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Setua, Sonali. "Development of targeted nanomedicine for glioblastoma therapy." Thesis, University of Cambridge, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708268.
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Kegelman, Timothy P. "MDA-9/Syntenin: From Glioblastoma Pathogenesis to Targeted Therapy." VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/4676.
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The most common malignant glioma, glioblastoma multiforme (GBM), remains an intractable tumor despite advances in therapy. Its proclivity to infiltrate surrounding brain tissue contributes greatly to its treatment failure and the grim prognosis of patients. Radiation is a staple in modern therapeutic regimens, though cells surviving radiation become more aggressive and invasive. Consequently, it is imperative to define further the cellular mechanisms that control GBM invasion and identify promising novel therapeutic targets. Melanoma differentiation associated gene-9 (MDA-9/Syntenin) is a highly conserved PDZ domain-containing scaffolding protein that promotes invasion and metastasis in human melanoma models. We show that MDA-9/Syntenin is robustly expressed in GBM cell lines and patient samples, and expression increases by tumor grade. These findings are confirmed through database analysis, which revealed MDA-9/Syntenin expression correlates with shorter survival times and patient tumors high in MDA-9/Syntenin have a worse prognosis when undergoing radiotherapy. Modulating MDA-9/Syntenin levels produced changes in invasion, angiogenesis, and signaling, indicating MDA-9/Syntenin enhances glioma pathogenesis. Overexpression of MDA-9/Syntenin enhances invasion, while knockdown inhibits invasion, migration, and anchorage-independent growth in soft agar. MDA-9/Syntenin increases activation of c-Src, P38MAPK, and NF-kB, leading to elevated MMP2 expression and IL-8 secretion. Through an orthotopic tumor model, we show that shmda-9 tumor cells formed smaller tumors and had a less invasive phenotype in vivo. Knockdown of MDA-9/Syntenin radiosensitizes GBM cells and significantly reduces post-radiation invasion gains through abrogation of radiation-induced Src and EphA2 activity. In efforts to pharmacologically inhibit MDA-9/Syntenin, we describe the effects of a novel small molecule, PDZ1i, which targets the PDZ1 domain of MDA-9/Syntenin and successfully reduces invasion gains in GBM cells following radiation. While it does not effect astrocyte radiosensitivity, PDZ1i radiosensitizes GBM cells. PDZ1i inhibits crucial GBM signaling including FAK and mutant EGFR, EGFRvIII, and can negate gains in secreted proteases, such as MMP2 and MMP9, following radiation. In a model of glioma, PDZ1i treatment combined with radiation results in less invasive tumors and extends survival. Our findings indicate that MDA-9/Syntenin is a novel and important mediator of GBM pathogenesis, and further identify it as a targetable protein that enhances radiotherapy for treatment in glioma.
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Gao, Yi. "Development of a novel hTERTC27 based cancer : gene therapy /." Click to view the E-thesis via HKUTO, 2007. http://sunzi.lib.hku.hk/HKUTO/record/B39557790.
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Frixa, Christophe. "Boronated tetraphenylporphyrins for use in boron neutron capture therapy of cancer." Thesis, University of Bath, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268747.
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Heywood, Richard Martyn. "NG2/CSPG4 promotes progression of glioblastoma multiforme by enhancing proliferation and resistance to therapy." Thesis, University of Cambridge, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.707912.
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Gao, Yi, and 高毅. "Development of a novel hTERTC27 based cancer: gene therapy." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B39557790.
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Pikhartova-Martinkova, Eva. "Combination of ellipticine chemotherapy and alpha5beta1 integrin-targeted therapy in human glioblastoma." Strasbourg, 2010. https://publication-theses.unistra.fr/restreint/theses_doctorat/2010/PIKHARTOVA-MARTINKOVA_Eva_2010.pdf.
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Les glioblastomes sont des tumeurs cérébrales agressives pour lesquelles les thérapies classiques se révèlent souvent inefficaces. Les intégrines peuvent aussi réguler l’angiogénèse, l’embryogenèse, la prolifération, la différentiation, la migration et la survie. Nous avons proposé l`intégrine α5β1 comme un cible thérapeutique pour les glioblastomes, comme elle est surexprimée dans les gliomes en fonction du grade tumoral et comme les travaux récents l`indiquent ayant un rôle central dans un réseau fonctionnel de la cellule tumoral. Les deux lignées cellulaires de glioblastome testés (U87MG et U373) ont été sensibles à l`ellipticine. Dans le contexte de la protéine p53 fonctionnelle (U87MG), l`ellipticine induit la sénescence, alors que dans U373 (p53mt), il induit l'apoptose. Les deux lignées cellulaires expriment des enzymes générant les métabolites de l'ellipticine connus pour se lier de façon covalente à l’ADN. Ensuite, nous montrons que en inhibant l'intégrine α5β1 avec ses deux ligands sélectifs (SJ749 et K34c) diminue la sénescence induite par la chimiothérapie et facilite l'apoptose dans un contexte p53 fonctionnelle. Lorsque la p53 est muté et inactif, la chimiothérapie provoque de l'apoptose p53-indépendante au lieu de la sénescence, ce qui n'a pas été améliorée par les antagonistes des intégrines. Les antagonistes de l'intégrine α5β1 modulent la p53 signalisation chimio-induite. Ce travail fournit des nouvelles preuves des avantages de la combinaison de la chimiothérapie conventionnelle avec la thérapie ciblée sur l'intégrine α5β1 sous-tendent l'importance de connaître les caractéristiques de base de la tumeur pour estimer le bénéfit de la thérapie finaleGliomas are highly aggressive and resistant brain tumors difficult to cure with conventional therapies. Therefore, targeted therapies are needed. Integrins are implicated in angiogenesis, cell proliferation, differentiation, migration and survival. We have identified the α5β1 integrin as a promising therapeutic target as its expression correlates with tumor grade and recent studies predispose it to play a key role in tumor cell functional network. Ellipticine was shown to be brain tumor specific. Its pharmacological efficiency and/or genotoxic side effects are dependent on its enzymatic activation. U87MG and U373 glioblastoma cell lines are sensitive to ellipticine. P53 plays an important role in their response to it. In the context of functional p53 (U87MG), ellipticine induced senescence, whereas in U373 (p53mt) it induced apoptosis. Both cell lines express enzymes generating ellipticine metabolites known to covalently bind to DNA. We next investigated whether blocking α5β1 integrin concomitantly with chemotherapy may impact the response to chemotherapy of human glioblastoma. Inhibiting α5β1 integrin with two selective ligands (SJ749 and K34c) decreases drug-induced senescence and facilitates cell apoptosis in a functional p53 background. When p53 is mutated and/or inactive, chemotherapy provoked cell apoptosis instead of senescence, which was not improved by integrin antagonists. Results were confirmed using multiple models. In summary, this work provides novel evidences of profitability of combining conventional chemotherapy with α5β1 integrin-targeted therapy underlying the importance of knowing basic tumor characteristics to may estimate the final therapy outcome
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Haseley, Amy M. "The Effect of the Tumor Microenvironment on Oncolytic Virus Therapy for Glioblastoma." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1350413344.
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Skog, Johan. "The quest for new improved adenovirus gene therapy vectors against glioma tumours." Doctoral thesis, Umeå : Umeå University, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-624.
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Agliardi, Giulia. "Development of a Chimeric Antigen Receptor (CAR)-based T cell therapy for glioblastoma." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/10025011/.
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High grade gliomas are aggressive brain tumours for which treatment is highly challenging due to the location within the central nervous system (CNS), which may reduce access of cytotoxic chemotherapy, and their infiltrative growth, which precludes complete surgical resection. Current treatment includes surgical removal – wherever possible - followed by radiotherapy and chemotherapy. However, recurrence is common, resulting in a survival of only 12 to 15 months after diagnosis. This highlights the need for new therapies. Chimeric antigen receptors (CARs) are synthetic molecules which combine the specificity of an antibody to the signalling domains of a T cell receptor (TCR), allowing T cells to directly recognise tumour antigens with no need for co-stimulation. CAR-T cells have shown promising responses in the treatment of haematological malignancies, inducing complete and durable responses in patients with chemo-refractory disease treated with CD19-redirected T cells. This therapeutic approach may be highly suitable for high grade gliomas as T cells have the ability to track to distant tumour sites. However, translation of this technology to solid tumours is proving more difficult, due to several challenges, including: requirement for an effective infiltration of CAR-T cells within the tumour and the immunosuppressive environment provided by solid malignancies. In this work, we developed an immunocompetent animal model of glioma, to study kinetics of migration and infiltration of CAR-T cells and the interplay between CAR-T cells, the tumour and the endogenous immune system to inform the design of T cell immunotherapy for this brain tumours. The tumour specific variant III of the epidermal growth factor receptor (EGFRvIII) – a mutation found in 30% of glioblastomas – was used as model antigen. A murine CAR was constructed based on the single chain fragment variant (ScFv) of EGFRvIII-specific antibody MR1.1 linked with a CD8 stalk to CD28-CD3ζ activation domains. A murine marker gene (truncated CD34) was co-expressed to allow for ex vivo analysis as well as firefly luciferase for in vivo tracking of CAR T-cells. The mouse glioma cell line GL261 was modified to express the mouse version of EGFRvIII and used to establish orthotopic tumours. After validation of function and specificity in vitro, efficacy of CAR-T cells was tested in vivo. Both bioluminescence imaging (BLI) and flow cytometry demonstrated that CAR T cells accumulated within the tumour in an antigen-dependent manner. MRI demonstrated that CAR T cells delayed tumour growth and increased survival. However, tumours were not consistently eradicated. Both immunohistochemistry and BLI indicated lack of long term persistence of T cells within the tumour. Analysis of tumour infiltrating lymphocytes (TILs) phenotype suggested that decreased functionality of CAR-T cells could be a result of their exhaustion in situ. We hypothesised that additional strategies were required to improve efficacy and persistence of CAR-T cells. We postulated that CAR-T cell fitness may be prolonged by: - Incorporation of 41BB as additional co-stimulatory domain in the CAR to provide a pro-survival signal. - Combination therapy with PD1 blockade to overcome T cell exhaustion (both on CAR and endogenous T cells) in situ. While the employment of third-generation CAR did not significantly improve survival and showed increased toxicity, combination therapy of CAR-T cells and PD-1 blockade promoted complete clearance of tumours resulting in long term survival. Immunohistochemistry and flow cytometry analysis suggested that combination therapy may increase persistence of CAR-T cells, leading to a more rapid and consistent tumour eradication compared to CAR-T cell administration alone. However, data presented here did not demonstrate a synergistic effect of CAR-T cell therapy and PD1 blockade, as an effect of PD1 blockade alone was also observed. Therefore, additional experiments are required to examine this further.
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Angara, Kartik Prasad. "CXCR2 Expressing Tumor Cells Drive Vascular Mimicry in Anti-angiogenic Therapy Resistant Glioblastoma." Thesis, Augusta University, 2018. http://pqdtopen.proquest.com/#viewpdf?dispub=10839522.
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Glioblastoma (GBM) is a hypervascular and hypoxic neoplasia of the central nervous system with an extremely high rate of mortality. Owing to its hypervascularity, anti-angiogenic therapies (AAT) have been used as an adjuvant to the traditional surgical resection, chemotherapy, and radiation to normalize blood vessels, control abnormal vasculatures and prevent recurrence. The benefits of AAT have been transient and the tumors were shown to relapse faster and demonstrated particularly high rates of AAT-induced therapy resistance due to activation of alternative neovascularization mechanisms. Vascular Mimicry (VM) is the uncanny ability of tumor cells to acquire endothelial-like properties, lay down vascular patterned networks reminiscent of host endothelial blood vessels and served as an irrigation system for the tumors to meet with the increasing metabolic and nutrient demands in the event of the ensuing hypoxia resulting from AAT. In our studies, we have demonstrated that AAT accelerates VM. We observed that Vatalanib (a VEGFR2 tyrosine kinase inhibitor) induced VM vessels are positive for periodic acid-Schiff (PAS) matrix but devoid of any endothelium on the inner side and lined by tumor cells on the outer side. Interestingly, 20-HETE synthesis inhibitor HET0016 significantly decreased GBM tumors through decreasing VM structures both at the core and at the periphery of the tumors. During our extensive studies to understand the tumor-inherent mechanisms of AAT-induced resistance, we identified a crucial chemokine, CXCL8 or IL-8, to be highly upregulated in the GBM tumors treated with AAT. IL-8 has been well established as a highly prevalent cytokine in GBM with potent pro-migratory and pro-angiogenic functions. AAT-treated groups had significantly higher populations of CXCR2+ glioma stem cells and endothelial-like subpopulations and these populations were decreased following treatment with HET0016 and SB225002 (a CXCR2 antagonist). CXCR2+ GBM tumor cells were shown to form VM-like vascular channels carrying functional RBCs. Knocking down CXCR2 led to smaller tumor size in the animals and improperly developed vascular structures without CXCR2+ GBM cells lining them. This confirms our hypothesis that CXCR2+ GBM cells initiate VM and contribute to AAT resistance in GBM. Our present study suggests that HET0016 and SB225002 have potential to target therapeutic resistance and can be combined with other antitumor agents in preclinical and clinical trials.
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Thomas, Sean Casey. "A Developed and Characterized Orthotopic Rat Glioblastoma Multiforme Model." Thesis, Virginia Tech, 2020. http://hdl.handle.net/10919/100772.
