Ontology highlight
ABSTRACT:
PROVIDER: PRJNA956444 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24298940_1.fastq.gz | Fastqsanger.gz | |||
| SRR24298940_2.fastq.gz | Fastqsanger.gz | |||
| SRR24298941_1.fastq.gz | Fastqsanger.gz | |||
| SRR24298941_2.fastq.gz | Fastqsanger.gz | |||
| SRR24298942_1.fastq.gz | Fastqsanger.gz |
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Project description:This is a Phase II, non-randomized, open-label study to evaluate temozolomide in combination with olaparib in patients with MGMT promoter hypermethylated advanced colorectal cancer.
| 2322183 | ecrin-mdr-crc
Project description:Temozolomide (TMZ) is an important first-line treatment for glioblastoma (GBM), but there are limitations to TMZ response in terms of durability and dependence on the promoter methylation status of the DNA repair gene O6-methylguanine DNA methyltransferase (MGMT). MGMT-promoter-hypermethylated (MGMT-M) GBMs are more sensitive to TMZ than MGMT-promoter-hypomethylated (MGMT-UM) GBMs. Moreover, TMZ resistance is inevitable even in TMZ-sensitive MGMT-M GBMs. Hence, epigenetic reprogramming strategies are desperately needed in order to enhance TMZ response in both MGMT-M and MGMT-UM GBMs. In this study, we present novel evidence that the epigenetic reactivation of Tumor Suppressor Candidate 3 (TUSC3) can reprogram sensitivity of GBM stem cells (GSCs) to TMZ irrespective of MGMT promoter methylation status. Interrogation of TCGA patient GBM datasets confirmed TUSC3 promoter regulation of TUSC3 expression and also revealed a strong positive correlation between TUSC3 expression and GBM patient survival. Using a combination of loss-of-function, gain-of-function and rescue studies, we demonstrate that TUSC3 reactivation is associated with enhanced TMZ response in both MGMT-M and MGMT-UM GSCs. Further, we provide novel evidence that the demethylating agent 5-Azacitidine (5-Aza) reactivates TUSC3 expression in MGMT-M GSCs, whereas the combination of 5-Aza and MGMT inhibitor Lomeguatrib is necessary for TUSC3 reactivation in MGMT-UM GSCs. Lastly, we propose a pharmacological epigenetic reactivation strategy involving TUSC3 that leads to significantly prolonged survival in MGMT-M and MGMT-UM orthotopic GSCs models. Collectively, our findings provide a framework and rationale to further explore TUSC3-mediated epigenetic reprogramming strategies that could enhance TMZ sensitivity and outcomes in GBM. Mechanistic and translational evidence gained from such studies could contribute towards optimal design of impactful trials for MGMT-UM GBMs that currently do not have good treatment options.
2024-11-26 | GSE282886 | GEO
Project description:Temozolomide (TMZ) has been used for the treatment of glioblastoma (GBM) since last decade, but its treatment benefits are limited by acquired resistance, a process that remains incompletely understood. Here we report that a novel enhancer, located between the promoters of Ki67 and O6-methylguanine-DNA-methyltransferase (MGMT) genes, is activated in TMZ-resistant patient-derived xenograft (PDX) lines as well as in recurrent tumor samples. Activation of the enhancer correlates with increased MGMT expression, a major known mechanism for TMZ resistance. We show that forced activation of the enhancer in cell lines with low MGMT expression results in elevated MGMT expression. Deletion of this enhancer in cell lines with high MGMT expression leads to reduced levels of MGMT and Ki67, increased TMZ sensitivity and impaired proliferation. Together, these studies uncover a novel mechanism that regulates MGMT expression, confers TMZ resistance and potentially regulates tumor proliferation.
2018-07-13 | GSE113816 | GEO
Project description:Acquired resistance of temozolomide (TMZ) is one of the major obstacle of glioblastoma clinical treatment and the mechanism of TMZ resistance is still not very clear. In the presented research we show that deletion of rs16906252-associated MGMT enhancer in MGMT negative glioma cells induced increase sensitivity to temozolomide and combination of RNA-seq and Capture HiC identified several long-range target genes of rs16906252-associated MGMT enhancer. In addition, HiC data shows alterations of chromatin structures in glioma cells survived from high-dosage TMZ treatment and changes of TADs influence rs16906252-associated MGMT enhancer’s long-range regulations of target genes. Our study suggests rs16906252-associated MGMT enhancer regulates glioma cells’ TMZ sensitivity by long-range regulations of several target genes, which is a novel mechanism of regulation of TMZ sensitivity in glioma cells.
2020-04-02 | GSE129476 | GEO
Project description:Microsatellite-stable (MSS) colorectal cancers (CRC) are largely unresponsive to immune checkpoint inhibition (ICI). The MAYA trial used temozolomide (TMZ) in MGMT-silenced MSS mCRC, hypothesizing that TMZ-induced hypermutation could sensitize tumors to ICI; the primary endpoint was met, showing durable responses with TMZ plus ipilimumab and nivolumab. We perform integrated spatial, transcriptomic, and immune profiling of longitudinal tumor and blood samples from patients treated on the MAYA trial. Post-TMZ increases in tumor mutational burden associate with improved progression-free survival. Spatial profiling demonstrates that clinical benefit is greatest in permissive tumor microenvironments. Responders exhibit enrichment of cytotoxic T cells across tumor and stromal compartments, whereas non-responders display heterogeneous cellular neighborhoods, with fibroblasts in close spatial proximity to T cells, consistent with barriers to immune mediated clearance. Longitudinal peripheral immune profiling shows that early upregulation of TIGIT and PD-1 following TMZ exposure predicts resistance. Together, these findings indicate that both mutational evolution and spatial immune architecture contribute to immune sensitization in MGMT-silenced MSS CRC.
