9 results on '"Estevez-Cebrero M"'
Search Results
2. P04.09 MicroRNA analysis of the invasive margin of Glioblastoma reveals druggable therapeutic targets in lipid metabolism pathways
- Author
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Alfardus, H, primary, de los Angeles Estevez Cebrero, M, additional, Rawlinson, J, additional, Lourdusamy, A, additional, Grundy, R, additional, McIntyre, A, additional, and Smith, S, additional
- Published
- 2018
- Full Text
- View/download PDF
3. P08.12 The efficacy and mechanism of therapeutic stimulating electrodes in Glioblastoma multiforme
- Author
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Branter, J., primary and Estevez Cebrero, M., additional
- Published
- 2016
- Full Text
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4. P08.07 MicroRNA regulation of intratumour metabolic heterogeneity in Glioblastoma Multiforme
- Author
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Alfardus, H., primary and Estevez-Cebrero, M., additional
- Published
- 2016
- Full Text
- View/download PDF
5. Characterisation of Expression the Arginine Pathway Enzymes in Childhood Brain Tumours to Determine Susceptibility to Therapeutic Arginine Depletion.
- Author
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Bishop E, Dimitrova M, Froggatt A, Estevez-Cebrero M, Storer LCD, Mussai F, Paine S, Grundy RG, and Dandapani M
- Subjects
- Adult, Arginase genetics, Arginine, Argininosuccinate Lyase, Child, Ependymoma, Humans, Ornithine Carbamoyltransferase, Brain Neoplasms genetics, Cerebellar Neoplasms, Glioma genetics, Medulloblastoma
- Abstract
Despite significant improvements in treatment and survival in paediatric cancers, outcomes for children with brain tumours remain poor. Novel therapeutic approaches are needed to improve survival and quality of survival. Extracellular arginine dependency (auxotrophy) has been recognised in several tumours as a potential therapeutic target. This dependency is due to the inability of cancer cells to recycle or synthesise intracellular arginine through the urea cycle pathway compared to normal cells. Whilst adult glioblastoma exhibits this dependency, the expression of the arginine pathway enzymes has not been delineated in paediatric brain tumours. We used immunohistochemical (IHC) methods to stain for arginine pathway enzymes in paediatric high-grade glioma (pHGG), low-grade glioma (pLGG), ependymoma (EPN), and medulloblastoma (MB) tumour tissue microarrays (TMAs). The antibodies detected protein expression of the metaboliser arginase (Arg1 and Arg2); recycling enzymes ornithine transcarbamoylase (OTC), argininosuccinate synthetase (ASS1), and argininosuccinate lyase (ASL); and the transporter SLC7A1. Deficiency of OTC, ASS1, and ASL was seen in 87.5%, 94%, and 79% of pHGG samples, respectively, consistent with an auxotrophic signature. Similar result was obtained in pLGG with 96%, 93%, and 91% of tumours being deficient in ASL, ASS1, and OTC, respectively. 79%, 88%, and 85% of MB cases were ASL, ASS1, and OTC deficient whilst ASL and OTC were deficient in 57% and 91% of EPN samples. All tumour types highly expressed SLC7A1 and Arginase, with Arg2 being the main isoform, demonstrating that they could transport and utilise arginine. Our results show that pHGG, pLGG, EPN, and MB demonstrate arginine auxotrophy based on protein expression and are likely to be susceptible to arginine depletion. Pegylated arginase (BCT-100) is currently in phase I/II trials in relapsed pHGG. Our results suggest that therapeutic arginine depletion may also be useful in other tumour types and IHC analysis of patient tumour samples could help identify patients likely to benefit from this treatment., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Eleanor Bishop et al.)
- Published
- 2022
- Full Text
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6. Genome-Wide Expression and Anti-Proliferative Effects of Electric Field Therapy on Pediatric and Adult Brain Tumors.