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This thesis project serves to fill experimental gaps needed to advance the goal of performing pre-clinical trials using an orthotopic rat glioblastoma model to evaluate the efficacy of high-frequency electroporation (H-FIRE) and QUAD-CTX tumor receptor-targeted cytotoxic conjugate therapies, individually and in combination, in selectively and thoroughly treating glioblastoma multiforme. In order to achieve this, an appropriate model must be developed and characterized. I have transduced F98 rat glioma cells to express red-shifted firefly luciferase, which will facilitate longitudinal tumor monitoring in vivo through bioluminescent imaging. I have characterized their response to H-FIRE relative to DI TNC1 rat astrocytes. I have demonstrated the presence of the molecular targets of QUAD in F98 cells. The in vitro characterization of this model has enabled preclinical studies of this promising glioblastoma therapy in an immunocompetent rat model, an important step before advancing ultimately to clinical human trials.Master of Science
Treating glioblastoma multiforme (GBM), a form of cancer found in the brain, has not been very successful; patients rarely live two years following diagnosis, and there have been no major breakthrough advances in treatment to improve this outlook for decades. We have been working on two treatments which we hope to combine. The first is high-frequency electroporation (H-FIRE), which uses electrical pulses to kill GBM cells while leaving healthy cells alive and blood vessels intact. The second is QUAD-CTX, which combines a toxin with two types of protein that attach to other proteins that are more common on the surface of GBM cells than healthy cells. We have shown these to be effective at disproportionately killing human GBM cells growing in a lab setting. Before H-FIRE and QUAD-CTX may be tested on humans, we need to show them to be effective in an animal model, specifically rats. I have chosen rat glioma cells that will behave similarly to human GBM and a rat species that will not have an immune response to them. I have made these cells bioluminescent so that we may monitor the tumors as they grow and respond to our treatments. I have also shown that QUAD-CTX kills these rat glioma cells, as does H-FIRE. Because of this work, we are ready to begin testing these two treatments in rats.
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Wu, W., J. L. Klockow, S. Mohanty, K. S. Ku, M. Aghighi, S. Melemenidis, Z. Chen, et al. "Theranostic nanoparticles enhance the response of glioblastomas to radiation." ivyspring, 2019. http://hdl.handle.net/10454/17326.
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YesDespite considerable progress with our understanding of glioblastoma multiforme (GBM) and the precise delivery of radiotherapy, the prognosis for GBM patients is still unfavorable with tumor recurrence due to radioresistance being a major concern. We recently developed a cross-linked iron oxide nanoparticle conjugated to azademethylcolchicine (CLIO-ICT) to target and eradicate a subpopulation of quiescent cells, glioblastoma initiating cells (GICs), which could be a reason for radioresistance and tumor relapse. The purpose of our study was to investigate if CLIO-ICT has an additive therapeutic effect to enhance the response of GBMs to ionizing radiation. Methods: NSG™ mice bearing human GBMs and C57BL/6J mice bearing murine GBMs received CLIO-ICT, radiation, or combination treatment. The mice underwent pre- and post-treatment magnetic resonance imaging (MRI) scans, bioluminescence imaging (BLI), and histological analysis. Tumor nanoparticle enhancement, tumor flux, microvessel density, GIC, and apoptosis markers were compared between different groups using a one-way ANOVA and two-tailed Mann-Whitney test. Additional NSG™ mice underwent survival analyses with Kaplan–Meier curves and a log rank (Mantel–Cox) test. Results: At 2 weeks post-treatment, BLI and MRI scans revealed significant reduction in tumor size for CLIO-ICT plus radiation treated tumors compared to monotherapy or vehicle-treated tumors. Combining CLIO-ICT with radiation therapy significantly decreased microvessel density, decreased GICs, increased caspase-3 expression, and prolonged the survival of GBM-bearing mice. CLIO-ICT delivery to GBM could be monitored with MRI. and was not significantly different before and after radiation. There was no significant caspase-3 expression in normal brain at therapeutic doses of CLIO-ICT administered. Conclusion: Our data shows additive anti-tumor effects of CLIO-ICT nanoparticles in combination with radiotherapy. The combination therapy proposed here could potentially be a clinically translatable strategy for treating GBMs.
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Cartiaux, Benjamin. "Etude de l'effet radio-sensibilisant de nanotubes de carbone dans le modèle de glioblastome canin spontané, en vue d'un développement chez l'Homme." Thesis, Toulouse 3, 2020. http://www.theses.fr/2020TOU30133.
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Les gliomes représentent les tumeurs primaires les plus fréquentes du système nerveux central avec le pronostic le plus mauvais, malgré une prise en charge précoce associée à un traitement agressif et multimodal. De nouvelles thérapies sont donc à l'étude afin d'améliorer la médiane de survie des patients. Parmi ces pistes de recherche, l'optimisation de la radiothérapie (RT) du glioblastome (GBM) est un enjeu majeur. Dans ce contexte, l'utilisation de nanotubes de carbone (NTC) est prometteuse : en plus d'être potentiellement radio-sensibilisants, les NTC contenant du gadolinium (Gd) peuvent aider à mieux délimiter le volume cible tumoral en Imagerie par Résonance Magnétique (IRM). Contrairement au modèle d'étude actuel qu'est la souris avec un certain nombre de limites, le chien est un modèle particulièrement adapté car il peut spontanément développer un GBM d'une taille suffisante pour utiliser le même matériel de RT et d'imagerie qu'en médecine humaine, facilitant ainsi la transposition directe des méthodes. Cette étude vise donc à valider la pertinence de modèles cellulaires de GBM canins en radio-oncologie comparée en caractérisant 5 lignées cellulaires de gliome canin et à évaluer la capacité des NTC à radio-sensibiliser des lignées de GBM canins. L'étude de ces 5 lignées cellulaires canines a montré de nombreuses analogies entre le chien et l'homme. La morphologie des cellules est identique, de même que le temps de doublement, le test de clonalité et le caryotype. L'étude immunohistochimique des protéines de surface, sur les lignées cellulaires et après injection stéréotaxique sur des souris révèle aussi une similarité étroite. Les cellules gliales canines et humaines ont un profil de radiosensibilité similaire. La pénétration des NTC au sein des cellules tumorales a pu être mis en évidence à l'aide de la microscopie bi-photonique. Des études complémentaires sont nécessaires pour démontrer un effet radiosensibilisant des NTC. L'excitation laser des NTC lors de l'observation au microscope bi-photonique a montré un effet photothermique intéressant qui pourrait être approfondi au cours d'études ultérieures. Le modèle canin et les nanotubes de carbone ont fourni des résultats intéressants, qui en font des éléments d'intérêt dans l'étude des gliomesDespite several aggressive and multimodal treatments, gliomas represent the most frequent brain tumor with the worst prognostic associated. In order to enhance median survival, researchers are looking for optimization of radiotherapy (RT) for glioblastoma (GBM). In this context, the use of carbon nanotubes (CNTs) is promising: in addition to being potentially radio-sensitizing, CNTs containing gadolinium (Gd) can help to better define the tumor target volume in Magnetic Resonance Imaging (MRI). Unlike the current study model of the mouse with its number of limitations, dog is a particularly suitable model because it can spontaneously develop a GBM of sufficient size to use the same RT and imaging equipment as in human medicine, facilitating thus the direct transposition of methods. This study therefore aims to validate the relevance of cell models of canine GBM in comparative radiation oncology by characterizing 5 cell lines of canine glioma and to assess the capacity of CNTs to radio-sensitize canine GBM lines. Study of these 5 canine cell lines shows numerous analogies between dogs and humans. Cell morphology is identical, such as doubling time, clonality test and karyotype. Immunohistochemical study of surface proteins, directly on cell lines and after stereotaxic injection in mice also reveals close similarity. Radiosensitivity profile of glial cells between human and dog is alike. CNT penetration into tumor cells is demonstrated using two-photon microscopy. Therefore, further studies are needed to demonstrate a radiosensitizing effect of CNTs. Laser excitation of CNTs with bi-photon microscope showed an interesting photothermal effect which could be further explored in further studies. The canine model and carbon nanotubes have provided interesting results which are elements of interest in the study of gliomas
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Mooney, Marie R. "Precision Medicine Approaches to Integrating Genomics with Cancer Therapy| Applications in Glioblastoma and Lymphoma." Thesis, Van Andel Research Institute, 2017. http://pqdtopen.proquest.com/#viewpdf?dispub=10275288.
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The word "cancer" rarely stands alone, usually prefaced with its anatomical location: lung cancer, prostate cancer, brain cancer. With the advancement of high-throughput omics approaches, specific oncogenic events are reorganizing the landscape of cancer classification, at once creating commonalities between cancers arising in diverse anatomical locations and dividing organ-centric classifications of cancer into a multitude of subtypes. The term "precision medicine" postulates that these new, data-driven groupings based on molecular characterization are the key to making rational therapeutic choices.
The majority of this dissertation addresses the disconnect between extensive molecular characterization and poor cancer therapy outcomes for patients with glioblastoma multiforme (GBM). Despite clear evidence that hyperproduction of the ligand for PDGFR (platelet-derived growth factor receptor α) is sufficient to generate GBM of the proneural subtype, anti-PDGFRα therapeutics have proven disappointing in clinical trials. Cell adaptation contributes to therapeutic escape. In GBM, proneural tumor cells adopt transcriptional profiles of the mesenchymal subtype. The interconversion between the proneural and mesenchymal transcriptional classes within a tumor population presents both a challenge and an opportunity for therapeutic approaches. The proneural subtype has a proliferation phenotype and presents druggable targets such as PDGFRα. The mesenchymal subtype presents an invasive phenotype, but the targets are more challenging to drug. The typical screening for combination therapies that synergize to induce cell death is not as advantageous here, where the disease management is expected to include cytostatic drugs that act on two different aspects of the phenotype: proneurally mediated proliferation and mesenchymally mediated invasion. This work examines the applicability of a combination approach against a proneural target, PDGFRα, and mesenchymal targets in the STAT3 (signal transducer and activator of transcription 3) pathway, in the context of a proneural model of GBM.
The work is concluded with collection of work applying precision medicine in other disease contexts, most notably canine lymphoma.
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Eagles, Lawrence. "Metformin as a potential therapy for malignant astrocytoma." Thesis, University of Wolverhampton, 2018. http://hdl.handle.net/2436/621724.
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Background Glioblastoma Multiforme (GBM) is the most commonly occurring tumour of the central nervous system (CNS). Currently GBM is considered an incurable malignancy with patients experiencing abysmal life expectancies. Lack of progress in the discovery of novel treatments has led to the repurposing of existing licenced medication as a possible alternative option. Metformin is from the biguanide family of drugs and is the most common medication used in the treatment of type 2 diabetes. Clinical studies have reported that, in type 2 diabetic patients, metformin might reduce cancer incidence and severity. Currently, metformin is being assessed in clinical trials as a treatment for a range of cancer types including GBM. The antineoplastic mechanisms utilized by metformin and other biguanides have not been fully elucidated. Methods The effects of metformin were evaluated, alone and in combination with other agents, on a panel of GBM cell cultures. Functional analysis of metformin mechanism of action was assessed through measurement of apoptosis, depolarisation of the mitochondria membrane, caspase pathway activation, cell cycle progression and the expression levels of micoRNAs. Results Analysis of fourteen GBM cell cultures showed a cytotoxic response to metformin that was significantly linked to the P53 status (p=0.0024). In combination drug testing, one of the four drugs showed a synergistic pairing with metformin. The kinase inhibitor sorafenib, showed synergism (CI ≤ 1) in eight GBM cell cultures. Flow cytometry of metformin treated GBM cells showed no significant increase (p > 0.005) in apoptotic cell populations. Caspase 3/7 levels showed no significant increase post metformin treatment (p > 0.005). Metformin caused depolarisation of the mitochondrial membrane in six GBM cell cultures. Four microRNAs were shown to have expression levels changes post-metformin treatment. Upregulation of expression was identified in miR-140, miR-192, let-7c. Downregulation was identified in miR-222. Conclusions Metformin was shown to have cytotoxic effect on a GBM cell cultures and has potential as GBM therapeutic agent and possible treatment synergy with sorafenib. The significance of P53 status to metformin sensitivity may suggest that its use should be directed to a sub-set of GBM patients. Mechanism for cell death by metformin was shown not to rely on apoptotic pathways but caspase 3/7 independent depolarization of mitochondrial cell membranes and cell cycle arrest. Investigations into autophagy may help to further define the pathways metformin is utilising to promote cell death. The impact of metformin on the expression profile of miR-222, miR-192 and let-7c is in line with clinical studies of other cancer types. This shows possible insight into the cancer independent actions of metformin. The interplay recorded between glucose availability and cell death indicates a possible key factor in the utilisation of metformin as a therapeutic agent. This finding may warrant the addition of dietary control regimes in clinical trials to maximise metformin efficacy. This work highlights the strong potential for biguanides in the development of new drug treatments and in expanding our knowledge of cancer metabolism.
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Adamski, Vivian [Verfasser]. "Analysis of chemotherapeutic-induced tumor dormancy in Glioblastoma Multiforme and alternative therapy approaches / Vivian Adamski." Kiel : Universitätsbibliothek Kiel, 2019. http://d-nb.info/1197612467/34.
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Rogers, William. "Profiling and targeting HOX-PBX dimers in adult and paediatric glioblastoma as a novel therapy." Thesis, University of Surrey, 2018. http://epubs.surrey.ac.uk/849922/.
