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Barbosa, Keila Cardoso. "Estudo de polimorfismos dos genes EGF e EGFR em astrocitomas difusamente infiltrativos." Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/5/5138/tde-24062008-150231/.
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INTRODUÇÃO: Os astrocitomas difusamente infiltrativos são os tumores mais freqüentes de Sistema Nervoso Central (SNC) com uma taxa de 5-7 novos casos por 100.000 pessoas ano. São tumores altamente invasivos e estão associados com alterações de alguns genes como EGF (fator de crescimento epidérmico) e o EGFR (receptor do fator de crescimento epidérmico), que podem criar um aumento da atividade mitogênica, acarretando aumento de proliferação e maturação celular, apoptose, angiogênese e metástase. O nível de expressão destes genes pode ser influenciado por alterações genéticas, como a presença de polimorfismos. Uma mudança única de base (SNP) pode alterar a expressão gênica e, sendo assim, estar associada ao aumento do risco de desenvolver astrocitomas. Nesse trabalho, foram analisados 2 SNPs na região não traduzida (c.-191C>A e c.-216G>T) e um SNP no exon 16 (c.2073A>T) do gene EGFR, e um outro SNP na região não traduzida no gene EGF (c.61A>G). Os SNPs foram associados a expressão gênica do EGFR e a sobrevida dos pacientes. MÈTODOS: Foi realizado um estudo caso-controle com 193 casos de astrocitomas difusamente infiltrativos e 200 controles por amplificação por PCR seguido de digestão enzimática. Os produtos digeridos das amostras foram analisados por eletroforese em gel de agarose e poliacrilamida e corados com brometo de etídeo. A expressão gênica foi realizada após extração de RNA do tecido tumoral seguida de transcrição reversa e PCR em tempo real. Testes de qui-quadrado, odds ratio (OR), intervalo de confiança 95% (IC95%), t de Student e curvas de Kaplan-Meier foram realizados para análises estatística. RESULTADOS: A análise das freqüências dos genótipos dos polimorfismos mostrou uma diferença na distribuição entre casos e controles para o polimorfismo c.2073A>T. Pacientes com o genótipo TT apresentou um menor risco para astrocitoma quando comparados com o genótipo AA (OR=0,51, IC95%=0,29-0,99). Nenhuma correlação foi encontrada para os outros polimorfismos analisados. Também não foi encontrada correlação entre os genótipos dos polimorfismos e os níveis de expressão de EGFR e a sobrevida dos pacientes. CONCLUSÃO: Nosso trabalho mostrou haver um possível fator de proteção quando o paciente é portador do genótipo TT, o que pode levar a uma diminuição do risco de desenvolver o tumor. Pacientes com genótipo TT do polimorfismo c.2073A>T do gene EGFR apresentam um menor risco para astrocitomas difusamente infiltrativos do que os com o genótipo AA.INTRODUCTION: Diffusely infiltrative astrocytomas are the most frequent tumors of the Central Nervous System (CNS) with a rate of 5-7 new cases in 100,000 individuals per year. They are highly invasive, and they are associated to alterations in some genes as EGF (epidermal growth factor) and EGFR (epidermal growth factor receptor), which may increase mitogenic activity, leading to increase of proliferation, cellular maturation, apoptosis, angiogenesis, and metastasis. Genetic alterations, as presence of polymorphisms of single nucleotide change (SNP) could influence their expression level, and thus could be associated to increased risk in developing astrocytomas. In the present study, two SNP of non-coding region (c.-191C>A and c.-216G>T) and one SNP in exon 16 (c.2073A>T) of EGFR, and another SNP of non-coding region of EGF (c.61A>G) were analyzed. The SNPs were associated to EGFR expression level and to survival time. METHOD: a case-control study of 193 of diffusely infiltrative astrocytomas and 200 controls was carried out, with PCR amplification and enzymatic digestion, which products were analyzed in agarose gel or polyacrylamide gel electrophoresis stained by ethidium bromide. EGFR expression level was studied by real time PCR after RNA extraction followed by reverse transcription of tumor tissues compared to epileptic non-neoplastic brain tissues. Stastistical analysis were performed by chi-square, odds ratio (OR), 95% confidence interval (95% CI), Student-t test and Kaplan Meier. RESULTS: The polymorphic genotype frequency was different between case and controls for the polymorphism c.2073A>T. Patients with TT genotype presented lower risk to develop astrocytoma when compared to genotype AA (OR=0.51, CI95%=0.29- 0.99). No other correlation was observed for the remaining studied polymorphisms. There was neither correlation between the polymorphic genotypes and the EGFR expression levels nor with survival time. CONCLUSION: The present study showed a possible protection factor in developing astrocytomas for the patients harboring the genotype TT of c.2073A>T polymorphism of EFGR, thus the patients presenting TT genotype have lower risk to develop diffusely infiltrative astrocytoma than patients presenting the genotype AA.
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Bauer, Philip [Verfasser]. "Der Einfluss der EGFR Expressionsdichte auf die EGFR Antikörper gerichteten Abwehrmechanismen / Philip Bauer." Kiel : Universitätsbibliothek Kiel, 2017. http://d-nb.info/1127044206/34.
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Hamilton, S. J. "An investigation of EGFR binding and modulation of EGFR signalling pathways using synthetic peptides." Thesis, Queen's University Belfast, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.403480.
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Balko, Justin M. "THE PHARMACOGENOMICS OF EGFR-DEPENDENT NSCLC: PREDICTING AND ENHANCING RESPONSE TO TARGETED EGFR THERAPY." Lexington, Ky. : [University of Kentucky Libraries], 2009. http://hdl.handle.net/10225/1062.
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Thesis (Ph. D.)--University of Kentucky, 2009.Title from document title page (viewed on September 17, 2009). Document formatted into pages; contains: viii, 175 p : ill. (some col.). Includes abstract and vita. Includes bibliographical references (p. 103-123).
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Januário, Mara Elisama da Silva. "Estudo da função de AP1y2 e Alix no direcionamento de proteínas para degradação em lisossomos ou liberação em vesículas extracelulares." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/17/17136/tde-23042018-164806/.
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A degradação lisossomal de proteínas de membrana endocitadas ocorre por meio do direcionamento destas proteínas para vesículas intralumenais (ILVs), formadas no lúmen dos corpos multivesiculares (MVBs), e subsequente fusão dos MVBs com lisossomos. Apesar de sua importância na degradação de proteínas transmembrana, os MVBs possuem outra importante função, a de produzir e liberar vesículas extracelulares (EVs). Neste processo os MVBs não se fundem com lisossomos, mas sim com a membrana plasmática o que resulta na liberação das vesículas residentes no interior dos MVBs para o meio extracelular. Diversas proteínas participam do direcionamento de cargas para os MVBs. Os estudos que delinearam a via de tráfego mediada por AP1 concentraram-se nos complexos contendo a subunidade ?1 que medeia o transporte de proteínas entre a rede trans-Golgi (TGN) e endossomos. Contudo, o genoma humano codifica uma segunda isoforma desta subunidade, denominada ?2, e evidências presentes na literatura e também observadas por nosso grupo indicam que AP1?2 pode regular uma via de tráfego distinta da via classicamente atribuída a AP1. Utilizando ensaios de uptake de EGF em condições onde foi realizado o KD de ?1 ou ?2, foi observado que o silenciamento de ?2 prejudica a degradação de EGF internalizado por seu receptor. Efeito também observado para o próprio receptor de EGF (EGFR) em ensaios de biotinilação da superfície celular. Demonstrando que a degradação lisossomal do complexo EGF-EGFR pela via canônica dos MVBs requer o complexo AP1?2, mas não AP1?1. Em conjunto com este estudo também foi analisado o mecanismo molecular de direcionamento da proteína Nef do HIV-1 para os MVBs associados a liberação de EVs. A proteína Nef do HIV é determinante na modulação do ambiente intracelular favorecendo a replicação do vírus e progressão à AIDS. Nef é ativamente secretado em EVs e sua liberação pode levar a apoptose de células vizinhas aceptoras dessas vesículas. Nef também medeia a redução dos níveis de CD4 e moléculas de MHC-I em EVs. Ainda não é conhecido o mecanismo molecular utilizado por Nef para ser exportado em EVs, mas sabe-se que Nef interage fisicamente com a proteína II acessória da maquinaria ESCRT, Alix, importante no processo de formação das ILVs e seleção das cargas que serão internalizadas nos MVBs. EVs coletadas de células HeLa e linfócitos T CD4+ silenciados para Alix demostraram reduções significativas na liberação de Nef. Estes resultados indicam que Nef requer Alix para sua eficiente liberação em EVs.Lysosomal degradation of endocytosed membrane proteins occurs through the targeting of these proteins to intraluminal vesicles (ILVs), formed in the multivesicular bodies (MVBs) lumen, and the subsequent fusion of MVBs with lysosomes. Despite its importance in the degradation of transmembrane proteins, MVBs have another important function, the production and release of extracellular vesicles (EVs). In this process, the MVBs do not fuse with lysosomes, but fuse with the plasma membrane resulting in the release of these vesicles that reside within MVBs to the extracellular environment. Several proteins regulate the targeting of cargo to MVBs. Studies that delineated the functions of AP1 in protein trafficking, focused on complexes containing the ?1 subunit, which mediates transport between trans-Golgi network (TGN) and endosomes. However, the human genome encodes a second isoform of this subunit, named ?2. Evidences from the literature, as well as results from our research group, indicate that AP1?2 regulates transport pathways that are distinct from the pathways classically attributed to AP1. By performing EGF-uptake assays under ?1 or ?2 knockdown (KD) conditions, it was observed that ?2 is required for degradation of internalized EGF, effect also observed for the EGF receptor (EGFR) using cell surface biotinylation assays. These results demonstrate that the lysosomal degradation of the EGFEGFR complexes via the canonical MVBs pathway requires the AP1?2 complex, but not AP1?1. In parallel with this study, we also analyzed the molecular mechanism of HIV-1 Nef targeting to MVBs associated with the EVs release. Nef is an important determinant in the modulation of the intracellular environment for efficient HIV replication and progression to AIDS. Nef is actively secreted via EVs and its release may lead to apoptosis of bystander acceptor cells. Moreover, Nef reduces the levels of CD4 and MHC-I molecules in EVs. Despite the importance of Nef release in EVs, the molecular mechanism used by Nef to be exported via EVs is unknown. Nef physically interacts with the ESCRT machinery accessory protein Alix, an important player in the process of ILVs formation and cargo selection. EVs released from HeLa cells and CD4+ T lymphocytes under Alix KD conditions demonstrated a significant IV reduction in Nef release via EVs. These results indicate that Nef requires Alix for its efficient release in EVs.
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Liccardi, G. "Nuclear EGFR modulation of DNA repair." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1335897/.
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Overexpression of the epidermal growth factor receptor (EGFR) is associated with resistance to chemotherapy and radiotherapy. EGFR involvement, in repair of radiation-induced DNA damage, is mediated by association with the catalytic subunit of DNA protein kinase (DNAPKcs). This study investigated the role of EGFR nuclear import, and its association with DNAPKcs, on DNA repair following treatment either with cisplatin or ionizing radiation (IR). EGFR- null murine NIH3T3 cells were transfected with wild type or with mutated EGFR (mutations found in human cancers L858R, EGFRvIII and mutations in the EGFR nuclear localization signal (NLS) sequence NLS123, LNLS123). Comet assay analysis, which measures unhooking of cisplatin crosslinks and repair of IR induced strand breaks, demonstrated that wtEGFR and EGFRvIII completely repair cisplatin and IR induced DNA damage. Immunoprecipitation studies show that repair is associated with the binding of both wtEGFR and EGFRvIII to DNAPKcs, which increases by 2- fold 18 hours following cisplatin treatment. Confocal analysis and proximity ligation assay indicated that this association takes place both in the cytoplasm and in the nucleus resulting in a significant increase of DNA-PK kinase activity. Intermediate levels of repair as shown by the L858R construct with impaired nuclear localization demonstrated that EGFR kinase activity is partially involved in repair but is not sufficient to determine EGFR nuclear expression. EGFR-NLS mutants showed impaired nuclear localization and impaired DNAPKcs association resulting in significant inhibition of DNA repair and downregulation of DNA-PK kinase activity. Our data suggest that EGFR nuclear localization is required for the modulation of cisplatin and IR induced DNA damage repair. The EGFR-DNAPKcs binding is triggered by cisplatin or IR and not by EGFR nuclear translocation per se. Understanding mechanisms regulating EGFR subcellular distribution in relation to DNA repair kinetics will be a critical determinant of improved molecular targeting and response to therapy.
