Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A DNA Hypomethylation Signature Predicts Novel Anti-Tumor Activity of LSD1 Inhibitors in SCLC (microarray)

ABSTRACT: Epigenetic dysregulation has emerged as an important mechanism in cancer. Alterations in epigenetic machinery have become a major focus for new targeted therapies. The current report describes the discovery and biological activity of a cyclopropylamine containing inhibitor of Lysine Demethylase 1 (LSD1), GSK2879552. This small molecule is a potent, selective, orally bioavailable, mechanism-based irreversible inhibitor of LSD1. A proliferation screen of cell lines representing a number of tumor types indicated that small cell lung carcinoma (SCLC) is sensitive to LSD1 inhibition. The subset of SCLC lines and primary samples that undergo growth inhibition in response to GSK2879552 exhibit DNA hypomethylation of a signature set of probes suggesting this may be used as a predictive biomarker of activity. The targeted mechanism coupled with a novel predictive biomarker make LSD1 inhibition an exciting potential therapy for SCLC, a highly prevalent, rarely cured, tumor type representing approximately 15% of all lung cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE66294 | GEO | 2015/07/14

SECONDARY ACCESSION(S): PRJNA276453

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

A DNA Hypomethylation Signature Predicts Novel Anti-Tumor Activity of LSD1 Inhibitors in SCLC (microarray)

Project description:Epigenetic dysregulation has emerged as an important mechanism in cancer. Alterations in epigenetic machinery have become a major focus for new targeted therapies. The current report describes the discovery and biological activity of a cyclopropylamine containing inhibitor of Lysine Demethylase 1 (LSD1), GSK2879552. This small molecule is a potent, selective, orally bioavailable, mechanism-based irreversible inhibitor of LSD1. A proliferation screen of cell lines representing a number of tumor types indicated that small cell lung carcinoma (SCLC) is sensitive to LSD1 inhibition. The subset of SCLC lines and primary samples that undergo growth inhibition in response to GSK2879552 exhibit DNA hypomethylation of a signature set of probes suggesting this may be used as a predictive biomarker of activity. The targeted mechanism coupled with a novel predictive biomarker make LSD1 inhibition an exciting potential therapy for SCLC, a highly prevalent, rarely cured, tumor type representing approximately 15% of all lung cancers. To gain insight into the mechanism of LSD1 inhibition in inhibiting growth in SCLC cell lines, the effect of GSK2879552 on gene expression was evaluated in 6 SCLC lines, three sensitive to the growth inhibitory effects of GSK2879552 and three resistant. Expression was measured on Affy HG-U133_PLUS_2 microarrays at three time points (2, 4, and 7 days) with replicates.

2015-07-14 | E-GEOD-66294 | biostudies-arrayexpress

A DNA Hypomethylation Signature Predicts Novel Anti-Tumor Activity of LSD1 Inhibitors in SCLC (ChIP-Seq)

Project description:Epigenetic dysregulation has emerged as an important mechanism in cancer. Alterations in epigenetic machinery have become a major focus for new targeted therapies. The current report describes the discovery and biological activity of a cyclopropylamine containing inhibitor of Lysine Demethylase 1 (LSD1), GSK2879552. This small molecule is a potent, selective, orally bioavailable, mechanism-based irreversible inhibitor of LSD1. A proliferation screen of cell lines representing a number of tumor types indicated that small cell lung carcinoma (SCLC) is sensitive to LSD1 inhibition. The subset of SCLC lines and primary samples that undergo growth inhibition in response to GSK2879552 exhibit DNA hypomethylation of a signature set of probes suggesting this may be used as a predictive biomarker of activity. The targeted mechanism coupled with a novel predictive biomarker make LSD1 inhibition an exciting potential therapy for SCLC, a highly prevalent, rarely cured, tumor type representing approximately 15% of all lung cancers. To investigate the mechanism of LSD1 efficacy in SCLC cell lines we used chromatin immunoprecipitation (ChIP) sequencing studies to examine the genomic distribution of LSD1 as well as H3K4me2 and H3K4me1 in NCI-H526 SCLC cells in the absence and presence of LSD1 inhibition.

2015-07-14 | E-GEOD-66297 | biostudies-arrayexpress

A DNA Hypomethylation Signature Predicts Novel Anti-Tumor Activity of LSD1 Inhibitors in SCLC (BeadChip)

Project description:Epigenetic dysregulation has emerged as an important mechanism in cancer. Alterations in epigenetic machinery have become a major focus for new targeted therapies. The current report describes the discovery and biological activity of a cyclopropylamine containing inhibitor of Lysine Demethylase 1 (LSD1), GSK2879552. This small molecule is a potent, selective, orally bioavailable, mechanism-based irreversible inhibitor of LSD1. A proliferation screen of cell lines representing a number of tumor types indicated that small cell lung carcinoma (SCLC) is sensitive to LSD1 inhibition. The subset of SCLC lines and primary samples that undergo growth inhibition in response to GSK2879552 exhibit DNA hypomethylation of a signature set of probes suggesting this may be used as a predictive biomarker of activity. The targeted mechanism coupled with a novel predictive biomarker make LSD1 inhibition an exciting potential therapy for SCLC, a highly prevalent, rarely cured, tumor type representing approximately 15% of all lung cancers. DNA methylation profiling was performed using Infinium 450K methylation arrays on SCLC cell lines, patient derived xenografts, and patient samples. Data was processed and normalized using GenomeStudio V2011.1

2015-07-14 | E-GEOD-66295 | biostudies-arrayexpress

A DNA Hypomethylation Signature Predicts Novel Anti-Tumor Activity of LSD1 Inhibitors in SCLC (ChIP-Seq)

