Tesi: "Cetuximab"

1

Angles, M., e John B. Bossaer. "Cetuximab-related Hypersensitivity Reactions in Northeast Tennessee". Digital Commons @ East Tennessee State University, 2012. https://dc.etsu.edu/etsu-works/2357.

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Primary Objective: To confirm the findings of several small studies conducted in the southeastern United States showing hypersensitivity infusion reaction (HIR) rates as high as 22% with the monoclonal antibody, cetuximab. Although well known for a risk of HIRs, early clinical studies showed much lower reaction rates of 3%.

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2

De, Angelis Maria Laura. "Cetuximab effect on human colon cancer stem cells". Doctoral thesis, Università di Catania, 2014. http://hdl.handle.net/10761/1488.

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Cancer Stem cells (CSCs), recently identified in the majority of solid tumors, are thought to drive tumor growth, giving rise to a cascade of differentiated cells composing the bulk of the tumor. Tumor relapse that most often follows treatment with anti-proliferative and cytotoxic drugs would be explained by selective resistance of CSC to these agents. Colon cancer stem cells (cCSCs), first isolated in the host laboratory from surgical specimens, can be grown in vitro as clusters called tumor spheres that maintain an undifferentiated state and are able, upon injection in immunodeficient mice, to generate a xenograft identical to the parental tumor, in terms of both antigen expression and histological tissue organization. Because of all these features cCSCs may represent predictive tools for patient s therapeutic response. Cetuximab (Erbitux), currently in use for metastatic colorectal cancer, is a recombinant chimeric human:murine immunoglobulin IgG1 that binds to EGFR displacing its natural ligands. Cetuximab also induces receptor internalization and degradation. Mutations in signaling pathway mediators acting downstream of EGFR, including KRAS, BRAF, NRAS, or PIK3CA are believed to determine resistance to the drug. In particular, KRAS-mutated patients are currently excluded from treatment. In order to verify whether Cetuximab treatment affects the stem cell compartment within tumors, in this study I analyzed its effect in a panel of cCSCs generated by individual patients, both in vitro and in xenografts. The data show that the effect of Cetuximab on individual cCSCs reflects the known clinical data on individual tumor mutations in the EGFR signaling pathway molecules. The study therefore confirms that panels of cCSCs generated by individual patients represent good predictive tools for the preclinical screening of pathway-oriented, cancer stem cell-directed therapeutics. Most importantly, the analysis of stem cell content in Cetuximab-treated xenografts by cytofluorimetry, agarose assay, and serial re-transplantation into secondary hosts clearly demonstrate that Cetuximab, differently than the classical chemotherapeutics currently in use for colon cancer, is able to effectively hit cCSC populations included in the tumors.

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3

Adams, C. B., D. S. Street e John B. Bossaer. "Incidence of Cetuximab-related Infusion Reactions in Northeastern Tennessee". Digital Commons @ East Tennessee State University, 2015. https://dc.etsu.edu/etsu-works/2351.

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4

Adams, C. B., D. S. Street e John B. Bossaer. "Incidence of Cetuximab-related Infusion Reactions in Northeastern Tennessee". Digital Commons @ East Tennessee State University, 2014. https://dc.etsu.edu/etsu-works/2352.

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5

Cyran, Carolin Anna Maria. "Immunologische Veränderungen bei Patienten mit akneiformem Exanthem unter Cetuximab-Therapie". Diss., lmu, 2010. http://nbn-resolving.de/urn:nbn:de:bvb:19-124322.

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6

Santoro, V. "The interaction of cetuximab with chemotherapeutic agents in colon cancer". Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1454999/.

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Cetuximab is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR) and is used for the treatment of metastatic colorectal cancer (mCRC) as monotherapy or in combination with chemotherapy. Recent clinical trials have shown little benefit in combining cetuximab with oxaliplatin in contrast to the positive interactions observed with irinotecan. This thesis aims to understand why a subset of colorectal cancers do not benefit from cetuximab and oxaliplatin combined treatment. In vitro drug combination assays showed that the addition of cetuximab to oxaliplatin resulted in antagonistic effects on cell proliferation as opposed to the synergism observed with 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan. Although both oxaliplatin and SN-38 increased the levels of reactive oxygen species (ROS), only oxaliplatin was able to induce ROS-mediated apoptosis via the activation of p38 Mitogen-Activated Protein Kinase (MAPK). RT-PCR oxidative stress array analysis revealed that oxaliplatin can produce ROS through the upregulation of the NADPH oxidase ROS generating enzyme Dual Oxidase 2 (DUOX2) and that cetuximab, by preventing DUOX2 induction, can inhibit ROS generation by oxaliplatin. Chromatin Immunoprecipitation (ChIP) of Signal Transducer and Activator of Transcription 1 (STAT1) following oxaliplatin treatment, indicated a role for this protein in the transcriptional upregulation of DUOX2 by direct promoter-binding. Cetuximab, by impairing STAT1 activation and DUOX2 upregulation, can antagonise ROS-mediated apoptosis by oxaliplatin through the activation of the p38 pathway. Microarray analysis was employed to identify deregulated genes in the p38 pathway following cetuximab and oxaliplatin treatment in order to better clarify the role that p38-regulated genes play in the negative interactions of these drugs. The results presented in this thesis highlight the importance of ROS generation for the cytotoxic effects of oxaliplatin and indicate that combination with ROS-reducing agents such as cetuximab can result in negative cellular effects. Understanding how these drug interactions lead to antagonistic effects will be useful for the optimisation of future therapeutic combinations in the clinical setting.

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SAXENA, GUNJAN. "SYNTHESIS AND CHARACTERIZATION OF DOXORUBICIN CARRYING CETUXIMAB-PAMAM DENDRIMER BIOCONJUGATES". VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/2788.