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HOX genes encode a family of transcription factors that play an essential role in embryonic patterning during foetal development. These genes are reported to be aberrantly expressed in numerous cancers, including glioblastoma (GBM). Previous research indicates that HOX genes are overexpressed in GBM tumours compared to normal human astrocytes (NHA). Three Amino Acid Loop Extension Homeobox (TALE) proteins act as important co-factors for HOX proteins, modulating their binding affinities to genomic targets. TALE members Pre-B-cell leukaemia homeobox (PBX) 1-4, bind anterior HOX proteins, facilitating cellular entry, while also limiting their degradation. HXR9, a small hexapeptide drug, has previously been shown to inhibit HOX-PBX dimers, causing rapid cell death in numerous solid and haemopoietic malignancies both in vitro and in vivo. HTL00-1 is a 2nd generation peptide based on HXR9, while ICT9119 is a small molecular inhibitor with the same binding site as the peptide inhibitors. We found clear evidence of overexpression of both HOX and TALE genes, in both adult and paediatric GBM cell lines. A further elevation in expression of these genes was visible in GBM cancer stem cells (CSCs). Normal adult brain tissue expressed low to undetectable levels of HOX genes, while paediatric brains expressed high levels between 0-4 years of age, before dramatically reducing from ages 5 onwards. HOX-PBX inhibitors are shown to be both cytostatic and cytotoxic when used to treat adult and paediatric GBM cells both in vitro and in vivo. GBM CSCs were more sensitive to HOX-PBX inhibition, alluding to their increased reliance on these genes. HTL00-1 and ICT9119 were shown to provide improved pharmacological effects compared to their predecessor HXR9. All HOX-PBX inhibitors cause apoptosis through induction of Fos Proto-Oncogene AP-1 Transcription Factor Subunit (C-Fos) expression, which results in the dimerization of C-Fos and Jun Proto-Oncogene AP-1 Transcription Factor Subunit (C-Jun) to form the Activator protein 1 (AP-1) complex. This directly and indirectly represses B-cell lymphoma 2 (Bcl-2) expression leading to the release, and subsequent cleavage of caspase 3 and 7. This triggers the caspase cascade that concludes with cellular apoptosis. Radiotherapy (RT), combined with ICT9119 treatment proved highly synergistic in terms of cell kill when applied in combination when cancer cells were exposed to RT 24 hours prior to ICT9119. When ICT9119 was delivered 24 hours prior to RT antagonistic effects were observed. Attempts to identify the molecular mechanisms behind differing sequential treatment outcomes proved inconclusive. However, our work did suggest a mixture of cell cycle sequestration, C-Jun induction and the opposing effects of dual specific phosphatase 1 (DUSP1) and Mitogen-activated protein kinases (MAPK) were at least partly involved. This study highlights the important role of HOX genes in paediatric and adult gliomas, the potential utility of HOX/TALE gene expression in the identification of CSC population in patients and potential for HOX-PBX inhibition as a highly targeted effective treatment for adult and paediatric GBM patients. This treatment can be administered in the form of a peptide, as in HXR9 or HTL00-1, or as a small molecular agent in the form of ICT9119, either as single agents, or in combination with RT. HOX-PBX disruption as described in this thesis could potentially be moved rapidly into the clinic, in an area of very high unmet need.
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Silva, Emanoel Pedro de Oliveira. "Estudos fotofísicos e fotobiológicos de sistemas de liberação contendo o fármaco fotossensível cloro-ftalocianina de alumínio para aplicação em terapia fotodinâmica." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/60/60137/tde-21102016-112503/.
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A terapia fotodinâmica (TFD) tem se apresentado nos últimos anos como uma alternativa para o tratamento de tumores cutâneos, viscerais e sistêmicos, demonstrando resultados promissores, tanto em estudos in vitro como in vivo. Trata-se de uma técnica simples e não invasiva. A terapia consiste na excitação de um fármaco fotossensibilizante por uma fonte de luz visível que depois de absorvida pela molécula, leva a produção espécies reativas de oxigênio (EROs) em presença do oxigênio molecular por uma sequencia de reações fotoquímicas. Nesse trabalho propõe-se a preparação, caracterização e detreminação da atividade fotodinâmica de uma nanoemulsão rica em colesterol e de lipossomas ultradeformáveis como novos sistemas de liberação para o fármaco fotossensibilizante cloro alumínio ftalocianina (PcAlCl), comparando com um sistema clássico de lipossoma convencional. Como modelo celular foram utilizadas células de glioblastoma (U87MG) e de melanoma (B16F10). As formulações apresentaram características desejáveis como reprodutibilidade, tamanho de partícula, estabilidade curto e em longo prazo e deformidade adequados para a utilização como meio de veiculação da PcAlCl. Pela análise dos estudos fotofísicos de rendimento quântico de fluorescência (?F), tempo de vida de fluorescência (?) e rendimento quântico de oxigênio singleto (??) da PcAlCl em etanol e incorporada nas formulações, pode-se observar que a incorporação a um veículo de liberação melhorou as características da PcAlCl. Nos estudos em células nenhum dos sistemas apresentou citotoxicidade na ausência de luz, mas apresentaram um aumento da atividade fotodinâmica da PcAlCl de até 80% quando comparadas à PcAlCl livre quando irradiadas. Todas as formulações apresentaram características que corrobora com o emprego como sistemas de liberação para o aumento da atividade fotodinâmica da PcAlCl podendo serem empregados no tratamento de glioblastoma e de melanomaThe Photodynamic therapy (PDT) has been an alternative for the treatment of skin, and brain tumors, and has shown promising results, both in vitro and in vivo, is a simple and non-evasive technique. The therapy consists into a light-sensitive drug excitation by a light visible source that once absorbed by the molecule lead to produce reactive oxygen species (ROS) in the molecular oxygen presence by a sequence of photochemical reactions. This work proposes the preparation and characterization of a cholesterol-rich nanoemulsion and ultradeformable liposomes as new delivery systems for the drug photosensitizer chloro aluminum phthalocyanine (PcAlCl) compared to a classical system as the conventional liposome and their photodynamic activity in glioblastoma cells line (U87MG) and melanoma cells line (B16F10). The formulations showed suitable characteristics such as reproducibility, particle size, short and long-term stability and deformity for their use as drug delivery for PcAlCl. For the photophysical studies: absorption, fluorescence, fluorescence quantum yield (?F), fluorescence lifetime (?) and quantum yield of singlet oxygen (??) of PcAlCl in ethanol and incorporated in the formulations demonstrated that the incorporation was able to improve its photophysical characteristics. In in vitro studies, the drug delivery systems showed no cytotoxicity in the absence of light, but demonstrated increased in PcAlCl photodynamic activity up to 80% over the PcAlCl free when irradiated. All formulations showed characteristics, which cooperates with the use of these drug delivery systems for, increased the PcAlCl photodynamic activity for glioblastoma and melanoma treatment
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Shi, Minghan. "Convection-enhanced delivery of platinum drugs and their liposomal formulations plus radiation therapy in glioblastoma treatment." Thèse, Université de Sherbrooke, 2016. http://hdl.handle.net/11143/8786.
Full textAbstract:
Abstract : Glioblastoma is the most common and aggressive brain cancer in adults. The current standard-of-care treatment includes surgical resection, radiation therapy with concomitant and adjuvant temozolomide (TMZ) chemotherapy. However, the addition of TMZ to radiation therapy only increased the median survival time (MeST) by 2.5 months. This limited improvement is partially attributable to the low accumulation of chemotherapeutic drugs in the brain tumor due to the blood-brain barrier (BBB). Thus, new delivery methods such as intra-arterial, BBB disruption and convection-enhanced delivery (CED) have been proposed to overcome this limitation. Besides, timing tumor irradiation to coincide with the maximal concentration of platinum-DNA adducts could result in improved tumor control.
In this study, CED of cisplatin and oxaliplatin, their respective liposomal formulations Lipoplatin™, Lipoxal™, and carboplatin with or without 15 Gy of radiation therapy has been carried out in F98 glioma bearing Fischer rats to assess their toxicity and MeST. The amount of platinum-DNA adducts in the tumor at 4 h and 24 h after CED was measured and irradiation was administered at these two different time periods to test the concomitant effect. In addition, four liposomal carboplatin formulations with different chemo-physical properties were prepared and their toxicity and MeST were also evaluated in this animal model.
Among the tested platinum drugs, carboplatin and Lipoxal™ demonstrated a highest maximum-tolerated dose of 25 µg and 30 µg respectively. CED of carboplatin showed the longest MeST of 38.5 days, and increased to 54.0 days with the addition of 15 Gy radiation therapy. However, radiation at 4 h after CED of either oxaliplatin or carboplatin did not show any survival improvement when compared to radiation at 24 h, although the quantity of platinum-DNA adducts at 4 h was higher than at 24 h after CED. In the four liposomal carboplatin formulations, anionic pegylated liposomal carboplatin showed the longest MeST of 49.5 days, due to its longer tumoral retention time and probably larger distribution volume in the brain.Résumé : Le glioblastome est le cancer primaire du cerveau le plus courant et agressif chez l’adulte. Le traitement standard comprend la résection chirurgicale, la radiothérapie et la chimiothérapie concomitante et adjuvante avec le témozolomide(TMZ). L'addition de TMZ combinée la radiothérapie a augmenté la survie médiane (MeST) de 2,5 mois. Cette faible amélioration est partiellement due à l'accumulation limitée de médicaments chimiothérapeutiques dans la tumeur cérébrale à cause de la barrière hémato-encéphalique (BBB). Ainsi, de nouvelles méthodes comme l’injection intraartérielle, la rupture osmotique de la barrière hémato-encéphalique, la livraison augmentée par convection (CED) ont été suggérées pour surmonter ce problème. En plus, l’optimisation de l’irradiation de la tumeur lorsque le maximum d’adduits platine-ADN est atteint pourrait aboutir à un meilleur contrôle de la tumeur. Dans cette étude, nous avons injecté par CED le cisplatine, l’oxaliplatine, avec leur formulation liposomale Lipoplatin™, Lipoxal™ ainsi que le carboplatine avec ou sans radiation de 15 Gy. La toxicité et le temps de MeST ont été mesurés chez des rats Fischer porteurs du gliome. La quantité d'adduits platine-ADN dans la tumeur a été mesurée 4 h et 24 h après CED. L’irradiation de la tumeur a été effectuée à ces deux temps pour tester l'effet concomitant. En plus, quatre formulations liposomales de carboplatine avec différentes propriétés chimiophysiques ont été préparées et leur toxicité et MeST combiné à la radiation ont également été évalués. Parmi les drogues de platine testées, le carboplatine et Lipoxal™ ont démontré respectivement la dose maximale tolérée la plus élevée, soit 25 µg et 30 µg. La MeST du carboplatine était la plus longue avec 38,5 jours qui a augmenté à 54,0 jours avec l’addition de 15 Gy de radiothérapie. Toutefois, l’irradiation à 4 h après CED effectuée avec l'oxaliplatine et le carboplatine n'a pas amélioré la MeST comparé à l’irradiation à 24 h, bien que la quantité d'adduits platine-ADN à 4 h était supérieure à celle mesurée à 24 h après CED. Pour les quatre formulations liposomales de carboplatine, celle pégylée négatif a démontré la plus longue MeST, soit 49,5 jours.
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Arias, Ramos Nuria. "Towards improvement of preclinical glioblastoma management: detection, therapy and assessment of response using magnetic resonance techniques." Doctoral thesis, Universitat Autònoma de Barcelona, 2019. http://hdl.handle.net/10803/667287.
Full textAbstract:
El Glioblastoma (GB) es el tumor primario agresivo más común, con mal pronóstico y sin cura actualmente. Aunque se aplique tratamiento agresivo (quimioterapia con Temozolamida, TMZ, y radioterapia) generalmente hay recidiva. Esta tesis se ha centrado en la mejora del diagnóstico, seguimiento de la respuesta a terapia y manejo del GB con técnicas de resonancia magnética (RM) (Imagen por Resonancia Magnética/IRM e Imagen Espectroscópica por Resonancia Magnética/IERM), utilizando el modelo preclínico de GB GL261.
Los agentes de contraste (AC) utilizados para diagnóstico de GB están basados en Gadolinio (Gd), que no está exento de riesgo en caso de patología renal. La mayoría de sus efectos se aprecian en IRM T1, aunque estudios recientes señalan las ventajas de ACs del tipo dual (T1-T2). En esta tesis, un conjunto de AC noveles se ha evaluado en colaboración con el ICN2 (Institut Català de Nanociència i Nanotecnologia) mediante una aproximación experimental ex vivo para seleccionar el mejor agente para estudios dinámicos de contraste in vivo. Las imágenes de algebra “dual enhancement” resaltan las propiedades duales de los CA estudiados. Se seleccionó un agente basado en hierro, resultando seguro en estudios de tolerabilidad y mostrando contraste en T1 y T2 in vivo en un período de tiempo corto. Ello permite obtener los dos tipos de información en la misma exploración, lo que conlleva un claro interés translacional.
Después del diagnóstico, los GB deben ser tratados y uno de los desafíos de la clínica es el seguimiento de la respuesta. En esta tesis se ha optimizado un análisis volumétrico IERM (tipo 3D) que ha sido aplicado a tumores GL261 controles y tratados con TMZ. Luego, se han generado imágenes nosológicas a partir del análisis semi-supervisado de reconocimiento de patrones, clasificando los tejidos como en respuesta, no respuesta y normal. Hemos establecido el parámetro TRI (del inglés Tumour Responding Index), permitiendo una categorización del nivel de respuesta a partir del porcentaje de tejido respondedor. Los sujetos se han estratificado en categorías arbitrarias: respuesta baja (low response, LR), intermedia (intermediate response, IR) y alta (high response, HR). Estudios histopatológicos confirmaron una relación inversa entre TRI y proliferación Ki67, utilizando células/mm2 en lugar de porcentaje debido a diferencias en morfología/volumen celular. El TRI ha presentado oscilaciones con frecuencia de 6-7 días, en contraposición con el volumen tumoral. Dicha oscilación podría corresponder a la presencia/activación del sistema inmune en la respuesta a la terapia, lo que concuerda con hallazgos histopatológicos de linfocitos infiltrando el tejido respondedor.
