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Identification of 17-DMAG as a novel KDM4B inhibitor for combination therapy

ABSTRACT: Identification of 17-DMAG as a novel KDM4B inhibitor for combination therapy

PROVIDER: PRJNA636501 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11879436.fastq.gz	Fastqsanger.gz
	SRR11879437.fastq.gz	Fastqsanger.gz
	SRR11879438.fastq.gz	Fastqsanger.gz
	SRR11879439.fastq.gz	Fastqsanger.gz
	SRR11879440.fastq.gz	Fastqsanger.gz

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Identification of 17-DMAG as a novel KDM4B inhibitor for combination therapy [ChIP-seq]

Project description:Histone demethylases such as KDM4B play critical roles in oncogenic pathophysiology and, therefore may be effective targets for anticancer therapy. Using a TR-FRET demethylation screen assay, in combination with multiple orthogonal validation approaches, we identified geldanamycin and its analog 17-DMAG as novel KDM4B inhibitors. In addition, we found that these Hsp90 inhibitors effect increased degradation of the alveolar rhabdomyosarcoma (aRMS) driver oncoprotein PAX3-FOXO1 and induce the H3K9me3 and H3K36me3 at genomic loci of PAX3-FOXO1 targets. We found that as monotherapy 17-DMAG significantly inhibits expression of PAX3-FOXO1 target genes and multiple oncogenic pathways, induces a muscle differentiation signature, delays tumor growth and extends survival in aRMS xenograft mouse models. The combination of 17-DMAG with conventional chemotherapy significantly enhances therapeutic efficacy, indicating that targeting KDM4B in combination with chemotherapy may serve as a novel therapy to PAX3-FOXO1-positive aRMS.

2020-12-22 | GSE151493 | GEO

Identification of 17-DMAG as a novel KDM4B inhibitor for combination therapy [RNA-seq]

Project description:Histone lysine demethylases (KDMs) are emerging as therapeutic targets in cancer. Development of potent KDM inhibitors may provide additional options for epigenomics-oriented therapies. Using a Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) functional demethylation assay, in combination with a high-content immunofluorescence imaging phenotypic screen, Matrix-Assisted Laser Desorption/Ionization- Fourier Transform Ion Cyclotron Resonance mass spectrometry (MALDI-FTICR MS) and Amplified Luminescent Proximity Homogeneous Assay (ALPHA), we identified geldanamycin, an inhibitor of heat shock protein 90 (Hsp90), as a novel inhibitor of JmjC-domain containing demethylases such as KDM4B. We further found that geldanamycin can destabilize the PAX3-FOXO1 fusion oncoprotein, an Hsp90 client, which is a driver of clinically unfavorable alveolar rhabdomyosarcoma (aRMS). We then hypothesized that dual inhibition of PAX3-FOXO1 and epigenetic modifiers of aRMS would have synergistic antitumor activity. We repurposed the geldanamycin analog 17-DMAG to target aRMS and found that 17-DMAG significantly delays tumor growth , extends survival in xenograft mouse models, and inhibits expression of PAX3-FOXO1 targets and multiple oncogenic pathways including MYC, E2F and NOTCH. In addition, the combination of 17-DMAG with conventional chemotherapy or the bromodomain inhibitor JQ1 significantly enhances therapeutic efficacy. In summary, we have identified geldanamycin and 17-DMAG as dual KDM/Hsp90 inhibitors and 17-DMAG is efficacious against PAX3-FOXO1-driven rhabdomyosarcoma.

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Identification of 17-DMAG as a novel KDM4B inhibitor for combination therapy [ChIP-seq]

Project description:Identification of 17-DMAG as a novel KDM4B inhibitor for combination therapy [ChIP-seq]

| PRJNA635950 | ENA

Identification of 17-DMAG as a novel KDM4B inhibitor for combination therapy [RNA-seq]

Project description:Identification of 17-DMAG as a novel KDM4B inhibitor for combination therapy [RNA-seq]

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17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) in Treating Patients With an Advanced Solid Tumor or Lymphoma

Project description:RATIONALE: Drugs used in chemotherapy, such as 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), work in different ways to stop cancer cells from dividing so they stop growing or die. PURPOSE: This phase I trial is studying the side effects and best dose of 17-DMAG in treating patients with an advanced solid tumor or lymphoma.

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Identification of 17-DMAG as a novel KDM4B inhibitor for combination therapy

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-12-22 | GSE151598 | GEO

17-DMAG treatment in primary CLL B cells

Project description:We used microarrays to analyze gene expression following treatment of leukemic B cells with the Hsp90 inhibitor 17-DMAG. Gene expression profiling reveals the role of SOCS3 in cytokine signaling in CLL Primary cells from CLL patients were isolated and treated in vitro with 17-DMAG. Cells were collected for viability, gene expression analysis and cell signaling and migration assays.

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17-DMAG treatment in primary CLL B cells

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Effects of 17-DMAG treatment on transcription in 4T1 cells populations resistant and non-resistant to 17-DMAG

Project description:Effects of 17-DMAG treatment on transcription in 4T1 cells populations resistant and non-resistant to 17-DMAG

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Combination therapy with HSP90 inhibitor 17-DMAG reconditions the tumor microenvironment to improve recruitment of therapeutic T cells.

Project description:Ineffective recognition of tumor cells by CD8+ T cells is a limitation of cancer immunotherapy. Therefore, treatment regimens that coordinately promote enhanced antitumor CD8+ T-cell activation, delivery, and target cell recognition should yield greater clinical benefit. Using an MCA205 sarcoma model, we show that in vitro treatment of tumor cells with the HSP90 inhibitor 17-DMAG results in the transient (proteasome-dependent) degradation of the HSP90 client protein EphA2 and the subsequent increased recognition of tumor cells by Type-1 anti-EphA2 CD8+ T cells. In vivo administration of 17-DMAG to tumor-bearing mice led to slowed tumor growth, enhanced/prolonged recognition of tumor cells by anti-EphA2 CD8+ T cells, reduced levels of myeloid-derived suppressor cells and regulatory T cells in the tumor microenvironment, and activation of tumor-associated vascular endothelial cells in association with elevated levels of Type-1 tumor-infiltrating lymphocytes. When combined with EphA2-specific active vaccination or the adoptive transfer of EphA2-specific CD8+ T cells, 17-DMAG cotreatment yielded a superior tumor therapeutic regimen that was capable of rendering animals free of disease. Taken together, our findings indicate that 17-DMAG functions as an immune adjuvant in the context of vaccines targeting EphA2.

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