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A tumor targeted dendrimer based drug delivery system was designed and synthesized to carry chemotherapy drug doxorubicin. Polyamidoamine (PAMAM) dendrimer G4.5 was chosen as the underlying carrier. Anionic G4.5 is a good option for drug delivery as it consists of 128 surface groups, is less cytotoxic and favorably biodistributed. The delivery system was synthesized using a layer-by layer arrangement of three functional entities: chemotherapy drug doxorubicin, monoclonal antibody Cetuximab against EGF receptor, and polyethylene glycol (PEG). Doxorubicin was attached via an acid-sensitive hydrazon linkage to the dendrimer. Macromolecules are taken in by cells through endocytosis. pH inside the early endosomes to lysosomes ranges from pH 6 to 4.5. These acidic conditions are favorable for release of drug bound to the dendrimer vehicle through acid-sensitive linkage. 35% of all solid tumors of brain express exceptionally high EGF receptors whereas normal brain tumors express less EGFR. This makes the EGFR a potent targeting moiety for targeted drug delivery. Cetuximab will serve as a targeting ligand to help the delivery system target tumor cells. PEG was incorporated as a linker between Cetuximab and dendrimer to avoid reticuloendothelial system (RES) uptake of the system, increase biocompatibility, increase drug half-life and other shortcomings associated with nanomaterials. Nuclear magnetic resonance spectroscopy (NMR), fluorescence anisotropy, and western blotting were used to confirm the conjugation of PEG, doxorubicin and cetuximab to the dendrimer. The synthesized delivery system was characterized using ultraviolet-visible spectroscopy (UV-Vis) to approximate the number of doxorubicin attached. Dynamic light scattering (DLS) and zeta potential were used to analyze the change in size and surface properties of dendrimer during the synthesis. Doxorubicin release studies were conducted at different pHs. Maximum doxorubicin was released at pH 4.5 indicating the successful acid-sensitive linkage between the drug and dendrimer. Cytotoxicity studies indicated that the addition of PEG increased the biocompatibility as compared to free doxorubicin whereas; combination of doxorubicin and cetuximab exerted a significant toxic effect over a period of 72 hours. The cellular uptake of the delivery system was higher than that of free doxorubicin. Free DOX localized mainly in the nucleus whereas, CTX-G4.5-PEG-DOX conjugate localized within both cytoplasm and nucleus after 6 hour incubation. The synthesized delivery system represents a potential targeted drug delivery system.

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8

Espinosa-Cotton, Madelyn. "Interleukin-1 signaling contributes to the anti-tumor efficacy of Cetuximab in head and neck squamous cell carcinoma". Diss., University of Iowa, 2018. https://ir.uiowa.edu/etd/6570.

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Despite the incorporation of the epidermal growth factor receptor (EGFR) inhibitor cetuximab into the clinical management of recurrent and metastatic (R/M) head and neck squamous cell carcinoma (HNSCC), only a small subset of patients responds to cetuximab, despite EGFR overexpression in virtually all of their tumors. At this time, there is a lack of validated predictive biomarkers to predict which patients will respond to cetuximab. Our previous work suggests that cetuximab activates the interleukin-1 (IL-1) pathway via tumor release of IL-1 alpha (IL-1α), although the implications of activating this pathway are unclear. The IL-1 pathway plays a central role in immune response and displays both pro-tumor and anti-tumor activities. IL-1 may promote tumor growth by upregulating the secretion of pro-inflammatory mediators involved in angiogenesis and metastasis. On the other hand, IL-1 signaling may promote antitumor immunity via enhancement of natural killer (NK)-cell mediated antibody-dependent cell-mediated cytotoxicity (ADCC) and T cell activity, which are important mechanisms of action of cetuximab. The goal of this work is to determine how modulation of the IL-1 pathway affects HNSCC tumor response to cetuximab and if IL-1 may serve as a predictive biomarker for patient response to cetuximab. Blockade of IL-1 signaling did not enhance the anti-tumor efficacy of cetuximab, while IL-1α overexpression and treatment with recombinant IL-1α and IL-1α nanoparticles increased HNSCC tumor response to cetuximab in immunodeficient and immunocompetent HNSCC mouse models. Mechanistically, these results appear to be due to activation of an anti-tumor NK and T cell-mediated immune response. Additionally, we found that both nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) and inducible nitric oxide synthase (iNOS) activity may be involved in the efficacy of IL-1-induced ADCC against cetuximab-coated HNSCC cells. Altogether, these results suggest that IL-1 signaling is necessary for HNSCC tumor response to cetuximab. Furthermore, we have shown that pre-treatment serum and tumor IL-1 ligands can predict progression-free survival of HNSCC patients treated with standard-of-care cetuximab and chemotherapy, cetuximab combined with other targeted therapies, and cetuximab monotherapy. Overall, we propose that IL-1α warrants further study as a novel therapeutic to enhance response to cetuximab and as a predictive biomarker for HNSCC response to cetuximab.

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9

Ziegler, Katharina Melanie. "Untersuchungen zur Stabilisierung und Interaktion von Cetuximab mit nicht-ionischen Tensiden". Diss., Ludwig-Maximilians-Universität München, 2013. http://nbn-resolving.de/urn:nbn:de:bvb:19-164761.

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10

Gomes, Ana Catarina Domingues. "O papel do cetuximab no tratamento do carcinoma colo-rectal matastizado". Master's thesis, Faculdade de Medicina da Universidade do Porto, 2010. http://hdl.handle.net/10216/61075.

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11

Gomes, Ana Catarina Domingues. "O papel do cetuximab no tratamento do carcinoma colo-rectal matastizado". Dissertação, Faculdade de Medicina da Universidade do Porto, 2010. http://hdl.handle.net/10216/61075.

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12

Trevizan, Lucas Noboru Fatori. "Avaliação do potencial de nanodispersões de cristal líquido funcionalizadas com cetuximabe na veiculação de docetaxel para o tratamento do câncer de próstata /". Araraquara, 2018. http://hdl.handle.net/11449/157268.

