Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Gene Expression Analysis of Melanoma Cells Treated with 6-Thio-dG In Vitro

ABSTRACT: Telomerase promoter mutations are highly prevalent in human tumors including melanoma. Telomere transcriptional signatures are enriched in a subset of therapy-naïve melanomas associated with worse overall survival, in BRAF-mutant intrinsically resistant melanoma cells that evade MAPK inhibitors (MAPKi), as well as in a subset of post-treatment tumor biopsies derived from patients who have disease progression on MAPKi or the immune checkpoint inhibitors, anti-CTLA-4 or anti-PD1. We demonstrate the efficacy of a telomerase-directed nucleoside, 6-thio-2'-deoxyguanosine (6-thio-dG) that results in telomere dysfunction and cell death in various models of therapy-resistant cells. Furthermore, 6-thio-dG significantly inhibits tumor growth of primary tumor biopsy cultures derived from patients who had disease progression on multiple therapies including anti-CTLA-4 or anti-PD1.

ORGANISM(S): Homo sapiens

PROVIDER: GSE99552 | GEO | 2017/06/02

SECONDARY ACCESSION(S): PRJNA388966

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Telomerase-mediated Strategy for Overcoming Non-Small Cell Lung Cancer Targeted Therapy and Multi-drug Chemotherapy Resistance

Project description:Standard and targeted therapies almost universally fail due to tumor heterogeneity/plasticity leading to intrinsic or acquired drug resistance. We used the telomerase substrate precursor 6-thio-2’-deoxyguanosine (6-thio-dG) to target telomerase-expressing targeted therapy and platin-doublet chemotherapy resistant cells. We observed that erlotinib, paclitaxel/carboplatin and gemcitabine/cisplatin resistant cells are sensitive to 6-thio-dG in xenograft, syngeneic immunocompetent and genetically engineered mouse models. We also show sensitivity to 6-thio-dG on a large panel of non-small cell lung cancer cell lines (73 of 77). The 4 resistant NSCLC lines clustered together, providing a molecular signature for patients that may not respond to 6-thio-dG. We find SLC43A3 as a top candidate in this molecular signature. Thus, 6-thio-dG may prolong disease control of therapy-resistant lung cancer patients.

2018-01-30 | GSE109821 | GEO

Digital Spatial Profiling of immuno-oncology proteins in mouse hepatocellular carcinoma xenograft treated with THIO-based combination immune therapie

Project description:THIO (6-thio-dG) is a nucleoside analog that induces telomeric DNA damage and triggers activation of anti-tumor immunity in several cancer types such as lung and colorectal cancers. To evaluate its effect in hepatocellular carcinoma (HCC), THIO in combination with the current standard care first-line therapy for advanced HCC, anti-PD-L1 and anti-analyze, was tested in immunocompetent mice subcutaneously implanted with syngeneic HCC cell line (Hep55.1c). Formalin-fixed paraffin-embedded (FFPE) tumor tissues were collected after the treatment, and therapeutic modulations of the tumor immune landscape were assessed with Digital Spatial Profiling of 38 immuno-oncology-related proteins in region of interest (ROI) and intra-ROI segments enriched for T cells, other leukocytes, and HCC/stromal cells.

2023-06-07 | GSE219108 | GEO

Exploring the Effect and Mechanisms of Telomerase Inhibition as A Novel Therapeutic Strategy for Glioma

Project description:The obejctive of this study is to establish the therapeutic role of 6-thio-dG for gliomas in vitro and in vivo and to elucidate the anti-tumor mechanisms of 6-thio-dG in glioma cells. And the ultimate goal of this proposal is to demonstrate the potential of 6-thio-dG as a novel strategy for primary and recurrent glioma.

2021-09-13 | GSE160619 | GEO

Exploring the Effect and Mechanisms of Telomerase Inhibition as A Novel Therapeutic Strategy for Glioma [2224, DBTGR-05MG, A172]

2021-09-13 | GSE180874 | GEO

mRNA expressions in pre-treatment melanomas undergoing anti-PD-1 checkpoint inhibition therapy

Project description:PD-1 immune checkpoint blockade provides significant clinical benefits for cancer patients. However, factors influencing innate sensitivity remain incompletely catalogued. We analyzed the somatic mutanomes and transcriptomes of pretreatment melanoma biopsies. Mutations in cell adhesion genes and the DNA repair gene BRCA2 were enriched in responding tumors, and a high mutational load associated with improved survival. Innately resistant tumors displayed frequent transcriptomic up-expression of genes that enriched for mesenchymal transition, cell adhesion, ECM organization, wound-healing and angiogenesis. The transcriptomes of innate resistance also enriched for signatures indicating up-regulation of these processes. Notably, MAPK-targeted therapy (MAPKi) induced similar signatures in melanoma, suggesting that a form of MAPKi resistance mediates cross-resistance to anti-PD-1 therapy. Co-enrichment of IPRIM (Innate anti-PD-1 Resistance Induced by MAPKi) signatures defined a transcriptomic subset across advanced cancers, suggesting that attenuating processes underlying these signatures may augment anti-PD1 responses. Thus, multi-factorial determinants influence anti-PD-1 patterns in melanoma.