- Author
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Branter J, Estevez-Cebrero M, Diksin M, Griffin M, Castellanos-Uribe M, May S, Rahman R, Grundy R, Basu S, and Smith S
- Subjects
- Cell Line, Tumor, Cell Survival genetics, Child, Combined Modality Therapy methods, Electric Stimulation Therapy methods, Endoplasmic Reticulum Stress genetics, G2 Phase genetics, Glioblastoma genetics, Glioblastoma therapy, Humans, Mitochondria genetics, Resting Phase, Cell Cycle genetics, Brain pathology, Brain Neoplasms genetics, Brain Neoplasms therapy, Cell Proliferation genetics
- Abstract
The lack of treatment options for high-grade brain tumors has led to searches for alternative therapeutic modalities. Electrical field therapy is one such area. The Optune™ system is an FDA-approved novel device that delivers continuous alternating electric fields (tumor treating fields-TTFields) to the patient for the treatment of primary and recurrent Glioblastoma multiforme (GBM). Various mechanisms have been proposed to explain the effects of TTFields and other electrical therapies. Here, we present the first study of genome-wide expression of electrotherapy (delivered via TTFields or Deep Brain Stimulation (DBS)) on brain tumor cell lines. The effects of electric fields were assessed through gene expression arrays and combinational effects with chemotherapies. We observed that both DBS and TTFields significantly affected brain tumor cell line viability, with DBS promoting G0-phase accumulation and TTFields promoting G2-phase accumulation. Both treatments may be used to augment the efficacy of chemotherapy in vitro. Genome-wide expression assessment demonstrated significant overlap between the different electrical treatments, suggesting novel interactions with mitochondrial functioning and promoting endoplasmic reticulum stress. We demonstrate the in vitro efficacy of electric fields against adult and pediatric high-grade brain tumors and elucidate potential mechanisms of action for future study.
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- 2022
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7. Intratumour heterogeneity in microRNAs expression regulates glioblastoma metabolism.
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Alfardus H, de Los Angeles Estevez-Cebrero M, Rowlinson J, Aboalmaaly A, Lourdusamy A, Abdelrazig S, Ortori C, Grundy R, Kim DH, McIntyre A, and Smith S
- Subjects
- Brain Neoplasms genetics, Brain Neoplasms pathology, Cell Line, Tumor, Chromatography, Liquid methods, Computational Biology methods, Gene Expression genetics, Gene Expression Profiling methods, Genetic Heterogeneity, Glioblastoma genetics, Humans, Oligonucleotide Array Sequence Analysis methods, Tandem Mass Spectrometry methods, Transcriptome genetics, Tumor Microenvironment genetics, Gene Expression Regulation, Neoplastic genetics, Glioblastoma metabolism, MicroRNAs genetics
- Abstract
While specific microRNA (miRNA) signatures have been identified in glioblastoma (GBM), the intratumour heterogeneity in miRNA expression has not yet been characterised. In this study, we reveal significant alterations in miRNA expression across three GBM tumour regions: the core, rim, and invasive margin. Our miRNA profiling analysis showed that miR-330-5p and miR-215-5p were upregulated in the invasive margin relative to the core and the rim regions, while miR-619-5p, miR-4440 and miR-4793-3p were downregulated. Functional analysis of newly identified miRNAs suggests their involvement in regulating lipid metabolic pathways. Subsequent liquid chromatography-mass spectrometry (LC-MS) and tandem mass spectroscopy (LC-MS/MS) profiling of the intracellular metabolome and the lipidome of GBM cells with dysregulated miRNA expression confirmed the alteration in the metabolite levels associated with lipid metabolism. The identification of regional miRNA expression signatures may underlie the metabolic heterogeneity within the GBM tumour and understanding this relationship may open new avenues for the GBM treatment., (© 2021. The Author(s).)
- Published
- 2021
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8. Metabolism-based isolation of invasive glioblastoma cells with specific gene signatures and tumorigenic potential.