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Orientador: Marlus Chorilli
Resumo: O câncer de próstata (CP) é a segunda neoplasia mais frequente entre homens no Brasil e é caracterizado por não apresentar sintomas em seus estágios iniciais, sendo diagnosticado em seu estágio avançado, o que muitas vezes dificulta o tratamento. Alguns fatores relacionados podem intensificar sua agressividade como, por exemplo, a superexpressão do receptor do fator de crescimento epidérmico (EGFR) em alguns subtipos de tumores de próstata. Neste contexto, a inibição do EGFR auxilia no combate da neoplasia, função essa que pode ser atribuída ao anticorpo monoclonal quimérico IgG1 (cetuximabe-CTX) que se liga à porção externa do EGFR, inibindo a proliferação celular, angiogênese e metástase, além de promover a apoptose. Dentre as formas de tratamento destacam-se a braquiterapia, a radioterapia e a quimioterapia utilizando o docetaxel (DTX), o qual apresenta vantagem de prolongar a sobrevivência em pacientes com CP metastático resistentes à terapia antiandrogênica. No entanto, a formulação comercial (Taxotere®) causa efeitos colaterais, como febre, anemia, retenção de líquidos, hipersensibilidades, mialgias, mucosite, neuropatias periféricas e toxidade a pele e unhas, tornando necessário o estudo de novas formas de veiculação para este fármaco Deste modo, o objetivo deste trabalho foi desenvolver uma nanodispersão de cristal líquido (NCL) de fase cúbica baseada em álcool cetílico etoxilado 20 e propoxilado 5 como tensoativo (T), ácido oleico, DSPE-PEG-MAL e fosfatidilcolina de ... (Resumo completo, clicar acesso eletrônico abaixo)
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13

Dalmases, Massegú Alba 1982. "Acquired resistance to the anti-EFGR monoclonal antibody cetuximab in colorectal cancer". Doctoral thesis, Universitat Pompeu Fabra, 2012. http://hdl.handle.net/10803/84183.

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EGFR is a transmembrane tyrosine kinase receptor from the HER family which, upon ligand stimulation, activates different signaling pathways involved in tumorogenesis. EGFR can be targeted by monoclonal antibodies, as cetuximab and panitumumab, which bind to EGFR preventing ligand stimulation of the receptor. Cetuximab and panitumumab are approved for colorectal cancer treatment. However, its clinical success is uniformily limited by the development of acquired drug resistance. We describe a new mechanism of acquired resistance to cetuximab in colorectal cancer that was due to a missense mutation in the EGFR ectodomain (S492R mutation). Upon chronic exposure to cetuximab, colorectal cancer cell lines acquired S492R mutation and became resistant to the treatment. We observed that cetuximab was not able to bind mutant EGFR. Notably, this amino acid change did not affect the ability of panitumumab to bind to EGFR, and panitumumab effectively suppressed growth of mutant cells. EGFRS492R mutation was detected in 2 out of 10 tumor specimens from patients following progression on cetuximab. One of these patients was subsequently treated with single agent panitumumab yielding a partial response. The S492R mutation defines a novel biomarker of resistance to cetuximab but not to panitumumab in colorectal cancer
EGFR és un receptor transmembrana tirosina cinasa de la família HER el qual, després de l’estimulació mitjançant lligands, activa vies de senyalització involucrades en processos tumorogènics. L’EGFR es pot inhibir amb anticossos monoclonals, com cetuximab i panitumumab, que s’uneixen al receptor prevenint-ne l’activació per part dels lligands. Cetuximab i panitumumab estan aprovats per al tractament del càncer colorectal, però el seu ús es veu limitat per el desenvolupament de resistència adquirida al tractament. Nosaltres describim un mecanisme de resistència adquirida a cetuximab en càncer colorectal degut a l’adquisió d’una mutació en el domini extracel•lular de l’EGFR, la mutació S492R. Durant l’exposició crònica a cetuximab, linies cel•lulars de càncer colorectal van adquirir la mutació S492R tornat-se resistents al tractament. Cetuximab no era capaç d’unir-se a l’EGFR mutat. Aquests canvi d’aminoàcid no afectava a l’habilitat que té panitumumab a unir-se al EGFR, pertant, panitumumab suprimia el creixement de les cèl•lules tumorals mutades. Vam detectar la mutació EGFRS492R en 2 de 10 mostres tumorals de pacients que havien recaigut al tractament amb cetuximab. Un d’aquest pacients va ser posteriorment tractat amb panitumumab obtenint-ne una resposta tumoral parcial. La mutació S492R defineix un nou mecanisme de resistència a cetuximab però no a panitumumab en el tractament del càncer colorectal.

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Zhang, Qian, e 张茜. "Retrospective analysis of bevacizumab and cetuximab in advanced Asian colorectal cancer patients". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2015. http://hdl.handle.net/10722/209506.

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Colorectal cancer is a serious health problem that has concerned people for decades. In Hong Kong, it is the most common cancer and the second leading cause of death. Among colorectal cancer patients, around 40-50% of them will develop metastatic disease. Chemotherapy is playing an important role all the time in the treatment of advanced colorectal cancer. In the past decade, the application of targeted therapies in treatment has largely improved efficacy and prolonged survival. Bevacizumab and cetuximab are two commonly used targeted agents in daily clinical practice of Hong Kong. Since multiple clinical trials have studied bevacizumab and cetuximab in combination with other chemotherapies, limited data is available in Asian patients. Therefore, we conduct three 5-year retrospective analyses based on patients received treatment in Hong Kong Queen Mary Hospital, to investigate the clinical efficacy and toxicity of those two drugs. The first study examined the use of bevacizumab in treating KRAS mutated type patients. We found the efficacy and results were consistent with historical data. In the next analysis of cetuximab, comparable data were shown which suggested the consistency with previous studies. The last study is aim to compare bevacizumab and cetuximab in previously untreated wild-type KRAS patients. Identical response rates, progression-free survival and overall survival were finally reported.
published_or_final_version
Medicine
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Master of Philosophy

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Balin-Gauthier, Diane. "Etude des interactions "Cetuximab/oxaliplatine" dans des modèles de tumeurs coliques humaines". Toulouse 3, 2006. http://www.theses.fr/2006TOU30166.

