Dual targeting of polyamine synthesis and uptake in diffuse intrinsic pontine gliomas
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PROVIDER: EGAS00001004905 | EGA |
REPOSITORIES: EGA
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Project description:Diffuse Intrinsic Pontine Glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and choosing therapies based on assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic make-up of this brain cancer with nearly 80% harboring a K27M-H3.3 or K27M-H3.1 mutation. However, DIPGs are still thought of as one disease with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs we integrated whole-genome-sequencing with methylation, expression and copy-number profiling, discovering that DIPGs are three molecularly distinct subgroups (H3-K27M, Silent, MYCN) and uncovering a novel recurrent activating mutation in the activin receptor ACVR1, in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer. Illumina Infinium 450K arrays were performed according to the manufacturer's directions on bisulfite converted gDNA extracted from fresh frozen biopsy and autopsy brain tissue from DIPG patients. CpG methylation profiling on Illumina Infinium 450K arrays was performed for 28 paediatric DIPG samples.
2014-03-31 | E-GEOD-50022 | biostudies-arrayexpress
Project description:Diffuse Intrinsic Pontine Glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and choosing therapies based on assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic make-up of this brain cancer with nearly 80% harboring a K27M-H3.3 or K27M-H3.1 mutation. However, DIPGs are still thought of as one disease with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs we integrated whole-genome-sequencing with methylation, expression and copy-number profiling, discovering that DIPGs are three molecularly distinct subgroups (H3-K27M, Silent, MYCN) and uncovering a novel recurrent activating mutation in the activin receptor ACVR1, in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from snap frozen biopsy and autopsy brain tissue from DIPG patients. Copy number analysis on Affymetrix 6.0 SNP arrays was performed for 45 paediatric DIPG samples, 27 matched normal brain samples, and HapMap samples.
2014-03-31 | E-GEOD-50024 | biostudies-arrayexpress
Project description:Diffuse Intrinsic Pontine Glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and choosing therapies based on assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic make-up of this brain cancer with nearly 80% harboring a K27M-H3.3 or K27M-H3.1 mutation. However, DIPGs are still thought of as one disease with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs we integrated whole-genome-sequencing with methylation, expression and copy-number profiling, discovering that DIPGs are three molecularly distinct subgroups (H3-K27M, Silent, MYCN) and uncovering a novel recurrent activating mutation in the activin receptor ACVR1, in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer. Illumina HT-12 arrays were performed according to the manufacturer's directions on RNA extracted from FFPE biopsy and autopsy brain tissue from DIPG patients. Gene expression profiling on Illumina HT-12 arrays was performed for 35 paediatric DIPG samples and 10 normal brain samples
2014-03-31 | E-GEOD-50021 | biostudies-arrayexpress
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
Project description:Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric brain tumor with limited therapeutic options. The majority of cases of DIPG exhibit a mutation in histone 3 (H3K27M) that results in oncogenic transcriptional aberrancies. We show here that DIPG is vulnerable to transcriptional disruption using either bromodomain inhibition or CDK7 blockade. We observe that targeting oncogenic transcription through either of these methods synergizes with HDAC inhibition and that DIPG cells resistant to HDAC inhibitor therapy retain sensitivity to CDK7 blockade. Furthermore, identification of super-enhancers in DIPG provides insights toward the cell of origin, highlighting oligodendroglial lineage genes, and reveals unexpected mechanisms mediating tumor viability and invasion, including potassium channel function and EPH-ephrin signaling. The findings presented here demonstrate transcriptional vulnerabilities of DIPG and elucidate previously unknown mechanisms of DIPG pathobiology.
2017-04-21 | GSE94259 | GEO
Project description:Diffuse Intrinsic Pontine Glioma (DIPG) is an aggressive incurable pediatric brainstem cancer. Due to its inoperable tumor location and resistance to conventional chemotherapy agents such as temozolomide, radiotherapy is the current standard treatment. This study aimed to identify potential therapeutic agents for DIPG treatment using a computational drug screening pipeline. We hypothesized that drugs that can reverse a disease gene signature can be potential drug candidates for that disease. Because of lack of normal brain samples as control for creating disease signature, we implemented a deep learning autoencoder to select reference control samples. Using a systematic computational approach with publicly available gene expression databases for DIPG signature and gene expression data of pre and post drug treated cancer cell lines, we identified drug hits with potential to reverse a DIPG gene signature to one that matches normal tissue background. We then tested the identified drugs at their IC50 concentration for 24 hours on patient-derived DIPG4 cell lines. Overall Design: mRNA profiles of DIPG4 cell lines treated with Triptolide (TPL), Triamterene(TRIAM), Mycophenolate mofetil (MMF) and DMSO as control
2022-10-20 | GSE193855 | GEO
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: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
Project description:Diffuse intrinsic pontine glioma (DIPG) is one of the most devastating of paediatric malignancies and one for which no effective therapy exists. A major contributor to the failure of therapeutic trials is the assumption that biologic properties of brainstem tumours in children are identical to cerebral high-grade gliomas of adults. A better understanding of the biology of DIPG itself is needed in order to develop agents targeted more specifically to these childrenâs disease. Here we address this lack of knowledge by performing the first high-resolution SNP-based DNA microarray analysis of a series of DIPGs. Eleven samples (nine post-mortem and two pre-treatment surgical samples), the largest series thus far examined, were hybridized to Affymetrix SNP arrays (250k or 6.0). The study was approved by the Research Ethics Board at our institution (Hospital for Sick Children, Toronto, Ontario, Canada). All Array findings were validated using quantitative-PCR, fluorescence in-situ hybridization, immunohistochemistry and/or microsatellite analysis. Analysis of DIPG copy number alterations showed recurrent changes distinct from those of paediatric supratentorial high-grade astrocytomas. 36% of DIPGs had gains in PDGFRA and all showed PDGF-R-α expression. Gains in PARP-1 were identified in 3 cases. Pathway analysis revealed genes with loss of heterozygosity were enriched for DNA repair pathways. Our data provides the first, comprehensive high-resolution genomic analysis of paediatric DIPG. Our findings of recurrent involvement of the PDGFR pathway as well as defects in DNA repair pathways coupled with gain of PARP-1 highlight two potential, biologically-based, therapeutic targets directed specifically at this devastating disease. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from snap frozen biopsy and autopsy brain tissue from DIPG patients. Copy number analysis of Affymetrix 250K and 6.0 SNP arrays was performed for 11 paediatric DIPG samples, 7 matched normal brain samples, and HapMap samples.
2010-06-16 | E-GEOD-18828 | biostudies-arrayexpress
Project description:Genomic studies have shown that several types of pediatric brain tumors have dysregulation of MYC family members (c-MYC and MYCN). In fact, it has been estimated that about 50% of all human cancers have increased MYC, and this is correlated with tumor aggression and poor survival. Here we focus on targeting the MYCN oncogene in diffuse intrinsic pontine glioma (DIPG). DIPG has the worst prognosis of any pediatric brain tumor and is in desperate need of viable treatment options. Here we demonstrate that using a 90-amino acid peptide, termed “Omomyc” we are able to down-regulate endogenous MYCN and inhibit growth of MYCN overexpressing DIPG cells. Furthermore, Omomyc binds to promoter regions normally occupied by MYCN to affect transcription of a subset of genes including PLK1 and LDHA, among others. In vivo expression of Omomyc in DIPG cells implanted in mice slows disease progression, suggesting that MYCN targets are important for driving rapid tumor growth and may offer insight into potential targets for treatment of MYCN driven DIPGs.
2023-12-01 | GSE201936 | GEO