2026-03-27 | GSE326101 | GEO
Project description:Glioblastoma (GBM) is an aggressive brain cancer that is notoriously resistant to chemotherapy, particularly to Temozolomide (TMZ). In this study, we examined a patient-derived TMZ-resistant GBM cell line and assessed the effects of the PARP inhibitor Olaparib. We observed that while Olaparib exhibited significant tumor inhibition, its required dosage exceeded clinically acceptable levels. Transcriptomic analysis revealed a notable upregulation of nicotinamide phosphoribosyltransferase (NAMPT) in the surviving tumor cells, suggesting that increased intracellular NAD+ levels contributed to their resistance against both Olaparib and TMZ. By optimizing the dosages of Olaparib and FK866, a NAMPT inhibitor, we were able to develop a combination therapy that effectively killed TMZ-resistant GBM cells while adhering to clinically applicable pharmacodynamic and toxicological standards for each drug. This combination was also tested across other TMZ-resistant cell lines and 3D organoids, showing promising potential for clinical application. Additionally, through profiling plasma-detectable circRNA species from the combination treatment, we identified circPTTG1IP as a potential biomarker with negative predictive value. Further analysis indicated that circPTTG1IP might regulate NAMPT expression and NAD+ levels, potentially through its interaction with miRNAs targeting NAMPT. This research provides insights into a novel therapeutic strategy for overcoming TMZ resistance in GBM.
2025-06-02 | GSE295766 | GEO
Project description:Patients diagnosed with glioblastoma (GBM) with sustained synthesis of the DNA repair enzyme, O6-methyl guanine DNA methytransferase (MGMT), are rendered resistant to Temozolomide (TMZ) chemotherapy. Here, we hypothesized that pretreatment with the proteasome inhibitor Bortezomib (BTZ, Velcade) might sensitize these GBM to TMZ by depleting MGMT.
2019-08-20 | PXD007193 | Pride
Project description:N6-methyladenosine (m6A) is a critical regulator of mRNA processing and function, playing roles in mRNA processing, translation, and decay. Changes in m6A status have been implicated in various cancers, including glioblastoma (GBM), where acquired chemoresistance to temozolomide (TMZ) remains a major clinical challenge. We developed cell culture models of acquired TMZ resistance in GBM and analyzed the regulation of resistance-associated genes and pathways by m6A. We find that key resistance-associated genes and pathways are regulated by m6A methylation, including MGMT, the enzyme that repairs primary TMZ-induced DNA damage. Inhibition of METTL3 with STM2457 treatment destabilizes MGMT mRNA. Intriguingly, other TMZ resistance-associated genes are similarly regulated by m6A, suggesting that METTL3 inhibition may represent a promising therapeutic approach for overcoming TMZ resistance.
2026-06-01 | GSE306559 | GEO
Project description:N6-methyladenosine (m6A) is a critical regulator of mRNA processing and function, playing roles in mRNA processing, translation, and decay. Changes in m6A status have been implicated in various cancers, including glioblastoma (GBM), where acquired chemoresistance to temozolomide (TMZ) remains a major clinical challenge. We developed cell culture models of acquired TMZ resistance in GBM and analyzed the regulation of resistance-associated genes and pathways by m6A. We find that key resistance-associated genes and pathways are regulated by m6A methylation, including MGMT, the enzyme that repairs primary TMZ-induced DNA damage. Inhibition of METTL3 with STM2457 treatment destabilizes MGMT mRNA. Intriguingly, other TMZ resistance-associated genes are similarly regulated by m6A, suggesting that METTL3 inhibition may represent a promising therapeutic approach for overcoming TMZ resistance.
2026-06-01 | GSE306560 | GEO
Project description:Temozolomide (TMZ) increases the overall survival of patients with glioblastoma (GBM), but its role in the clinical management of diffuse low-grade gliomas (LGG) is still being defined. DNA hypermethylation of the O 6 -methylguanine-DNA methyltransferase (MGMT) promoter is associated with an improved response to TMZ treatment, while inactivation of the DNA mismatch repair (MMR) pathway is associated with therapeutic resistance and TMZ-induced mutagenesis. We previously demonstrated that TMZ treatment of LGG induces driver mutations in the RB and AKT-mTOR pathways, which may drive malignant progression to secondary GBM. To better understand the mechanisms underlying TMZ-induced mutagenesis and malignant progression, we explored the evolution of MGMT methylation and genetic alterations affecting MMR genes in a cohort of 34 treatment-naïve LGGs and their recurrences. Recurrences with TMZ-associated hypermutation had increased MGMT methylation compared to their untreated initial tumors and higher overall MGMT methylation compared to TMZ-treated non-hypermutated recurrences. A TMZ-associated mutation in one or more MMR genes was observed in five out of six TMZ-treated hypermutated recurrences. In two cases, pre-existing heterozygous deletions encompassing MGMT, or an MMR gene, were followed by TMZ-associated mutations in one of the genes of interest. These results suggest that tumor cells with methylated MGMT may undergo positive selection during TMZ treatment in the context of MMR deficiency.
| EGAS00001001179 | EGA