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L’objectif de l’étude est d’évaluer les interactions entre l’oxaliplatine et l’inhibition de la voie de signalisation de l’EGFR par le cetuximab (anticorps monoclonal humanisé) sur des modèles de tumeurs coliques humaines. Notre étude s’est effectuée in vitro et in vivo sur quatre lignées cellulaires de tumeurs coliques présentant différents niveaux d’expression de l’EGFR. Ces modèles nous ont permis de démontrer une synergie d’action des deux produits in vitro et in vivo sur les lignées cellulaires HT-29 et HCT-8 et une séquence-dépendance de cette synergie dans les cellules HCT-8. L’exposition à l’association oxaliplatine/cetuximab permet d’augmenter le taux d’adduits d’oxaliplatine via l’inhibition de la protéine ERCC1. L’association induit le blocage des cellules dans le cycle cellulaire et l’inhibition de la voie de survie. L’étude de ces mécanismes a également permis d’identifier l’inhibition de l’initiation de la réplication comme signature moléculaire de la réponse synergique
The effects of cetuximab, a chimeric monoclonal antibody anti-EGFR, combined with oxaliplatin were assessed in a panel of 4 colorectal cancer cell lines expressing different level of EGFR. Results show that cetuximab exosure induces, in vivo and in vitro, synergistic interaction with oxaliplatin in HT-29 and HCT-8 cell lines. Synergistic effect of the oxaliplatin/cetuximab combination in HCT-8 cells involves multiple interaction between oxaliplatin pharmacology and EGFR signaling transduction pathway. First, cetuximab inhibits NER activity through the down-regulation of ERCC1 expression which results in the stabilization of platinum-DNA adducts level. Oxaliplatin/cetuximab combination accelerates apoptotic effect of oxaliplatin concomitantly with an inhibition of AKT activation. The analysis of cell cycle distribution and modulation of various gene expression highlight the inhibition of the initiation of DNA replication as a signature of oxaliplatin/cetuximab synergistic interaction

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Adams, Brooke C., Sierra D. Street, Melanie Crass e John B. Bossaer. "Low Rate of Cetuximab Hypersensitivity Reactions in Northeast Tennessee: An Appalachian Effect?" Digital Commons @ East Tennessee State University, 2015. https://dc.etsu.edu/etsu-works/2323.

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Purpose: Cetuximab is a monoclonal antibody with a known risk of hypersensitivity reactions. Early studies showed hypersensitivity reaction rates of 3%, but there appears to be a higher incidence in the southeastern United States. To confirm the findings from nearby institutions that cetuximab-associated hypersensitivity reactions occur in approximately 20% of patients in the southeastern United States. Methods: A retrospective chart review was conducted at Johnson City Medical Center in Johnson City, Tennessee. Each patient’s first infusion was analyzed for hypersensitivity reaction, as well as for demographic information such as allergy and smoking history, pre-medications, and malignancy type. Results: Data from the first infusion of cetuximab were collected for a total of 71 patients with various malignancies. The overall rate of grade 3 or higher hypersensitivity reaction was 1.4%, and total rate of hypersensitivity reaction was 8.5%. These findings more closely correlate to the early clinical trials and package insert. Both severe (p = 0.001) and any-grade (p = 0.002) hypersensitivity reaction occurred less frequently in one Southeastern Appalachian medical center compared to academic medical centers directly to the east and west. Conclusions: Patients in southern Appalachia may be less likely to develop cetuximab hypersensitivity reactions compared to surrounding areas in the Southeastern U.S. These results lend support to the theory that exposure to lonestar ticks (Amblyomma americanum) may be responsible for the development of IgE antibodies to cetuximab that cause hypersensitivity reactions. The development of quick and reliable bedside predictors of cetuximab hypersensitivity reactions may aid clinicians considering the use of cetuximab.

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Benedetto, Raquel. "89Zr-Imuno-PET/111In-Imuno- SPECT: desenvolvimento radiofarmacêutico de agentes de imagem molecular para receptores EGF". Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/85/85131/tde-16022018-150129/.

