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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE180874 | GEO | 2021/09/13

REPOSITORIES: GEO

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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

Inhibition of Mitochondrial Biogenesis and Tumor Bioenergetics for Glioma [A172 and U87MG]

Project description:The obejctive of this study is to To establish the therapeutic role of Gamitrinib for gliomas in vitro and in vivo and to elucidate the anti-tumor mechanism of Gamitrinib in glioma cells. And the ultimate goal of this proposal is to identify a novel Gamitrinib-based combination therapy for primary and recurrent gliomas.

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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.

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Inhibition of Mitochondrial Biogenesis and Tumor Bioenergetics for Glioma

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

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

| PRJNA749803 | ENA

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

Project description: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.

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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.

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Metabolic changes related to the IDH1 mutation in gliomas preserve TCA-cycle activity: an investigation at the protein level

Project description:The discovery of the IDH1 R132H (IDH1 mut) mutation in low-grade glioma and the associated change in function of the IDH1 enzyme has increased the interest in glioma metabolism. In an earlier study, we found that changes in expression of genes involved in the aerobic glycolysis and the TCA-cycle are associated with IDH1 mut. Here we apply proteomics to FFPE samples of diffuse gliomas with or without IDH1 mutations, in order to map changes in protein levels associated with this mutation. We observed significant changes in the enzyme abundance associated with aerobic glycolysis, glutamate metabolism and the TCA-cycle in IDH1 mut gliomas. Specifically, the enzymes involved in the metabolism of glutamate, lactate and enzymes involved in the conversion of α-ketoglutarate were increased in IDH1 mut gliomas. In addition, the bicarbonate transporter (SLC4A4) was increased in IDH1 mut gliomas, supporting the idea that a mechanism preventing intracellular acidification is active. We also found that enzymes that convert proline, valine, leucine and isoleucine into glutamate were increased in IDH1 mut glioma. We conclude that in IDH1 mut glioma metabolism is rewired (increased input of lactate and glutamate) to preserve TCA cycle activity in IDH1 mut gliomas.

2020-03-09 | PXD016697 | Pride

Metabolic changes related to the IDH1 mutation in gliomas preserve TCA-cycle activity: an investigation at the protein level

2020-03-09 | PXD016698 | Pride

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

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

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