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Housden, B. "Notch targets and EGFR pathway regulation." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.604264.
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Previous work in the lab identified potential Notch targets in a muscle related Drosophila cell line using a combination of genome wide expression array, chromatin immunoprecipitation (ChIP) and bioinformatics approaches. My project was focussed on investigating the regulation of EGFR pathway components by Notch signalling and unravelling mechanisms by which this crosstalk is dependent on context. Previous genetic studies have demonstrated extensive crosstalk between the Notch and EGFR pathways. The unexpected result from the genome wide studies was the overrepresentative of EGFR pathway components that were direct targets. This group of nine targets included both positive and negative regulators of the pathway. One of my first goals was to validate these as direct targets, for which I used a combination of luciferase and in-vivo reporter assays. To address the question of how activation and inhibition of the EGFR pathway is resolved into a final effect on EGFR output the temporal profiles of the different components was investigated. Initial results show that there are distinct temporal activation profiles for different EGFR related genes following Notch activation. This is predicted to lead to an initial inhibition of EGFR signalling (due to fast initial inhibitor accumulation) followed by an activation of signalling (due to inhibitor decrease and activator production). Current work on this project is focussed on identifying different classes of temporal response at the genome wide scale and asking whether there is any consistency in the types of genes that adopt specific profiles. One of the challenges in dissecting the response to Notch is understanding why genes respond only in certain contexts. Argos, which encodes an EGFR inhibitor, is one example of a gene whose response to Notch signalling is context dependent. My results show that argos is positively regulated in the muscle progenitors. However, in the wing pouch, argos expression is reduced upon Notch activation. I have mapped these contrasting responses to separable enhancers, one active in the muscle precursors that I have shown to be directly regulated by Notch and the other active in the wing pouch where it integrates both EGFR and Notch signals. The latter is mediated by the Notch target E(spl)mβ and is therefore indirectly affected by Notch. Further studies to distinguish the components acting through the different enhancers revealed that the bHLH protein Twist is required for Notch activation of the muscle precursor enhancer and the wing pouch enhancer activity appears to involve an interplay between general activation and restricted repressors.
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Lee, Richard William. "MET-EGFR dimerisation in lung adenocarcinoma is dependent on EGFR mutations and altered by MET kinase inhibition." Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/metegfr-dimerisation-in-lung-adenocarcinoma-is-dependent-on-egfr-mutations-and-altered-by-met-kinase-inhibition(3a738a35-f82d-4eb6-83a3-150160d12045).html.
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Prognosis in advanced stage lung cancer is extremely poor with few effective therapies. EGFR tyrosine kinase inhibitors (TKIs) have high response rates in patients with activating EGFR mutations and are now an established part of therapy in selected patients. Such advances herald a previously unprecedented enthusiasm for the possibilities of targeted therapy. Acquired resistance however is widespread - the EGFR T790M mutation in particular represents approximately 50% of these. MET amplification is also an important route of resistance and preclinical data suggests synergy between therapies targeting these two receptors. We hypothesized that EGFR mutation status determines the EGFR-MET interaction and response to MET inhibition. We tested this hypothesis by using cells derived from NCI-H1975, which possess L858R and T790M EGFR mutations. This cell model and a derived murine xenograft experiment provided a platform with which to test these ideas by using assays of tumorigenicity in vitro; tumour growth/stroma formation in vivo and a selective MET kinase inhibitor, SGX523. EGFR-MET interaction was assessed by a Förster Resonance Energy Transfer (FRET) Fluorescence Lifetime Imaging Microscopy (FLIM) assay developed as part of this thesis that quantified EGFR-MET dimer formation. SGX523 significantly reduced cell proliferation, xenograft tumour growth and ERK phosphorylation in the presence of the EGFR L858R-T790M mutations but not with EGFR L858R alone where SGX523 reduced stroma formation but not growth. SGX523 reduced EGFR-MET dimerisation in the EGFR L858R-T790M mutant but increased EGFR-MET interaction in the presence of EGFR L858R alone. Little effect was seen with EGFR WT in response to SGX523 for any of these indices. This thesis provides novel data for the mechanistic understanding of EGFR-MET heterodimerisation and the accompanying discussion explores how this is relevant for EGFR and MET targeted therapies.
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Oliveira, Carolina Barbara Nogueira de, Ivan Andrade de Araújo Penna, and Antonio Marcos Saraiva. "Avaliação de polimorfismos nos genes EGF e EGFR e a susceptibilidade à pré-eclâmpsia severa." Universidade Federal Fluminense, 2012. https://app.uff.br/riuff/handle/1/4715.
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Conselho Nacional de Desenvolvimento Científico e Tecnológico
Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Fundação Oswaldo Cruz. Instituto Nacional de Controle de Qualidade em Saúde (INCQS-Fiocruz)
Cerca de 10-15% das causas de mortalidade e morbidade materna em países desenvolvidos e 37% das causas de morte obstétricas diretas no Brasil podem ser associadas à pré-eclâmpsia. A pré-eclâmpsia é uma patologia multissistêmica definida por uma hipertensão associada a uma proteinúria, após a 20ª semana de gestação. As manifestações clínicas desta doença podem se apresentar como uma síndrome materna ou fetal e de acordo com a gravidade podem ser classificadas em leve ou severa e de início precoce ou tardio. Apesar do conhecimento limitado sobre esta patologia, existem fortes evidências de envolvimento do componente genético na etiologia da pré-eclâmpsia. O fator de crescimento epidérmico (EGF) desempenha um papel importante na regulação do crescimento, proliferação e diferenciação celular, através da ligação ao seu receptor, o EGFR. Acredita-se que este fator esteja relacionado com a regulação do crescimento e da função placentária durante a gestação. Variações na sequência do DNA desses genes podem levar a uma alteração nos níveis de transcrição gênica e, como consequência, ser responsável por mudanças nos níveis de produção e/ou atividade desses fatores. O polimorfismo EGF +61 G>A está associado com a produção in vitro da proteína EGF e os polimorfismos EGFR -216 G>T e -191 C>A estão correlacionados a mudanças na atividade do promotor e na expressão de RNAm desse gene. O objetivo geral do nosso estudo foi avaliar uma possível associação entre polimorfismos funcionais nos genes EGF (+61 G>A) e EGFR (-216 G>T e -191 C>A) e a susceptibilidade à pré-eclâmpsia severa na população de gestantes do Estado do Rio de Janeiro, através de um estudo caso-controle. Como objetivos específicos, além de analisarmos uma possível interação entre os polimorfismos no desenvolvimento da pré-eclâmpsia severa, buscamos associar os polimorfismos ao histórico familiar da doença. O estudo foi composto por dois grupos, pareados por etnia: um grupo caso composto por 98 mulheres com pré-eclâmpsia severa e um grupo controle com 98 mulheres saudáveis. Os polimorfismos EGF (+61 G>A) e EGFR (-216 G>T e -191 C>A) foram avaliados pela reação em cadeia da polimerase seguida por análise de polimorfismos por tamanho de fragmentos de restrição (PCR-RFLP). As variáveis categóricas, frequências alélicas e genotípicas foram comparadas através do teste do exato de Fisher, e o teste t de Student foi utilizado para comparação das variáveis contínuas em cada grupo. Os resultados demonstram que o alelo A do polimorfismo -191 do gene EGFR está associado com a susceptibilidade à pré-eclâmpsia severa (p<0,05). Não houve associação significativa entre os outros polimorfismos (EGF +61 G>A e EGFR -216 G>T) e a susceptibilidade à pré-eclâmpsia severa (p>0,05), assim como também não foi encontrada relação entre a interação dos polimorfismos, histórico familiar e o desenvolvimento da pré-eclâmpsia severa. Além desses resultados, também foram encontradas diferenças significativas ao avaliarmos as características demográficas e clínicas entre os grupos. Este é o primeiro estudo a avaliar associações entre pré-eclâmpsia severa e os polimorfismos -216 G>T e -191C>A do gene EGFR e o primeiro estudo na população brasileira a investigar a associação do polimorfismo EGF +61 G>A e a doença. Com esse achado, podemos sugerir que o polimorfismo, o -191C>A do gene EGFR, possa ser o responsável por alguma regulação na produção do EGFR, e que através dessa regulação possa desempenhar algum papel importante na susceptibilidade à pré-eclâmpsia severa em mulheres do Estado do Rio de Janeiro.
About 10-15% of maternal deaths in development countries and approximately 37% of direct obstetrics deaths in Brazil can be assigned to preeclampsia. Preeclampsia is a multisystem disorder that usually occurs after 20 week of pregnancy and it is determined by the presence of hypertension associated with proteinuria. The clinical findings of preeclampsia can manifest as either a maternal syndrome or fetal syndrome. In addition, the preeclampsia can be classified as mild to severe, and in early or late-onset preeclampsia. Despite the limited knowledge of this pathology, there is a strong evidence of involvement of the genetic component in the etiology of preeclampsia. The epidermal growth factor (EGF) plays an important role in regulating cell growth, proliferation and differentiation, through binding its receptor, EGFR. Evidences suggest that this growth factor and its receptor are involved in growth regulation of placental function during the pregnancy. Variations in the DNA sequence in the EGF and EGFR genes can lead to an altered gene transcription and consequently can be responsible for changes in production and/or activity of these factors. The EGF +61 G>A polymorphism is significantly associated with in-vitro EGF protein production and the EGFR -216 G>T and -191 C>A polymorphisms are correlated with changes in promoter activity and expression of EGFR mRNA. The aim of this study was to verify the association between EGF +61 G>A, EGFR -216 G>T and -191 C>A polymorphisms and susceptibility to severe preeclampsia in the population of Rio de Janeiro through a case-control design. The specific objectives were to assess the association between these polymorphisms and the history family of preeclampsia, and also to analyze a possible interaction among these polymorphisms on the development of severe preeclampsia. The study was composed by two groups matched by ethnicity: the case group with 98 women with severe preeclampsia and the control group with 98 healthy women. Polymerase chain reaction restriction fragment length polymorphism analyses (PCR-RFLP) were performed to genotype EGF +61 G>A, EGFR -216 G>T and -191 C>A polymorphisms. Categorical variables, allelic and genotype frequencies were compared in each group applying Fisher´s exact test and a Student t test was used for continuous variables. The results showed that the A allele of the -191 C>A polymorphism of the EGFR gene is associated with susceptibility to severe preeclampsia (P<0,05). There were no significant association between severe preeclampsia and +61 G>A EGF and -216 G>T EGFR polymorphisms (P>0,05), as well as no correlation was found between the interaction of these polymorphisms, history family and the development of severe preeclampsia. We also found differences when we evaluated demographic and clinical characteristics between the two groups. This is the first study to assess the associations between -191 C>A and -216 G>T EGFR genetics polymorphisms and severe preeclampsia and the first study in Brazilian population to investigate the association between +61 G>A EGF polymorphism and severe preeclampsia. These findings suggest that the polymorphism-191C>A of the EGFR gene may be responsible for some regulation in the production of the EGFR, and that through this regulation this polymorphism might play an important role in the susceptibility to severe preeclampsia in women from Rio de Janeiro.