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A baixa seletividade dos métodos convencionais para diagnóstico e terapia de neoplasias, bem como o fato de nem sempre alcançarem o sucesso terapêutico desejado, configuram dificuldades para a prática oncológica. Diante disso, os anticorpos monoclonais (AcMs) radiomarcados, aplicados em técnicas diagnósticas, têm se destacado, visto que permitem a entrega seletiva da radiação ao alvo de interesse. A metodologia Radioimunodiagnóstico (RID), utilizando AcM anti-EGFR radiomarcado, possibilita triagem prévia, avaliando a resistência ao tratamento e estratificando pacientes que possam apresentar benefícios à imunoterapia com cetuximabe. Além disso, permite monitorar a progressão da terapia, visando tratamento mais efetivo e direcionado, promulgando a abordagem da medicina personalizada. No Brasil, ainda não há radioimunoconjugado disponível para diagnóstico e seguimento do câncer. Nesse contexto, o objetivo com este trabalho foi o de desenvolver uma formulação farmacêutica para padronizar uma rotina de produção dos radiofármacos para radioimunodiagnóstico de câncer de cabeça e pescoço e de câncer colorretal: cetuximabe-DTPA-111In e cetuximabe-DFO-89Zr. Em adição, corroborar na elucidação dos mecanismos de resistência das células tumorais à terapia com o cetuximabe, através da realização de estudos de ligação do radioimunoconjugado à receptores celulares. Em relação aos radiofármacos estudados, destaca-se que os processos de conjugação do cetuximabe com os quelantes DTPA, na razão molar 1:20, e com o DFO, 1:5, foram bem-sucedidos e otimizados, demonstrando boa reprodutibilidade. Os imunoconjugados apresentaram preservação da imunorreatividade e alta estabilidade quando armazenados a -20°C por até seis meses. Esses imunoconjugados, quando radiomarcado com 111In e 89Zr, exibiram pureza radioquímica superior a 95%, sem necessidade de purificação pós-marcação, e estabilidade por tempo que possibilita seu transporte às clínicas distantes do centro produtor. As análises in vitro do cetuximabe-DTPA-111In em células FaDu-C10 (linhagem resistente) demonstraram percentual inexpressivo de ligação e internalização do radioimunoconjugado, congruindo na explanação do modelo de resistência conferido à linhagem. O estudo de corpo inteiro em MicroPET/TC revelou redução no perfil de captação no grupo de bloqueio, com excesso de cetuximabe não marcado, e intensa captação do cetuximabe-DFO-89Zr pelo tumor de células escamosas no grupo sem bloqueador, confirmando a especificidade in vivo do radioimunoconjugado. Os estudos de biodistribuição dos radiofármacos foram compatíveis com os descritos em literatura e validaram os resultados obtidos por imagens em MicroSPECT/TC e MicroPET/TC, além de apresentarem apreciável captação tumoral, considerando os tempos analisados. A estabilidade alta in vivo e a eficácia da marcação foram confirmadas pela baixa captação óssea e em tecidos não alvos. O melhor intervalo pós-injeção do radiofármaco para avaliação in vivo foi após cinco dias da administração. Conclui-se, portanto, que os radioimunoconjugados para imuno-SPECT e imuno-PET, cetuximabe-DTPA-111In e cetuximabe-DFO-89Zr, são ferramentas promissoras para diagnóstico e monitoramento de câncer receptor específico (EGFR) e para estratificação de pacientes à terapia anti-EGFR, encorajando a continuidade deste projeto para futuros estudos clínicos.
The low selectivity of conventional methods for cancer diagnosis and therapy, as well as the fact that these methods could not achieve the desired therapeutic success, constitute difficulties for the oncological practice. In this regard, radiolabeled monoclonal antibodies (mAbs) applied in diagnostic techniques have been highlighted, since they allow the selective delivery of the radiation to the specific target. The radioimmunodiagnosis methodology (RID), using radiolabeled anti-EGFR mAbs, enables previous screening, evaluating resistance to treatment and stratifying patients who may present benefits to cetuximab immunotherapy. In addition, it allows monitoring the progression of the therapy, aiming for a more effective and directed treatment, leading the personalized medicine approach. A radioimmunoconjugate is not yet available for diagnosis and management of cancer in Brazil. In this context, this research was carried out to develop a pharmaceutical formulation to standardize a routine production of radiopharmaceuticals for diagnosis and monitoring head and neck cancer and colorectal carcinoma: 111In-DTPA-cetuximab and 89Zr-DFO-cetuximab. In addition, corroborate in the elucidation of the tumor cells resistance mechanisms to EGFR-targeted therapy, through in vitro and in vivo radioimmunoconjugate binding studies to cellular receptors. Regarding to the radiopharmaceuticals studied, cetuximab was conjugated to DTPA chelator at 1:20 molar ratio and to DFO at 1: 5, and these processes were successful and optimized, showing good reproducibility. Immunoconjugates showed preservation of immunoreactivity and high stability when stored at -20 °C for up to 6 months. These immunoconjugates when radiolabeled with 111In and 89Zr have exhibited radiochemical purity above 95%, without any post-labeling purification, and the radioimmunoconjugates have demonstrated stability for a time that allows them to be transported to clinics far from the producer center. 111In-DTPA-cetuximab in vitro analyzes in FaDu-C10 cells (resistant cell line) has presented an inexpressive percentage of binding and internalization of the radioimmunoconjugate, ensuring the resistance model conferred to this cell line. The MicroPET/CT imaging study has revealed a reduction in uptake profile for \"Blocking\" group, with an excess of unlabeling cetuximab, and an intense 89Zr-DFO-cetuximab uptake in squamous cell tumor for \"Non-blocking\" group, that evidenced the in vivo radioimmunoconjugate specificity. The biodistribution studies of the radiopharmaceuticals were well-matched with those described in the literature and they validated the results obtained through the MicroSPECT/CT and MicroPET/ CT images. In addition, these studies in vivo have displayed a substantial tumor uptake, according with the analyzed time points. The radioimmunoconjugate showed high in vivo stability and labeling procedures efficiency, which were confirmed by low bone and non-target tissues uptake. The best post-injection interval for in vivo evaluation is after 5 days of radioimmunoconjugate administration. In conclusion, the radioimmunoconjugates for immuno-SPECT and immuno-PET, 111In-DTPA-cetuximab and 89Zr-DFO-cetuximab, are promising tools for diagnosis and monitoring of specific receptor cancer (EGFR), as well as for stratification of patients to anti-EGFR therapy, and thus encourages the continuity of this project for future clinical trials.

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Mesia, Nin Ricard. "Introducción de Cetuximab en el tratamiento del carcinoma escamoso de cabeza y cuello". Doctoral thesis, Universitat de Barcelona, 2014. http://hdl.handle.net/10803/291437.