El potencial de nanopartículas de oro (NP) para hipertermia se ha investigado como tratamiento alternativo para el GB. Para ello, se ha puesto a punto el equipo para irradiación láser (NIR, Near infrared irradiation) dentro del escáner RM, para experimentos ex vivo/in vivo con ratones wt y con tumores GL261. Se han estudiado Nanopartículas de oro huecas y Nanorods obteniéndose resultados discretos en cuanto a calentamiento diferencial.
Nanopartículas de oro huecas con PEG no han afectado la viabilidad de células GL261 en cultivo y se han internalizado por un 30% de estas células. A resultas de este estudio, se han formulado una serie de advertencias en relación a la hipertermia: es necesario mejorar la tolerabilidad disminuyendo los valores de endotoxina en las NP; es necesario evitar la subida abrupta de la temperatura cerebral; hay riesgos en la irradiación NIR dentro del escáner y hace falta un sistema de seguridad para evitar incendios; los modelos ortotópicos de tumores cerebrales conllevan desafíos para la consecución de estos estudios, tanto por la necesidad de acúmulo de NP en dichos tumores, como por la disipación de NIR antes de alcanzar la parte interna del cerebro.Glioblastoma (GB) is the most common and aggressive primary brain tumour with poor prognosis and survival, with no cure available at present. Relapse usually takes place in a short time even after aggressive standard treatment (chemotherapy with Temozolomide, TMZ and radiotherapy). This PhD thesis was focused in the improvement of GB diagnosis, therapy follow-up and management with Magnetic Resonance (MR) techniques (Magnetic Resonance Imaging, MRI and Magnetic Resonance Spectroscopic Imaging, MRSI) in the preclinical GB GL261 mice model. Contrast agents (CA) currently used in GB diagnosis are based in Gadolinium (Gd) which is not exempt of risks in case of patients with renal pathology. In addition, most of its effects are appreciated in T1w MRI although novel studies are pointing to the potential advantages of using dual (T1-T2) agents. In this thesis, a set of novel CA with dual potential was evaluated in collaboration with ICN2 (Institut Català de Nanociència i Nanotecnologia), with a well established path of ex vivo studies for selecting the best agent to proceed with in vivo contrast-enhanced dynamic studies. Dual enhancement MRI image algebra calculated showed the dual properties of candidate CAs. An Fe-based agent was chosen for in vivo studies. This CA proved to be safe in tolerability studies and to show both T1 and T2 effects in a short time frame, allowing to gather both type of data in the same exploration. This type of agents could have clear translational potential in the near future. Once diagnosed, GB should be treated and one of the challenges faced by clinicians is the therapy response follow-up. We have optimized a volumetric, 3D-like MRSI analysis which was applied to GL261 GB tumour-bearing mice either untreated or under TMZ treatment. Then, nosological images were obtained through semi-supervised pattern recognition analysis and classifying tissues in responding, unresponsive or normal. We established the parameter TRI, Tumour Responding Index, which allowed objective categorization of the response level taking into account the percentage of “responding” tissue detected. Mice were then categorized within arbitrary cut-off values: low response (LR), intermediate response (IR) and high response (HR). Histopathological studies confirmed an inverse correlation between the TRI and Ki67 proliferation rate, provided Ki67 cells/mm2 was used instead of percent, due to variable cell morphology and cellular volume. The TRI presented an oscillatory pattern with peak maxima every 6-7 days, as opposed to tumour volume changes. This 6-7 day oscillation would be in agreement with host immune system recruitment for therapy response, also supported by histopathological findings of lymphocyte-like cells infiltrating responding tissue. The potential of gold nanoparticles (NP) for hyperthermia was investigated as an alternative treatment in GL261 GB. For this, a set-up for laser NIR irradiation inside the MR scanner was implemented for hyperthermia ex vivo/in vivo with wt and GL261 tumour-bearing mice. Hollow Gold Nanospheres and Nanorods were studied for heating potential in vitro and ex vivo, achieving discrete results. In vitro studies showed that PEGylated Hollow Gold Nanospheres did not affect GL261 cell viability and were internalized by ca 30% of GL261 cells. Several words of caution resulted from this study, namely: tolerability issues should be improved through new NP synthesis with suitable levels of endotoxin; care should be taken in order to avoid excessive/abrupt brain temperature increase; NIR irradiation inside the MR scanner is not exempt of risks and a whole safety system was developed to prevent fire break incidents; the use of orthotopic brain tumours is challenging for NIR irradiation, due to either need of high accumulation of NP inside tumours and NIR dissipation through tissues until reaching the inner part of the brain.
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Langer, Julia. "Metabolic profiling of ASS1 negative and ASS1 positive glioblastoma subtypes to identify novel targets for therapy." Thesis, Imperial College London, 2016. http://hdl.handle.net/10044/1/47973.
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Glioblastoma multiforme (GBM) are the most common and most malignant brain tumours. Despite treatment advances, average survival remains unacceptably low with 15-months, hence novel therapies are desperately needed. Cellular metabolism plays a central role in cancers. Sensitivity towards arginine-deprivation via pegylated arginine deaminase (ADI-PEG20) therapy has been identified in GBM, arresting proliferation in methylated arginino-succinate-synthetase-1 (ASS1M) and not unmethylated ASS1 (ASS1U) GBM cells. Advances of biochemical techniques and analysis have facilitated therapeutic target identification as well as biomarker discovery. Complimentary gas-chromatography coupled with mass spectrometry and 1-hydrogen nuclear-magnetic-resonance spectroscopy of in vitro GBM cells identified distinct metabolic profiles in ASS1 subtypes. Intracellular and extracellular analysis of GBM cells exposed to ADI-PEG20 treatment elucidated metabolic perturbations in the arginine, creatine, glycolytic, uridine, citric acid, thymine and glutamine pathways, induced by arginine deprivation. Transcriptional analysis of perturbed pathways elucidated differentially altered enzymatic expression in ASS1 GBM subtypes upon ADI-PEG20 treatment. Significantly modulated enzymes included transcriptional down-regulation of thymidylate synthase (TYMS) in ASS1M GBM cells, whereas ASS1U remained unaltered. Significantly altered enzymatic mRNA expression also identified modulation of glutamic pyruvate transaminase 2 (GPT2) in ASS1M cells, as well as thymidine kinase 2 (TK2) and alanine-glyoxylate aminotransferase 2 (AGXT2) in ASS1U GBM. Targeting the de novo thymine and creatine metabolic pathway, demonstrated that phytic acid (IP6) arrests proliferation in GBM cells, whereas creatine supplementation boosted proliferation. IP6 arrested proliferation in a time- and dose-dependent manner, irrespective of ASS1 status. Combining IP6 and ADI-PEG20, showed arrested proliferation was enhanced, compared to either treatment alone in ASS1M GBM cells.
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Kühnle, Matthias. "Experimental therapy and detection of glioblastoma : investigation of nanoparticles, ABCG2 modulators and optical imaging of intracerebral xenografts." kostenfrei, 2010. http://epub.uni-regensburg.de/13008/.
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Volmar, Marie Nhery Murielle [Verfasser], and Rainer [Akademischer Betreuer] Glaß. "Cannabidiol for glioblastoma therapy : models, molecular pathways, and predictive markers / Marie Nhery Murielle Volmar ; Betreuer: Rainer Glaß." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/1214593313/34.
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Meisen, Walter Hans. "Improving Oncolytic Viral Therapy for Primary and Metastatic Tumors in the Brain." The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429187113.
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Hasslacher, Sebastian [Verfasser]. "In vitro effect of ionizing radiation on primary glioblastoma cells as a basis for multitarget therapy / Sebastian Hasslacher." Ulm : Universität Ulm, 2020. http://d-nb.info/1205001751/34.
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Peters, Tanja [Verfasser]. "Development and in vitro testing of liposomal gadolinium-formulations for neutron capture therapy of glioblastoma multiforme / Tanja Peters." Mainz : Universitätsbibliothek Mainz, 2013. http://d-nb.info/1043939555/34.
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Ivey, Jill Winters. "Investigating the Applications of Electroporation Therapy for Targeted Treatment of Glioblastoma Multiforme Based on Malignant Properties of Cells." Diss., Virginia Tech, 2017. http://hdl.handle.net/10919/78806.
Full textAbstract:
Glioblastoma multiforme (GBM) is the most common and lethal primary brain cancer with an average survival time of 15 months. GBM is considered incurable with even the most aggressive multimodal therapies and is characterized by near universal recurrence. Irreversible electroporation (IRE) is a cellular ablation method currently being investigated as a therapy for a variety of cancers. Application of IRE involves insertion of electrodes into tissue to deliver pulsed electric fields (PEFs), which destabilize the cell membrane past the point of recovery, thereby inducing cell death. While this treatment modality has numerous advantages, the lack of selectivity for malignant cells limits its application in the brain where damage to healthy tissue is especially deleterious. In this dissertation we hypothesize that a form of IRE therapy, high-frequency IRE (H-FIRE), may be able to act as a selective targeted therapy for GBM due to its ability to create an electric field inside a cell to interact with altered inner organelles. Through a comprehensive investigation involving experimental testing combined with numerical modeling, we have attained results in strong support of this hypothesis. Using tissue engineered hydrogels as our platform for therapy testing, we demonstrate selective ablation of GBM cells. We develop mathematical models that predict the majority of the electric field produced by H-FIRE pulses reach the inside of the cell. We demonstrate that the increased nuclear to cytoplasm ratio (NCR) of malignant GBM cells compared to healthy brain—evidenced in vivo and in in vitro tissue mimics—is correlated with greater ablation volumes and thus lower electric field thresholds for cell death when treated with H-FIRE. We enhance the selectivity achieved with H-FIRE using a molecularly targeted drug that induces an increase in NCR. We tune the treatment pulse parameters to increase selective malignant cell killing. Finally, we demonstrate the ability of H-FIRE to ablate therapy-resistant GBM cells which are a focus of many next-generation GBM therapies. We believe the evidence presented in this dissertation represents the beginning stages in the development of H-FIRE as a selective therapy to be used for treatment of human brain cancer.Ph. D.
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Guhasarkar, Dwijit. "A Walk on the Fine Line Between Reward and Risk: AAV-IFNβ Gene Therapy for Glioblastoma: A Dissertation." eScholarship@UMMS, 2007. http://escholarship.umassmed.edu/gsbs_diss/843.
Full textAbstract:
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. The current standard-of-care treatment including surgery, radiation and temozolomide (TMZ) chemotherapy does not prolong the survival satisfactorily. Here we have tested the feasibility, efficacy and safety of a potential gene therapy approach using AAV as gene delivery vehicle for treatment of GBM.
Interferon-beta (IFNβ) is a cytokine molecule also having pleiotropic anticancerous properties. Previously it has been shown by our group that AAV mediated local (intracranial) gene delivery of human IFNβ (hIFNβ) could be an effective treatment for non-invasive human glioblastoma (U87) in orthotopic xenograft mouse model.But as one of the major challenges to treat GBM effectively in clinics is its highly invasive property, in the current study we first sought to test the efficacy of our therapeutic model in a highly invasive human GBM (GBM8) xenograft mouse model.
One major limitation of using the xenograft mouse model is that these mice are immune-compromised. Moreover, as IFNβ does not interact with cross-species receptors, the influence of immune systems on GBM remains largely untested. Therefore to test the therapeutic approach in an immune-competent mouse model, we next treated a syngeneic mouse GBM model (GL261) in an immune-competent mouse (C57B6) with the gene encoding the species-matched IFNβ (mIFNβ). We also tested if combination of this IFNβ gene therapy with the current standard chemotherapeutic drug (TMZ) is more effective than any one of the therapeutic modes alone. Finally, we tested the long term safety of the AAV-mIFNβ local gene therapy in healthy C57B6 mice.
Next, we hypothesized that global genetic engineering of brain cells expressing secretory therapeutic protein like hIFNβ could be more beneficial for treatment of invasive, migratory and distal multifocal GBM. We tested this hypothesis using systemic delivery of AAV9 vectors encoding hIFNβ gene for treatment of GBM8 tumor in nude mice.
Using in vivo bioluminescence imaging of tumor associated firefly luciferase activity, long term survival assay and histological analysis of the brains we have shown that local treatment of AAV-hIFNβ for highly invasive human GBM8 is therapeutically beneficial at an early growth phase of tumor. However, systemic delivery route treatment is far superior for treating multifocal distal GBM8 tumors. Nonetheless, for both delivery routes, treatment efficacy is significantly reduced when treated at a later growth phase of the tumor.
In syngeneic GL261 tumor model study, we show that local AAV-mIFNβ gene therapy alone or in combination with TMZ treatment can provide significant survival benefit over control or only TMZ treatment, respectively. However, the animals eventually succumb to the tumor. Safety study in the healthy animals shows significant body weight loss in some treatment groups, whereas one group shows long term survival without any weight loss or any noticeable changes in the external appearances. However, histological analysis indicates marked demyelinating neurotoxic effects upon long term exposures to mIFNβ over-expressions in brain. Overall, we conclude from this study that AAV-IFNβ gene therapy has great therapeutic potential for GBM treatment in future, but the therapeutic window is small and long term continuous expression could have severe deleterious effects on health.