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Vanlandingham, Phillip Allen. "Rab7 regulation of EGFR trafficking and signaling." Oklahoma City : [s.n.], 2009.
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CONTE, ALEXIA. "INTEGRATION OF MODELING AND EXPERIMENTS TO DEFINE PRINCIPLES OF EGFR ACTIVATION AND UBIQUITINATION." Doctoral thesis, Università degli Studi di Milano, 2016. http://hdl.handle.net/2434/362616.
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Epidermal growth factor receptor (EGFR)-dependent signaling is involved in numerous physiological processes, and its deregulation leads to cellular dysfunctions and pathologies, first and forecast, cancer. Endocytosis has a crucial impact on the downstream EGFR signaling response and it is regulated by ligand concentration. Indeed, depending on the EGF dose, the EGFR can be internalized through clathrin-mediated endocytosis (CME) or non-clathrin endocytosis (NCE). The switch between these two internalization mechanisms occurs over a narrow range of EGF concentrations (1-10 ng/ml). Importantly, EGFR ubiquitination shows a threshold response over the same range of EGF doses and is responsible for the commitment of EGFR to NCE, and thus, for EGFR signal extinction through receptor degradation.
In this project, we were interested in elucidating the cellular mechanisms that regulate and coordinate the choice between these two endocytic routes, in addition, we aim to clarify how the integration of the two pathways influences EGFR downstream signaling. In order to deal with the complexity of the system, we adopted an integrated research approach combining mathematical modeling with wet-lab experiments. To this purpose, in collaboration with the Systems Biology group at our Institute, we developed a mathematical model of early EGFR activation that quantitatively accounts for the ubiquitination threshold observed at 2 minutes of EGF stimulation. The ‘early model’ was able to generate important predictions; in particular, it predicts a weakness in the system that is unveiled in the presence of high EGF concentrations and EGFR overexpression, two conditions frequently observed in cancer.
We tested these predictions using different cell-based model systems subjected to varying perturbations. A challenge in the biological validation of the model, was obtaining quantitative reproducible data. To this aim, we optimized a quantitative ELISA-based assay to measure EGFR ubiquitination/phosphorylation upon different perturbations. This assay revealed to be powerful and allowed us to validate the predictions generated by the model. Thanks to our integrative approach, we identified Cbl as the limiting and weak element of the system.
We expect that our model of EGFR activation will provide novel insights into the role of EGFR endocytosis, controlling the balance between EGFR signaling and downmodulation, frequently altered in cancer.
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Magalhães, Paula Lima. "Imunomarcação dos receptores de EGF (EGFR e c-ErbB2) no carcinoma de células escamosas em cães." Universidade Federal de Goiás, 2017. http://repositorio.bc.ufg.br/tede/handle/tede/7724.
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Squamous cell carcinoma (SCC) is one of the most common malignant cutaneous tumors in all species, as well as in the human species, ranging from young animals to the elderly. It has development associated with environmental factors such as prolonged exposure to solar rays and epidermal hypopigmentation. According to the literature, 80% of malignancies originate in environmental stimuli, due to exposure to carcinogens. Despite the multifactorial etiology, the search for clarification of the causes and mechanisms of cancer evolution must be incessant, since innumerable neoplasms can be prevented, especially when induced by exogenous factors. The aim of this study was to study canine cutaneous SCC in the light of different histomorphological patterns of the neoplasia, evaluating its immunophenotype response to EGFR and c-erbB2 epidermal growth factor receptors. For that, the cases of canine SCC were analyzed from the archive of the Animal Pathology Sector of the EVZ / UFG from 2006 to 2015. For the epidemiological study, registration information was considered, including breed, sex, age and anatomical location. Regarding the histomorphological evaluation and malignancy criteria, the lesions were classified according to the system recommended by the Müller e Kirk’s. Anti-EGFR (HER1) and anti-c-erbB-2 (HER2) antibodies were used for the immunohistochemical study to better understand the role of these proteins in the mechanisms involved in the genesis, proliferation and evolution of SCC in dogs. Considering the histomorphological and immunophenotypic analyzes, the correlation between its variables was tested, and a correlation was verified between the EGFR immunostaining and the degree of SCC differentiation (r = 0.26, p = 0.02). On the other hand, there was no correlation between c-erbB2 immunostaining and histomorphological differentiation (r = 0.02; p = 0.83). When the correlation between EGFR and c-erbB2 immunoblots was tested, a positive correlation was also observed, but not statistically significant (r = 0.21, p = 0.06). It is concluded that there is a propensity that the increase in EGFR immunoexpression is directly proportional to the degree of SCC differentiation, and that it does not occur with c-erbB2 immunostaining. Also, SCCs in dogs seems to exhibit simultaneous increase of EGF receptor immunostaining.
O carcinoma de células escamosas (CCE) é um dos tumores cutâneos malignos mais comuns em todas as espécies animais, assim como na espécie humana, podendo acometer desde animais jovens a idosos. Tem desenvolvimento associado a fatores ambientais como exposição prolongada aos raios solares e hipopigmentação epidermal. Os estudos revelam que, 80% das neoplasias malignas têm origem em estímulos ambientais, em decorrência a exposição a carcinógenos. Apesar da etiologia multifatorial, a busca pelo esclarecimento das causas e dos mecanismos de evolução do câncer deve ser incessante, pois inúmeras neoplasias podem ser prevenidas, especialmente quando induzidas por fatores exógenos. Assim, este trabalho teve por objetivo estudar o CCE cutâneo canino à luz dos diferentes padrões histomorfológicos da neoplasia, avaliando o seu imunofenótipo quanto aos receptores do fator de crescimento epidérmico EGFR e c-erbB2. Para tal, foram avaliadas os casos de CCE canino provenientes do arquivo do Setor de Patologia Animal da EVZ/UFG no período de 2006 a 2015. Para o estudo epidemiológico foram consideradas as informações de registro, incluindo raça, sexo, idade e localização anatômica. Quanto à avaliação histomorfológica e critérios de malignidade, as lesões foram classificadas de acordo com o sistema preconizado por Müller e Kirk’s. Para o estudo imunoistoquímico foram utilizados os anticorpos anti-EGFR (HER1) e anti-c-erbB-2 (HER2), com o intuito de melhor compreender a participação dessas proteínas nos mecanismos envolvidos na gênese, proliferação e evolução do CCE em cães. Considerando as análises histomorfológica e imunofenotípica foi testada a correlação entre suas variáveis, sendo constatada correlação entre a imunomarcação para EGFR e o grau de diferenciação do CCE (r=0,26; p=0,02). Por outro lado, não houve correlação entre a imunomarcação de c-erbB2 e a diferenciação histomorfológica (r=0,02; p=0,83). Quando testada a correlação entre as imunomarcações de EGFR e c-erbB2, também foi observada correlação positiva, porém sem significância estatística (r=0,21; p=0,06). Conclui-se que há propensão de que o aumento na imunoexpressão de EGFR seja diretamente proporcional ao grau de diferenciação do CCE, sendo que o mesmo não ocorre com a imunomarcação de c-erbB2. Também, os CCE em cães parecem apresentar aumento simultâneo da imunomarcação dos receptores de EGF.
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Liffers, Katrin [Verfasser], and Katrin [Akademischer Betreuer] Lamszus. "Identifikation von Resistenzmechanismen gegenüber EGFR-Tyrosinkinase Inhibitoren in EGFR-amplifizierten und EGFRvIII-positiven Glioblastomen / Katrin Liffers. Betreuer: Katrin Lamszus." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2015. http://d-nb.info/107464249X/34.
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Kramer, Elizabeth L. "Role of the EGFR Pathway in Lung Remodeling and Disease." University of Cincinnati / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1250206890.
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Hennes, Nadine Regina. "Untersuchungen zur Expression und Lokalisation des epidermalen Wachstumsfaktors (EGF) und seines Rezeptors (EGFR) im Intestinaltrakt des Schweines." Diss., kostenfrei, 2008. http://edoc.ub.uni-muenchen.de/9013/.
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Escalante, Escalante Paula Isabel. "Polimorfismos genéticos de P53, COX-2 , EGF y EGFR como marcadores de riesgo de cáncer de laringe." Tesis, Universidad de Chile, 2017. http://repositorio.uchile.cl/handle/2250/147248.
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Magíster en farmacologíaEl carcinoma escamoso de laringe es una enfermedad altamente invalidante ya que puede afectar la capacidad del habla, respiración y deglución del paciente que lo sufre. Los principales factores causales identificados son cigarro y alcohol. Las vías de respuesta inflamatoria, proliferativa y de reparación de ADN pueden contribuir al riesgo de cáncer de laringe. El objetivo de este estudio es determinar asociaciones entre variantes genéticas COX-2 rs20417, COX-2 rs689466, EGF rs4444903, EGFR rs2227983, P53 rs1042522 y el riesgo de cáncer de laringe en la población chilena. Se realizó un estudio casos y controles, con 100 pacientes con cáncer escamoso de laringe y 139 voluntarios adultos sin cáncer. La genotipificación se realizó mediante PCR-RLFP. Se observa que estos polimorfismos son capaces de incrementar el riesgo de cáncer de laringe asociado a la combinación de consumo de tabaco y alcohol en una razón de 0,34 veces para COX-2 rs20417, 0,5 veces para EGF rs4444903, 0,56 veces para P53 rs1042522, 1,72 veces para EGFR rs2227983 y 4,7 veces para COX-2 rs689466. Esto sugiere que las variantes COX-2 rs20417, COX-2 rs689466, EGF rs4444903, EGFR rs2227983 y P53 rs1042522 actúan como modificadores de riesgo de cáncer de laringe.
Laryngeal squamous cell carcinoma is a kind of cancer that can be highly disabling to the patient, affecting speech, swallowing and respiratory skills, and leading to impaired quality of life. Smoking and alcohol abuse are principal risk factors linked to this disease. Inflammation signaling pathways, mitogens and DNA repair genes are factors that can be involved in carcinogenesis. The aim of this research is to assess the effect of COX-2 rs20417, COX-2 rs689466, EGF rs4444903, EGFR rs2227983, P53 rs1042522 single nucleotide polymorphisms in the risk of laryngeal cancer development in Chilean population. For this case control study, we recruited 100 cancer patients and 139 healthy volunteers. SNP genotype was analyzed from genomic DNA by PCR-RFLP. We observed that these SNPs are capable of increase the smoking plus alcohol risk of laryngeal cancer in a ratio of 0,34 fold for COX-2 rs20417 SNP, 0,5 fold for EGF rs4444903 SNP, 0,56 fold for P53 rs1042522 SNP, 1,72 fold for EGFR rs2227983 SNP and 4,7 fold for COX-2 rs689466 SNP. These findings suggest that COX-2 rs20417, COX-2 rs689466, EGF rs4444903, EGFR rs2227983 and P53 rs1042522 single nucleotide polymorphisms acts as risk modifier factors for laryngeal cancer.
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Bollée, Guillaume. "Rôle de l'Heparin-Binding Epidermal Growth Factor (HB-EGF) et du récepteur EGFR dans la glomérulonéphrite extracapillaire." Paris 7, 2011. http://www.theses.fr/2011PA077140.