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Esta tesis versa sobre el desarrollo clínico del anticuerpo monoclonal Cetuximab en el tratamiento del carcinoma escamoso de cabeza y cuello, en diferentes momentos de la enfermedad. En la enfermedad recurrente y metastásica, se ha realizado un estudio fase III que comparó en 1ª línea tratamiento la asociación de quimioterapia sola (esquema con Platino y 5-FU) con el mismo esquema de quimioterapia asociado a Cetuximab (esquema EXTREME). Los resultados de eficacia favoreciereon la combinación de quimioterapia con cetuximab, sin excesiva adición de toxicidad y sin repercusión en la calidad de vida evaluada por los propios pacientes. Las conclusiones han sido: 1. En comparación con el esquema de platino/fluorouracilo, la misma combinación con cetuximab mejora de forma significativa la supervivencia global en primera línea de la enfermedad recurrente/metastásica. 2. Todos los demás parámetros de eficacia (supervivencia libre de progresión, mejor respuesta global, control de la enfermedad y tiempo al fallo terapéutico) también favorecieron a la combinación con cetuximab. 3. EXTREME añade las toxicidades propias de cetuximab: cutánea, infusionales e hipomagnesisemia. Además, existe un 5% de sepsis en los pacientes con la combinación que no se dan en el grupo de QT sola. 4. La adición de cetuximab a la QT con platino/fluorouracilo no afecta de forma adversa la calidad de vida de los pacientes con enfermedad recurrente/metastásica. Además, mejoran algunos de los síntomas asociados al CECC (como el dolor o la deglución), por lo que le dan más relevancia a la combinación en una fase de la enfermedad donde el control sintomático es fundamental. 5. El número de copias del EGFR tumoral no es un biomarcador predictivo de la eficacia de la combinación de cetuximab, platino y FU en primera línea de la enfermedad recurrente/metastásica. Por tanto, el análisis de este parámetro antes del inicio de un tratamiento no aportará ninguna información relevante al clínico. Por tanto, también podemos decir que el beneficio asociado a la combinación de quimioterapia y cetuximab es independiente del número de copias del EGFR. El segundo estudio fue en enfermedad localmente avanzada, específicamente en cáncer de orofaringe y fue un estudio fase II randomizado que evaluó la eficacia y la toxicidad de la adición de 12 semanas de tratamiento adyuvante con Cetuximab semanal una vez finalizado un tratamiento concomitante con radioterapia y cetuximab. Aunque el control loco-regional al año fue un 12% superior en la rama de cetuximab adyuvante, no existieron diferencias en ningún parámetro de eficacia a partir del segundo año. Por tanto la conclusión fue, doce semanas de tratamiento adyuvante con cetuximab tras un tratamiento radical con RT + cetuximab es posible y seguro, y mejora el control de la enfermedad al final del tratamiento, y el control loco-regional al primer año. No obstante, el bloqueo en solitario del EGFR durante 12 semanas no es suficiente para eliminar la enfermedad mínima residual tras el tratamiento radical y por tanto no es capaz de mantener ese mayor control en el tiempo, con un incremento de recidivas loco-regionales en el segundo año de seguimiento, y ningún impacto sobre la supervivencia.
This thesis deals on the clinical development of the monoclonal antibody Cetuximab for the treatment of squamous cell carcinoma of head and neck, at different stages of the disease. In metastatic/recurrent disease, there has been a phase III study that compared in 1st line treatment a combination of chemotherapy alone (schema with Platinum and 5-FU) with the same scheme of chemotherapy associated with Cetuximab (schema EXTREME). The conclusions have been: 1. In comparison with the Platinum/fluorouracil, the same combination with cetuximab significantly improves overall survival. 2. All other parameters of efficacy (progression free survival,best overall response, control of the disease) also favored the combination with cetuximab. 3. EXTREME toxicities of cetuximab added: skin, infusionales and hipomagnesisemia. 4. The addition of cetuximab to the chemotherapy with Platinum/fluorouracil form does not affect adversely the quality of life of patients with recurrent/metastatic disease. 5. EGFR copy number is not a predictive biomarker of the efficacy of the combination of cetuximab, Platinum and FU in recurrent/metastatic disease. The second study in locally advanced disease, specifically in oropharyngeal cancer and was a randomized phase II study that evaluated the efficacy and the toxicity of the addition of 12 weeks of adjuvant treatment with Cetuximab weekly once completed a concomitant treatment with radiotherapy and cetuximab. Although a year locoregional control was a 12% higher in the branch of adjuvant cetuximab, there were no differences in any parameter of efficiency from the second year. Therefore the conclusion was, twelve weeks of adjuvant treatment with cetuximab after radical treatment with RT + cetuximab is possible and secure, and improves the control of the disease at the end of the treatment, and first-year locoregional control. However, the blockade of EGFR during 12 weeks alone is not enough to eliminate minimal residual disease after radical treatment and therefore is not able to maintain greater control over time, with increased loco-regional recurrences in the second year of follow-up, and no impact on survival.

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Dreier, Agnieszka [Verfasser]. "Charakterisierung der Auswirkungen von Cetuximab auf EGFR und EGFRvIII im Zellkulturmodell / Agnieszka Dreier". Aachen : Hochschulbibliothek der Rheinisch-Westfälischen Technischen Hochschule Aachen, 2012. http://d-nb.info/1028001940/34.

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Pareek, Tirusha. "Fed-batch bio-process development and optimization of cetuximab production at lab scale". Thesis, Uppsala universitet, Institutionen för biologisk grundutbildning, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-444795.

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21

Mriouah, Jihane. "Etude de l'impact de la perte d'expression de PTEN sur la réponse au cetuximab et l'induction de l'angiogenèse par un modèle cellulaire de carcinome épidermoïde de la tête et du cou". Thesis, Nancy 1, 2010. http://www.theses.fr/2010NAN10099/document.

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Le cetuximab est indiqué, en monothérapie pour les carcinomes épidermoïdes de la tête et du cou récurrents et/ou métastatiques. Cependant sur les tumeurs primaires, il s'est révélé d'une efficacité modeste. Dans divers types tumoraux, il a été montré que la perte d'expression de PTEN est associée à une résistance aux thérapies anti-EGFR, il s'agit d'un évènement relativement fréquent dans les carcinomes épidermoïdes de la tête et du cou.Cette étude est la première à investiguer directement le rôle de la perte d'expression de PTEN dans la réponse au cetuximab des carcinomes épidermoïdes de la tête et du cou. Aussi, la mise au point d'un modèle PTEN déficient montre que la perte d'expression de PTEN dans les cellules Cal 27 conduit à une suractivation des voies de la survie et de prolifération cellulaire qui n'aboutit cependant pas à une résistance au cetuximab. Ces travaux montrent que les cellules Cal 27 sont plus dépendantes de l'activation de la voie PI3K/AKT que de l'activité de l'EGFR pour leur croissance, expliquant l'effet modeste du cetuximab.Notre étude de l'angiogenèse par un modèle d'anneaux aortiques cultivé en milieux conditionnés, montre que le bourgeonnement endothélial n'est pas dépendant du VEGF. Le silencing de PTEN dans ces cellules, régule positivement les facteurs anti-angiogéniques TSP1 et IGFBP 3 et diminue la capacité d'induction du bourgeonnement endothélial.Dans les carcinomes épidermoïdes de la tête et du cou, la perte d'expression de PTEN ne semble pas être un évènement important dans la tumorigenèse mais avoir un impact déterminant en tant qu'évènement tardif. L'ensemble des données fournies par notre modèle permet de proposer, pour la perte d'expression de PTEN, un rôle d'initiation du processus métastatique dans les carcinomes épidermoïdes de la tête et du cou
Cetuximab has been recently accepted as a single agent to treat recurrent and/or metastatic head and neck squamous cell carcinoma. However, modest efficacy of cetuximab used as a single agent has been reported on primary tumor. In many tumor types, loss of PTEN expression has been described to be associated to resistance to anti-EGFR therapies. Loss of PTEN expression is a frequent event in head and neck squamous cell carcinoma.This study is the first one to directly investigate the role of PTEN loss of expression in response of head and neck squamous cell carcinoma to cetuximab. PTEN-deficient cellular model shows that loss of PTEN expression leads to an overactivation of the signaling pathways ruling cell survival and proliferation but do not impact on cetuximab efficacy. According to our data, Cal 27 cells growth rather depends on PI3K/AKT activation than on EGFR.Observation of angiogenesis, using an aortic ring assay cultured in conditioned media, shows that endothelial sprouting is not dependent on VEGF. PTEN silencing in Cal 27 cells induces anti-angiogenic TSP1 and IGFBP 3 levels in the conditioned medium and reduces the sprouting induction ability by Cal 27 cells.Finally, it is likely that loss of PTEN expression is not a key event in head and neck squamous cell carcinoma tumorigenesis, but might be determinant when occurring as a late event. Taken together, our data suggest that loss of PTEN expression could be involved in initiating metastasis process in head and neck squamous cell carcinomas