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Guhasarkar, Dwijit. "A Walk on the Fine Line Between Reward and Risk: AAV-IFNβ Gene Therapy for Glioblastoma: A Dissertation." eScholarship@UMMS, 2016. https://escholarship.umassmed.edu/gsbs_diss/843.
Full textAbstract:
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. The current standard-of-care treatment including surgery, radiation and temozolomide (TMZ) chemotherapy does not prolong the survival satisfactorily. Here we have tested the feasibility, efficacy and safety of a potential gene therapy approach using AAV as gene delivery vehicle for treatment of GBM.
Interferon-beta (IFNβ) is a cytokine molecule also having pleiotropic anticancerous properties. Previously it has been shown by our group that AAV mediated local (intracranial) gene delivery of human IFNβ (hIFNβ) could be an effective treatment for non-invasive human glioblastoma (U87) in orthotopic xenograft mouse model.But as one of the major challenges to treat GBM effectively in clinics is its highly invasive property, in the current study we first sought to test the efficacy of our therapeutic model in a highly invasive human GBM (GBM8) xenograft mouse model.
One major limitation of using the xenograft mouse model is that these mice are immune-compromised. Moreover, as IFNβ does not interact with cross-species receptors, the influence of immune systems on GBM remains largely untested. Therefore to test the therapeutic approach in an immune-competent mouse model, we next treated a syngeneic mouse GBM model (GL261) in an immune-competent mouse (C57B6) with the gene encoding the species-matched IFNβ (mIFNβ). We also tested if combination of this IFNβ gene therapy with the current standard chemotherapeutic drug (TMZ) is more effective than any one of the therapeutic modes alone. Finally, we tested the long term safety of the AAV-mIFNβ local gene therapy in healthy C57B6 mice.
Next, we hypothesized that global genetic engineering of brain cells expressing secretory therapeutic protein like hIFNβ could be more beneficial for treatment of invasive, migratory and distal multifocal GBM. We tested this hypothesis using systemic delivery of AAV9 vectors encoding hIFNβ gene for treatment of GBM8 tumor in nude mice.
Using in vivo bioluminescence imaging of tumor associated firefly luciferase activity, long term survival assay and histological analysis of the brains we have shown that local treatment of AAV-hIFNβ for highly invasive human GBM8 is therapeutically beneficial at an early growth phase of tumor. However, systemic delivery route treatment is far superior for treating multifocal distal GBM8 tumors. Nonetheless, for both delivery routes, treatment efficacy is significantly reduced when treated at a later growth phase of the tumor.
In syngeneic GL261 tumor model study, we show that local AAV-mIFNβ gene therapy alone or in combination with TMZ treatment can provide significant survival benefit over control or only TMZ treatment, respectively. However, the animals eventually succumb to the tumor. Safety study in the healthy animals shows significant body weight loss in some treatment groups, whereas one group shows long term survival without any weight loss or any noticeable changes in the external appearances. However, histological analysis indicates marked demyelinating neurotoxic effects upon long term exposures to mIFNβ over-expressions in brain. Overall, we conclude from this study that AAV-IFNβ gene therapy has great therapeutic potential for GBM treatment in future, but the therapeutic window is small and long term continuous expression could have severe deleterious effects on health.
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Krasheninnikova, Maria Alieva. "Adipose tissue mesenchymal stromal cells as therapeutic vehicles against glioblastoma." Doctoral thesis, Universitat de Barcelona, 2012. http://hdl.handle.net/10803/97086.
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Lately adipose tissue mesenchymal stem cells (hAMSCs) have emerged as cellular vehicles for therapy of solid tumors, due to their ease of isolation and manipulation, and wound/tumor homing capacity. HAMSCs have been successfully used in suicide gene therapy, employing the prodrug activating system based on Herpes simplex virus type I thymidine kinase (HSV-TK)/ganciclovir (GCV). In the current study we demonstrate an effective model of glioblastoma therapy based on the use of genetically modified hAMSCs and in vivo monitoring of tumor and therapeutic cells.
Due to the capacity of photons to pass through living tissue, non-invasive monitoring by bioluminescence imaging has become a cutting edge technology for the study of ongoing biological processes in small lab animals. This technique uses photoproteins as cell reporters that generate light photons as byproducts of chemical reaction. Luciferases catalyze the oxidation of a substrate (luciferin) in the presence of ATP and oxygen to generate oxiluciferin, ADP and light photons. In spite of the apparent opacity of tissues, light can be detected at several millimeters of depth in live animals. Combination of several types of luciferases allows simultaneous monitoring of different cell populations proliferation or differentiation. We stably transduced hAMSCs for expression of Renilla luciferase, HSV-TK and red fluorescent protein, generating RLuc-R-TK-AMSC and U87MG human malignant glioma cells for expression of Firefly luciferase and green fluorescent protein, generating Pluc-G-U87 cells. SCID mice were stereotactically implanted in the brain first with Pluc-G-U87 and RLuc-R-TK-AMSC afterwards. Mice were subjected to GCV treatment and the therapeutic process was evaluated in real time. Tumor response was monitored in vivo by BLI. Therapeutic cell differentiation was assessed by labeling the above Renilla luciferase expressing hAMSCs with a Firefly luciferase reporter regulated by the CD31, endothelial specific promoter and in vivo monitorization. Endothelial lineage differentiation of hAMSC was impaired, by Notch1 shRNA, and therapeutic effect was assessed by BLI monitorization of tumor response.
In our model of therapy, we show that tumor size can be continuously monitored by BLI and is significantly reduced (99,9% relative to control untreated tumours) by repeated inoculations in the tumours with thymidine kinase expressing hAMSCs followed by the prodrug ganciclovir. Moreover treatment resulted in a significant prolongation of survival time. In addition, the combination of BLI and confocal microscopy analysis of therapeutic cells suggests that efficient tumor eradication results from hAMSCs homing to tumor vessels, where they differentiate to endothelial cell lineage, intensifying their cytotoxic effect by destroying tumor vasculature and negating nutrient supply. Besides, hAMSCs endothelial differentiation inhibition resulted in an inefficient therapeutic effect compared to normal hAMSC (64% vs 6% respectively). Close association between hAMSCs and gliomas stem cells integrated in the tumor vascular system seems to be essential for an effective tumor reduction.
We suggest that efficient tumor eradication is due to hAMSCs endothelial differentiation and tube location that intensifies its cytotoxic function, destroying tumor vasculature and inhibiting nutrient supply to tumor cells. Thus we propose adipose tissue hAMSCs as useful vehicles for clinical applications to deliver localized therapy to glioma surgical borders after tumor resection.
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Mucha, Birte [Verfasser], and Ulrich [Akademischer Betreuer] Hahn. "Magnetically induced directed Cell Migration as a new Approach for Therapy of Glioblastoma multiforme / Birte Mucha. Betreuer: Ulrich Hahn." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2012. http://d-nb.info/1020931280/34.
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Ferrer, Font Laura. "Tuning response to therapy in preclinical GL261 glioblastoma through CK2 targeting and temozolomide metronomic approaches: non-invasive assessment with MRI and MRSI-based molecular imaging strategies." Doctoral thesis, Universitat Autònoma de Barcelona, 2017. http://hdl.handle.net/10803/402400.
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El treball descrit en aquesta tesi fa referència al tractaments de glioblastomes (GBM) GL261 preclínics que creixen en ratolins C57BL/6, també al seguiment no invasiu de la resposta a la teràpia, usant tècniques de ressonància magnètica (RM). El model immunocompetent GL261 GBM s’indueix per injecció estereotàctica de cèl·lules GL261 a l’estriat de ratolins WT C57BL/6. Tres agents terapèutics s’han provat en aquest model: el CX-4945®, inhibidor de la proteïna kinasa II (CK2), i dos agents alquilants d’administració oral usats habitualment en pràctica clínica pel tractament de GBM: la temozolamida (TMZ) i la ciclofosfamida (CPA). La CK2 ha estat descrita com a diana potencial pel tractament del càncer, ja que contribueix en el desenvolupament tumoral, proliferació i supressió de l’apoptosi. A més, nivells elevats d’expressió s’han demostrat en varis tipus de càncer. Malgrat això, el CX-4945, el qual està en fase clínica I/II, no va produir l’efecte beneficiós desitjat descrit per altres autors quan es va usar amb el nostre model de GBM GL261. A més, el tractament d’aquest model amb 3 cicles de TMZ, ja ha estat descrit en el nostre grup amb un augment significatiu de la supervivència. Per contra, la teràpia combinada de 3 cicles TMZ amb CX-4945, inesperadament, va revertir l’efecte beneficiós de la TMZ, el que va suggerir una interferència amb el sistema immunitari relacionat amb el desenvolupament i tractament del càncer. Això ens va portar a considerar l’ús d’un esquema de teràpia metronòmic (administració de dosis baixes separades per períodes iguals i sense llargs períodes de repòs entremig) descrit amb resultats prometedors a la literatura. La CPA, la TMZ i el CX-4945 van ser analitzats en un esquema de teràpia metronòmic a dosis diferents. Dins les diferents estratègies analitzades, els millors resultats es van obtenir amb el protocol metronòmic de teràpia combinada, cada 6 dies, de TMZ i CX-4945, mostrant un increment significatiu en la supervivència. Aquests resultats també van apuntar cap a la probable participació del sistema immunitari en resposta a la teràpia, tot i que es necessitaran futurs estudis d’histopatologia per confirmar aquesta hipòtesis.
Altres resultats interessants addicionals van ser: en primer lloc, l’aparició d’un clar edema peritumoral durant moments concrets del tractament quimioterapèutic. En segon lloc, que la metodologia no-invasiva per determinar la resposta a la teràpia basat en l’anàlisi semi-supervisat de fonts d’imatge espectroscòpica de ressonància magnètica (MRSI), prèviament desenvolupat en el nostre grup amb ratolins tractats amb TMZ, també va demostrar ser viable per detectar la resposta induïda pel CPA en el nostre model preclínic. Això suggeriria que es pot observar un “patró metabolòmic de resposta” comú sota diferents estratègies terapèutiques. I en tercer lloc, l’aparició de limfomes trobats en les necròpsies de ratolins curats després de dosis cumulatives elevades de TMZ (480-1400 mg/Kg), suggerint que cal investigar estratègies per disminuir la dosi administrada d’agents alquilants per evitar efectes perjudicials en els ratolins tractats.Work described in this thesis deals with the treatment of GL261 preclinical glioblastoma (GBM) growing in C57BL/6 mice, as well as with the non-invasive assessment of response to therapy using magnetic resonance (MR) techniques. The GL261 GBM is an immunocompetent model induced by stereotactic injection of GL261 cells into the striatum of C57BL/6 WT mice. Three different therapeutic agents have been tested in this model: CX-4945®, a protein kinase II (CK2) inhibitor, and two oral alkylating agents commonly used in the clinic for GBM treatment, temozolomide (TMZ) and cyclophosphamide (CPA). CK2 has been described as a potential suitable target for cancer treatment because it contributes to tumour development, proliferation, and apoptosis suppression in cancer. In addition, elevated CK2 expression levels have been demonstrated in several cancer types. Nevertheless, CX-4945, which already reached phase I/II clinical trials, did not produce the expected beneficial effect described by others when applied to our GL261 GBM model. Moreover, the GL261 GBM treatment with 3 TMZ cycles had been already described by our group with significant survival improvement. Nevertheless, the combined therapy 3 cycle-TMZ+CX-4945, unexpectedly, reverted the beneficial effect of TMZ, which suggested an interference with the immune cycle related with cancer development and treatment. This lead us to consider the use of a metronomic schedule (administration of low and equally spaced doses of drugs without long rest periods in between) described with promising results in the literature. CPA, TMZ and CX-4945 were assessed in a 6-day schedule metronomic schedule at different doses. Among the different strategies evaluated, best results were obtained with the combined metronomic administration, every 6 days, of TMZ and CX-4945 drugs, showing significant improved survival. This also pointed to the probable paticipation of the host mice immune system in therapy response, although further histopathological studies will be needed to fully confirm this hypothesis. Additional interesting findings were: firstly, a clear peritumoral brain edema appearance during certain stages of chemotherapeutic treatment. Secondly, that the non-invasive method for therapy response assessment based in semi-supervised source analysis of Magnetic Resonance Spectroscopy Imaging (MRSI) data, previously developed in our group with TMZ-treated mice, also proved useful for detecting CPA-induced response in our preclinical model. This would suggest that a common “metabolomics responding pattern” can be observed under different therapeutic strategies. And thirdly, the necropsy findings in mice cured from GL261 GBM after high TMZ cumulative dosage (480-1400 mg/Kg), which presented relevant lymphoma incidence, suggesting that strategies to decrease the administered dose should be investigated to avoid harmful effects in mice treated with alkylating agents.
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Villamañán, de Santiago Lucía. "Unraveling CK2 inhibition and temozolomide contribution to therapy response in preclinical GL261 glioblastoma: immune system implications and magnetic resonance based nosological imaging." Doctoral thesis, Universitat Autònoma de Barcelona, 2019. http://hdl.handle.net/10803/666881.
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El glioblastoma (GB) es el tumor primario más común en adultos. Debido a su mal prognóstico, es urgente encontrar mejoras en su tratamiento. El objetivo de esta tesis es estudiar el efecto de inhibidores de CK2 y del agente alquilante Temozolamida (TMZ) a la respuesta a terapia en el modelo de GB preclínico GL261 utilizando tanto métodos in vitro (línea celular GL261) como in vivo (ratones GL261 con tumores).