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Les glomérulonéphrites extracapillaires (GNEC) ou glomérulonéphrites rapidement progressives (GNRP) représentent la forme la plus sévère d'atteinte glomérulaire. Les lésions se manifestent par une prolifération extracapillaire ("croissants") impliquant les lymphocytes T les macrophages, ainsi que la prolifération des podocytes et des cellules épithéliales pariétales, menant à la destruction rapide du glomérule et l'insuffisance rénale. Nous montrons l'induction de l'expression de l'Heparin Binding-Epidermal Growth Factor (HB-EGF) dans les cellules épithéliales glomérulaires au cours de la GNEC induite chez la souris par un sérum néphrotoxique, et également dans les GNEC humaines. L'induction de l'HB-EGF entraîne la phosphorylation du récepteur EGFR au cours de la GNEC murine. Chez les souris déficientes en HB-EGF, l'activation de l'EGFR est absente et la sévérité de la GNEC est atténuée. In vitro, l'HB-EGF stimule la prolifération et la migration des podocytes par un mécanisme autocrine. La délétion spécifique du gène Egfr dans les podocytes diminue également la sévérité de la GNEC. L'administration à la souris d'un inhibiteur pharmacologique de l'EGFR au cours de la GNEC entraine une diminution de l'albuminurie, une préservation de la fonction rénale et une amélioration de la survie. Ce traitement est efficace même administré 4 jours après l'induction de la GNEC. Les effets délétères de l'activation de l'EGFR pourraient être médiés par l'activation de STAT3 et l'administration à la souris d'un inhibiteur de STAT3 réduit la sévérité de la GNEC. Nos résultats suggèrent que des traitements ciblant la voie HB-EGF/EGFR pourraient s'avérer bénéfique dans les GNEC humainesCrescentic glomerulonephritis or rapidly progressive glomerulonephritis (RPGN) is the most severe form of glomerular disease. Glomerular injury manifests as a proliferative histological pattern, accumulation of T cells and macrophages, proliferation of intrinsic glomerular cells, accumulation of cells in Bowman's space ("crescents"), and rapid deterioration of renal function. Here we show de novo induction of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in intrinsic glomerular epithelial cells (podocytes) from mice with RPGN induced by nephrotoxic serum and also in human RPGN. HB-EGF induction increases phosphorylation of the EGFR/ErbB 1 receptor in mice with RPGN. In HB-EGF-deficient mice, EGFR activation in glomeruli is absent and the course of RPGN is markedly improved. Autocrine HB-EGF induces a phenotypic switch in podocytes in vitro. Conditional deletion of the Egfr gene from podocytes of mice alleviates crescentic glomerulonephritis and the clinical features that accompany RPGN. Pharmacological blockade of EGFR also prevents nephrotic syndrome, infiltration of T cells and macrophages, necrotizing crescentic glomerulonephritis, acute renal failure and death in mice. This approach is effective even when started 4 days after the induction of experimental RPGN. The deleterious effects of EGFR activation may be mediated by activation of STAT3 and the severity of RPGN in mice is reduced by the administration of a STAT3 inhibitor. Our results suggest that targeting the HB-EGF/EGFR pathway could be clinically beneficial for treatment of human RPGN
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Roetzer, Silvia. "Fraktionierte lokoregionale Radioimmuntherapie mit 213Bi-anti-EGFR-MAk." Diss., Ludwig-Maximilians-Universität München, 2013. http://nbn-resolving.de/urn:nbn:de:bvb:19-160591.
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Pfäffle, Heike. "Defective DNA repair in EGFR-mutant lung cancer." Diss., Ludwig-Maximilians-Universität München, 2013. http://nbn-resolving.de/urn:nbn:de:bvb:19-162407.
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In patients with lung cancer whose tumors harbor activating mutations in the EGF receptor (EGFR), increased responses to platinum-based chemotherapies are seen compared with wild-type cancers. However, the mechanisms underlying this association have remained elusive. Here, we describe a cellular phenotype of crosslinker sensitivity in a subset of EGFR-mutant lung cancer cell lines that is reminiscent of the defects seen in cells impaired in the Fanconi anemia pathway, including a pronounced G2–M cell-cycle arrest and chromosomal radial formation. We identified a defect downstream of FANCD2 at the level of recruitment of FAN1 nuclease and DNA interstrand crosslink (ICL) unhooking. The effect of EGFR mutation was epistatic with FANCD2. Consistent with the known role of FANCD2 in promoting RAD51 foci formation and homologous recombination repair (HRR), EGFR-mutant cells also exhibited an impaired RAD51 foci response to ICLs, but not to DNA double-strand breaks. EGFR kinase inhibition affected RAD51 foci formation neither in EGFR-mutant nor wild-type cells. In contrast, EGFR depletion or overexpression of mutant EGFR in wild-type cells suppressed RAD51 foci, suggesting an EGFR kinase-independent regulation of DNA repair. Interestingly, EGFR-mutant cells treated with the PARP inhibitor olaparib also displayed decreased FAN1 foci induction, coupled with a putative block in a late HRR step. As a result, EGFR-mutant lung cancer cells exhibited olaparib sensitivity in vitro and in vivo. Our findings provide insight into the mechanisms of cisplatin and PARP inhibitor sensitivity of EGFR-mutant cells, yielding potential therapeutic opportunities for further treatment individualization in this genetically defined subset of lung cancer.
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Willems, Sofie Henriëtte. "ADAMs as EGFR ligand sheddases in prostate cancer." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609342.
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Alves, Alice Manuela Santos. ""EGFR, e Lesões Displásticas do Colo do Útero"." Master's thesis, Instituto de Ciências Biomédicas Abel Salazar, 2010. http://hdl.handle.net/10216/57198.
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White, Audrey Lucille, and Audrey Lucille White. "Signaling Crosstalks: EGFR and TAZ in Breast Cancer." Thesis, The University of Arizona, 2017. http://hdl.handle.net/10150/625241.
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Breast cancer is driven by multiple molecular aberrations, transforming benign
epithelial cells into metastatic cancer. Identification of key signaling nodes underlying
metastasis and resistance to treatment is crucial to improving targeted therapies. This
review examines two oncogenes driving epithelial to mesenchymal transition (EMT) and
the acquisition of cancer stem cell properties. The epidermal growth factor receptor
(EGFR), a well-established oncogene driving migration, survival, and proliferation,
activates several downstream signaling cascades including the AKT and MAPK
pathways. EGFR overexpression, mutation, and mislocalization are frequently observed
in breast cancer. TAZ, transcriptional coactivator with PDZ-binding motif, induces and
sustains EMT and is required for the acquisition of breast cancer stem cell traits. The
emerging crosstalk between these pathways yields insights into early mammary
tumorigenesis, epithelial plasticity, and the metastatic niche, suggesting novel avenues
for the development of targeted therapies.
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Lee, Tang-Cheng Threadgill David W. "Functional analysis of EGFR using a conditional allele." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2008. http://dc.lib.unc.edu/u?/etd,1730.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2008.Title from electronic title page (viewed Sep. 16, 2008). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum of Genetics & Molecular Biology." Discipline: Genetics and Molecular Biology; Department/School: Medicine.
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Alves, Alice Manuela Santos. ""EGFR, e Lesões Displásticas do Colo do Útero"." Dissertação, Instituto de Ciências Biomédicas Abel Salazar, 2010. http://hdl.handle.net/10216/57198.
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Lue, Hui-wen. "LIV-1 Promotes Prostate Cancer Epithelial-to-Mesenchymal Transition and Metastasis Through HB-EGF Shedding and EGFR-mediated ERK Signaling." Digital Archive @ GSU, 2012. http://digitalarchive.gsu.edu/biology_diss/115.
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LIV-1, a zinc transporter, is an effector molecule downstream from soluble growth factors. This protein has been shown to promote epithelial-to-mesenchymal transition (EMT) in human pancreatic, breast, and prostate cancer cells. Despite the implication of LIV-1 in cancer growth and metastasis, there has been no study to determine the role of LIV-1 in prostate cancer progression. Moreover, there is no clear delineation of the molecular mechanism underlying LIV-1 function in cancer cells. In this study, we found increased LIV-1 expression in a progresssive manner in benign, PIN, primary and bone metastatic human prostate cancer. We characterized the mechanism by which LIV-1 drives prostate cancer EMT in an androgen-refractory human prostate cancer cell (ARCaP) bone metastasis model. LIV-1, when overexpressed in ARCaPE cells (derivative cells of ARCaP with epithelial phenotype), promoted EMT irreversibly. LIV-1 overexpressed ARCaPE cells had elevated levels of HB-EGF and matrix metalloproteinase (MMP) 2 and MMP 9 proteolytic enzyme activities, without affecting intracellular zinc concentration. The activation of MMPs resulted in the shedding of heparin binding-epidermal growth factor (HB-EGF) from ARCaPE cells, eliciting constitutive epidermal growth factor receptor (EGFR) phosphorylation and its downstream extracellular signal regulated kinase (ERK) signaling. Further investigation of the HB-EGF promoter revealed that both Stat3 and AP-1 controlled HB-EGF promoter activity. Ectopic LIV-1 overexpression induced AP-1 and Stat3 activation. Blockade of both Stat3 and AP-1 by specific inhibitors or dominant negative expression vectors diminished the HB-EGF promoter activity induced by LIV-1 overexpression. These results suggest that LIV-1 is involved in prostate cancer progression as an intracellular target of growth factor receptor signaling which promotes EMT and cancer metastasis. LIV-1 could be an attractive therapeutic target for the eradication of pre-existing human prostate cancer and bone and soft tissue metastases.
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Su, Hsin-Yuan. "Therapeutic Potential of EGFR Derived Peptides in Breast Cancer." Diss., The University of Arizona, 2013. http://hdl.handle.net/10150/293486.
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The epidermal growth factor receptor (EGFR) belongs to the erbB family of receptor tyrosine kinases which consists of four members (EGFR, ErbB2, ErbB3 and ErbB4). Upon ligand binding, the EGFR is capable of dimerization with other erbB receptors and propagates signals regulating a diverse array of cellular physiologies, including cell growth, migration and survival. Dysregulation of the EGFR is important for development and progression of different types of cancers, including breast cancer. Breast cancer is the second leading cause of cancer death in women. EGFR overexpression has been observed in about 15% of all breast cancers. Moreover, in triple negative breast cancer (TNBC), which is a more aggressive type of breast cancer and lacks effective therapies, up to 50% of tumors are found to overexpress EGFR. Targeted therapy against EGFR has been used in TNBC. However, limited efficacy has been observed in TNBC due to intrinsic and acquired resistant mechanisms. In order to overcome this issue, we have developed two novel therapeutic peptides derived from the nuclear localization signal (NLS) sequence and juxtamembrane domain of EGFR and investigated their efficacy in regard to inhibiting EGFR translocation and activation in TNBC. EGFR has been found to translocate into the nucleus and nuclear EGFR can affect gene transcription, cell proliferation, stress response and DNA repair through interacting with different components in the nucleus. Importantly, these functions of nuclear EGFR correlate with cancer prognosis and therapeutic resistance. We found that an EGFR NLS-derived peptide (ENLS peptide) could inhibit activated EGFR (pY845) undergoing nuclear translocation. We also showed that this ENLS peptide sensitized breast cancer cells to AG1478 (EGFR tyrosine kinase inhibitor) treatment. The juxtamembrane domain of EGFR regulates its trafficking to the nucleus and mitochondria, interaction with calmodulin and calcium signaling, and participates in dimerization and activation of EGFR. These non-traditional kinase related functions of EGFR represent a novel target for EGFR therapy. We found that a mimetic peptide of the juxtamembrane domain of EGFR (EJ1 peptide) could effectively inhibit EGFR activation through promoting inactive dimer formation. It could also effectively kill cancer cells through processes of apoptosis and necrosis. Mechanistically, this EJ1 peptide affects membrane integrity thereby leading to calcium influx, disruption of mitochondrial membrane potential and reactive oxygen species (ROS) accumulation. Importantly, EJ1 peptide appeared to be effective in inhibition of tumor growth and metastasis in a transgenic mouse model of breast cancer and showed no observable toxicity. ErbB3, another member of the erbB family, represents an important driver of the parallel signaling pathway to EGFR as well as a key regulator of PI3K/AKT activity which is important for therapeutic resistance. ErbB3 has been shown to interact with MUC1. The interaction between MUC1 and EGFR promotes EGFR stability through recycling of receptors. We found that MUC1 expression also affected ErbB3 activity and stability through ErbB3/EGFR/MUC1 complex formation. In conclusion, we demonstrated that two EGFR-derived peptides, working through novel strategies, represent a new foundation of effective therapeutic agents to breast cancer. ErbB3/EGFR/MUC1 complex formation under MUC1 expression also represents a druggable target for ErbB3 activity and stability.