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Pueyo, Castells Gemma. "Avaluació preclínica de l'efecte antitumoral de cetuximab sobre la malaltia microscòpica residual post-radioteràpia". Doctoral thesis, Universitat Autònoma de Barcelona, 2010. http://hdl.handle.net/10803/3837.

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En els malalts amb càncer, la hiperactivitat del receptor del factor epidèrmic de creixement (EGFR) té mal pronòstic. L'EGFR està sobreexpressat en diferents tipus de tumors, entre els que destaquen el càncer de colon, pulmó, pàncrees i cap i coll. La majoria d'aquestes neoplàsies requereixen tractament amb radioteràpia amb el que s'aconsegueix, en un elevat percentatge de casos, una bona resposta. No obstant, la persistència després de la radioteràpia de cèl·lules resistents a la radiació enfosqueix el control tumoral.
La recerca d'estratègies per a contrarestar aquesta resistència ha donat lloc a tractaments de radioteràpia hiperfraccionada i de concomitància (radioquimioteràpia) que han mostrat un augment significatiu del control local, tot i que a expenses d'una major toxicitat. Recentment, la síntesi d'inhibidors de l'EGFR i la translació a la clínica d'aquestes substàncies ha demostrat l'existència d'una estratègia menys tòxica per a compensar la resistència tumoral, essent paradigmàtic l'augment de supervivència en tumors de cap i coll localment avançat tractats amb la combinació de radioteràpia i cetuximab. L'èxit d'aquesta combinació ha provocat un creixent interès en el desenvolupament d'estudis clínics per avaluar el seu ús com a potencial tractament adjuvant. D'acord amb aquesta idea, vam iniciar un programa d'investigació preclínica per avaluar el paper de l'anticòs monoclonal anti-EGFR cetuximab com a tractament adjuvant.
En aquesta tesi hem demostrat que la irradiació indueix, en les cèl·lules que sobreviuen a la radioteràpia, un fenotip agressiu que implica un creixement tumoral accelerat i que cetuximab bloqueja el creixement dels xenoempels derivats de cèl·lules radioresistents. Aquest bloqueig es tradueix en una inhibició de l'angiogènesi i proliferació cel·lular per diferents vies moleculars. En conjunt, els resultats obtinguts en aquest treball tenen rellevància clínica i proporcionen una base per a la conducció d'estudis clínics per examinar el manteniment de cetuximab després de la radioteràpia.
Hyperactivity of Epidermal Growth Factor Receptor (EGFR) in cancer patients is associated with poor prognosis. EGFR is overexpressed in a wide range of tumors, including lung, pancreas and head and neck carcinomas. Most of these tumors require treatment with radiation therapy which is effective in a high percentage of cases. However, the persistence of radioresistant cells after radiotherapy leads to the appearance of recurrences.
Recently, it has been developed different EGFR inhibitors such as cetuximab which is a chimeric human-mouse antibody that binds specifically to human EGFR (ErbB1) blocking receptor activation. EGFR overexpression is present in most head and neck squamous cell carcinomas (HNSCCs) and cetuximab has been found to have an antitumorigenic effect when added to radiotherapy in the treatment of locally advanced HNSCCs. The success of radiotherapy and cetuximab has fueled interest in cetuximab as a potential adjuvant treatment following radiotherapy. The main objective of this study was to assess the effects of adjuvant cetuximab in a mouse model on tumors derived from a subpopulation of previously irradiated cells, and investigated the mechanisms of action.
Our results showed that the subpopulation of cells that survived to radiation displayed
an increase in EGFR pathway activity associated with an aggressive tumor phenotype involving an accelerated tumor growth. In addition, cetuximab efficiently inhibited tumor progression despite the malignant growth characteristics of tumors derived from irradiated cells. Furthermore, cetuximab inhibited angiogenesis and cellular proliferation through different molecular mechanisms. Overall, the results reported here have clinical relevance and provide a basis for conducting clinical studies to examine the maintenance of cetuximab after radiotherapy.

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Kareemaghay, Sedigeh. "Investigating the role of ADAM10 and ADAM17 in cetuximab resistance in head and neck squamous cell carcinoma". Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:dd59b38e-ac07-4a6b-b458-74397b76d883.