- Author
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Smith SJ, Rowlinson J, Estevez-Cebrero M, Onion D, Ritchie A, Clarke P, Wood K, Diksin M, Lourdusamy A, Grundy RG, and Rahman R
- Abstract
Background: Glioblastoma (GBM) is a highly aggressive brain tumor with rapid subclonal diversification, harboring molecular abnormalities that vary temporospatially, a contributor to therapy resistance. Fluorescence-guided neurosurgical resection utilizes the administration of 5-aminolevulinic acid (5-ALA) generating individually fluorescent tumor cells within a background population of non-neoplastic cells in the invasive tumor region. The aim of the study was to specifically isolate and interrogate the invasive GBM cell population using a novel 5-ALA-based method., Methods: We have isolated the critical invasive GBM cell population by developing 5-ALA-based metabolic fluorescence-activated cell sorting. This allows purification and study of invasive cells from GBM without an overwhelming background "normal brain" signal to confound data. The population was studied using RNAseq, real-time PCR, and immunohistochemistry, with gene targets functionally interrogated on proliferation and migration assays using siRNA knockdown and known drug inhibitors., Results: RNAseq analysis identifies specific genes such as SERPINE1 which is highly expressed in invasive GBM cells but at low levels in the surrounding normal brain parenchyma. siRNA knockdown and pharmacological inhibition with specific inhibitors of SERPINE1 reduced the capacity of GBM cells to invade in an in vitro assay. Rodent xenografts of 5-ALA-positive cells were established and serially transplanted, confirming tumorigenicity of the fluorescent patient-derived cells but not the 5-ALA-negative cells., Conclusions: Identification of unique molecular features in the invasive GBM population offers hope for developing more efficacious targeted therapies compared to targeting the tumor core and for isolating tumor subpopulations based upon intrinsic metabolic properties., (© The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)
- Published
- 2020
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9. Overall Survival in Malignant Glioma Is Significantly Prolonged by Neurosurgical Delivery of Etoposide and Temozolomide from a Thermo-Responsive Biodegradable Paste.
- Author
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Smith SJ, Tyler BM, Gould T, Veal GJ, Gorelick N, Rowlinson J, Serra R, Ritchie A, Berry P, Otto A, Choi J, Skuli N, Estevez-Cebrero M, Shakesheff KM, Brem H, Grundy RG, and Rahman R
- Subjects
- Animals, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cell Line, Tumor, Disease Models, Animal, Drug Delivery Systems, Drug Liberation, Etoposide pharmacokinetics, Glioma diagnosis, Glioma pathology, Humans, Nanoparticles, Polyesters, Polyethylene Glycols, Temozolomide pharmacokinetics, Treatment Outcome, Xenograft Model Antitumor Assays, Drug Carriers, Etoposide administration & dosage, Glioma mortality, Glioma therapy, Temozolomide administration & dosage
- Abstract
Purpose: High-grade glioma (HGG) treatment is limited by the inability of otherwise potentially efficacious drugs to penetrate the blood-brain barrier. We evaluate the unique intracavity delivery mode and translational potential of a blend of poly( DL -lactic acid-co-glycolic acid; PLGA) and poly(ethylene glycol; PEG) paste combining temozolomide and etoposide to treat surgically resected HGG., Experimental Design: To prolong stability of temozolomide prodrug, combined in vitro drug release was quantitatively assessed from low pH-based PLGA/PEG using advanced analytic methods. In vitro cytotoxicity was measured against a panel of HGG cell lines and patient-derived cultures using metabolic assays. In vivo safety and efficacy was evaluated using orthotopic 9L gliosarcoma allografts, previously utilized preclinically to develop Gliadel., Results: Combined etoposide and temozolomide in vitro release (22 and 7 days, respectively) was achieved from a lactic acid-based PLGA/PEG paste, used to enhance stability of temozolomide prodrug. HGG cells from central-enhanced regions were more sensitive to each compound relative to primary lines derived from the HGG-invasive margin. Both drugs retained cytotoxic capability upon release from PLGA/PEG. In vivo studies revealed a significant overall survival benefit in postsurgery 9L orthotopic gliosarcomas, treated with intracavity delivered PLGA/PEG/temozolomide/etoposide and enhanced with adjuvant radiotherapy. Long-term survivorship was observed in over half the animals with histologic confirmation of disease-free brain., Conclusions: The significant survival benefit of intracavity chemotherapy demonstrates clinical applicability of PLGA/PEG paste-mediated delivery of temozolomide and etoposide adjuvant to radiotherapy. PLGA/PEG paste offers a future platform for combination delivery of molecular targeted compounds., (©2019 American Association for Cancer Research.)
- Published
- 2019
- Full Text
- View/download PDF
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