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Raimbourg, Judith. "Effets du cisplatine sur la sensibilité des cancers bronchiques non à petites cellules EGFR sauvage aux inhibiteurs de tyrosine kinase anti EGFR." Thesis, Nantes, 2018. http://www.theses.fr/2018NANT1028/document.
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Les inhibiteurs de tyrosine kinase (ITK) anti EGFR ont très nettement amélioré la survie des patients atteints de cancers bronchiques non à petites cellules (CBNPC) métastatiques porteurs d’une mutation activatrice d’EGFR. En l’absence de mutation activatrice, le bénéfice de ces traitements est marginal et semble conditionné par l’utilisation préalable de la chimiothérapie. Dans cette étude, l’exposition préalable de cellules de CBNPC EGFR sauvage à des doses sub-léthales de cisplatine induit une augmentation de la phosphorylation d’EGFR augmentant la sensibilité de ces cellules à l’erlotinib, ITK anti-EGFR, in vitro et in vivo, contrairement à l’effet observé sur des cellules EGFR mutées. Cette activation d’EGFR est liée à la transactivation du récepteur par Src selon un mécanisme indépendant des ligands d’EGFR mais impliquant l’IL6. Cette activation d’EGFR ligand indépendante est corrélée à l’activation de la voie interféron de type 1 en particulier de TBK1, IRF3 et l’augmentation de l’expression de deux de leurs gènes cible IFIT1 et IFI27. L’augmentation de l’expression d’IFIT1 et d’IFI27 ainsi que de l’IL6 sont des marqueurs robustes de la sensibilisation aux ITK induite par le cisplatine in vitro et in vivo. Enfin les résultats de notre étude suggèrent un rôle important dans cette sensibilisation de la localisation mitochondriale d’EGFR possiblement induite par la phosphorylation de la tyrosine 845, cible privilégiée de Src. Cette sensibilisation pourrait être liée au rôle joué par l’EGFR mitochondrial dans la dynamique et la morphologie mitochondriale ainsi que dans le métabolisme cellulaireAnti-EGFR tyrosine kinase inhibitors (ITKs) have markedly improved the overall survival of patients with metastatic non-small cell lung cancer (NSCLC) with an EGFR activating mutation. In the absence of activating mutation, the benefit of these treatments is marginal and seems conditioned by the prior use of chemotherapy. In this study, prior exposure of wild-type EGFR NSCLC cells to sub-lethal doses of cisplatin induces an increase in EGFR phosphorylation increasing the sensitivity of these cells to erlotinib, anti-EGFR TKI, in vitro and in vivo, contrary to the effect observed on mutated EGFR cells. This activation of EGFR is related to the transactivation of the receptor by Src according to an independent mechanism of the EGFR ligands but involving IL6. This independent ligand activation of EGFR is correlated with the activation of the type 1 interferon pathway, in particular TBK1, IRF3, and the increase in the expression of two of their targeted genes IFIT1 and IFI27. Increasing expression of IFIT1 and IFI27 as well as IL6 are robust markers of cisplatin-induced ITK sensitization in vitro and in vivo. Finally the results of our study suggest an important role in this sensitization of the mitochondrial localization of EGFR, possibly induced by the phosphorylation of tyrosine 845, tyrosine target of Src. This sensitization could be related to the role played by the mitochondrial EGFR in the dynamics and the mitochondrial morphology as well as in the cellular metabolism
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Bu, Yubai. "New synthetic routes to nitrogen heterocycles : natural products and novel drug scaffolds." Thesis, Loughborough University, 2017. https://dspace.lboro.ac.uk/2134/27482.
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This thesis is divided into three main sections. The first chapter contains a brief review of nitrogen heterocyclic chemistry. The second chapter reports the results and their discussion of new heterocyclic chemistry, and the experimental details are provided in the fourth chapter.
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Menezes, Sharleen Valerie. "Understanding the molecular mechanisms that underlie the anti-cancer activity of the metastasis suppressor, NDRG1 in the treatment of cancer." Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/20193.
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Pancreatic cancer is an aggressive disease that continues to be associated with low survival rates, therefore there is a need for more targeted therapies. This thesis sought to elucidate the mechanism of action of a well-known metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1). In addition, this thesis proposed a promising therapeutic strategy, exploring the use of a potent new class of di-2-pyridylketone thiosemicarbazone anti-cancer agents that up-regulate NDRG1. NDRG1 can suppress the epithelial mesenchymal transition, a key step in metastasis. We demonstrated that NDRG1 inhibited the oncogenic effects of transforming growth factor-β (TGF-β) in PANC-1 pancreatic cancer cells, mediated by the reduction of three transcriptional repressors of E-cadherin, namely SNAIL, SLUG, and ZEB1. Interestingly, NDRG1 also comprehensively inhibited oncogenic NF-κB signalling at multiple sites. The novel di-2-pyridylketone thiosemicarbazones, down-regulated the E-cadherin repressors in-vitro and in-vivo, demonstrating their marked potential. Furthermore, considering the broad effects of NDRG1 on a plethora of oncogenic signaling, it was shown that NDRG1 inhibited the ErbB family of receptors including the epidermal growth factor (EGFR), which are master regulators of oncogenesis, in order to elicit its reported and vast effects. This was mediated by the ability of NDRG1 to promote the tumour suppressor, MIG6 in order to disrupt its signalling, and cause its degradation. Collectively, these findings have expanded our knowledge of the mechanisms that underpin the molecular roles of NDRG1. Through the implementation of the novel di-2-pyridylketone thiosemicarbazones, this thesis has highlighted that targeting NDRG1 has tremendous therapeutic potential for the treatment of cancer.
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Kvarnbrink, Samuel. "The importance og LRIG1 in lung cancer." Thesis, Umeå universitet, Onkologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-57834.
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Albuschat, Rica. "Neue EGFR-Tyrosinkinase-Inhibitoren mit Salicyloyl- oder Chinazolin-Teilstrukturen." [S.l.] : [s.n.], 2003. http://www.diss.fu-berlin.de/2003/189/index.html.
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Schäfer, Beatrix. "Transactivation of the EGFR Signal in Human Cancer Cells." Diss., lmu, 2004. http://nbn-resolving.de/urn:nbn:de:bvb:19-23041.
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Brown, K. E. "EGFR signalling and ommatidial orientation in the Drosophila eye." Thesis, University of Cambridge, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.596973.
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I have investigated the role of Epidermal Growth Factor Receptor (EGFR) signalling in the control of ommatidial orientation. Both over- and under-activation of the pathway lead to significant defects in ommatidial orientation, while leaving the polarity of ommatidial unaffected. This previously unrecognised function of EGFR signalling further adds to the multiple functions of the pathway in Drosophila eye development. I have shown that the initial rotational event proceeds normally in EGFR pathway mutants, but that orientation becomes disrupted later in development, leading to the severe adult phenotypes seen. It is unclear which of the EGFR ligands is responsible for mediating its function in rotation: both Keren and Spitz may be important. At present, no mutant exist in keren. I have conducted a P element excision screen in an attempt to generate a keren mutant; characterisation of potential mutants is still ongoing. Hopefully, this will allow resolution of the question as to which ligand activates EGFR signalling to control orientation, and will also allow analysis of other potential functions of Keren. Very little is known about the cell biological processes underlying ommatidial rotation. As a first step towards gaining some insight into the mechanism by which ommatidial orientation is achieved, I have investigated a possible role for E-cadherin in this process. E-cadherin interacts genetically with EGFR signalling in rotation; however, it remains unclear whether cadherin-based adhesion has a primary function in the control of ommatidial orientation. I propose a model for the role of EGFR signalling in ommatidial orientation, in which the pathway acts in the 3rd instar disc, to lock ommatidial in place once they have reached their appropriate positions; in the absence of such a lock, ommatidial orientation can become disrupted during the remodelling of the larval disc into an adult eye.
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Klinghammer, Konrad [Verfasser]. "Primäre und sekundäre Resistenzmechanismen der EGFR Blockade / Konrad Klinghammer." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2019. http://d-nb.info/1200409442/34.
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Mao, Yanlan. "Adhesion molecules in Drosophila EGFR signalling and retinal development." Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612274.
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Albukhari, Ashwag. "Targeting EGFR signalling pathway in triple negative breast cancer." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:85d4bb10-385e-4187-8576-cf04f15f2871.
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Epidermal growth factor receptor (EGFR) is frequently overexpressed in the majority of triple negative breast cancer patients (TNBC). However, the molecular determinants behind their limited response to EGFR-targeted therapies are poorly understood. Here, both the acute and chronic responses of TNBC to the EGFR-targeted therapy, cetuximab (CTX), have been investigated. The expression of EGFR has been analyzed in a cohort of 2000 breast cancer tumours from the public dataset as well as in a panel of breast cancer cell lines. Furthermore, the response of TNBC cell lines to CTX has been investigated using conventional biochemical methods. Finally, a comprehensive transcriptomic profiling of an acquired CTX-resistant TNBC model by RNA sequencing has been performed to understand the molecular determinants of acquired CTX resistance. The results confirmed that EGFR is highly expressed in TNBC in comparison to non-TNBC breast cancer tumours and cell lines, which was associated with adverse clinical outcomes. Targeting EGFR in TNBC cell lines using CTX failed to completely inhibit the EGFR signalling pathway and was associated with an increase in ADAMs-mediated release of endogenous EGFR ligands, EGF and TGFα. Inhibition of ADAMs (ADAM10 and ADAM17) significantly enhanced the anti tumour efficacy of CTX both in vitro and in vivo. Furthermore, transcriptomic profiling of the acquired CTX-resistant TNBC cell line (MDA-MB-468CR) revealed an activation of several key oncogenic pathways and genes, including the TGFβ/BMP pathway. Blocking BMP receptors (BMPRs) restored the sensitivity of resistant cells to CTX treatment. Collectively, current findings offer alternative strategies that could enhance the CTX response in TNBC. We further reported that simultaneous targeting of both EGFR and BMPR pathways could overcome CTX resistance, which might have important implications for the treatment of TNBC.
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Strieder, Luciana Rocha [UNESP]. "Análise da proteína EGFR em carcinoma espinocelular de lábio." Universidade Estadual Paulista (UNESP), 2015. http://hdl.handle.net/11449/132902.
