HYPERMUTATION AND MALIGNANT PROGRESSION IN LOW-GRADE GLIOMA PATIENTS
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ABSTRACT:
PROVIDER: EGAS00001002368 | EGA |
REPOSITORIES: EGA
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Project description:In this study, MMRd metastatic colorectal cancer (mCRC) patients who failed standard therapies will undergo treatment with pembrolizumab, while RAS-extended mutated MMR-proficient mCRC patients will be tested for o6-methylguanine-DNA-methyltransferase (MGMT) expression (IHC) and then for MGMT promoter methylation. MGMT IHC-negative, promoter methylation positive patients will be treated with temozolomide (TMZ). Patients progressing under temozolomide will be tested for tumor mutational burden (TMB) and proceed to pembrolizumab if TMB is > 20 mutations/Mb. The primary study hypothesis is that tumors with acquired resistance to temozolomide become hypermutated and are sensitive to pembrolizumab.
| 2272487 | ecrin-mdr-crc
Project description:Ribba2012 - Low-grade gliomas, tumour growth inhibition model
Using longitudinal mean tumour diameter (MTD) data, this model describe the size evolution of low-grade glioma (LGG) in patients treated with chemotherapy or radiotherapy.
This model is described in the article:
A tumour growth inhibition model for low-grade glioma treated with chemotherapy or radiotherapy
Ribba B, Kaloshi G, Peyre M, Ricard D, Calvez V, Tod M, Cajavec-Bernard B, Idbaih A, Psimaras D, Dainese L, Pallud J, Cartalat-Carel S, Delattre JY, Honnorat J, Grenier E, Ducray F.
Clin. Cancer Res. 2012 Sep; 18(18): 5071-5080
Abstract:
PURPOSE: To develop a tumor growth inhibition model for adult diffuse low-grade gliomas (LGG) able to describe tumor size evolution in patients treated with chemotherapy or radiotherapy.
EXPERIMENTAL DESIGN: Using longitudinal mean tumor diameter (MTD) data from 21 patients treated with first-line procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea, and vincristine (PCV) chemotherapy, we formulated a model consisting of a system of differential equations, incorporating tumor-specific and treatment-related parameters that reflect the response of proliferative and quiescent tumor tissue to treatment. The model was then applied to the analysis of longitudinal tumor size data in 24 patients treated with first-line temozolomide (TMZ) chemotherapy and in 25 patients treated with first-line radiotherapy.
RESULTS: The model successfully described the MTD dynamics of LGG before, during, and after PCV chemotherapy. Using the same model structure, we were also able to successfully describe the MTD dynamics in LGG patients treated with TMZ chemotherapy or radiotherapy. Tumor-specific parameters were found to be consistent across the three treatment modalities. The model is robust to sensitivity analysis, and preliminary results suggest that it can predict treatment response on the basis of pretreatment tumor size data.
CONCLUSIONS: Using MTD data, we propose a tumor growth inhibition model able to describe LGG tumor size evolution in patients treated with chemotherapy or radiotherapy. In the future, this model might be used to predict treatment efficacy in LGG patients and could constitute a rational tool to conceive more effective chemotherapy schedules.
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2024-09-02 | BIOMD0000000521 | BioModels
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.
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Project description:Treatment modalities for patients with low grade glioma (LGG) WHO grade II are controversial. Overall survival ranges from 2 to over 15 years depending on molecular and clinical factors. Hence, risk adjusted treatments are required to preserve cognitive function and quality of life. We aim at identifying mechanisms and associated molecular markers predicting benefit from radiotherapy (RT) or temozolomide (TMZ) on progression free survival in 120 isocitrate dehydrogenase 1 or 2 (IDHmt) mutant LGG treated in the randomized phase III trial EORTC 22033. IDH mutations, the characteristic hallmark of LGG, are associated with a CpG island methylator phenotype (CIMP). Given the genotoxic treatments in this study we determined the DNA methylome of DNA damage response (DDR) genes and assessed the association with progression free survival (PFS). We identified 62 functional CpGs corresponding to 24 of 410 DDR genes in the multidimensional LGG dataset from The Cancer Genome Atlas. Despite the low-powered study, the simulations suggested that seven CpGs, associated with 4 genes could be predictive for PFS in EORTC 22033. Most interestingly, two of the CpGs correspond to MGMT and consisted of the 2 probes used in the MGMT-STP27 classifier. The extent of methylation was predictive for PFS in the TMZ, but not the RT arm. LGG IDHmt and 1p and 19q codeleted that overlap largely with oligodendroglioma displayed a higher extent of MGMT methylation than the IDHmt non-codeleted tumors based on several independent LGG datasets. This is consistent with a better PFS of codeleted patients in the TMZ arm as compared to the non-codeleted patients, while no difference was observed in the RT-arm.
