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Therapeutic opportunities for diffuse midline glioma identified from high-throughput combination drug screening

ABSTRACT: Therapeutic opportunities for diffuse midline glioma identified from high-throughput combination drug screening

PROVIDER: PRJNA508087 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8272120.fastq.gz	Fastqsanger.gz
	SRR8272121.fastq.gz	Fastqsanger.gz
	SRR8272122.fastq.gz	Fastqsanger.gz
	SRR8272123.fastq.gz	Fastqsanger.gz
	SRR8272124.fastq.gz	Fastqsanger.gz

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Therapeutic opportunities for diffuse midline glioma identified from high-throughput combination drug screening

Project description:Diffuse midline gliomas (DMG) are a group of molecularly related malignancies occurring in midline structures of the childhood central nervous system, including thalamus, pons, and spinal cord. These cancers are characterized by high prevalence of the histone-3K27M mutation and are universally lethal, with median survival of only 9-11 months for pontine DMG (a.k.a. DIPG). In search of novel therapeutic options, we examined multiple cell models in sequential, quantitative high-throughput screens of approved and investigational drugs. This effort generated a total of 17,456 single-agent dose responses that inspired a subsequent series of HTS-enabled drug combination assessments encompassing a total of 8883 drug-drug examinations. Top combinations were validated across a panel of patient-derived cell lines representing the major DMG genotypes. In vivo testing in patient-derived xenograft models validated the combination of the multi-HDAC inhibitor panobinostat and the proteasome inhibitor marizomib as a promising therapeutic approach. Transcriptional and metabolomic surveys revealed substantial alterations to the cellular unfolded protein response and key metabolic processes following treatment with panobinostat and marizomib. Rescue of drug induced cytotoxicity and basal mitochondrial respiration with exogenous application of nicotinamide mononucleotide (NMN) or exacerbation of these phenotypes when blocking NAD+ production via NAMPT inhibition demonstrated that metabolic catastrophe drives the combination-induced cytotoxicity. This study represents the most comprehensive single-agent and combinatorial drug screen for DIPG reported to date and identifies concomitant HDAC and proteasome inhibition as a promising therapeutic strategy that underscores under-recognized metabolic vulnerabilities in DIPG. The combined screening outcomes represent a public resource for the DMG community.

2019-11-29 | GSE123278 | GEO

ONC201 in combination with paxalisib for the treatment of H3K27-altered diffuse midline glioma

Project description:Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of all childhood cancers. Palliative radiotherapy is the only proven life-prolonging treatment, with patient survival 9-11 months. ONC201 shows preclinical and emerging clinical efficacy in DIPG. Currently, little is known about the mechanisms of sensitivity/resistance of DIPGs to ONC201, or whether recurring genomic features influence response. Using a systems-biological approach, we show ONC201 elicits potent agonism of the mitochondrial protease, CLPP, driving proteolysis of electron transport chain (ETC) and tricarboxylic acid (TCA) cycle proteins. DIPGs harboring TP53-mutations show reduced sensitivity to ONC201. Molecular mechanisms identify metabolic adaptation and resistance to ONC201 regulated by redox-activated PI3K/Akt signaling, counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib, in both wt-TP53 and TP53-mutant DIPGs. The discoveries described within, coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib inform the DIPG/DMG phase II combination clinical trial NCT05009992.

2023-05-25 | PXD036245 | Pride

Venetoclax cooperates with ionizing radiation to attenuate Diffuse Midline Glioma tumor growth

Project description:This article highlights the radiation induced cytotoxic effect of the BCL2 inhibitor, venetoclax, in diffuse midline gliomas (DMG). 1. RNA-seq: We performed bulk RNA sequencing of DMG cells exposed to 6Gy radiation and found the genes upregulated after radiation compared to unirradiated controls. 2. DNA Repair shRNA screen: We also performed a DNA Repair shRNA screen and identified the genes which are responsible for radioresistance in DMG.

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Gene expression profile at single cell level of Anaplastic ependymoma (EPN) and H3K27M-mutant diffuse midline glioma (BG)

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Patch-seq of human patient-derived diffuse midline glioma xenografts

Project description:Treatment-resistance of lethal high-grade brain tumors including H3K27M diffuse midline gliomas is thought to arise in part from transcriptional and electrophysiological heterogeneity. These phenotypes are readily studied in isolation using single-cell RNA-seq and whole-cell patch clamping, respectively, but their simultaneous capture is now possible by aspirating a cell's contents into a patch pipet after electrophysiology recordings using a method called 'patch-seq'. Here, we adapt this method to characterize the gene expression programs and functional responses of patient-derived glioma xenografts to neuronal firing at single-cell resolution.

2023-03-01 | GSE222398 | GEO

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Project description:PDGFRA and H3.3 mutations cooperate in an iPSC-based model of diffuse midline glioma to alter tumor biology.