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Fundação de Amparo à Pesquisa do Estado do Amazonas (FAPEAM)
O carcinoma espinocelular de lábio (CEC) é uma das neoplasias malignas mais comuns, acometendo principalmente lábio inferior devido à exposição solar. Este trabalho teve como objetivo avaliar 3 métodos de gradação histológica (OMS, BD e MRH), analisar a expressão da proteína EGFR no CEC de lábio, comparar com queilite actínica (QA) e correlaciona-las com o prognóstico. Dados de 53 pacientes com CEC de lábio foram coletados para a avaliação clinicopatológica e histológica. 22 casos de CEC e 19 de QA foram submetidos à reação imuno-histoquímica com a proteína EGFR e analisados por um analisador automatizado para avaliação da expressão proteica. A média de idade foi de 65 anos, 69,8% foram homens, o lábio inferior foi o local de predileção com 94,4% e 66,03% dos pacientes estavam em estadios precoces (T1+T2). 28 (52,83%) e 34 (64,15%) casos respectivamente foram graduados em baixo risco prognóstico ou grau 1 pelas escalas BD e OMS, o modelo MRH graduou a 29 (54,72%) casos como médio risco prognóstico ou grau 2. O modelo de gradação mais simples e fácil de ser aplicado em CEC de lábio foi a Escala BD e o mais eficaz, pois quando em alto grau histológico foi associado à menor sobrevida global (P=0,045). A sobrevida global foi de 87,8% em 5 anos. Estadiamento clínico avançado (T3+T4) e envolvimento linfonodal (N1) foram associados à menor sobrevida global e sobrevida livre de recorrência (P=0,002; 0,005; 0,007 e 0,01). O tratamento cirúrgico combinado ao radioterápico foi associado à menor sobrevida livre de recorrência (P=0,03). Na expressão da proteína EGFR não houve diferença estatisticamente significante entre QA e CEC de lábio. O CEC de lábio quando em estadios e graus histológicos avançados, é associado a um pior prognóstico, o diagnóstico precoce é essencial para a escolha do melhor tratamento e sobrevida dos pacientes, evitando mutilações e consequentemente, perda na qualidade de vida.
Lip squamous cell carcinoma (SCC) is one of the most common malignancies affecting especially lower lip due to sun exposure. This study aimed to evaluate three methods of histological grading (WHO, BD and MRH), analyze the expression of EGFR protein on the lip of SCC, compared with actinic cheilitis (AC) and correlates them with the prognosis. Data from 53 patients with lip SCC were collected for the clinicopathological and histological evaluation. 22 cases of SCC and 19 AC underwent immunohistochemical reaction with EGFR protein and analyzed by an automated analyzer for evaluation of protein expression. The average age was 65 years, 69,8% were men, lower lip was the site of predilection with 94,4% and 66,03% of patients were in early stages (T1 + T2). 52.83% and 64.15% cases respectively were graduates in low risk prognosis or grade 1 by BD and WHO scales, the MRH model graduated 54.72% cases as medium risk prognosis or grade 2. The simplest grading model and easy to apply in lip SCC was the BD scale and more efficient because when in high histological grade was associated with lower overall survival (P = 0.045). Overall survival was 87,8% at 5 years. Advanced clinical stage (T3 + T4) and lymph node involvement (N1) were associated with lower overall survival and recurrence-free survival (P = 0.002; 0.005; 0.007 and 0.01). Surgical treatment combined with radiotherapy was associated with lower recurrence-free survival (P = 0.03). The expression of EGFR protein had no statistically significant difference between AC and lip SCC. The lip SCC when in advanced stages and high histological grades, is associated with a worse prognosis, early diagnosis is essential for choosing the best treatment and survival of patients, avoiding mutilation and consequently, loss in quality of life.
FAPEAM: 1271/2012
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Pretto, Guilherme Gonçalves. "EGFR na sequência DRGE, BARRETT e adenocarcinoma de esôfago." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2011. http://hdl.handle.net/10183/39671.
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Sharif, Ariane. "Contrôle du phénotype astrocytaire par le couple TGFα-EGFR." Paris 6, 2005. http://www.theses.fr/2005PA066636.
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Strieder, Luciana Rocha. "Análise da proteína EGFR em carcinoma espinocelular de lábio /." São José dos Campos, 2015. http://hdl.handle.net/11449/132902.
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Orientador: Estela Kaminagakura TangoBanca: Yasmin Rodarte Carvalho
Banca: Cláudia Malheiros Coutinho Camillo
Resumo: O carcinoma espinocelular de lábio (CEC) é uma das neoplasias malignas mais comuns, acometendo principalmente lábio inferior devido à exposição solar. Este trabalho teve como objetivo avaliar 3 métodos de gradação histológica (OMS, BD e MRH), analisar a expressão da proteína EGFR no CEC de lábio, comparar com queilite actínica (QA) e correlaciona-las com o prognóstico. Dados de 53 pacientes com CEC de lábio foram coletados para a avaliação clinicopatológica e histológica. 22 casos de CEC e 19 de QA foram submetidos à reação imuno-histoquímica com a proteína EGFR e analisados por um analisador automatizado para avaliação da expressão proteica. A média de idade foi de 65 anos, 69,8% foram homens, o lábio inferior foi o local de predileção com 94,4% e 66,03% dos pacientes estavam em estadios precoces (T1+T2). 28 (52,83%) e 34 (64,15%) casos respectivamente foram graduados em baixo risco prognóstico ou grau 1 pelas escalas BD e OMS, o modelo MRH graduou a 29 (54,72%) casos como médio risco prognóstico ou grau 2. O modelo de gradação mais simples e fácil de ser aplicado em CEC de lábio foi a Escala BD e o mais eficaz, pois quando em alto grau histológico foi associado à menor sobrevida global (P=0,045). A sobrevida global foi de 87,8% em 5 anos. Estadiamento clínico avançado (T3+T4) e envolvimento linfonodal (N1) foram associados à menor sobrevida global e sobrevida livre de recorrência (P=0,002; 0,005; 0,007 e 0,01). O tratamento cirúrgico combinado ao radioterápico foi associado à menor sobrevida livre de recorrência (P=0,03). Na expressão da proteína EGFR não houve diferença estatisticamente significante entre QA e CEC de lábio. O CEC de lábio quando em estadios e graus histológicos avançados, é associado a um pior prognóstico, o diagnóstico precoce é essencial para a escolha do melhor tratamento e sobrevida dos pacientes, evitando mutilações e consequentemente, perda na qualidade de vida
Abstract: Lip squamous cell carcinoma (SCC) is one of the most common malignancies affecting especially lower lip due to sun exposure. This study aimed to evaluate three methods of histological grading (WHO, BD and MRH), analyze the expression of EGFR protein on the lip of SCC, compared with actinic cheilitis (AC) and correlates them with the prognosis. Data from 53 patients with lip SCC were collected for the clinicopathological and histological evaluation. 22 cases of SCC and 19 AC underwent immunohistochemical reaction with EGFR protein and analyzed by an automated analyzer for evaluation of protein expression. The average age was 65 years, 69,8% were men, lower lip was the site of predilection with 94,4% and 66,03% of patients were in early stages (T1 + T2). 52.83% and 64.15% cases respectively were graduates in low risk prognosis or grade 1 by BD and WHO scales, the MRH model graduated 54.72% cases as medium risk prognosis or grade 2. The simplest grading model and easy to apply in lip SCC was the BD scale and more efficient because when in high histological grade was associated with lower overall survival (P = 0.045). Overall survival was 87,8% at 5 years. Advanced clinical stage (T3 + T4) and lymph node involvement (N1) were associated with lower overall survival and recurrence-free survival (P = 0.002; 0.005; 0.007 and 0.01). Surgical treatment combined with radiotherapy was associated with lower recurrence-free survival (P = 0.03). The expression of EGFR protein had no statistically significant difference between AC and lip SCC. The lip SCC when in advanced stages and high histological grades, is associated with a worse prognosis, early diagnosis is essential for choosing the best treatment and survival of patients, avoiding mutilation and consequently, loss in quality of life
Mestre
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Lohse, Stefan [Verfasser]. "Charakterisierung rekombinanter IgA-Antikörper gegen den EGFR / Stefan Lohse." Kiel : Universitätsbibliothek Kiel, 2010. http://d-nb.info/1020002476/34.
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Yin, Dongsheng [Verfasser]. "Biophysical studies of EGFR conformation and interaction / Dongsheng Yin." Bonn : Universitäts- und Landesbibliothek Bonn, 2019. http://d-nb.info/1208937553/34.
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Ribeiro, Daniela Cotta. "Avaliação imunoistoquímica do EGFR / Her -1 em leucoplasias bucais." Universidade Federal de Minas Gerais, 2009. http://hdl.handle.net/1843/ZMRO-7V9KHX.
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Leukoplakia is the most common precancerous lesion of the oral cavity.
The presence of epithelial dysplasia and clinical characteristics such as tobacco consumption and location are important predicting factors of malignant transformation. Epidermal Growth Factor Receptor (EGFR) is a member of a family of tyrosine-kinase receptor that plays an important role in the control of cell growth. A high expression of EGFR is frequently observed in many solid tumors including Oral Squamous Cell Carcinoma (OSCC). The aim of the present study was to evaluate the immunoexpression of EGFR on 48 oral leukoplakias searching the association of EGFR with tobacco consumption, location (high/low risk), grade of epithelial dysplasia, and cell proliferation through immunohistochemistry for Ki-67 and p27. EGFR was positive in 62,5%
of leukoplakias. EGFR immunoexpression showed a significant difference between leukoplakias of high and low risk sites. p27 immunoexpression was also significantly different between positive and negative EGFR leukoplakias. The p27 index lowered with the severity of dysplasia. We did not find an association of EGFR with tobacco and Ki-67 immunoexpression. The results show that EGFR is expressed in leukoplakias independently of dysplasia. The association of EGFR and p27 merits further investigation.A leucoplasia é a principal lesão cancerizável da boca. Fatores como a localização das lesões, hábito de tabagismo e atipia histológica têm sido associados ao potencial de transformação maligna dessas lesões, até o momento, no entanto, sem resultados definitivos. O EGFR é uma proteína de transmembrana, receptora de fatores de crescimento e com atividade tirosina quinase, pertencente à família dos receptores c-erbB. A expressão aumentada da proteína está relacionada com a progressão de tumores epiteliais, entre outras formas, através da alteração na proliferação celular. A proteína Ki-67 é um antígeno nuclear expressado em células proliferativas, muito utilizado como marcador de proliferação celular. A p27 é uma proteína com ação CDKI (inibidor das quinases dependentes de ciclina), que atua na inibição do ciclo celular. O objetivo do trabalho foi avaliar a associação da imunoexpressão do EGFR com atipia epitelial, tabagismo, localização das leucplasias e com a expressão de Ki-67 e p27. Avaliou-se ainda a associação entre a proliferação celular avaliada pelo Ki-67 e p27 com a atipia epitelial. Quarenta e oito lesões diagnosticadas como leucoplasias foram recuperadas do arquivo do laboratório de Patologia Bucal da FO-UFMG. As lâminas foram revisadas e dados clínicos (gênero, localização e tabagismo) recuperados. A imunoexpressão do EGFR mostrou associação positiva com a localização e com o total de célula positivas para p27. Não foi encontrada associação entre o EGFR e os demais dados clínico patológicos. Conclui-se que o EGFR está expresso em grande parte das leucoplasias bucais avaliadas independentemente do grau histológico de atipia. Os casos positivos para o EGFR foram localizados, em sua maioria, nas regiões de alto risco. As associações encontradas entre EGFR, localização das lesões e p27 devem ser melhor investigadas.
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Biagiotti, M. "PEPTIDE-POLYMER CONJUGATES AS TOOLS TO SELECTIVELY TARGET EGFR." Doctoral thesis, Università degli Studi di Milano, 2014. http://hdl.handle.net/2434/244888.
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Nanoparticles (NPs) made of biodegradable and biocompatible polymers present several advantages as carriers for therapeutics. Targeted polymeric NPs, able to hit specific tissues and cells, can be obtained by synthesis of hybrid or biointegrated nanosystems where the combination of polymers with biomolecules such as peptides, proteins, or monoclonal antibodies offers opportunities to design precise and versatile nanoscale systems. The central challenge towards these “smart” materials is represented by the optimal interplay of biophysicochemical parameters that confer molecular targeting, immune evasion, and optimal drug release, and allow to overcome the physiological barriers in vivo.
