Дисертації з теми "Tyrosine Kinase Inhibitors Targeting"
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Aljohani, Hashim M. "Targeting Tyrosine Kinase Drug Resistance Mechanisms and Metastatic Pathways in Brain Tumors." University of Cincinnati / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1595846160285645.
Повний текст джерелаPadi, Sathish K. R., Libia A. Luevano, Ningfei An, Ritu Pandey, Neha Singh, Jin H. Song, Jon C. Aster, Xue-Zhong Yu, Shikhar Mehrotra, and Andrew S. Kraft. "Targeting the PIM protein kinases for the treatment of a T-cell acute lymphoblastic leukemia subset." IMPACT JOURNALS LLC, 2017. http://hdl.handle.net/10150/624055.
Повний текст джерелаZielger, David Women's & Children's Health Faculty of Medicine UNSW. "Targeting anti-apoptotic mechanisms in malignant gliomas." Awarded by:University of New South Wales. Women's & Children's Health, 2009. http://handle.unsw.edu.au/1959.4/43713.
Повний текст джерелаMukhtar, Lenah. "Targeting the Mevalonate Pathway Enhances the Efficacy of Epidermal Growth Factor Receptor – Tyrosine Kinase Inhibitors in Head and Neck Squamous Cell Carcinoma." Thesis, Université d'Ottawa / University of Ottawa, 2020. http://hdl.handle.net/10393/40391.
Повний текст джерелаHamilton, Julie Anne. "Targeting epithelial-to-mesenchymal transition (EMT) in feline oral squamous cell carcinoma (FOSCC)." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/31357.
Повний текст джерелаFujita, Haruyuki. "The tyrosine kinase inhibitor dasatinib suppresses cytokine production by plasmacytoid dendritic cells by targeting endosomal transport of CpG DNA." Kyoto University, 2013. http://hdl.handle.net/2433/174784.
Повний текст джерелаKatsoulas, Athanasia. "Design and mechanism of action of novel agents termed "combi-molecules" engineered for tandem targeting for Bcr-abl expressing leukemia cells." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111884.
Повний текст джерелаLai, Damian. "Targeting tyrosine kinase inhibitor-insensitive chronic myeloid leukemia stem/progenitor cells by effective inhibition of a novel PP2A-AHI-1-BCR-ABL-JAK2-complex." Thesis, University of British Columbia, 2015. http://hdl.handle.net/2429/54591.
Повний текст джерелаMedicine, Faculty of
Medicine, Department of
Experimental Medicine, Division of
Graduate
Sørum, Christopher. "Synthesis of new tyrosine kinase inhibitors." Thesis, Norges teknisk-naturvitenskapelige universitet, Institutt for kjemi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:no:ntnu:diva-6863.
Повний текст джерелаDoepfner, Kathrin T. "Targeting receptor tyrosine kinase signaling in acute myeloid leukemia /." Zürich, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000253043.
Повний текст джерелаMcHugh, Lynsey A. "Tyrosine kinase inhibitors as adjuncts to chemotherapy in bladder cancer." Thesis, University of Leicester, 2007. http://hdl.handle.net/2381/29860.
Повний текст джерелаWalter, Harriet Sarah. "Studies of Bruton's tyrosine kinase inhibitors in B-cell malignancies." Thesis, University of Leicester, 2018. http://hdl.handle.net/2381/42887.
Повний текст джерелаRecondo, Gonzalo. "Resistance Mechanisms to ALK Tyrosine Kinase Inhibitors (TKIs) in NSCLC." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS248/document.