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Specific cPRC1 complexes are co-opted to mediate oncogenic gene repression in diffuse midline glioma

Project description:Summary Diffuse midline glioma (DMG) is a fatal childhood brain tumour characterised primarily by mutant histone H3 (H3K27M). H3K27M causes a global reduction in Polycomb Repressive Complex 2 (PRC2)-mediated H3K27me3 by inhibiting PRC2 enzymatic activity. Paradoxically, PRC2 is essential in DMG tumour cells where residual complex activity is required for oncogenic gene repression, although the molecular mechanisms acting downstream of PRC2 in this context are poorly understood. Here, we’ve discovered this oncogenic gene repression is mediated by specific canonical PRC1 (cPRC1) formations. By combining CRISPR screening, biochemical and chromatin mapping approaches with functional perturbations we show that cPRC1 complexes containing CBX4 and PCGF4 drive oncogenic gene repression downstream of H3K27me3 in DMG cells. Remarkably, the altered H3K27me3 modification landscape characteristic of these tumours rewires the distribution of cPRC1 complexes on chromatin. CBX4 and PCGF4 containing cPRC1 accumulate at sites of H3K27me3 while other cPRC1 formations are displaced. Despite accounting for <5% of cPRC1 complexes in DMG, CBX4/PCGF4-containing complexes predominate as gene repressors. Our findings link the altered distribution of H3K27me3 with imbalanced cPRC1 function, promoting oncogenic gene repression in DMG cells, revealing new disease mechanisms and highlighting potential therapeutic opportunities in this incurable childhood brain tumour.

2025-06-24 | PXD047451 | Pride

Specific cPRC1 complexes are co-opted to mediate oncogenic gene repression in diffuse midline glioma

Project description:Diffuse midline glioma (DMG) is a fatal childhood brain tumour characterised primarily by mutant histone H3 (H3K27M). H3K27M causes a global reduction in Polycomb Repressive Complex 2 (PRC2)-mediated H3K27me3 by inhibiting PRC2 enzymatic activity. Paradoxically, PRC2 is essential in DMG tumour cells where residual complex activity is required for oncogenic gene repression, although the molecular mechanisms acting downstream of PRC2 in this context are poorly understood. Here, we’ve discovered this oncogenic gene repression is mediated by specific canonical PRC1 (cPRC1) formations. By combining CRISPR screening, biochemical and chromatin mapping approaches with functional perturbations we show that cPRC1 complexes containing CBX4 and PCGF4 drive oncogenic gene repression downstream of H3K27me3 in DMG cells. Remarkably, the altered H3K27me3 modification landscape characteristic of these tumours rewires the distribution of cPRC1 complexes on chromatin. CBX4 and PCGF4 containing cPRC1 accumulate at sites of H3K27me3 while other cPRC1 formations are displaced. Despite accounting for <5% of cPRC1 complexes in DMG, CBX4/PCGF4-containing complexes predominate as gene repressors. Our findings link the altered distribution of H3K27me3 with imbalanced cPRC1 function, promoting oncogenic gene repression in DMG cells, revealing new disease mechanisms and highlighting potential therapeutic opportunities in this incurable childhood brain tumour.

2025-06-24 | PXD058532 | Pride

Patch-seq of human patient-derived diffuse midline glioma xenografts

Project description:Patch-seq of human patient-derived diffuse midline glioma xenografts

| PRJNA921869 | ENA

Specific cPRC1 complexes are co-opted to mediate oncogenic gene repression in H3K27M-mutant diffuse midline glioma.

Project description:Diffuse midline glioma (DMG) is a fatal childhood brain tumour characterised primarily by mutant histone H3 (H3K27M). H3K27M causes a global reduction in Polycomb Repressive Complex 2 (PRC2)-mediated H3K27me3 by inhibiting the enzymatic activity of the complex. Paradoxically, PRC2 histone methyltransferase activity is essential in for oncogenic gene repression in DMG tumour cells though downstream molecular mechanisms that are poorly understood. Here, we discover that this oncogenic gene repression is mediated by specific canonical PRC1 (cPRC1) formations containing CBX4. By combining CRISPR screening, biochemical and chromatin mapping approaches with functional perturbations we show that cPRC1 complexes containing CBX4-cPRC1 is co-opted to drive repression downstream of H3K27me3 in DMG cells. Remarkably, the altered H3K27me3 landscape characteristic of H3K27M-mutant DMG rewires the distribution of distinct cPRC1 complexes such that CBX4-cPRC1 accumulates at sites of H3K27me3 while other cPRC1 formations are reduced. Despite CBX4-cPRC1 accounting for less than 5% all cPRC1 H3K27M-mutant DMG, it acts as the predominant repressor of (Polycomb target) neural differentiation genes in this setting. Our findings link the altered distribution of H3K27me3 with imbalances of CBX-cPRC1 functions and consequent oncogenic gene repression, revealing new disease mechanisms and potential therapeutic opportunities in this incurable childhood brain tumour.

2025-06-24 | PXD047401 | Pride

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