbalances in 43 DIPGs from 40 patients and in 8 low-grade exophytic brainstem gliomas. Gene expression arrays were used to evaluate expression signatures from 27 DIPGs, 6 low-grade exophytic brainstem gliomas and 66 low-grade gliomas arising outside the brainstem. Results: Frequencies of specific large-scale and focal imbalances varied significantly between DIPGs and pediatric glioblastomas outside the brainstem. Focal amplifications of genes within the receptor tyrosine kinase-Ras-PI3-kinase signaling pathway were found in 47% of DIPG, with PDGFRA and MET showing the highest frequency. 30% of DIPG contained focal amplifications of cell-cycle regulatory genes controlling RB phosphorylation, and 21% had concurrent amplification of genes from both pathways. Some tumors showed heterogeneity in amplification patterns. DIPGs showed distinct gene expression signatures relating to developmental processes compared to pediatric glioblastomas arising outside the brainstem, while expression signatures of low-grade exophytic brainstem gliomas were similar to low-grade gliomas outside the brainstem. Copy number analaysis: 43 DIPG samples, 8 Low Grade Gliomas using SNP6.0. Available matched normals are also profiled with SNP6.0. Expression analysis: 29 DIPG samples, 6 Low grade samples Please contact Suzanne Baker at Suzanne.Baker@stjude.org for CEL files and genotype calls.

2011-09-20 | E-GEOD-26576 | biostudies-arrayexpress

Potent anti-tumor efficacy of palbociclib in H3K27M-mutant diffuse intrinsic pontine glioma

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

RNAseq of nestin-expressing murine brainstem progenitors infected with ACVR1 WT or R206H ACVR1 with and without H3.1K27M

Project description:Diffuse intrinsic pontine glioma (DIPG) is an incurable pediatric brain tumor, resulting in the death of 200-300 children each year in the United States. Recently it was discovered that approximately 25% of all DIPG cases harbor activating mutations in ACVR1, a gene that encodes Activin A receptor (ALK2), a receptor in the bone morphogenetic protein (BMP) pathway, and that DIPGs with ALK2 mutations commonly harbor an H3.1K27M mutation. Herein, we used the RCAS/TVA retroviral system to study the effects of ACVR1 mutations and H3.1K27M on DIPG pathogenesis. In vitro expression of R206H ACVR1 with and without H3.1K27M in nestin-expressing brainstem progenitors resulted in upregulation of mesenchymal markers and gene set enrichment analysis (GSEA) revealed Stat3 pathway activation. Neonatal expression of ACVR1 R206H or G328V in combination with H3.1K27M and p53 deletion in nestin-expressing brainstem progenitors induced glioma-like lesions expressing mesenchymal markers with Stat3 activation but was not sufficient for full gliomagenesis. In combination with platelet-derived growth factor A (PDGFA) signaling, ACVR1 R206H and H3.1K27M significantly decreased survival and increased tumor incidence. We demonstrate that targeting the BMP signaling pathway may be an effective therapeutic strategy to treat ACVR1 R206H mutant DIPGs. Exogenous Noggin expression at tumor initiation significantly increased tumor latency and treatment of ACVR1 R206H mutant murine DIPGs with LDN212854, an ACVR1 inhibitor, significantly prolonged their survival. We confirm relevance of our model to the human disease as human DIPG models with ACVR1 mutations were also sensitive to treatment with LDN212854 in vitro. Altogether, our studies demonstrate that ACVR1 R206H and H3.1K27M promote tumor initiation, accelerate gliomagenesis, promote a mesenchymal profile in part due to Stat3 activation, and identify LDN212854 as a promising compound to treat children with DIPG.

2019-01-25 | GSE125627 | GEO

H2A.Z histone variants facilitate HDACi-dependent removal of H3.3K27M mutant protein in paediatric high-grade glioma cells

Project description:Diffuse intrinsic pontine gliomas (DIPG) are paediatric malignant gliomas developing in the brainstem, where resection is unattainable, leaving palliative radiotherapy as the major standard of care. Patients with DIPG have dismal prognosis of 9-12 months of survival and currently there is no effective therapy. Over 80% of DIPGs harbour a mutation in histone 3 (H3.3 or H3.1) resulting in a lysine to methionine substitution (H3K27M). H3K27M causes global epigenetic alterations (a loss of H3K27 trimethylation and an increase H3K27 acetylation) resulting in aberrant gene expression. To date, no therapeutic strategy exists to suppress the levels of oncogenic H3K27M. We show that pan-HDAC inhibitors (HDACi) lead to the temporary but significant reduction in the H3.3K27M protein (up to 80%) in multiple glioma cell lines expressing the H3.3K27M histone variant, without changes in the H3F3A mRNA expression. The H3.3K27M occupancy at the chromatin is greatly reduced upon HDACi (SB939) treatment, as shown by ChIPseq analysis. H3.3K27M loss is most striking at SB939-upregulated genes suggesting re-expression of repressed genes. Certain H3K27M-dependent genes become downregulated in response to SB939 treatment. We discover that the SB939-mediated loss of H3.3K27M is partially blocked by a lysosomal inhibitor chloroquine. Moreover, the loss of H3.3K27M is facilitated by co-occurrence of H2A.Z, as evidenced by the knock-down of H2A.Z histone isoforms. ChIPseq analysis confirms the occupancy of H3.3K27M and H2A.Z at the same SB939-inducible genes. Altogether, we provide new insight into disease-specific mechanism of HDAC inhibition and demonstrate pharmacological modulation of the oncogenic H3.3K27M protein levels. These findings open a new possibility to directly target the H3.3K27M oncohistone, which may be exploited in future therapies.

2024-05-01 | GSE232283 | GEO

The effects of H3.3K27M mutation on developing mouse brain and cooperation with Trp53 on enhancing tumorigenesis in the genetic model of H3.3K27M [Exome-Seq]

Project description:Diffuse intrinsic pontine gliomas (DIPG) are devastating pediatric brain tumors for which there is no effective therapy. A lack of pre-clinical genetic models has affected efforts to develop therapies targeted to DIPG. Over 60% of DIPG patients carry a mutation in the histone H3F3A gene (H3.3K27M) that is often accompanied by a mutation in the TP53 gene. Here we created a genetic model in which H3.3K27M is expressed under the mouse Fabp7 promoter. These mice have disrupted embryonic development and increased susceptibility to development of lymphomas. Crosses to Trp53 knockout mice further accelerated lymphomagenesis and led to brain tumour development. Some but not all tumours acquired additional oncogenic alterations. The brain tumours faithfully recapitulate the expression profiles of DIPG patients, and brain tumours and lymphomas share significant similarities in pathway alterations, pointing to a core H3.3K27M transcriptome. Overall, this mouse model provides key insights into how H3.3K27M mutations regulate DIPG at the cellular and tumour level.

2020-10-27 | GSE120883 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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