Повний текст джерелаThe molecular study and classification of lung adenocarcinomas has led to the development of selective targeted therapies aiming to improve disease control and survival in patients. The anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor from the insulin tyrosine kinase receptor family, with a physiologic role in neural development. Gene rearrangements involving the ALK kinase domain occur in ~3-6% of patients with lung adenocarcinoma. The fusion protein dimerizes leading to transactivation of the ALK kinase domain in a ligand-independent and constitutive manner. Lorlatinib is a third generation ALK inhibitor with high potency and selectivity for this kinase in vitro and in vivo, and elevated penetrance in the central nervous system. Lorlatinib can overcome resistance mediated by over 16 secondary kinase domain mutations occurring in 13 residues upon progression to first - and second - generation ALK TKI. In addition, treatment with lorlatinib is effective for patients who have been previously treated with a first and a second generation or a second generation ALK TKI upfront and is currently approved for this indication. The full spectrum of biological mechanisms driving lorlatinib resistance in patients remains to be elucidated. It has been recently reported that the sequential acquisition of two or more mutations in the kinase domain, also referred as compound mutations, is responsible for disease progression in about 35% of patients treated with lorlatinib, mainly by impairing its binding to the ALK kinase domain. However, the effect of these compound mutations on the sensitivity to the repertoire of ALK inhibitors can vary, and other resistance mechanisms occurring in most patients are unknown. My PhD thesis aimed at exploring resistance to lorlatinib in patients with ALK-rearranged lung cancer through spatial and temporal tumor biopsies and development of patient-derived models. Within the institutional MATCH-R study (NCT02517892), we performed high-throughput whole exome, RNA and targeted next-generation sequencing, together with plasma sequencing to identify putative genomic and bypass mechanisms of resistance. We developed patient-derived cell lines and characterized novel mechanisms of resistance and personalized treatment strategies in vitro and in vivo. We characterized three mechanisms of resistance in four patients with paired biopsies. We studied the induction of epithelial-mesenchymal transition (EMT) by SRC activation in a patient-derived cell line exposed to lorlatinib. Mesenchymal cells were sensitive to combined SRC and ALK co-inhibition, showing that even in the presence of an aggressive and challenging phenotype, combination strategies can overcome ALK resistance. We identified two novel ALK kinase domain compound mutations, F1174L/G1202R, C1156Y/G1269A, occurring in two patients treated with lorlatinib. We developed Ba/F3 cell models harboring single and compound mutations to study the differential effect of these mutations on lorlatinib resistance. Finally, we characterized a novel mechanism of resistance caused by NF2 loss of function at the time of lorlatinib progression through the development of patients derived PDX and cell lines, and in vitro validation of NF2 knock-out with CRISPR/CAS9 gene editing. Downstream activation of mTOR was found to drive lorlatinib resistance by NF2 loss of function and was overcome by providing treatment with mTOR inhibitors.This study shows that mechanisms of resistance to lorlatinib are more diverse and complex than anticipated. Our findings also emphasize how longitudinal studies of tumor dynamics allow deciphering TKI resistance and identifying reversing strategies
Luzac, Michal Leonie. "Small Molecules as Potential Inhibitors of the Met Tyrosine Kinase Receptor." Thesis, University College London (University of London), 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.498510.
Повний текст джерелаMyers, Samuel Harry. "Development of novel receptor tyrosine kinase inhibitors by a chemocentric approach." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28769.
Повний текст джерелаCooper, Margaret S. "Anti-cancer peptides containing modified tyrosine residues." Thesis, University of Nottingham, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.246193.
Повний текст джерелаBibi, Siham. "Nouvelles approches thérapeutiques au cours des mastocytoses systémiques avancées KIT D816V+ résistantes aux inhibiteurs de tyrosine kinases." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS551.