2018-01-31 | GSE104293 | GEO
Project description:Tumor recurrence following treatment is the major cause of mortality for glioblastoma multiforme (GBM) patients. Thus, insights on the evolutionary process at recurrence are critical for improved patient care. Here, we describe our genomic analyses of 38 GBM patients with the initial and recurrent tumor specimens for each individual. A substantial divergence in the landscape of driver alterations was associated with distant appearance of a recurrent tumor from the initial tumor, suggesting that the genomic profile of the initial tumor can mislead targeted therapies for the distally recurred tumor. In addition, in contrast to IDH1-mutated gliomas, IDH1-wild-type primary GBMs rarely developed hypermutation following temozolomide (TMZ) treatment, indicating low risk of TMZ-induced hypermutation for these patients under the standard regimen.
| EGAS00001001041 | EGA
Project description:Glioblastoma (GBM) is the most common lethal primary brain cancer in adults. Despite treatment regimens including surgical resection, radiotherapy, and temozolomide (TMZ) chemotherapy, growth of residual tumor leads to therapy resistance and death. At recurrence, a quarter to a third of all gliomas have hypermutated genomes 5, with mutational burdens orders of magnitude greater than in normal tissue. Here, we quantified the mutational landscape progression in a patient’s primary and recurrent GBM, and uncovered Cas9-targetable repeat elements. We show that CRISPR-mediated targeting of highly repetitive loci enables rapid elimination of GBM cells, an approach we term “Genome Shredding”. Importantly, in the patient’s recurrent GBM, we identified unique repeat sequences with TMZ mutational signature and demonstrate that their CRISPR targeting enables cancer-specific cell ablation. “Cancer Shredding” leverages the non-coding genome and therapy-induced mutational signatures for targeted GBM cell depletion and provides an innovative paradigm to develop treatments for hypermutated glioma.
2023-10-05 | GSE244497 | GEO
Project description:Tumor recurrence following a standard treatment is the major cause of mortality for glioblastoma (GBM) patients. However, insights on the evolutionary process of the tumor have been limited due to the lack of longitudinally sampled cases. Here, we describe our genomic analyses of 38 GBM patients with pre- and post-treatment samples for each individual (78 tumor samples in total; aCGH data were obtained for 36 among the 78). A substantial shift in the landscape of driver alterations was associated with distant appearances of the recurrent tumors from the initial tumor, suggesting that the genomic profile of an initial tumor can mislead targeted therapies for the distant recurrent tumor. In addition, in contrast to the previous work on IDH1-R132H low-grade gliomas, our GBM patients rarely developed hypermutation following the standard treatment, supporting the safety of temozolomide for IDH1-wild type, primary GBMs under the current standard regimen.
2015-10-06 | GSE63035 | GEO
Project description:Temozolomide (TMZ) resistance may contribute to the treatment failure in patients with glioblastoma (GBM). Hence, understanding the underlying mechanisms and developing effective strategies against TMZ resistance are highly desired in the clinic. long non-coding RNAs (lncRNAs) have emerged as new regulatory molecules with diverse functions in biological processes and been deregulated in many pathologies, involved in the therapeutic resistance. It is urgent to elucidate the underlying lncRNA-based mechanisms of TMZ resistance in GBM patients.
2019-04-12 | GSE113510 | GEO
Project description:Glioblastoma (GBM) carries a dismal prognosis largely due to acquired resistance to the standard treatment, which incorporates the chemotherapy temozolomide (TMZ). Inhibiting the proteasomal pathway is an emerging strategy, where combination treatments are under clinical investigation. We hypothesized that pre-treatment of GBM with bortezomib (BTZ) might sensitize glioblastoma to TMZ by abolishing autophagy survival signals to augment DNA damage and apoptosis. P3 patient-derived GBM cells as well as the tumor cell lines U87, HF66, A172 and T98G were investigated for clonogenic survival after single or combined treatment with TMZ and BTZ in vitro. Change in autophagic flux was examined after experimental treatments in conjunction with inhibitors of autophagy or downregulation of autophagy-related genes -5 and -7 (ATG5 and ATG7, respectively). Autophagic flux was increased in TMZ-resistant P3 and T98G cells as indicated by diminished levels of the autophagy markers LC3A/B-II and increased STX17, higher protein degradation and no formation of p62 bodies nor induction of apoptosis. In contrast, BTZ treatment attenuated ULK1 mRNA, total and phosphorylated protein, and accumulated LC3A/B-II, p62 and autophagosomes analogously to Baf1 and chloroquine autophagy inhibitors. These autophagosomes did not fuse with lysosomes, indicated by attenuated STX17 expression and reduced degradation of long-lived proteins, which culminated in enhanced caspase-3/8 dependent apoptosis. BTZ synergistically enhanced TMZ efficacy, attenuated tumor cell proliferation, triggered ATM/Chk2 DNA damage signalling to further augment caspase-3/8 mediated apoptosis in the TMZ resistant P3 and T98G GBM cells. Genetic or chemical inhibition of autophagy (with CRISPR-CAs9 ATG5, ATG7 shRNA, MRT68921 or VPS34-IN1) abrogated BTZ efficacy and rescued BTZ+ TMZ treated GBM cells from death. We conclude that Bortezomib ameliorates temozolomide resistance through ATG5/7-dependent abrogated autophagic flux and may be amenable in combination treatment regimens for TMZ refractory GBM patients.
2023-03-10 | PXD021828 | Pride
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