2016-03-18 | GSE78220 | GEO

Assessing the Tolerance and Clinical Benefit of feCAl tranSplantation in patientS With melanOma

Project description:Recent studies suggest that patients with metastatic melanoma whose gut microbiome is colonized by eubiotic bacteria have a stronger anti-cancer response to anti CTLA-4 and anti PD1. The hypothesis of this research is that a pooled standardized fecal microbiome transfer (FMT) will shift melanoma patients’ gut microbiome towards a composition close to that associated with a better response, and will therefore increase the response to a combination of anti CTLA-4 and anti PD1, without affecting the safety of these drugs. The present trial is the first randomized trial of FMT in patients with unresectable or metastatic melanoma. It will include patients who have neither been exposed to anti CTLA-4 nor anti PD1 or PDL-1, prior to inclusion in the study. The pooled standardized fecal microbiome transfer administered in this study is an experimental drug MaaT013, a microbiome restoration biotherapeutic, produced by MaaT Pharma, and composed of pooled-donor, full-ecosystem intestinal microbiome. The MaaT013 product has a standardized richness (in number of species present) higher than a product obtained from a mono donor (455 species approximately against 274 on average) and contains bacteria species (mentioned in the rationale) associated with better response to anti- CTLA-4 and anti PD1.

| 2385375 | ecrin-mdr-crc

Whole Exome Predictors Immune Checkpoint Therapy Response in Renal Cell Carcinoma

Project description:<p>Immune checkpoint therapies, including monoclonal antibodies to programmed cell death-1 (PD-1) and cytotoxic % lymphocyte associated protein-4 (CTLA-4), yield durable clinical responses across many tumor types, including metastatic melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). However, predictors of response to these therapies in RCC are still unknown. Genomic characterization of large clinical cohorts of patients treated with anti-CTLA-4 and anti-PD-1 agents in melanoma and NSCLC have suggested that high mutational burden, high neoantigen burden, and high expression of certain genes in pre-treatment tumors may be associated with patient response to these therapies. In this study, we sought to investigate genomic predictors of response to anti-PD1 therapy in metastatic RCC in two independent clinical cohorts using whole exome and whole transcriptome sequencing.</p>

| phs001493 | dbGaP

Disruption of ZC3H15 Compromises Telomere Length Maintenance by Sequestering Telomerase within Cajal bodies

Project description:Telomere homeostasis, crucial for various biological processes, relies on telomerase activity. We identified ZC3H15 as a novel telomerase-interacting protein. Its deletion unexpectedly increased telomerase activity but led to shortened telomeres and cellular senescence. ZC3H15 interacts with telomerase and itself, regulating telomerase activity in an RNA-dependent manner. Proximity labeling showed ZC3H15's interaction with proteins involved in organelle assembly and RNA processes. Loss of ZC3H15 sequestered TERC in the Cajal body, reducing telomerase recruitment to telomeres during S phase. These findings unveil ZC3H15's role in telomere dynamics and cellular senescence, suggesting its potential as a target for cancer therapy or anti-aging interventions.

2024-05-06 | PXD052036 |

Supplementation with α-ketoglutarate improved the efficacy of anti-PD1 melanoma treatment through epigenetic modulation of PD-L1

Project description:Patients with advanced melanoma have shown an improved outlook after receiving anti-PD1 therapy, but the low response rate restricts clinical benefit; therefore, enhancing anti-PD1 therapy efficacy remains a major challenge. Here, our findings show significantly higher abundance of α-KG in healthy controls, anti-PD1-sensitive melanoma-bearing mice, and anti-PD1-sensitive melanoma patients; moreover, supplementation with α-KG enhanced the efficacy of anti-PD1 immunotherapy and increased PD-L1 expression in melanomas via STAT1/3. We also found that supplementation with α-KG significantly increased methylcytosine dioxygenase TET2/3, which led to an increased 5-hydroxymethylcytosine (5-hmC) level in the PD-L1 promoter. As a consequence, STAT1/3 had been recognized and stabilized in PD-L1 promoter to upregulate PD-L1 expression. Importantly, single-cell sequencing of preclinical samples and analysis of clinical data revealed that the TET2/3-STAT1/3-CD274 signaling was associated with sensitivity to anti-PD1 treatment in melanoma. Taken together, we provide a novel insight into α-KG's function in melanoma anti-PD1 treatment and supplement of α-KG is a novel promising strategy to improve the efficacy of anti-PD1 therapy.

2023-03-08 | GSE223110 | GEO

RNAseq of immune features in melanoma patients

Project description:RNAseq data from tumors obtained from melanoma patients with advanced disease and treated with anti-PD1 inhibitors.

2022-12-31 | E-MTAB-11729 | biostudies-arrayexpress