Повний текст джерелаSystemic mastocytosis (SM) is a heterogeneous group of rare diseases characterized by abnormal accumulation of malignant mast cells (MCs) in the bone marrow (BM) and other extra-cutaneous organs. The majority of SM patients have an activating mutation in the KIT gene, usually the D816V point mutation, which is found in more than 90% of all patients. This mutation induces constitutive activation of the KIT receptor by triggering a cascade of signaling pathways, including the PI3K/AKT and the JAK/STAT5 pathways, resulting in the inhibition of apoptosis and increased survival and proliferation of malignant mast cells. However, the efficacy of the tyrosine kinase inhibitors (TKIs) on this mutation is limited due to resistance and/or toxicity associated with a lack of specificity. It is therefore critical to find new therapeutic approaches to overcome this resistance to TKIs, particularly for advanced KIT D816V+ SM. In the present thesis, we have used an approach consisting in targeting molecules activated downstream of KIT D816V, such as AKT and STAT5, using pharmacological inhibitors in combination. This allowed us to identify a synergistic combination of an AKT inhibitor (GSK690693) and an inhibitor of STAT5 (BP-1-102). These compounds are able to inhibit proliferation of KIT D816V+ cells, alone or in combination, but at very high concentrations, unfortunately not useful therapeutically. Nevertheless, these initial results have validated STAT5 and AKT as potential targets for the treatment of advanced SM. The second approach used was to target directly the KIT D816V receptor by pharmacological inhibitors. After a large screening, we identified three compounds - BLU2317, BLU2718 and DCC-2618 - which selectively inhibit the phosphorylation of KIT D816V. These compounds inhibit the proliferation of ROSAKIT D816V and HMC-1.2 cells, and induce apoptosis of these cells in a dose-dependent manner. Although the effects of these three compounds are similar, the DCC-2618 compound acts at lower concentrations relative to BLU2317 and BLU2718 compounds. In order to assess the in vivo efficacy of DCC-2618, we first established a new model of SM based on intravenous injection of cells expressing Gaussia luciferase (Gluc), ROSAKIT D816V-Gluc cells, in NSG mice. The presence of the secreted Gluc in ROSAKIT D816V-Gluc cells facilitates the detection of engraftment and allows precise monitoring of disease progression. This model reproduced within four weeks, in all grafted mice, an advanced SM similar to the one found in humans, with neoplastic MCs infiltration in BM, blood, spleen and liver, while the terminal deterioration of the clinical condition of the mice was observed after 12 weeks. Thus, this new in vivo model allows modulating the aggressiveness of the disease by varying the number of injected cells. It provides sufficient time to explore the kinetics of disease progression and especially to conduct preclinical pharmacological studies. We then evaluated the effect of DCC-2618 compound in vivo on this model. Surprisingly, DCC-2618 was not able to inhibit disease progression in treated mice, although it reached high concentrations in the BM and the plasma of treated mice. Nevertheless, we showed that the compound was able to inhibit the phosphorylation of the KIT receptor in cells derived from the BM of treated mice. In addition, contrasting to the effects observed in vitro, DCC-2618 induced an over-expression of phospho-ERK1/2 in the malignant cells of transplanted mice. This suggests that ERK1/2 may play a critical role in the resistance to DCC-2618, and possibly to other TKIs, independently of the KIT receptor. ERK1/2 could thus be a new interesting therapeutic target in the treatment of advanced SM resistant to TKIs
Dominguez-Escrig, J. L. "Tyrosine kinase and prenyl transferase inhibitors as potential therapeutics in urothelial carcinoma." Thesis, University of Newcastle upon Tyne, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.427275.
Повний текст джерелаFrancis, Sebastian. "Factors affecting the response to tyrosine kinase inhibitors in chronic myeloid leukaemia." Thesis, University of Liverpool, 2015. http://livrepository.liverpool.ac.uk/2050461/.
Повний текст джерелаReiff, Sean. "Utilizing Reversible Bruton’s Tyrosine Kinase Inhibitors to Circumvent Acquired Resistance to Ibrutinib." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1523372591057698.
Повний текст джерелаD'Cunha, Ronilda Raymond. "Treatment strategies to reverse efflux transporter-mediated resistance to Tyrosine kinase inhibitors." Diss., University of Iowa, 2018. https://ir.uiowa.edu/etd/6563.
Повний текст джерелаLogan, John Gordon. "Targeting bone-microenvironment-tumour cell interactions : IGF-1 receptor kinase inhibitors." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/8184.
Повний текст джерелаDillon, Anne M. R. "An investigation of protein tyrosine phosphorylation in equine blood platelets." Thesis, University of Cambridge, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.390250.
Повний текст джерелаKnights, Victoria E. E. "Tumour cell responses to novel fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors." Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608393.
Повний текст джерелаFilho, Pedro Aurio Maia. "Genotoxicity and mutagenicity in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors." Universidade Federal do CearÃ, 2017. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=19044.
