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Integrated clinical and genomic evaluation of guadecitabine (SGI-110) in peripheral T-cell lymphoma [CRISPR screen]

ABSTRACT: Integrated clinical and genomic evaluation of guadecitabine (SGI-110) in peripheral T-cell lymphoma [CRISPR screen]

PROVIDER: PRJNA779436 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16905106.fastq.gz	Fastqsanger.gz
	SRR16905107.fastq.gz	Fastqsanger.gz
	SRR16905108.fastq.gz	Fastqsanger.gz
	SRR16905109.fastq.gz	Fastqsanger.gz

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Integrated clinical and genomic evaluation of guadecitabine (SGI-110) in peripheral T-cell lymphoma

Project description:Integrated clinical and genomic evaluation of guadecitabine (SGI-110) in peripheral T-cell lymphoma

| PRJNA779431 | ENA

Integrative Epigenetic Analysis Reveals Therapeutic Targets to the DNA Methyltransferase Inhibitor SGI-110 in Hepatocellular Carcinoma Cells [gene expression]

Project description:There is an urgent need for developing more effective therapies for aggressive hepatocellular carcinoma (HCC). Guadecitabine (SGI-110) is a second-generation DNA methyltransferase inhibitor (DNMTi) currently in clinical trials for HCC and shows greater stability and performance over first generation DNMTis. The aim of this study is to identify potential therapeutic targets of SGI-110 for clinical trials.

2018-06-26 | GSE105065 | GEO

Integrated clinical and genomic evaluation of guadecitabine (SGI-110) in peripheral T-cell lymphoma [RNA-seq]

Project description:Integrated clinical and genomic evaluation of guadecitabine (SGI-110) in peripheral T-cell lymphoma [RNA-seq]

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Integrated clinical and genomic evaluation of guadecitabine (SGI-110) in peripheral T-cell lymphoma.

Project description:Peripheral T-cell lymphoma (PTCL) is a rare, heterogenous malignancy with dismal outcomes at relapse. Hypomethylating agents (HMA) have an emerging role in PTCL, supported by shared mutations with myelodysplasia (MDS). Response rates to azacitidine in PTCL of follicular helper cell origin are promising. Guadecitabine is a decitabine analogue with efficacy in MDS. In this phase II, single-arm trial, PTCL patients received guadecitabine on days 1-5 of 28-day cycles. Primary end points were overall response rate (ORR) and safety. Translational sub-studies included cell free plasma DNA sequencing and functional genomic screening using an epigenetically-targeted CRISPR/Cas9 library to identify response predictors. Among 20 predominantly relapsed/refractory patients, the ORR was 40% (10% complete responses). Most frequent grade 3-4 adverse events were neutropenia and thrombocytopenia. At 10 months median follow-up, median progression free survival (PFS) and overall survival (OS) were 2.9 and 10.4 months respectively. RHOAG17V mutations associated with improved PFS (median 5.47 vs. 1.35 months; Wilcoxon p = 0.02, Log-Rank p = 0.06). 4/7 patients with TP53 variants responded. Deletion of the histone methyltransferase SETD2 sensitised to HMA but TET2 deletion did not. Guadecitabine conveyed an acceptable ORR and toxicity profile; decitabine analogues may provide a backbone for future combinatorial regimens co-targeting histone methyltransferases.

| S-EPMC9162925 | biostudies-literature

Next-generation hypomethylating agent SGI-110 primes acute myeloid leukemia cells to IAP antagonist by activating extrinsic and intrinsic apoptosis pathways

Project description:Therapeutic efficacy of first-generation hypomethylating agents (HMAs) is limited in elderly acute myeloid leukemia (AML) patients. Therefore, combination strategies with targeted therapies are urgently needed. Here, we discover that priming with SGI-110 (guadecitabine), a next-generation HMA, sensitizes AML cells to ASTX660, a novel antagonist of cellular Inhibitor of Apoptosis Protein 1 and 2 (cIAP1/2) and X-linked IAP (XIAP). Importantly, SGI-110 and ASTX660 synergistically induced cell death in a panel of AML cell lines as well as in primary AML samples while largely sparing normal CD34+ human progenitor cells, underlining the translational relevance of this combination. Unbiased transcriptome analysis revealed that SGI-110 alone or in combination with ASTX660 upregulated the expression of key regulators of both extrinsic and intrinsic apoptosis signaling pathways such as TNFRSF10B (DR5), FAS and BAX. Individual knockdown of the death receptors TNFR1, DR5 and FAS significantly reduced SGI-110/ASTX660-mediated cell death, whereas blocking antibodies for TRAIL or FASLG failed to provide protection. Also, TNF-blocking antibody Enbrel had little protective effect on SGI110/ASTX660-induced cell death. Further, SGI-110 and ASTX660 acted in concert to promote cleavage of caspase-8 and BID, thereby providing a link between extrinsic and intrinsic apoptotic pathways. Consistently, sequential treatment with SGI-110 and ASTX660 triggered loss of mitochondrial membrane potential (MMP) and BAX activation, which contributes to cell death as BAX silencing significantly protected from SGI-110/ASTX660-mediated apoptosis. Together, these events culminated in activation of caspases-3/-7, nuclear fragmentation and cell death. In conclusion, SGI-110 and ASTX660 cooperatively induced apoptosis in AML cells by engaging extrinsic and intrinsic apoptosis pathways, highlighting the therapeutic potential of this combination for AML.

2019-10-03 | GSE138322 | GEO

Integrated clinical and genomic evaluation of guadecitabine (SGI-110) in peripheral T-cell lymphoma [CRISPR screen]

Project description:Investigation of epigenetic regulators that module hypomethylating agent response in T-cell lymphoma.

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Phase I/II Study of SGI-110 With Irinotecan Versus Regorafenib or TAS-102 in Metastatic Colorectal Cancer

Project description:This is a phase I/II study of the combination of Guadecitabine (SGI-110) and previously treated metastatic colorectal cancer patients. This study will be conducted in two components. First, patients will be enrolled in a phase I study of SGI-110 combined with irinotecan in a standard 3+3 design. After the maximum tolerated dose (MTD) is determined, patients will subsequently be enrolled in a 2:1 randomized phase II study of SGI-110 and irinotecan versus the standard of care regorafenib or Lonsurf (TAS-102).

| 2148118 | ecrin-mdr-crc

Effects of SGI-110 on A2780 ovarian cancer xenografts

Project description:Genome-wide DNA methylation profiles of SGI-110-treated ovarian cancer xenografts were obtained using next generation Illumina Infinium 450k assay which includes over 450,000 GpG sites. DNA from 6 samples were hybridized to the Illumina's Infinium HumanMethylation 450 BeadChip

2014-10-02 | E-GEOD-55613 | biostudies-arrayexpress

Effects of SGI-110 on A2780 ovarian cancer xenografts

2014-10-02 | GSE55613 | GEO

Gene expression profiling of SGI-110-treated MDA-MB-231 cells

Project description:In this study we analyse the effect og DNMT inhibitor SGI-110 on the gene expression of MDA-MB-231 cells

2020-12-19 | GSE163468 | GEO