The epidermal growth factor receptor (EGFR) is a cell-surface receptor of extracellular protein ligands of the epidermal growth factor family. Mutations that lead to EGFR overexpression or overactivity have been associated with a wide spectrum of human cancers of epithelial origin, including breast and colorectal cancers, and with autoimmune disorders like rheumatoid arthritis. Recently, several studies have reported the successful identification, by screening phage display libraries, of a peptide ligand, named GE11 (YHWYGYTPQNVI), with high binding capacity to EGFR but with low mitogenic activity.
Poly(gamma-glutamic acid) (gamma-PGA) is an extracellular bacterial water-soluble polymer with variable molecular weight produced by several members of the genus Bacillus, composed of D and/or L-glutamic acid monomers, connected by amide bonds between alpha-amino and gamma-carboxyl groups. gamma-PGA is readily biodegraded by a good number of bacteria, it is non-immunogenic and completely innocuous and so it seems to meet most of the requirements of polymers for drug delivery. In addition, it bears pendant carboxylic groups in α-position which are available for chemical derivatization allowing the modification of its molecular properties or the attachment of biologically active molecules.
The use of gamma-PGA, however, presents some inherent and not negligible issues. First of all, chemical modification of the material is very arduous: this is a consequence of its structure but also of its scarce solubility in most organic solvents. Consequently, studies are necessar to find a feasible and efficient way to exploit it for drug delivery purposes.
This PhD work aimed to find a way to valorize gamma-PGA peculiar characteristics in drug delivery field, particularly in the preparation of GE11 directed nanocarriers. We operated on two different sides: on one hand we performed intense studies on the biopolymer exploring its chemical-physical properties (mainly MW and solubility), its structure and its reactivity. On the other hand we studied and optimized methods to functionalize a well known and widely used biopolymer, poly lactic-co-glycolic acid (PLGA), with peptides. Starting from these conjugates we also prepared and characterized nanoparticles intended to be used as a drug delivery tools to EGFR overexpressing cells.
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Woessner, N. C. "CHARACTERIZATION OF THE ROLE OF USP25 IN EGFR ENDOCYTOSIS." Doctoral thesis, Università degli Studi di Milano, 2015. http://hdl.handle.net/2434/261932.
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The epidermal growth factor receptor (EGFR) is involved in a broad range of cellular responses. Deregulated EGFR signalling is a significant feature in different stages of oncogenesis and it contributes to several cancer types. One important mechanism whereby cancer cells can obtain increased and uncontrolled EGFR signalling is to escape down-modulation of the receptor. Ubiquitination of EGFR and of members of the endocytic machinery has a key role in this process, regulating receptor internalization, trafficking and degradation. Deubiquitinating enzymes (DUBs) can reverse the ubiquitination process, antagonizing or even promoting receptor degradation.
To identify DUBs altering EGFR degradation we undertook a genome-wide small interfering RNA screen targeting all known active DUBs. In addition to previously described AMSH, USP8, USP2 and OTUD7B enzymes, we identified twelve novel DUBs affecting EGFR degradation by using immunoblot-based approaches complemented by an ELISA-based assay. Among them USP25, a member of the ubiquitin-specific protease (USP) family, displayed one of the strongest effects. We found that the degradation rate of EGFR is enhanced upon USP25 knock-down. Quantitative internalization assays revealed that depletion of USP25 leads to a faster internalization rate of EGFR. Consistently, overexpression of wild-type USP25, but not its catalytic inactive mutant, partially blocked EGFR internalization. Pathway analyses suggest that upon knock-down of USP25 a dynamin-independent endocytic route is activated, accounting for the increased EGFR internalization.
Furthermore, we scored an increase in the EGFR ubiquitination upon USP25 knock-down, in particular at early time points post EGF stimulation, suggesting that EGFR is a direct target of USP25. Details regarding the kind of ubiquitin chains attached to the EGFR in the absence of USP25 are still lacking and are currently under investigation. We also validated the E3 ligase component Cullin 3 (CUL3) as USP25 interactor and we found that USP25 preferentially binds the neddylated active form of CUL3. Initial analyses with CUL3 suggest that ablation of USP25 and CUL3 have opposite effects on EGFR internalization and that the observed phenotypes compensate each other in double knock-down. Our data suggest that USP25 and CUL3 may form a stable complex with opposing activity on EGFR internalization, and led us to hypothesize that they are involved in a novel “quality control” mechanism working at the plasma membrane.
Taken together our study identifies USP25 as a novel negative regulator of EGFR ubiquitination and endocytosis, involved in early internalization events. USP25 may represent a suitable “druggable” target for pathological conditions where EGFR is deregulated and opens up a promising direction for future investigations.
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GIORDANO, FEDERICA. "Investigating the role of p65BTK as an emerging therapeutic target in NSCLC." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2019. http://hdl.handle.net/10281/241339.
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Il tumore al polmone è la principale causa di morte per tumore al mondo sia negli uomini che nelle donne. Il tumore polmonare non a piccole cellule (NSCLC) è il più frequente ed è relativamente insensibile a chemioterapia e radioterapia. Nonostante lo sviluppo di terapie molecolari personalizzate contro specifiche “mutazioni driver” e la combinazione di chemioterapia e terapie a bersaglio molecolare, la mortalità per tumore al polmone rimane molto alta a causa dello sviluppo di resistenza alle diverse terapie. Pertanto, rimane particolarmente urgente ricercare nuove terapie per NSCLC. Recentemente nel nostro laboratorio abbiamo scoperto p65BTK, una nuova isoforma della tirosina chinasi di bruton (BTK), la quale è risultata essere un nuovo oncogene a valle del pathway di RAS. Abbiamo dimostrato che la sua inibizione diminuisce la crescita e la sopravvivenza delle cellule di cancro del colon e ri-sensibilizza cellule tumorali resistenti ai trattamenti.
Gli obiettivi di questo progetto sono: studiare il ruolo di p65BTK nel NSCLC e verificare se p65BTK può essere un nuovo target teranostico nel NSCLC.
Studiando una coorte di 382 pazienti abbiamo dimostrato che p65BTK è espresso nel 50% dei tumori di pazienti con NSCLC e la sua espressione correla con l'istotipo, l’abitudine al fumo e lo stato mutazionale di EGFR. In particolare, abbiamo trovato una maggiore espressione di p65BTK in pazienti con adenocarcinoma, non fumatori e con EGFR non mutato. Generalmente questi pazienti non sono eleggibili per la terapia con inibitori di EGFR a causa della mancanza di EGFR mutato. Tramite western blot, abbiamo confermato l’over-espressione di p65BTK sia in linee cellulari umane di NSCLC mutate per RAS o per uno dei geni del pathway di RAS, che in cellule primarie derivate da tumori di topi Kras/Trp53 null, suggerendo una correlazione tra l’aumentata espressione di p65BTK e la iper-attivazione del pathway di RAS nel NSCLC.
In seguito, abbiamo dimostrato che l'inibizione di p65BTK tramite diversi inibitori di BTK (Ibrutinib, AVL-292, RN486) riduce efficacemente la proliferazione e la clonogenicità di linee di NSCLC con differenti background genetici. Per determinare se p65BTK può essere considerato un nuovo bersaglio terapeutico nel NSCLC, abbiamo trattato linee resistenti di NSCLC con chemioterapia (Cisplatino, Gemcitabina, Pemetrexed) o inibitori di EGFR (Gefitinib, Erlotinib) in singolo, o in combinazione con concentrazioni non tossiche degli inibitori di BTK, valutandone l’effetto sulla vitalità cellulare. Gli inibitori di BTK usati in combinazione con gli inibitori di EGFR o con la chemioterapia sono risultati più efficaci nel ri-sensibilizzare le linee di NSCLC scarsamente responsive ai trattamenti standard e le diverse combinazioni hanno mostrato diversi gradi di sinergia. In conclusione, abbiamo dimostrato che p65BTK è over-espressa nei tumori di pazienti con NSCLC e in linee cellulari umane e murine di NSCLC. Pertanto, i nostri dati indicano p65BTK come un emergente target nel NSCLC e suggeriscono che la combinazione di inibitori di BTK e chemioterapia o terapia a bersaglio molecolare potrebbe rappresentare un nuovo approccio per superare la resistenza alle terapie nel NSCLC. I prossimi passi saranno volti a validare gli effetti dell'inibizione di p65BTK in modelli ex vivo (sferoidi derivati da cellule di NSCLC) e in vivo in modelli murini di NSCLC.Lung cancer is the leading cause of cancer-related death worldwide both in men and women. In particular, Non-Small Cell Lung Cancer (NSCLC) is the most common subtype and is relatively insensitive to chemotherapy and radiation therapy. Despite the development of personalized molecular targeted therapies against specific driver mutations and the combination of chemotherapy with targeted therapy, lung cancer mortality remains very high because of intrinsic and acquired resistance. Thus, new strategies to overcome these limitations are needed. Recently, we discovered a new isoform of the Bruton Tyrosine Kinase (BTK), referred as p65BTK. We characterized p65BTK as a novel oncogene and a pivotal downstream effector of RAS. Moreover, we showed that its inhibition affected growth and survival of colon cancer cells and reverted resistance to chemotherapy. The aims of this project were: study the role of p65BTK in NSCLC cell biology and verify whether p65BTK may be a novel theranostic target in NSCLC. Studying a cohort of 382 patients, we observed that p65BTK was expressed in 50% of NSCLC patients’ tumors and its expression correlated with histotype, smoke habit and EGFR mutational status. In particular, we found p65BTK significantly more expressed in adenocarcinoma than in squamous carcinoma histotype and in non-smoker as compared to smoker patients. Moreover, its expression was significantly higher in non-smoker patients bearing wild type EGFR. Notably, these patients are not eligible for treatments with EGFR inhibitors due to a lack of EGFR mutation. By western blot analysis we confirmed p65BTK overexpression both in vitro, in NSCLC human cell lines with mutations in RAS or in one of the components of the RAS/MAPK pathway, and ex vivo, in tumor-derived primary cells from Kras/Trp53 null mice, suggesting that p65BTK overexpression correlate with a hyper-activated RAS/MAPK pathway also in NSCLC. Then, we showed that p65BTK inhibition by different BTK inhibitors (Ibrutinib, AVL-292, RN486) strongly impaired proliferation and clonogenicity of NSCLC cell lines with different genetic backgrounds. To determine if p65BTK could be a new theranostic target in NSCLC, representative resistant cell lines were treated with chemotherapy (Cisplatin, Gemcitabine, Pemetrexed) or EGFR-targeted therapy (Gefitinib, Erlotinib) alone or in combination with non-toxic concentrations of BTK inhibitors and then their viability was assessed. We found that BTK inhibitors were effective in re-sensitizing NSCLC cells scarcely responsive to the current treatments when used in combination with EGFR-targeted therapy or chemotherapy. However, the different BTK inhibitors’ combinations showed a better or worse synergy depending on which EGFR inhibitor or chemotherapeutic drug they were combined with. Thus, we demonstrate that p65BTK is overexpressed in NSCLC patients’ tumors and in human and murine NSCLC cells. Moreover, our data indicate p65BTK as an emerging actionable target in NSCLC and suggest that the combination of BTK inhibitors with chemotherapy or targeted therapy may represent a novel therapeutic approach to overcome drug resistance in NSCLC. As future perspectives, we will validate the effects of p65BTK inhibition in ex-vivo (spheroids derived from NSCLC cells) models and in in vivo mouse model of NSCLC.
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Al-Akhrass, Hussein. "Un rôle inédit de la sortiline dans le contrôle du transport rétrograde de l'EGFR pour limiter la croissance tumorale." Thesis, Limoges, 2017. http://www.theses.fr/2017LIMO0035/document.