Повний текст джерелаChronic myelogenous leukemia (CML) is a myeloproliferative disease of hematopoietic stem cells, characterized by the presence of the Philadelphia (Ph) chromosome, originating from a reciprocal translocation between the long arms of chromosomes 9 and 22, forming the gene BCR-ABL, which encodes a BCR-ABL oncoprotein with constitutive tyrosine kinase activity. The clinical course of CML is often divided into three phases: chronic, accelerated, and blast. The treatment of choice for the chronic phase is the first-generation tyrosine kinase inhibitor (TKI), imatinib mesylate, and for refractory patients, second-generation TKIs (dasatinib or nilotinib) are used. Studies have shown that residual leukemia may persist even in the best responders to TKI, since therapy is not curative. In this context, the present study aimed to evaluate the genotoxicity and mutagenicity of TKI in patients with CML followed at the hematology clinic of the Walter CantÃdio University Hospital (HUWC). It is a cross-sectional study with 44 patients with clinical and molecular diagnosis of CML. Patients were stratified into three groups: diagnosis (CML D) (n = 5), use of first generation TKI (CML) (n = 31) and use of second generation TKI (CML) (n = 8). The control group (CG) consisted of apparently healthy individuals. Genotoxicity and mutagenicity were analyzed by the comet assay and micronucleus test. Statistical analysis of the data was performed using the GraphPad Prism 6.0 program using the Kruskal-Wallis or ANOVA, Mann Whitney or T-student tests, depending on the normality of the data and the level of significance was 5% (p < 0.05). Patients with CML had a statistically higher ADN damage index (DI) compared to CG (p < 0.0001). When the patients were stratified, a progressive increase of the DNA ID was verified in the groups: CML D, CML G1 and CML G2, respectively, relative to GC (p < 0.05). Patients with CML had a statistically higher micronucleus index (NMI), nucleoplasmic bridge index (NPI) and nuclear bud index (NBI) compared to the CG (p < 0.05). By stratifying patients with CML, it was found that patients in the G1 and G2 CML groups had statistically higher NMI and NPI compared to CG (p <0.001). NMI was also elevated in the CML G2 group in relation to the patients in the CML D group (p <0.01). The nuclear bud index (NBI) did not present statistical difference in the analyzes performed after the stratification of the groups. The TKI revolutionized CML therapy, improving patient survival. However, these results point to the relevance of studies that evaluate the possible genotoxic and mutagenic effects of this therapy in the long term. The mechanisms involved should be elucidated for the purpose of improving treatment as well as assessing the clinical impact this harm may cause.
A leucemia mielÃide crÃnica (LMC) à uma doenÃa mieloproliferativa das cÃlulas-tronco hematopoÃticas, caracterizada pela presenÃa do cromossomo Philadelphia (Ph), originado a partir de uma translocaÃÃo recÃproca entre os braÃos longos dos cromossomos 9 e 22, formando o gene BCR-ABL, que codifica uma oncoproteÃna BCR-ABL com atividade tirosino-quinase constitutiva. O curso clÃnico da LMC à frequentemente dividido em trÃs fases: crÃnica, acelerada e blÃstica. O tratamento de escolha para a fase crÃnica à o inibidor de tirosino-quinase (ITK) de primeira geraÃÃo, mesilato de imatinibe, e para os pacientes refratÃrios, utiliza-se os ITK de segunda geraÃÃo (dasatinibe ou nilotinibe). Estudos tÃm demonstrado que a leucemia residual pode persistir mesmo nos melhores respondedores aos ITK, uma vez que a terapia nÃo à curativa. Nesse contexto, o presente estudo objetivou avaliar a genotoxicidade e mutagenicidade dos ITK em pacientes com LMC acompanhados no ambulatÃrio de hematologia do Hospital UniversitÃrio Walter CantÃdio (HUWC). Trata-se de um estudo transversal com 44 pacientes com diagnÃstico clÃnico e molecular de LMC. Os pacientes foram estratificados em trÃs grupos: ao diagnÃstico (LMC D) (n=5), em uso de ITK de primeira geraÃÃo (LMC G1) (n=31) e em uso de ITK de segunda geraÃÃo (LMC G2) (n=8). O grupo controle (GC) foi composto por indivÃduos aparentemente saudÃveis. A genotoxicidade e mutagenicidade foram analisadas atravÃs do ensaio cometa e teste de micronÃcleos. A anÃlise estatÃstica dos dados foi realizada atravÃs do programa GraphPad Prism 6.0 utilizando-se os testes de KruskalâWallis ou ANOVA, Mann Whitney ou T-student, dependendo da normalidade dos dados e o nÃvel de significÃncia foi de 5% (p < 0,05). Pacientes com LMC apresentaram Ãndice de dano (ID) no DNA estatisticamente mais elevado em comparaÃÃo ao GC (p < 0,0001). Quando os pacientes foram estratificados, foi verificado um aumento progressivo do ID no DNA nos grupos: LMC D, LMC G1 e LMC G2, respectivamente, em relaÃÃo ao GC (p < 0,05). Pacientes com LMC apresentaram Ãndice de micronÃcleos (IMN), Ãndice de pontes nucleoplasmÃticas (IPN) e Ãndice de buds nucleares (IBN) estatisticamente mais elevados em comparaÃÃo com o GC (p < 0,05). Ao se estratificar os pacientes com LMC, foi verificado que pacientes dos grupos LMC G1 e G2 apresentaram IMN e IPN estatisticamente mais elevados em comparaÃÃo ao GC (p < 0,001). O IMN tambÃm foi elevado no grupo LMC G2 em relaÃÃo aos pacientes do grupo LMC D (p < 0,01). O Ãndice de bud nuclear (IBN) nÃo apresentou diferenÃa estatÃstica nas anÃlises realizadas apÃs a estratificaÃÃo dos grupos. Os ITK revolucionaram a terapia da LMC, melhorando a sobrevida dos pacientes. No entanto esses resultados alertam para a relevÃncia de estudos que avaliem os possÃveis efeitos genotÃxicos e mutagÃnicos dessa terapia a longo prazo. Os mecanismos envolvidos devem ser elucidados com a finalidade de aprimorar o tratamento, bem como avaliar o impacto clÃnico que esse dano pode causar.