2015-07-14 | GSE66297 | GEO

A DNA Hypomethylation Signature Predicts Novel Anti-Tumor Activity of LSD1 Inhibitors in SCLC (BeadChip)

2015-07-14 | GSE66295 | GEO

LSD1 inhibitor T-3775440 inhibits SCLC cell proliferation by disrupting LSD1 interactions with SNAG domain proteins INSM1 and GFI1B

Project description:T-3775440 is an irreversible inhibitor of the chromatin demethylase LSD1. Here we describe the anti-cancer effects and mechanism of action of T-3775440 in small cell lung cancer (SCLC). T-3775440 inhibited proliferation of SCLC cells in vitro and retarded SCLC tumor growth in vivo. Our results argue that LSD1 plays an important role in neuroendocrine-associated transcription and cell proliferation of SCLC via interactions with the SNAG domain proteins INSM1 and GFI1B. Targeting these critical interactions with LSD1 inhibitors offers a novel rational strategy to therapeutically manage SCLC.

2018-02-01 | GSE100169 | GEO

Effect of 48h treatment with 100nM GSK2879552 on T-ALL cell lines HSB2 and RPMI8402

Project description:RNA sequencing was performed on biological triplicates of HSB2 and RPMI8402 cells treated with 100nM GSK2879552 for 48h versus their corresponding DMSO treatment controls. GSK2879552 is a potent, selective and orally bioavailable inhibitor of the lysine-specific histone demethylase 1 (LSD1). Gene expression was severely affected by LSD1 inhibition. Pathway analysis performed on the differentially expressed genes following 48hrs of LSD1i treatment clearly showed an increased apoptotic gene signature (CASP3, CASP8) and enhanced expression of genes associated with TRAIL signaling. Furthermore, pre-ranked Gene Set Enrichment Analysis (GSEA) revealed that genes upregulated after LSD1 inhibition in HSB2 showed significant enrichment for transcripts that are down in hematopoietic stem cells and early T lymphocytes. In contrast, important components of the Notch, WNT and SMAD signalling complex were significantly down regulated upon short-term LSD1i treatment in HSB2 cells. In line with this notion, pre-ranked GSEA also revealed that LSD1i resulted in decreased expression of genes that significantly overlap with an oncogenic MYC signature.

2017-02-03 | GSE90657 | GEO

Effect of 48h treatment with 100nM GSK2879552 on T-ALL cell lines LOUCY and PEER

Project description:RNA sequencing was performed on biological triplicates of LOUCY and PEER cells treated with 100nM GSK2879552 for 48h versus their corresponding DMSO treatment controls. GSK2879552 is a potent, selective and orally bioavailable inhibitor of the lysine-specific histone demethylase 1 (LSD1). Gene expression was severely affected by LSD1 inhibition. Pathway analysis performed on the differentially expressed genes following 48hrs of LSD1i treatment clearly showed an increased apoptotic gene signature (CASP3, CASP8) and enhanced expression of genes associated with TRAIL signaling. Furthermore, pre-ranked Gene Set Enrichment Analysis (GSEA) revealed that genes upregulated after LSD1 inhibition in LOUCY showed significant enrichment for transcripts that are down in hematopoietic stem cells and early T lymphocytes. In contrast, important components of the Notch, WNT and SMAD signalling complex were significantly down regulated upon short-term LSD1i treatment in LOUCY cells. In line with this notion, pre-ranked GSEA also revealed that LSD1i resulted in decreased expression of genes that significantly overlap with an oncogenic MYC signature.

2017-02-03 | GSE83126 | GEO

Inhibition of LSD1 with bomedemstat sensitizes small cell lung cancer to immune checkpoint blockade and T cell killing

Project description:The addition of immune checkpoint blockade (ICB) to platinum/etoposide chemotherapy changed the standard of care for small cell lung cancer (SCLC) treatment. However, ICB addition only modestly improved clinical outcomes, likely reflecting the high prevalence of an immunologically “cold” tumor microenvironment in SCLC, despite high mutational burden. Nevertheless, some patients clearly benefit from ICB and recent reports have associated clinical responses to ICB in SCLC with A) decreased neuroendocrine characteristics and B) activation of NOTCH signaling. We previously showed that inhibition of the LSD1 demethylase activates NOTCH and suppresses neuroendocrine features of SCLC, leading us to investigate whether LSD1 inhibition would enhance the response to PD1 inhibition in SCLC.

2022-08-17 | GSE208614 | GEO

Effect of 24h treatment with 100nM GSK2879552 on the murine T-ALL cell with and without Zeb2 overexpression

Project description:RNA sequencing was performed on biological triplicates of p53 null T-ALL cells with ZEB2 overexpression (P53/R26-Zeb2tg/tg) versus p53 null T-ALL cells without Zeb2 overexpression (P53/R26+/+) treated with 100nM GSK2879552 for 24h versus their corresponding DMSO treatment controls. P53/R26+/+ and P53/R26-Zeb2tg/tg tumor lines displayed a very distinct gene expression signature under baseline (DMSO) conditions in line with our previous observations that Zeb2 driven thymomas reflect a more immature T-ALL subtype. GSK2879552 is a potent, selective and orally bioavailable inhibitor of the lysine-specific histone demethylase 1 (LSD1). LSD1i treatment in control P53/R26+/+ cell lines only caused limited effects on overall transcription. In contrast, gene transcription was more severely affected by LSD1 perturbations in the P53/R26-Zeb2tg/tg lines with significant changes in the expression transcripts enriched for signalling pathways essential for embryonic development (like TGFbeta and Wnt signalling), genes involved in transcriptional repression/regulation, apoptosis and DNA replication/repair. All together, these results demonstrate that Zeb2 overexpression modulates murine T-ALL responsiveness to LSD1 inhibitors.

2017-02-03 | GSE83127 | 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