La enzima CK2 es un tetrámero compuesto por dos subunidades catalíticas (α/ α') y dos subunidades reguladoras (β). En esta tesis, se describe el contenido diferencial de la subunidad CK2 α' en células GL261 con alto y bajo estado de proliferación. Esta diferencia podría afectar potencialmente a la susceptibilidad de estas células al tratamiento con inhibidores de CK2, dependiendo de su estado de proliferación. Además, el efecto del inhibidor dual de CK2 y Pim-1, TDB ha sido evaluado a nivel celular y sistémico utilizando el modelo GL261. Mientras el TDB ejerce efectos muy potentes en células tumorales in vitro, no hemos sido capaces de detectar ningún efecto inhibitorio en CK2 en la masa tumoral de animales GL261 tras la administración del fármaco. Estos resultados apuntan a que sería necesaria la reformulación del fármaco para mejorar su biodisponibilidad y sus efectos.
Resultados preliminares de nuestro grupo mostraron una mayor supervivencia en ratones con tumor tratados con una terapia metrónomica inmunogénica (1 dosis cada 6 días) con la combinación de TMZ y el inhibidor de CK2 CX-4945, a pesar de que con otros esquemas de administración no se observara ninguna mejora. En este sentido, se ha descrito que ciertos fármacos inmunogénicos son capaces de desencadenar en células tumorales la exposición y liberación de señales de peligro que provocan la activación de una potente respuesta antitumoral por parte del sistema inmune del huésped. En esta tesis, se han realizado experimentos in vitro para determinar la presencia de señales de peligro en células tratadas con ambos tratamientos, ya sea por separado o en combinación. Los resultados muestran que las células tratadas con TMZ y con la combinación CX-4945+TMZ exponen calreticulina, una señal de daño temprana en la cascada inmunogénica. Además, las células tratadas con CX-4945 y CX-4945+TMZ liberan ATP, otra señal de daño que contribuye a la activación del sistema inmune.
Por último, la evolución de ratones con tumores GL261 tratados con TMZ con un esquema de administración inmunogénico ha sido evaluada mediante imágenes nosológicas basadas en la acquisición secuencial en 2 dimensiones de resonancia magnética espectroscópica de imagen (MRSI) para el seguimiento de la respuesta a terapia no invasiva. Nuestro grupo ha descrito biomarcadores basados en imagen capaces de distinguir zonas del tumor respondedoras y no respondedoras, que podrían indicar cambios metabólicos locales, incluyendo la acción del sistema inmune del huésped en el tumor. Los resultados se muestran en forma de imágenes creadas con un código de colores (las llamadas nosológicas) analizadas por machine learning a partir de datos MRSI. El seguimiento de ratones tratados con TMZ mostró que el porcentaje de áreas tumorales identificadas como respondedoras oscilaba con los ciclos de terapia. Este periodo de oscilación (de una duración aproximada de 6 días) coincide con el ciclo inmunogénico descrito en ratones como respuesta al daño producido por TMZ. Esta información puede resultar de ayuda en la predicción de la respuesta y efectividad de una terapia y en el desarrollo de estrategias terapéuticas personalizadas.
En conclusión, el uso de terapias no mutagénicas y de ciclos de administración de terapia respetuosos con el sistema inmune, combinado con un seguimiento preciso de la respuesta a terapia mediante estrategias no invasivas, podrían contribuir a la mejora del prognóstico del glioblastoma.Glioblastoma is the most common primary brain tumor in adults with a very poor prognosis, for which urgent improvements in treatment are needed. The aim of this thesis was to unravel the contribution of the CK2 inhibitors and the alkylating agent Temozolomide (TMZ) to therapy response in the preclinical glioblastoma (GB) murine model GL261 using in vitro (GL261 cell line) and in vivo (GL261 tumor bearing mice) approaches. The enzyme CK2 is a tetramer composed by two catalytic subunits (α/ α') and two regulatory subunits (β). In this Thesis, a differential content of the CK2 α' subunit was observed in highly and slowly proliferating GL261 cells, which could potentially affect the susceptibility of these cells to the treatment with CK2 inhibitors depending on their proliferative status. Moreover, the effect of the dual CK2 and Pim-1 inhibitor TDB was evaluated in the GL261 cell line and in GL261-tumor bearing mice. While TDB showed a potent effect in vitro, we were not able to detect any inhibitory effect on CK2 in the tumor site after administration to tumor-bearing animals, suggesting that changes in the formulation of this drug would be needed to improve bioavailability and performance. Preliminary results from our group showed an increased survival in GL261-tumor bearing mice when treated in a immune-enhanced metronomic schedule (1 dose every 6 days) with the combination of TMZ and the CK2 inhibitor CX-4945, although other administration schedules did not result in such improvement. In this sense, it has been described that tumor cells treated with certain immunogenic drugs expose and release certain molecules called danger signals, leading to the activation of a potent antitumoral host immune response. We have performed in vitro studies in order to assess danger signals after both treatments alone or in combination. Results showed that TMZ and TMZ+CX-4945 GL261 treated cells expose calreticulin, an early danger signal of the immune cycle cascade. Also, CX-4945 and CX-4945+TMZ has been shown to release ATP, another danger signal that binds to P2 receptors, also contributing to the activation of the immune system. Moreover, the evolution of GL261-tumor bearing mice treated with TMZ in an immune enhanced metronomic schedule was evaluated using multislice magnetic resonance spectroscopic image (MRSI) based nosological images for noninvasive therapy response follow-up. Our group has described imaging-based biomarkers that are able to distinguish responding and non-responding tumor zones, probably sampling local changes which include host immune system action over the tumor. Results are shown as a color-coded image (the aforementioned nosological image) resulting from machine learning analysis of MRSI data. The follow-up of TMZ treated mice showed an oscillatory behavior in the percentage of tumor area identified as “responding” within the tumor mass during the transient response to therapy. This oscillation period (ca. 6 days) is in agreement with the immune system cycle in mice in response to damage produced after TMZ administration. This information would be helpful in the future for prediction of therapy response/effectiveness and in the development of personalized therapeutic strategies. In conclusion, the use of non-mutagenic therapies and immune system respectful cycles for therapy administration combined with an accurate therapy response follow-up using non-invasive strategies could help to improve the poor outcome of glioblastoma.
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Li, Min [Verfasser], and Rainer [Akademischer Betreuer] Glaß. "Studies on the two secretory peptides Apelin and Humanin to target the tumor microenvironment for glioblastoma therapy / Min Li ; Betreuer: Rainer Glaß." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2020. http://d-nb.info/121195725X/34.
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Paula, Leonardo Barcelos de. "Efeitos da Nanoemulsão de Ftalocianina Cloro-Alumínio na Regulação da Via do Fator de Crescimento Epidermal em Glioblastoma e Meduloblastoma." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/17/17135/tde-22052015-155141/.
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O glioblastoma multiforme (GBM) pode desenvolver-se rapidamente sem evidências clínicas, radiológicas ou morfológicas de um tumor precursor menos maligno. Entretanto, um novo tumor pode desenvolver-se a partir de células gliais normais ou de suas precursoras, sendo chamado de GBM primário. Já meduloblastoma é um tumor embrionário maligno do cerebelo, cuja incidência ocorre preferencialmente em crianças de até 7 anos. Os tumores de cérebro se diferem entre si em nível molecular. A amplificação do gene EGFR (Receptor do Fator de Crescimento Epidermal) com consequente elevação da expressão do receptor de EGF (Fator de Crescimento Epidermal) é mais proeminente em GBM primário quando comparado com GBM secundário e está presente também em meduloblastoma. O presente trabalho consiste em investigar o perfil de expressão gênica da via EGF e o perfil proteico de genes supressores de tumor e oncogenes de linhagens de células tumorais de glioblastoma e meduloblastoma após o tratamento com terapia fotodinâmica (TFD). O conhecimento da ação da TFD em tumores cerebrais em nível molecular permitiu a detecção de genes que participam da regulação da expressão gênica de outras vias de sinalização como RTK/Ras/PI3-K e AKT/MAPK que são responsáveis pela proliferação celular aumentada, sobrevivência ou resistência a apoptos e perda de aderência e migração, podendo revelar alto grau de invasividade. Portanto, o tratamento com terapia fotodinâmica em células tumorais do cérebro acrescenta informações relevantes sobre o processo de proliferação celular e da biologia do câncer.Glioblastoma multiforme (GBM) can develop quickly without clinical, radiological or morphological of a less malignant precursor tumor. However, a new tumor can grow from normal glial cells or their precursors, is called the primary GBM. Medulloblastoma is also a malignant embryonic tumor of the cerebellum, whose incidence occurs preferentially in children under 7 years. Brain tumors differ from between them at the molecular level. The amplification of the EGFR gene (Growth Factor Receptor Epidermal) with an increase in the expression of EGF receptor (Epidermal Growth Factor) is the main cause in primary GBM compared to secondary GBM and is also present in medulloblastoma. This work to investigate the gene expression profile of the EGF pathway and the protein profile of tumor suppressor genes and oncogenes tumor cell lines of glioblastoma and medulloblastoma after treatment with photodynamic therapy (PDT). PDT\'s share knowledge in brain tumors at the molecular level allowed to discovery of genes that participate in the regulation of gene expression of other RTK/Ras/PI3-K and AKT/MAPK signaling pathways such as that are responsible for the increased cell proliferation, survival or resistance to apoptosis and loss of adhesion and migration, and may reveal a high degree of invasiveness. For this reason, treatment with photodynamic therapy in brain tumor cells adds relevant information about the process of cellular proliferation and cancer biology.
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Mihaliak, Alicia M. "Clinically Relevant Doses of Chemotherapy Drugs Selectively and Reversibly Block Glioblastoma Neurosphere Proliferation in vitro: A Dissertation." eScholarship@UMMS, 2010. https://escholarship.umassmed.edu/gsbs_diss/492.
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My thesis research began with a project in which we were trying to determine the function of embryonic stem cell (ESC)-specific miRNAs. Using luciferase constructs containing miRNA binding sites, luciferase expression was inhibited by endogenous miRNAs in ESCs, and by exogenous miRNAs in HeLa cells. Inhibition of luciferase expression by miRNAs was inhibited in HeLa cells using 2’O-methyl-oligonucleotides. In ESCs, 2’O-methyl-oligonucleotides were only effective in partially inhibiting miR290 function. Partial inhibition of miR290 did not result in any obvious phenotypic changes in mESCs. Later studies using 2’O-methyl-oligonucleotides in ESCs were also unsuccessful. The function of ESC-specific miRNAs has since been studied by re-introducing miRNAs into Dicer -/- cells which cannot make miRNAs. These studies have shown that ESC-specific miRNAs are involved in de novo DNA methylation, self-renewal, and cell-cycle regulation.
Newly diagnosed glioblastoma (GBM) patients rarely survive more than two years even after surgery, radiotherapy, and chemotherapy using temozolomide (TMZ) or 1,3-bis(2-chloroethy)-1-nitrosourea (BCNU). Eventual regrowth of the tumor indicates that some tumor cells are resistant to therapy. GBM neurosphere-initiating cells (NICs) are thought to be similar to tumor-initiating cells in vivo, and will form invasive tumors in mice, making neurosphere cultures a good model system for studying GBMs. To test whether GBM NICs were resistant to chemotherapy, we used a neurosphere formation assay to measure the number of proliferating NICs in the presence of TMZ or BCNU.
The concentrations of chemotherapy drugs required to inhibit neurosphere formation were much less than those required to inhibit bulk cell proliferation or to induce cell death in our neurosphere cultures. For some cultures, there was a robust recovery of neurosphere formation after chemotherapy treatment which appeared to be DNA damage independent. Some of the cultures that showed significant recovery of neurosphere formation underwent reversible cell cycle arrest, possibly reducing chemotoxicity in these cultures. Collectively, these results indicate that GBM neurosphere cultures can regrow after being treated with clinically relevant doses of chemotherapy drugs. Chemotherapy-treated neurosphere cultures remained viable, and formed tumors when injected into mice. Our experiments show that these in vitro assays may be useful in predicting in vivo responses to chemotherapeutic agents.
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Toussaint, Magali. "Thérapies par rayonnements appliquées au cas du glioblastome : intérêt du suivi par spectroscopie et imagerie de diffusion par résonance magnétique : vers une thérapie bimodale." Thesis, Université de Lorraine, 2016. http://www.theses.fr/2016LORR0188/document.