Gregory, T., and John Bossaer. "Pharmacogenomics Guided Dosing of Tyrosine Kinase Inhibitors in a Patient with Renal Cell Carcinoma." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/etsu-works/7796.
Повний текст джерелаJunker, Bernd. "Lokale Therapie der Sauerstoff-induzierten angioproliferativen Retinopathie im Mausmodell small molecule receptor tyrosine kinase inhibitors /." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=971428387.
Повний текст джерелаAbe, Mineo. "Development of peptide inhibitors of the receptor tyrosine kinase activity in a novel inhibitory mechanism." 京都大学 (Kyoto University), 2010. http://hdl.handle.net/2433/120515.
Повний текст джерелаNuseibeh, Samir. "Modulation of mucin expression in respiratory epithelial cells : effect of ErbB receptor tyrosine kinase inhibitors." Thesis, Imperial College London, 2009. http://hdl.handle.net/10044/1/8229.
Повний текст джерелаHervieu, Vilches Alexia. "Understanding and targeting PI3K downstream of oncogenic Met mutant." Thesis, Queen Mary, University of London, 2015. http://qmro.qmul.ac.uk/xmlui/handle/123456789/33935.
Повний текст джерелаLougheed, Caroline. "Targeting focal adhesion signaling in cancer and acquired resistance to focal adhesion kinase inhibitors." Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=94996.
Повний текст джерелаDans la progression du cancer, le développement de métastases est caractéristique de la phase terminale et rend le traitement difficile. Afin que des métastases se dévelopment, les cellules cancéreuses doivent acquérir de la motilité ainsi qu'un phénotype invasif. Considéré come l'une des plus importantes protéines participant dans la motilité cellulaire, la prot éine Focal Adhesion Kinase (FAK) a émergé comme une bonne cible thérapeutique pour l'inhibition de métastases par la création de drogues ciblées et de petites molécules inhibitrices. Par conséquent, une molécule inhibitrice de l'activation de FAK et sa signalisation a été récemment développée. Cependant, J'ai demontré que la résistance est commune parmis ces drogues. Le dévelopement et la classification des clones de cellules résistantes ont permi d'élucider un mécanisme impiquant en partie une amplification de l'activité FAK; ce mécanisme permetter a de découvrir des analogues de deuxième génération pour surmonter ou éviter la résistance. L'ensemble de données présentées ci-dessous supportet le rôle de FAK comme une cible importante dans la prévention de métastases et exposent les futur directions pour contourner la résistance aux inhibiteurs de FAK.
Lazrek, Yassamine. "Ciblage tumoral du récepteur HER3 à l’aide d’anticorps : vers de nouvelles pistes thérapeutiques." Thesis, Montpellier 1, 2013. http://www.theses.fr/2013MON13524.
Повний текст джерелаDue to their implication in the cellular proliferation, the invasion and their surexpression in numerous cancers, the tyrosine kinase receptors of HER family constitute one of the best targets in oncology. Within this family, the human epidermal growth factor receptor 3 (HER3) plays a role in tumorigenesis of different cancers (Breast, melanoma, pancreas and ovary). This receptor is implicated in drug resistance and he is over expressed in cancers that are not eligible for the currently approved targeted therapies. To this end, we generated specific antibodies (Abs) against domain 1 (D1) and domain 3 (D3) of HER3 that recognize epitopes that do not overlap with the neuregulin-binding site. The fully human H4B-121 Ab and the mouse monoclonal Abs 16D3-C1 and 9F7-F11 inhibited tumor growth in nude mice xenografted with epidermoid, pancreatic, or triple-negative breast cancer cells independently of NRG addiction, HER2 status and p53/PTEN mutations. The combination of one anti-HER3 Ab and trastuzumab improved tumor growth inhibition in mice xenografted with HER2(low) cancer cell lines, for which trastuzumab alone shows no or moderate efficiency. Ab-induced disruption of tumor growth was associated with G1 cell cycle arrest, proliferation inhibition, and apoptosis of cancer cells. Anti-HER3 Abs blocked HER2/HER3 heterodimerization and HER3 phosphorylation at the cell membrane, leading to inhibition of phosphorylation of the downstream AKT targets murine double minute 2, X-linked inhibitor of apoptosis, and forkhead box O1. Anti-HER3 Abs can also induice antibody dependant cell-mediated cytotoxicity. This study demonstrates that anti-HER3 D1 and D3 Abs could represent a new option for immunotherapy of pancreatic and triple-negative breast cancers
Lella, Divya Jyothi. "Functionalization and Modification of Naphthaquinone Analogs as HER2 Kinase Inhibitors." TopSCHOLAR®, 2014. http://digitalcommons.wku.edu/theses/1325.