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Le cancer du poumon est le troisième cancer le plus fréquent chez les femmes et le deuxième chez les hommes, il est la cause principale de décès par cancer dans le monde, avec une mortalité annuelle supérieure à 1 million. Malgré des progrès remarquables dans la thérapie ciblée, la majorité des patients atteints de cancer du poumon sont diagnostiqués dans un stade avancé où ils ne connaissent pas d'amélioration significative de leur survie globale. Les récepteurs à domaine tyrosine kinase, tels que le récepteur du facteur de croissance épidermique (EGFR), traduisent les informations du microenvironnement dans la cellule en activant des voies de signalisation homéostatiques. L'internalisation et la dégradation de l'EGFR suite à la liaison du ligand limitent l'intensité de la signalisation proliférative, ce qui contribue à maintenir l'intégrité cellulaire. Dans les cellules cancéreuses, la dérégulation du trafic de l’EGFR aboutit à des effets divers sur la progression tumorale. Dans cette étude, nous avons identifié la sortiline comme un régulateur clé de l'internalisation de l'EGFR à partir de la membrane plasmique. La perte de l’expression de la sortiline dans les cellules tumorales augmente la prolifération cellulaire en soutenant la signalisation de l’EGFR à la surface de la cellule, ce qui accélère la croissance tumorale. Chez les patients atteints de cancer du poumon, l'expression de la sortiline diminue avec l’augmentation du grade pathologique et l’expression de son gène, SORT1, est fortement corrélée à une meilleure survie globale, en particulier chez les patients présentant une forte expression de l'EGFR. Ainsi, la sortiline représente un nouveau régulateur du trafic intracellulaire de l’EGFR, elle agit en contrôlant l'internalisation de ce récepteur et en limitant la croissance tumoraleLung cancer is the third most common cancer in women and the second in men, it is the leading cause of cancer-related death worldwide, with an annual mortality of more than 1 million. Despite remarkable advances in targeted therapy, the majority of patients with lung cancer are diagnosed at an advanced stage where they do not experience a significant improvement in overall survival. Tyrosine kinase receptors such as the epidermal growth factor receptor (EGFR) transduce information from the microenvironment into the cell and activate homeostatic signalling pathways. Internalisation and degradation of EGFR after ligand binding limits the intensity of its proliferative signalling, thereby helping to maintain cell integrity. In cancer cells, deregulation of EGFR trafficking has a variety of effects on tumour progression. Here, we report that sortilin is a key regulator of EGFR internalisation. Loss of sortilin in tumour cells promotes cell proliferation by sustaining EGFR signalling at the cell surface, ultimately accelerating tumour growth. In lung cancer patients, sortilin expression decreases with increased pathologic grade, and the expression of SORT1 (the gene encoding sortilin) is strongly correlated with a better survival, notably in patients with high EGFR expression. Thus, sortilin is a novel regulator of EGFR intracellular trafficking acting by controlling receptor internalisation and limiting tumour growth
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Das, Gupta Paromita Clinical School Prince of Wales Hospital Faculty of Medicine UNSW. "Gene profiling in soft tissue sarcoma: predictive value of EGFR in sarcoma tumour progression and survival." Publisher:University of New South Wales. Clinical School - Prince of Wales Hospital, 2007. http://handle.unsw.edu.au/1959.4/43259.
Full textAbstract:
Despite improvements in the clinical management of soft tissue sarcomas (STS), 50% of patients will die of metastatic disease that is largely unresponsive to conventional chemotherapeutic agents. The aims of this study were to identify genes and pathways that are dysregulated in progressive and metastatic STS. In addition to this, cell lines from fresh tumours were initiated and established, thus increasing the repository of cell lines available for functional studies. Recent advances in the understanding of the molecular biology of STS have thus far not resulted in the use of molecular markers for clinical prognostication. Identifying novel genes and pathways will lead to molecular diagnostic methods to better stratify prognostic groups and could identify cellular targets for more efficacious treatments. Gene expression profiling of sarcoma cell lines of increasing metastatic potential revealed over-expression of genes involved in the epidermal growth factor (EGF) and transforming growth factor beta (TGFb) pathways. Factors involved in invasion and metastasis such as integrins and MMPs were over-expressed in the cell lines with higher metastatic potential. The developmental Notch pathway and cell cycle regulators were also dysregulated. NDRG1 was significantly over-expressed in the high grade sarcoma cell line, a novel finding in sarcomas. The expression of EGFR, NDRG1 and other genes from the above pathways was validated using quantitative RT-PCR in real time (qRT-PCR). A tissue microarray (TMA) comprising STS of varying tumour grades was constructed for high throughput assessment of target proteins. EGFR, its activated form and its signal transducers were investigated using immunohistochemistry (IHC). Activated EGFR (HR 2.228, p < 0.001) and phosphorylated Akt (HR 2.032, p = 0.003) were found to be independent predictors of overall survival and both correlated with tumour grade. Of the several STS cultures initiated and maintained, two of these cell lines were fully characterised in terms of cytogenetics, telomerase and alternate lengthening of 5 telomeres (ALT) status, KIT and TP53 mutation and the expression of certain biomarkers using both qRT-PCR and IHC. In summary, transcript profiling identified several potential biomarkers of tumour progression and metastasis in STS. Crucially, activated EGFR and pAkt were found in a cohort of STS samples to correlate with clinical outcome, identifying them as potential diagnostic and therapeutic targets in the treatment of STS. Activated EGFR can be used as a diagnostic marker for patient selection, as well as for target effect monitoring. Furthermore, the cell lines established in this project will serve as valuable tools in future preclinical studies.
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Ryan, Sean P. "Autosomal Recessive Polycystic Kidney Disease Epithelial Cell Model Reveals Multiple Basolateral EGF Receptor Sorting Pathways." Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1274887553.
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Fraguas, Garcia Susanna. "Regulació de la regeneració anterior a través de la via egfr-3/egr-4 en la planària Schmidtea mediterranea." Doctoral thesis, Universitat de Barcelona, 2014. http://hdl.handle.net/10803/277417.
Full textAbstract:
Les planàries d'aigua dolça s’han convertit en un bon model per estudiar la regeneració a nivell genètic i molecular, gràcies a la seva capacitat de reconstruir qualsevol fragment danyat a conseqüència d’una amputació, des de qualsevol eix corporal i formar un nou organisme adult en un termini de temps molt curt. Al mateix temps, durant l’estadi adult en l’absència d’una ferida, les planàries són capaces de reemplaçar les cèl•lules diferenciades dels teixits vells mitjançant una proliferació i diferenciació constant de les cèl•lules mare o neoblasts.
Tenim al nostre abast un ampli coneixement sobre diverses rutes de senyalització que controlen l’estricte procés de la regeneració en les planàries. D’altra banda, avui dia encara es desconeix la funció d’algunes de les vies principals i queden molts elements desconeguts per entendre el fenomen de la regeneració. En aquesta tesi doctoral, hem pogut analitzar la funció concreta de la via dels EGFR, sobretot durant la formació del blastema i la regulació del creixement i la diferenciació de les noves estructures anteriors. Mitjançant estudis funcionals a través de la tècnica d’interferència de l’ARN (ARNi) dels tres EGFR identificats, hem observat la participació d’aquesta via en múltiples processos biològics durant la regeneració de les planàries i la homeòstasi. Smed-egfr-1 és necessari per a la regeneració de les cèl•lules pigmentàries dels ulls i la faringe. A més a més, el seu silenciament ocasiona una clara hiperproliferació i la formació d’uns bonys dorsals característics, tant en animals intactes com regenerants. D’altra banda, no es manifesta cap efecte evident després de silenciar Smed-egfr-2. Finalment, podem concloure que Smed-egfr-3 és necessari per la formació del blastema i per la diferenciació de determinats tipus cel•lulars, generalment neuronals.
En aquesta tesi ens hem centrat sobretot amb l’estudi del Smed-egfr-3. Amb l’objectiu d’identificar possibles gens diana d’aquest gen i caracteritzar la funció de la via dels EGFR en més detall durant la regeneració de les planàries, hem utilitzat l’eina DGE (“Digital Gene Expression”), que ens permet comparar el transcriptoma dels animals on s’ha silenciat un gen d’interès (en el nostre cas, Smed-egfr-3) amb el dels controls. Així, a partir d’anàlisis del DGE hem pogut conèixer i quantificar l’expressió de possibles gens diana regulats (tant “up” com “down-regulated”) per la via dels EGFR; un d’aquests gens “downregulated” després d’inhibir Smed-egfr-3 és l’egr-4, un membre de la família gènica dels “early growth response”.
egr-4 s’expressa majoritàriament en el sistema nerviós central i s’indueix ràpidament després de qualsevol tipus de ferida. El seu silenciament inhibeix la regeneració anterior, mostrant defectes durant la formació dels blastemes anteriors, però sense afectar la regeneració posterior. Aquests organismes tractats exhibeixen uns ganglis cefàlics més petits o fins I tot en alguns casos absents. La diferenciació d’altres tipus cel•lulars presents en la regió anterior també es mostren alterats després de silenciar egr-4. Tot i així, l’expressió primerenca dels determinants de la polaritat que intervenen en el restabliment de la polaritat anterior es mostren inalterats.
Experiments simultanis del silenciament d’egr-4 i elements de la via Wnt/beta-cat revelen que egr-4 és necessari per la diferenciació del primordi del cervell. A més a més, els resultats d’aquests experiments suggereixen que egr-4 promou la regeneració cefàlica inhibint l’activitat de beta-catenin en condicions normals. A partir dels resultats obtinguts en aquesta tesi suggerim que egr-4 és un dels primers gens coneguts necessaris per la diferenciació del primordi del cervell durant la regeneració de la planària.
En resum, suggerim una relació entre la diferenciació primerenca del cervell i la correcta progressió de la regeneració del cap en les planàries, que podria estar regulada gràcies a l’activació del gen egr-4 a través de la via EGFR, concretament Smed-egfr-3.During freshwater planarians regeneration, polarity and patterning programs play essential roles in determining whether a head or a tail regenerates at anterior or posterior-facing wounds. This decision is made very soon after amputation. The pivotal role of the Wnt/beta-•catenin and Hh signaling pathways in re-establishing anterior4 posterior polarity has been well documented. However, the mechanisms that control the growth and differentiation of the blastema in accordance with its anteriorposterior identity are less well understood. Conserved signa ling pathways play important roles in morphogenesis in all animals. One such pathway is the epidermal growth factor receptor (EGFR) pathway, which regulates multiple biological processes including cell proliferation, differentiation, apoptosis and cell survival. In this thesis, we show that silencing of Smed-egfr4 3, a planarian homologue of epidermal growth factor receptors, impairs regeneration and blastema growth in these organisms, probably by disrupting cellular differentiation. In order to better characterize the function of the EGFR signaling pathway during planarian regeneration, we conducted "Digital Gene Expression" analyses to identify putative target genes of Smed-egfr-3. One of the isolated candidate genes that is downregulated after silencing Smed-egfr-3 is egr-4, a member of the early growth response gene family. egr-4 is mainly expressed in the central nervous system and rapidly induced after different types of injury. While early egr-4 expression after injury is independent of EGFR signa ling, it becomes Smed-egfr4 34 dependent from the second day of regeneration. Functional analyses based on RNA interference (RNAi) reveals that egr-4 is required for head regeneration but not for posterior regeneration; egr-4 silencing impairs the formation of anterior blastemas; these animals exhibit either small cephalic ganglia or a total absence of new brain tissue. Single and combinatorial RNAi to target different elements of the Wnt/beta-•catenin pathway, together with expression analysis of brain4 and anterior4 specific markers, reveal that egr-4 is necessary for the brain primordia differentiation in the early stages of regeneration and it appears to antagonize the activity of the Wnt/~-catenin pathway to allow head regeneration. Our results suggest that a conserved EGFRjegr pathway plays an important role in cell differentiation during planarian regeneration and indicate an association between early brain differentiation and the progression of head regeneration.