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Les limitations rencontrées aujourd'hui dans le traitement du glioblastome (GBM) concernent notamment la qualité de l'exérèse dont dépend le pronostic et le manque de contrôle local de la croissance tumorale, sachant que les récidives apparaissent dans plus de 80% des cas dans le volume cible de radiothérapie. Dans ce contexte, la thérapie photodynamique interstitielle (iPDT) se présente comme un outil complémentaire prometteur qui permettrait d'améliorer le contrôle local de la tumeur. La première partie de ce travail de thèse a porté sur le suivi longitudinal par Imagerie par Résonance Magnétique (IRM) de la réponse tumorale post-iPDT sur un modèle de rat nude xenogreffé en orthotopique par un modèle de GBM humain. Le suivi par IRM et Spectroscopie par Résonance Magnétique (SRM) a fourni des indicateurs précoces de l'efficacité du traitement, permettant de discriminer dès un jour post-iPDT les animaux répondeurs des non-répondeurs. Cependant, une des limitations de la PDT, demeure la faible profondeur de pénétration de la lumière visible utilisée pour activer le photosensibilisateur et induire les réactions de photo-oxydations. La seconde partie de ce travail a porté sur l'évaluation d'un nouveau concept appelé "PDTX" permettant de coupler l'effet photodynamique à celui de la radiothérapie pour une radiothérapie photodynamique, en jouant notamment sur la complémentarité des espèces réactives de l'oxygène générées et des effets RX-induits. Pour cela, nous avons validé l'intérêt d'une nanoparticule hybride de type AGuIX® composée de terbium et de porphyrine, le terbium étant le scintillateur capable d'être excité par les rayons X et d'émettre des photons à une longueur d'onde appropriée pour activer le photosensibilisateur. Le transfert d'énergie par FRET (Förster Resonance Energy Transfer) entre le terbium et la porphyrine a été mis en exergue. Les résultats in vitro démontrent le potentiel thérapeutique de ce nouveau nano-objet à basse énergieThe limitations encountered today in the treatment of glioblastoma (GBM) involve the quality of the resection on which depends prognosis and the lack of local control of the tumor, knowing that relapses occur in 80% of cases in the radiotherapy target tumor volume. In this context, interstitial photodynamic therapy (iPDT) is a promising additional tool that would allow to improve local control of the tumor. The first part of this thesis focused on the longitudinal follow-up by Magnetic Resonance Imaging (MRI) of the post-iPDT tumor response in a nude rat model of orthotopic xenograft of human GBM cell line. MRI and Magnetic Resonance Spectroscopy (MRS) monitoring provided early indicators of the effectiveness of treatment, for discriminate from one day post-IPDT non-responders from responders animals. However, one of the limitations of PDT remains the low penetration of visible light used to activate the photosensitizer and induce reactions of photo-oxidation. This is why the second part of this research focused on the evaluation of a new concept called "PDTX" for coupling the photodynamic effect with radiotherapy effect for a photodynamic radiotherapy, playing especially on the complementarity of reactive species of oxygen generated and RX-induced effects. For this, we validated the interest of an AGuIX®-type hybrid nanoparticle composed of terbium and porphyrin, terbium being the scintillator capable of being excited by X-rays and emits photons at an appropriate wavelength in order to activate the photosensitizer. The energy transfer FRET (Förster Resonance Energy Transfer) between terbium and porphyrin was highlighted. In vitro results demonstrate the therapeutic potential of this new nano-object at low-energy
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Schoenfeld, Joshua David. "The role of redox-active iron metabolism in the selective toxicity of pharmacological ascorbate in cancer therapy." Diss., University of Iowa, 2018. https://ir.uiowa.edu/etd/6273.
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Pharmacological ascorbate, intravenous administration of high-dose vitamin C aimed at peak plasma concentrations ~ 20 mM, has recently re-emerged, after a controversial history, as a potential anti-cancer agent in combination with standard-of-care radiation and chemotherapy-based regimens. The anti-cancer effects of ascorbate are hypothesized to involve the auto-oxidation or metal-catalyzed oxidation of ascorbate to generate H2O2, and preclinical in vitro and in vivo studies in a variety of disease sites demonstrate the efficacy of adjuvant ascorbate. Furthermore, phase I clinical trials in pancreatic and ovarian cancer have demonstrated safety and tolerability in combination with chemotherapy and preliminary results suggest therapeutic efficacy. Both preclinical in vitro and in vivo studies as well as phase I clinical trials suggest a cell-intrinsic mechanism of selective toxicity of cancer cells as compared to normal cells; however, the mechanism(s) for cancer cell-selective toxicity remain unknown.
The current study aims to investigate the preclinical therapeutic efficacy of pharmacological ascorbate in combination with standard cancer therapies in three novel disease sites: non-small cell lung cancer (NSCLC), glioblastoma multiforme (GBM), and some histological subtypes of sarcoma. In vitro experiments demonstrate cancer cell-selective susceptibility to pharmacological ascorbate as compared to normal cells of identical cell lineages. Furthermore, in vivo murine xenograft models of NSCLC, GBM, and fibrosarcoma demonstrate therapeutic efficacy of pharmacological ascorbate in combination with chemotherapy and/or radiation as compared to chemotherapy and/or radiation alone without any additional therapeutic toxicity. Additionally, a phase I clinical trial in GBM subjects demonstrates the safety and tolerability of ascorbate in combination with radiation and temozolomide therapy. Although not powered for efficacy, preliminary results suggest that ascorbate may be efficacious in these subjects (median survival 18.2 months vs. 14.6 months in historical controls), and, importantly, that ascorbate therapy may be independent of MGMT promoter methylation status (median survival 23.0 months vs. 12.7 months in historical controls with absent MGMT promoter methylation). Preliminary results from a phase II clinical trial of ascorbate in combination with carboplatin/paclitaxel chemotherapy in advanced stage NSCLC subjects also demonstrate promising preliminary results related to efficacy (objective response rate (ORR) 29% and disease control rate (DCR) 93% vs. historical control ORR 15-19% and DCR 40%).
In addition to demonstrating the potential efficacy of pharmacological ascorbate in combination with standard anti-cancer therapies, this work demonstrates that the selective toxicity of ascorbate may be mediated by perturbations in cancer cell oxidative metabolism. Increased mitochondrial-derived O2- and H2O2 disrupts cellular iron metabolism, resulting in increased iron uptake via Transferrin Receptor and a larger intracellular labile iron pool. The larger pool of labile iron in cancer cells underlies the selective sensitivity of cancer cells to ascorbate toxicity through pro-oxidant chemistry with ascorbate-produced H2O2. This mechanism is further supported by the finding of increased levels of O2- and labile iron in patient lobectomy-derived NSCLC tissue as compared to adjacent normal fresh frozen tissue. Together, these studies demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in NSCLC, GBM, and sarcoma therapy and propose that further investigations of tumor and systemic iron metabolism are required to determine if these alterations can be exploited to enhance therapeutic efficacy or serve as therapeutic biomarkers.
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Tavallai, Seyedmehrad. "Lapatinib and Sorafenib Kill GBM Tumor Cells in a Greater than Additive Manner." VCU Scholars Compass, 2013. http://scholarscompass.vcu.edu/etd/3234.
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Glioblastoma multiforme (GBM) is the most common and malignant brain tumor in adults, affecting thousands of people worldwide every year, with a life expectancy, post diagnosis of 12 months. Surgery, radiotherapy and chemotherapy together, result in an overall mean survival not exceeding 15 months. Targeted therapeutic agents sorafenib, an oral multi kinase inhibitor, and lapatinib, an epidermal growth factor receptor (EGFR) inhibitor, used in combination have been shown to kill GBM cells be through inhibition of major growth mediating signaling pathways that are frequently over expressed in gliomas, including mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase/ protein kinase B (PI3K/AKT). Sorafenib can restore lapatinib induced cytotoxicity by down regulation of myeloid cell leukaemia-1 (Mcl-1) expression. Prior studies have shown Mcl-1 to play an important role in resistance to lapatinib. Furthermore, data indicated that this drug combination is able to trigger activation of autophagic and apoptotic pathways and induce endoplasmic reticulum (ER) stress response in GBM cells, collectively resulting in cell death. In conclusion, data presented here demonstrates that the combination of sorafenib and lapatinib can kill GBM cells in a greater than additive fashion, through induction of autophagy, apoptotic events (extrinsic and intrinsic) and ER stress.
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Tabouret, Emeline. "Glioblastome et angiogenèse : profils évolutifs, interaction avec l'invasivité et implications thérapeutiques." Thesis, Aix-Marseille, 2015. http://www.theses.fr/2015AIXM5012/document.
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Les glioblastomes sont les tumeurs primitives cérébrales les plus agressives de l’adulte. Elles sont caractérisées par une importante néo-angiogenèse, conduisant au développement des anti-VEGF chez ces patients. L’objectif de cette thèse était d’identifier de potentiels marqueurs prédictifs de l’activité du bevacizumab et d’analyser le profil évolutif des facteurs de l’angiogenèse. En situation de récidive d’un gliome de haut grade, si aucun facteur clinique ne semble permettre d’identifier un sous-groupe de patients bénéficiant particulièrement du bevacizumab, les taux plasmatiques avant traitement de MMP2 et MMP9, inversement corrélés entre eux suggérant un rôle biologique distinct mais relié, semblent associés à la réponse, la survie sans progression et la survie globale de patients porteurs de gliome de haut grade traités à la récidive par bevacizumab. Le rôle potentiel de ces marqueurs est renforcé par la cinétique de leurs taux plasmatiques observé sous traitement, Nous avons mis en évidence des résultats superposables chez des patientes porteuses de cancers du sein inflammatoires traités par bevacizumab en situation néo-adjuvante, renforçant l’intérêt de ces marqueurs. Par ailleurs, l’analyse de la signature angiogénique tissulaire des glioblastomes nouvellement diagnostiqués et récidivants nous a permis d’observer une modification de l’expression des facteurs de l’angiogenèse avec un possible switch de la voie VEGFR2-HIF1α en faveur de la voie CXCL12-CXCR4 à la récidive. Ces différents résultats permettent d’ouvrir de nouvelles perspectives dans le ciblage de l’angiogenèse et dans l’approche thérapeutique de patients porteurs de gliome de haut gradeGlioblastomas are the most frequent and aggressive primary brain tumors for adult. They are characterized by a high angiogenesis leading to the evaluation of the bevacizumab. Our aim was to identify potential predictive biomarkers of bevacizumab activity and to analyze the evolutive profile of the angiogenic factors during the disease. If no clinical factor allows the identification of patient subgroup benefiting of bevacizumab, MMP2 and MMP9 plasma level at baseline were correlated to response, progression-free survival and overall survival of patients with recurrent high grade glioma treated by bevacizumab. Moreover, plasma levels of these markers change during treatment and significantly varied at the time of progression. We observed similar results for patients with inflammatory breast cancer treated with neoadjuvant bevacizumab, reinforcing the potential value of these prebiomarkers. In tumor tissue, while we did not observed changes in MMP2/MMP9 expression between the initial diagnosis and the recurrence post radio-chemotherapy, we observed a modification of the expression of angiogenic factors with a potential switch from the VEGFR2-HIF1α to the CXCL12-CXCR4 pathway. These results lead to new perspectives in angiogenic modulation and glioblastoma treatment
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Ngwabyt, Bikeye Sandra-Nadia. "Etude par ARN interférence de l’expression du gène ASPM dans les cellules souches tumorales des gliomes de haut grade." Thesis, Paris 11, 2011. http://www.theses.fr/2011PA11T030/document.
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Les gliomes sont les tumeurs cérébrales primitives les plus fréquentes de l’adulte. Le glioblastome (grade IV) en est la forme la plus agressive, caractérisé par sa résistance aux traitements actuels (chirurgie, chimiothérapie et radiothérapie). La mortalité de cette pathologie est quasi constante (survie médiane de 15 mois), ce qui justifie l’importance de découvrir de nouvelles cibles thérapeutiques. Le challenge est d'arriver à identifier des marqueurs spécifiques pour proposer un schéma thérapeutique alignant des stratégies de thérapies ciblées qui vont améliorer la prise en charge clinique, la survie globale et la survie sans progression des patients atteints de ces pathologies. Deux axes sont au centre des recherches fondamentales, translationnelles et cliniques. Le premier axe se définit autour du développement de molécules inhibitrices des voies de signalisation et le second autour du concept de cellules souches tumorales (CST) de glioblastomes (GBM) découvertes récemment dans le cerveau et qui révolutionnent la conception de la transformation tumorale.ASPM (Abnormal Spindle Like Microcéphaly Associated) est une cible candidate pertinente susceptible de participer au développement des gliomes (Horvath et al., 2007 ; Hagmann et al., 2008). Cette protéine régule la prolifération des neuroblastes, elle est fortement exprimée au stade embryonnaire, mais, reste faiblement exprimée dans le cerveau adulte. Par ailleurs, ASPM est impliquée dans divers processus de cancérisation (surexprimée dans les cancers du sein, du foie et du cerveau…), toute fois, le mécanisme responsable de cette dérégulation n’est pas encore bien caractérisé.Nos études menées sur une série de 169 gliomes humains, sélectionnés à partir de notre cohorte de patients, montrent que le gène ASPM est un marqueur de la progression vers la malignité, les grades les plus élevés exprimant le plus fortement ASPM. En outre, nous avons également montré que le niveau des transcrits d’ASPM est augmenté dans les récidives de gliomes et qu’en in vitro, ASPM contrôle la formation des gliomasphères (CST de GBM) avec une augmentation de l’expression de ses transcrits dans les cultures in vitro au fil des passages. En continuité de ces observations, nous avons alors développé un sh-miR-RNA spécifique d’ASPM permettant l’extinction post-transcriptionnelle de ce gène. Les résultats obtenus in vitro montrent que la perte d’expression d’ASPM conduit à un arrêt de la prolifération et aboutit à une mort cellulaire massive.Actuellement, des modèles de greffe de gliomasphères chez la souris (orthotopique) sont en cours de développement pour confirmer les effets observés in vitro et vérifier in vivo la validité de notre approche thérapeutique. En perspective, nous tenterons d’étudier les effets du silencing d’ASPM sur la voie de signalisation la plus dérégulée (pRB / E2F ou PI3K / AKT). Enfin, nous étudierons le rôle potentiel de cette protéine dans le contrôle du cycle cellulaire, et, in fine la mise en évidence de ses partenaires…Glioblastoma (GBM) is the most frequent and aggressive form of primary brain tumors in adults; it is characterized by its resistance to current treatments (surgery, chemotherapy and radiotherapy). The prognosis is grim with a median survival of only 15 months underlining the importance to develop new therapeutic strategies. The recent development of the “tumor stem cell” (TSC) concept in hemopathies has been secondarily applied to gliomas with the identification of subpopulations of GBM cells which express neural stem cell markers and fulfill the criteria for stemness. Some evidences also suggest that this subpopulation could play a primary role in resistance to radio- and chemotherapy.ASPM (Abnormal Spindle Like Microcephaly Associated) is a protein regulating the proliferation of neuroblasts, highly expressed in the embryonic stage but weakly expressed in the adult brain. Preliminary reports suggesting that it could be involved in the development of gliomas (Horvath et al., 2007, Hagemann et al., 2008) prompted us to analyze further the role of this protein, focusing on its potential as a relevant candidate therapeutic target. In a series of 175 gliomas samples of various grades, we found that ASPM mRNA expression was strongly correlated with increasing tumor grade. We also found that ASPM expression increased at recurrence when compared to the initial lesion. Subsequently, we could demonstrate in vitro and in vivo that ASPM expression also increased over serial passages in gliomaspheres and in a mouse glioma xenograft model. In a therapeutic perspective, the effect of lentivirus-mediated shRNA post-transcriptional silencing of ASPM was evaluated in two different gliomasphere models and a dramatic proliferation arrest and cell death was observed. Taken together, these data suggest that ASPM is involved in the malignant progression of gliomas, possibly through expansion of a cancer stem cell compartment, and could be an attractive therapeutic target in glioblastoma multiforme.Another potential candidate tumor stem cell target in glioma is the sonic hedgehog pathway (hedgehog-Gli) which is required for GBM growth and stem cell expansion. In a collaborative study, it was found that NANOG, a transcription factor critically involved with self-renewal of undifferentiated embryonic stem cells, modulates gliomasphere clonogenicity, CD133+ stem cell behavior and proliferation. NANOG was regulated by hedgehog-Gli signalling and was essential for GBM tumourigenicity in orthotopic xenografts suggesting that it could also be a useful potential therapeutic target.Conclusions: Accumulating evidences suggest that tumor stem cells play an important role in the oncogenesis of gliomas and in their resistance to treatment. Our data support this concept and suggest that specific stemness markers may become useful targets to improve treatment of this devastating disease
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Pietschmann, Sophie. "Charakteristika, Therapie und Prognose von Patienten mit metastasierten WHO Grad IV Gliomen - Eine Metaanalyse individueller Patientendaten." Doctoral thesis, Universitätsbibliothek Leipzig, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-216728.