Повний текст джерелаBroadbridge, Robert James. "Design and synthesis of novel inhibitors to the SH2 domain of the protein tyrosine kinase p56lck." Thesis, University of Southampton, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.494712.
Повний текст джерелаGrockowiak, Élodie. "Role of the Bone Morphogenetic Proteins pathway in tyrosine kinase inhibitors resistance in Chronic Myeloid Leukemia." Thesis, Lyon, 2017. http://www.theses.fr/2017LYSE1253.
Повний текст джерелаChronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm caused by the expression of the oncogenic protein kinase, BCR-ABL. The Tyrosine Kinase Inhibitors (TKI) specifics of BCR-ABL kinase dramatically changed the outcome of CML, turning a life-threatening disease into a chronic illness. However, TKI are not yet curative since most CML patients still retain progenitors and leukemic stem cells (LSC) in bone marrow permanently. Thus, approximately 60% of patients that achieve Complete Molecular Remission =2 years relapse following TKI withdraw. Moreover, some patients develop true resistance to TKI, with ~30% due to unknown mechanisms. In chronic phase CML (CP-CML), LSC survive, sustain interactions with their niche where resistance mechanisms can occur, responsible for disease persistence and relapse following treatment cessation. In normal bone marrow, Bone Morphogenetic Proteins (BMP) pathway regulate the fate and proliferation of normal hematopoietic stem cells, as well as interactions with their niche. The deregulations of this pathway drive early steps of CML development. In newly diagnosed CP-CML patients, high concentration of BMP2/4 in the leukemic niche allows LSC maintenance and sustains a permanent pool of leukemic progenitors expressing elevated levels of BMPR1b receptor. Here, we report that alterations of the BMP pathway persist in TKI-CML resistant patients. As compared to patients in Complete Cytogenetic Remission (CCyR), cells isolated from TKI-resistant patients display a high level of BMPR1b expression in immature cells and high levels of BMP2/4 in bone marrow, provided by the niche and by the leukemic immature cells themselves. BMP allow leukemic stem cells resistance to treatments through binding to BMPR1b. Interestingly, BMP2/4-treated cells overexpressed TWIST-1, a transcription factor that we previously identified as a predictive factor of CML resistance
Šramel, Peter. "A synthesis and biological screening of predicted inhibitors of Tyrosine Kinases, e.g. KDR, designed in silico." Thesis, Strasbourg, 2017. http://www.theses.fr/2017STRAF064.
Повний текст джерелаProtein kinases represent a group of enzymes responsible for phosphorylation - transfer of aphosphate group from adenosine triphosphate (ATP) to tyrosine or serine/threonine residues. Protein phosphorylation is one of the most important tools regulating a cell activity. A cell "signalization" through an endothelial receptor tyrosine kinase VEGFR2 TK (KDR) is the important pathway influencing growth of a tumor. Small-molecule inhibitors of VEGFR2 TK (VEGFR2 TKls) have become an important tool for the treatment of various types of cancer. This dissertation thesis resulted in a discovery of 16 biologically active N,5-diaryloxazol-2-amines (IC50, VEGFR2 TK). Very good results were achieved especially with compounds 189, 191, 211, 214, 220, 221, 223 and 4 exhibiting the activity under 500 nM
Atatreh, Noor Aldeen S. A. "Design, synthesis and evaluation of inhibitors for Src tyrosine kinase and their impact on colorectal cancer cells." Thesis, University of Manchester, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.492836.
Повний текст джерелаRogers, Susanne Jane. "Towards the Mechanistic Effects of Tyrosine Kinase Inhibitors in Squamous Cell Carcinoma of the Head and Neck." Thesis, Institute of Cancer Research (University Of London), 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.516267.
Повний текст джерелаBhosle, J. "Modulation of DNA strand break induction and repair by tyrosine kinase inhibitors targeted against EGFR and HER2." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1344180/.
Повний текст джерелаRoos, Kelly. "The effect of sunitinib on neuroblastoma and glioblastoma cell growth." University of the Western Cape, 2020. http://hdl.handle.net/11394/7952.
Повний текст джерелаCancer is a global health catastrophe, with neuroblastoma, the most common solid childhood tumor, and glioblastoma, a deadly brain tumor, being aggressive and unresponsive to current treatment modalities. These tumors are known to utilize uncontrollable cell proliferative capabilities as a mechanism for tumor survival. Therefore, malignant cell growth can be mitigated by targeting the essential proteins that regulate cell growth, such as receptor tyrosine kinases (RTKs). Under normal physiological conditions, RTKs bind with varying affinity to mitogenic stimuli such as growth factors such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) which, in turn, leads to receptor phosphorylation and activation.
Saleem, Mohammed Umer. "Preclinical evaluation of pharmacological strategies designed to enhance the activity of established and novel anti-cancer drugs : synopsis - evaluation of pharmacological strategies designed to modulate the Warburg effect, enhance the activity of tyrosine kinase inhibitors and novel analogues of Temozolomide." Thesis, University of Bradford, 2014. http://hdl.handle.net/10454/13842.
Повний текст джерелаGraf, Michael Georg Eduard. "Inhibition of ErbB2 by receptor tyrosine kinase inhibitors causes myofibrillarstructural damage without cell death in adult rat cardiomyocytes /." [S.l.] : [s.n.], 2009. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
Повний текст джерелаSkoglund, Karin. "Influence of CYP3A enzymes and ABC transporters on the activity of tyrosine kinase inhibitors in chronic myeloid leukemia." Doctoral thesis, Linköpings universitet, Avdelningen för läkemedelsforskning, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-97427.
Повний текст джерелаLou, Qiang 1962. "Identification of peptide substrates and development of pseudosubstrate-based peptide inhibitors for p60(C-SRC) protein tyrosine kinase." Diss., The University of Arizona, 1996. http://hdl.handle.net/10150/282230.
Повний текст джерелаKamath, Jayesh Ramrao. "Development of pseudosubstrate-based peptide and peptidomimetic inhibitors of p60ᶜ⁻ˢʳᶜ protein tyrosine kinase using combinatorial chemistry technology". Diss., The University of Arizona, 2000. http://hdl.handle.net/10150/289173.
Повний текст джерелаShor, Audrey Cathryn. "Src kinase inhibitors for the treatment of sarcomas : cellular and molecular mechanisms of action." [Tampa, Fla] : University of South Florida, 2007. http://purl.fcla.edu/usf/dc/et/SFE0001906.
Повний текст джерелаFilho, TarcÃsio Paulo de Almeida. "Expression and mutational profile of BCR-ABL gene in patients with chronic mieloid leukemia treated with tyrosine kinase inhibitors." Universidade Federal do CearÃ, 2017. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=19145.
Повний текст джерелаMost patients with chronic myeloid leukemia (CML) express the transcripts b2a2, b3a2 or both of the BCR-ABL gene. The role of these transcripts in the prognosis of patients undergoing treatment with tyrosine kinase inhibitors (ITKs) has been poorly investigated and remains unclear to date. In this study, we evaluated the prognostic value of the main transcripts in patients with CML, by evaluating the expression and mutational profile of the BCR-ABL gene in patients treated with ITKs. Sixty patients with CML were evaluated transversally. Demographic, hematological, and clinical data and mutation profile of CML patients treated with ITKs were obtained from medical records. Molecular analyzes for the determination of transcripts and mutations (T315, E255V and Y253H) were performed by the qPCR technique. Statistical analyzes were performed using the Kruskal-Wallis or one-way ANOVA tests, depending on the normality of the data. The level of significance was 0.05 and p values of less than 0.05 were considered significant. Of the sixty patients, 12 (20%) expressed the b2a2 transcript, 18 (30%) the b3a2 transcript, 10 (16.7%) both b2a2/b3a2 transcripts and 20 (33.3%) had undetectable levels. Twenty-eight patients (46.7%) were female and 32 (53.3%) were males, with a mean age of 46.5 Â 15.7 years (ranging from 19-82). The comparative analysis of hematological data with transcripts showed a significant difference in the number of leukocytes in patients expressing the b2a2 and b3a2 transcripts (p <0.05), with patients with the b2a2 transcript associated with lower amounts. The other data, hematological and clinical, did not show statistically significant differences in relation to transcripts (p>0.05). Regarding mutations of the kinase domain, the presence of the T315, E255V and Y253H mutations in the study patients was not evidenced. These are the first results found in this population, being necessary more studies with a greater number of individuals and evaluation of the cytogenetic and molecular responses to the treatment. If confirmed as a prognostic factor capable of providing better outcomes and response to treatment, the transcripts could be used in the elaboration of new mathematical models for patient risk stratification and in the selection of the best therapy with ITKs for patients with CML.