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Da hochgradige Gliome nur eine geringe Tendenz zur Metastasierung aufweisen, beschränkte sich das klinische Wissen über diesen seltenen Krankheitsverlauf bisher im Wesentlichen auf die Erkenntnisse aus Einzelfallberichten und kleineren Fallserien. Eine detaillierte Analyse der beschriebenen Fälle war bisher nicht verfügbar. Die vorliegende Arbeit stellt eine systematische Auswertung der wissenschaftlichen Literatur über Patienten mit metastasierten Glioblastomen oder Gliosarkomen dar. Unser Ziel war es, sämtliche Publikationen zu berücksichtigen, welche bis April 2013 veröffentlicht worden sind.
Mit Hilfe einer systematischen Literaturrecherche in den beiden Datenbanken PubMed und Web of Science konnten 215 Arbeiten identifiziert werden, welche insgesamt 357 Fallberichte enthielten.
Die Prognose nach Diagnose einer Metastasierung ist infaust. In der untersuchten Patientenkohorte betrug die mediane Überlebenszeit lediglich 3.0 ± 0.4 Monate. Eine univariate Datenanalyse ergab, dass Geschlecht, Alter, der histologische Subtyp und das Zeitintervall zwischen der Diagnose des Primärtumors und der Metastasen die Überlebenszeit nicht beeinflussten. Im Gegensatz dazu war eine Metastasierung, die ausschließlich außerhalb des zentralen Nervensystems (ZNS) auftrat, mit längeren Überlebenszeiten verbunden. In den letzten Jahrzehnten wurden offenbar keine entscheidenden therapeutischen Fortschritte erzielt. Fälle, die in Publikationen bis zum Jahr 2000 Erwähnung fanden, wiesen keine schlechteren Überlebenszeiten auf als die nach der Jahrtausendwende publizierten Fälle. Aktuell gibt es keinen Datensatz, der geeignet wäre, die vielfältigen Therapieansätze systematisch auf ihre Wirksamkeit hin zu überprüfen. Wir sehen hier die Notwendigkeit, ein zentrales Register zu etablieren.
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Davanzo, Nathalia Nossi. "Desenvolvimento de nanopartículas proteicas polimerizadas para veiculação de fotoativos aplicáveis ao tratamento de câncer do sistema nervoso central." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/59/59138/tde-23012017-163848/.
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Glioblastoma multiforme (GBM) é o tipo mais comum e agressivo de tumor cerebral em adultos. O tempo de vida do paciente diagnosticado com GBM é, em média, 14 meses, apesar dos tratamentos convencionais, como a radioterapia, neurocirurgia e quimioterapia. A terapia fotodinâmica (TFD), juntamente com a nanotecnologia, são tratamentos alternativos e promissores para o combate do câncer do sistema nervoso central. Sendo assim, foi desenvolvido e avaliado nanopartículas de soro albumina humano (PAM), para veiculação controlada de fotoativos (AlClPc e curcumina) aplicáveis no tratamento fotodinâmico do câncer do sistema nervoso central. As nanopartículas de albumina foram preparadas por dois métodos distintos (crosslinking químico e térmico), e para avaliar qual formulação apresentou as características desejáveis foram feitas caracterizações físico-químicas como tamanho médio de partícula, índice de polidispersividade, potencial zeta e taxa de associação dos fármacos fotossensibilizadores incorporados. A formulação preparada pelo crosslinking químico (PAMQ) exibiu características físico-quimicas satisfatórias para os estudos in vitro, obtendo tamanho médio de partículas de 250 nm, distribuição homogênea (PDI < 0,3), potencial zeta negativo (-25 mV), e quantidades de ativos incorporados na nanopartícula de albumina foi de aproximadamente 20% para a AlClPc e 40% para a curcumina. A análise morfológica foi realizada através de microscopia de força atômica (MFA), pela qual se observou o formato esférico, e composição heterogênea das nanopartículas. A formulação apresentou estabilidade com previsão de shelf life de aproximadamente 9 meses. A PAMQ apresentou ainda biocompatibilidade in vitro, na ausência de ativação fotodinâmica, frente à linhagem celular de gliobastoma humano, pelos ensaios de MTT (atividade mitocondrial in vitro). Sob irradiação de luz visível em uma dose máxima de 700 mJ.cm-2, o efeito fototóxico provocado pela PAMQAlClPc (3 ?M) reduziu a viabilidade celular a 22%, enquanto que sob irradiação de luz visível em uma dose máxima de 2000 mJ.cm-2, o efeito fototóxico provocado pela ii PAMQCurcumina (10 ?M) reduziu a viabilidade celular a 59%. Para potencializar o fotodano da célula de glioblastoma humano com a formulação PAMQAlClPc+Curcumina foi feito ensaio em diferentes tempos de irradiação, sendo que no intervalo de 6 horas, a morte celular foi de 77%, provocando um efeito fototóxico desejável para o tratamento fotodinâmico. Portanto, os resultados obtidos neste trabalho indicam que as nanopartículas protéicas apresentam grande potencial para veiculação de fármacos fotossensibilizadores para aplicação da TFD com o propósito do tratamento de câncer do sistema nervoso, incentivando estudos posteriores baseados em ensaios fotobiológicos in vitro e in vivo.Glioblastoma multiform (GBM) is the most common and aggressive type of brain tumor in adults. The lifetime of the patient diagnosed with GBM is on average 14 months, despite conventional treatments, such as radiotherapy, neurosurgery, and chemotherapy. Photodynamic therapy (PDT) with nanotechnology is an innovative and promising alternative treatment to combat central nervous system cancer. So, this work proposed to develop albumin nanoparticles (PAM) associated with photosensitizers chloro-aluminiumphtalocyanine (AlClPc) and curcumin for PDT application. Albumin nanoparticles were prepared by two different methods (chemical and thermal crosslinking), to evaluate which formulation showed desirable characteristics were performed physicochemical characterizations as mean size, polydispersity index, zeta potential and association rate of photosensitizing drugs incorporated. The formulation prepared by chemical crosslinking (PAMQ) exhibited satisfactory physicochemical characteristics for in vitro studies, obtaining an average diameter of 250 nm, low distribution (around 0,3), negative zeta potential (about -25 mV) and an active uptake rate around 20% for AlClPc and 40% for curcumin. Morphological analysis was performed using atomic force microscopy (AFM), in which was observed the spherical shape and heterogenic composition of nanoparticles. The formulation shows stability with estimated shelf-life of approximately 9 months. The PAM also demonstrated biocompatibility in the absence of photodynamic activation, using cell lines of human glioblastoma by MTT assays. Under irradiation of visible light at a maximum dose of 700 mJ cm-2, induce phototoxic by PAMQAlClPc (at 3 ?M) reduced cell viability to 22%. while under visible light of 418 nm nm the maximum dose of 2000 mJ cm-2, showed phototoxic effect caused by PAMQCurcumina (at 10 ?M) reduced cell viability to 59%. To potentialize photodamage in human glioblastoma cell with PAMQAlClPc+Curcumin was testing at different times of irradiation, wherein in the range of 6 hours, cell death was 77%, causing a desired phototoxic effect for the photodynamic treatment. Therefore, the results obtained in this study indicate that iv albumin nanoparticles have great potential to photosensitizing drugs for application of PDT for the purpose of treatment of cancer of the nervous system, encouraging further studies based in the in vitro and in vivo photobiologicals assays.
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Hardcastle, Jayson James. "Vstat120 modulates inhibits oncolytic viral therapy induced angiogenesis and innate pro-inflamatory response, augmenting oncolytic viral thereapy of glioblastom multiforme." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1305920551.
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Kratzsch, Tobias [Verfasser]. "Die zielgerichtete Therapie des Glioblastoma multiforme : Präklinische experimentelle Studien zur Wirksamkeit neuer Tyrosinkinase-Inhibitoren sowie epigenetisch wirksamer Substanzen an unterschiedlichen Glioblastom-Mausmodellen / Tobias Kratzsch." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2015. http://d-nb.info/1079524525/34.
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Clark, Aaron J. "The Expression and Function of Wilms' Tumor 1 in Malignant Glioma." VCU Scholars Compass, 2006. http://hdl.handle.net/10156/1665.
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Beyer, Stefanie. "Charakteristika, Therapie und Outcome von Patienten mit spinalem Glioblastom oder Gliosarkom - Ein systematischer Review." Doctoral thesis, Universitätsbibliothek Leipzig, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-209213.
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Gliome stellen mit 30-40 % die häufigsten intrakraniellen Tumoren dar. Darunter ist das Glioblastom, auch als Glioblastoma multiforme bezeichnet, mit ca. 50 % am stärksten vertreten und macht somit allein etwa 20 % aller Hirntumoren aus (Russell und Rubinstein 1989). Neben einer Metastasierung über den Liquor können diese Tumoren auch sehr selten als primäre Neubildung im Rückenmark vorkommen. Ebenso ist dort die Entwicklung eines sekundären Glioblastoms aus dem fortschreitenden Wachstum eines niedriggradigen Astrozytoms heraus möglich (Sure et al. 1997). Aufgrund ihres diffus infiltrativen Wachstums sowie der infausten Prognose wird das Glioblastom in der WHO-Klassifikation dem Tumorgrad IV zugeordnet (Louis et al. 2007).
Ziel dieser vorliegenden medizinischen Dissertation ist es, mit Hilfe einer Meta-Analyse individueller Patientendaten einen integrativen Überblick über die bereits vorhandene Forschung dieser seltenen Erkrankung zu erlangen. Aus einer umfangreichen Literaturrecherche resultierten 82 geeignete Publikationen, sodass von insgesamt 157 Patienten unter anderem Daten zum Veröffentlichungszeitraum, Alter und Geschlecht des Patienten, Tumorbiologie und –lokalisation sowie Therapie und Outcome erhoben werden konnten. In der statistischen Auswertung wurde die Korrelation dieser Faktoren eingehend untersucht mit dem Ziel, signifikante Aspekte herauszufiltern, die das Überleben von Patienten mit spinalem Glioblastom positiv beeinflussen können.
Trotz einer stetigen Verbesserung der bildgebenden Diagnostik durch Magnetresonanztomographie und Computertomographie sowie multimodaler Tumortherapie zeigte sich in der Auswertung der Ergebnisse, dass das mediane Überleben der Patienten mit spinalem Glioblastom bzw. Gliosarkom auf nur rund neun Monate zu beziffern ist.
Dabei konnten sowohl das Alter bei Diagnosestellung als auch das Jahr der Veröffentlichung der jeweiligen Patientenfälle als statistisch signifikante und somit bedeutende prognostische Faktoren im Hinblick auf die Überlebenszeit der Patienten identifiziert werden.
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Linz, Ute. "Ein neues Therapieschema für Glioblastoma multiforme Ergebnis einer Analyse heutiger Behandlungskonzepte sowie der Biologie und Genetik des Tumors /." Jülich : Forschungszentrum Jülich, Zentralbibliothek, 2003. http://deposit.d-nb.de/cgi-bin/dokserv?idn=969263147.
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Brünner, Jeanette [Verfasser]. "Antiangiogene Therapie in Kombination mit Temozolomid beim experimentellen MGMT-methylierten Glioblastom / Jeanette Brünner." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2013. http://d-nb.info/1042940363/34.
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