A maioria dos pacientes com leucemia mieloide crÃnica (LMC) expressam os transcritos b2a2, b3a2 ou ambos do gene BCR-ABL. O papel desses transcritos no prognÃstico dos pacientes em tratamento com inibidores de tirosina quinase (ITKs) tem sido pouco investigado e atà o momento permanece incerto. Neste estudo, foi avaliado o valor prognÃstico dos principais transcritos nos pacientes com LMC, atravÃs da avaliaÃÃo da expressÃo e perfil mutacional do gene BCR-ABL em pacientes tratados com ITKs. Sessenta pacientes com LMC foram avaliados transversalmente. Os dados demogrÃficos, hematolÃgicos, clÃnicos e o perfil de mutaÃÃes dos pacientes com LMC tratados com ITKs foram obtidos atravÃs dos prontuÃrios. As anÃlises moleculares para a determinaÃÃo dos transcritos e das mutaÃÃes (T315, E255V e Y253H) foram realizadas pela tÃcnica de qPCR. As anÃlises estatÃsticas foram realizadas atravÃs dos testes Kruskal-Wallis ou one-way ANOVA dependendo da normalidade dos dados. O nÃvel de significÃncia foi de 0,05 e valores de p inferiores a 0,05 foram considerados significativos. Dos sessenta pacientes, 12 (20%) expressavam o transcrito b2a2, 18 (30%) o transcrito b3a2, 10 (16,7%) ambos os transcritos b2a2/b3a2 e 20 (33,3%) apresentaram nÃveis indetectÃveis. Vinte e oito pacientes (46,7%) eram do sexo feminino e 32 (53,3%) do sexo masculino, com mÃdia de idade 46,5  15,7 anos (variando de 19-82). A anÃlise comparativa dos dados hematolÃgicos com transcritos mostrou diferenÃa significante na quantidade de leucÃcitos nos pacientes que expressavam os transcritos b2a2 e b3a2 (p<0,05), sendo os pacientes com o transcrito b2a2 associados a quantidades inferiores. Os demais dados, hematolÃgicos e clÃnicos, nÃo mostraram diferenÃa estatisticamente significantes com relaÃÃo aos transcritos (p>0.05). Quanto Ãs mutaÃÃes do domÃnio quinase, nÃo foi evidenciada a presenÃa das mutaÃÃes T315, E255V e Y253H nos pacientes em estudo. Estes sÃo os primeiros resultados encontrados nesta populaÃÃo, sendo necessÃrio mais estudos com um nÃmero maior de indivÃduos e avaliaÃÃo das respostas citogenÃticas e moleculares ao tratamento. Se confirmado como fator de prognÃstico capaz de proporcionar melhores desfechos e resposta ao tratamento, os transcritos poderÃo ser empregados na elaboraÃÃo de novos modelos matemÃticos para estratificaÃÃo de risco dos pacientes e na seleÃÃo da melhor terapia com ITKs para pacientes com LMC.
Djerf, Emelie. "Studies on the effect of ErbB tyrosine kinase inhibitors on malignant melanoma growth and survival in vitro." Licentiate thesis, Linköping : Department of Clinical and Experimental Medicine, Linköping University, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-19949.
Повний текст джерелаDe, Benedittis Caterina <1983>. "Next-Generation Sequencing-Based Mutations Scanning Strategy of the BCR-ABL Kinase Domain in Patients with PhiladelPhia-Chromosome Positive Leukemias Treated with Tyrosine Kinase Inhibitors." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2015. http://amsdottorato.unibo.it/6753/.
Повний текст джерелаAnanthula, Hari Krishna. "Pharmacokinetic Evaluation and Modeling of Tyrosine Kinase Inhibitors Nilotinib and Imatinib in Preclinical Species to Aid their Repurposing As Anti-Viral Agents." University of Cincinnati / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504802233495176.
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