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Epithermal Growth Factor Receptor (EGFR) is overexpressed in up to 90% of head and neck squamous cell carcinoma (HNSCC). Cetuximab is the first and the only anti-EGFR monoclonal antibody which received approval from FDA for the treatment of HNSCC. However, most patients either do not respond to cetuximab or develop acquired resistance. The aim of my D.Phil. study was to investigate the role of ADAM10 and 17 in resistance mechanisms of cetuximab in HNSCC. Chronic exposure to cetuximab led to an activation of HER receptors and downstream signalling pathways in HNSCC cell lines. Higher levels of ADAM10 and 17 and their substrates, BTC and NRG-1 were found in cetuximab resistant cells compared to their parental cells, suggesting the involvement of ADAM-mediated ligands’ release in reactivation of HER receptors. Inhibition or knockdown of ADAM10 and 17 enhanced cetuximab response and reversed cetuximab resistance in HNSCC cells. In addition, results from this study showed that the combination of cetuximab with EGFR-TKIs had greater effect in parental cells and reversed cetuximab resistance in HNSCC cells. Upregulation of ADAM10 and 17 also was observed in HNSCC TMAs compared to normal head and neck TMAs. High nuclear ADAM10 and cytoplasmic ADAM17 expression levels were associated with shorter DFS. By evaluating tumour excision samples from HNSCC patients who underwent a cetuximab window study high ADAM10 and 17 expression levels were found to be associated with poor response to cetuximab. In conclusion cetuximab-induced ADAM-mediated ligands’ release is a potential mechanism of resistance to cetuximab in HNSCC. Thus, targeting ADAM10/17 or subsequent HER activations may represent an important strategy in overcoming resistance to cetuximab in HNSCC. Results from this study also suggest the implication of ADAM10 and 17 as potential prognostic and predictive biomarkers in HNSCC although further validation is required.

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Marzi, Laetitia. "Implication de p38 et p53 dans le mécanisme d’action du cetuximab dans le cancer colorectal". Thesis, Montpellier 1, 2014. http://www.theses.fr/2014MON13525/document.

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Le cetuximab est une thérapie ciblée dirigée contre le récepteur du facteur de croissance épidermique (EGFR) utilisée dans le cancer colorectal (CCR) en combinaison avec des chimiothérapies (5-FU, irinotécan et oxaliplatine). Sa fixation inhibe les voies de signalisation en aval du récepteur conduisant à une diminution de la prolifération et de la survie des cellules ciblées. Cependant, chez les patients atteint de CCR présentant une protéine KRAS mutée, le cetuximab est inefficace, de plus, la moitié des patients présentant une protéine KRAS wild-type ne répond pas non plus au cetuximab. Afin de découvrir des nouveaux biomarqueurs de sélection des patients qui pourraient bénéficier de ce traitement ou d'améliorer la réponse des patients, une meilleure connaissance des mécanismes d'action du cetuximab est nécessaire. Par exemple récemment, des études ont montré que la protéine p53 participait à la réponse au cetuximab. Il serait intéressant de savoir si le statut de cette protéine peut constituer un bon marqueur de réponse. Précédemment, nous avons montré que l'activation de la « mitogen activated protein kinase » p38 (MAPK p38) induit une résistance à l'irinotécan in vitro et in vivo et est un marqueur de non réponse à cette drogue. De plus, d'autres équipes ont montré que la MAPK p38 bloque également la réponse au 5-FU et participe à la cytotoxicité de l'oxaliplatine. Il semble alors que la MAPK p38 soit impliquée dans les mécanismes d'action des anti-tumoraux. Il est donc intéressant de savoir si la MAPK p38 participe également à la cytotoxicité des thérapies ciblées comme le cetuximab. Pour répondre à ces questions nous avons choisi de comparer deux lignées cellulaires de CCR KRAS wild-type mais au statut TP53 différent et qui répondent différemment au cetuximab: la lignée Caco2 (30% d'inhibition de la survie, TP53 muté) et la lignée DiFi (80% d'inhibition de la survie, TP53 sauvage). Nous avons effectué des tests de cytotoxicité combinant le cetuximab et l'inhibition transcriptionnelle ou pharmacologique de p38 ou l'inhibition transcriptionnelle de p53. Nous avons également testé l'apoptose et la prolifération induite par le cetuximab en l'absence de la MAPK p38 ou de p53. Enfin nous avons testé l'expression des gènes BIM, p27 et PUMA impliqués dans l'apoptose et la prolifération. Dans cette étude, nous avons démontré que la MAPK p38 et p53 participent à l'effet cytotoxique du cetuximab dans les cellules DiFi. En revanche, dans les cellules Caco2, la MAPK p38 bloque partiellement l'effet du cetuximab. Nous avons également montré l'implication de p38 et p53 dans l'apoptose induite par le cetuximab et l'implication de p38 dans l'inhibition de la prolifération. La protéine p38 est impliquée dans la régulation de ERK et dans la localisation nucléaire de FOXO3a responsable de l'expression des gènes BIM et p27. Enfin, nous avons montré que p38 a également un rôle dans le mécanisme d'action d'inhibiteurs de tyrosine kinase ciblant l'EGFR (lapatinib et erlotinib). Pour conclure, nous avons déterminé que p38 et p53 sont impliquées dans le mécanisme d'action du cetuximab. Nous avons décris l'implication de la voie p38-FOXO3a dans le mécanisme d'action du cetuximab. Enfin, p38 et p53 semblent être de bons biomarqueurs de réponse au cetuximab
Cetuximab is used in colorectal cancer (CRC), as targeted therapy against the Epithelial Growth Factor receptor (EGFR), in association with chemotherapy (5-FU, oxaliplatin and irinotecan). Its binding inhibits signaling pathways downstream to the receptor leading to a decrease in proliferation and surviving. In KRAS mutated CRC patients, Cetuximab is ineffective, and half of KRAS Wild Type (WT) patients does not respond to Cetuximab either. Thus, a better knowledge of Cetuximab mechanism of action will help to improve response rate and to find new biomarkers of response. Recently, studies have shown that p53 protein is involved in the response to cetuximab. It would be interesting to know if the status of this protein could be a biomarker of response. Previously, we have shown that activation of the mitogen activated protein kinase p38 (p38MAPK) induces irinotecan resistance in vitro and in vivo and is a predictive factor of response to irinotecan. Moreover, others teams found that p38 MAPK also partially block 5-FU response and participate to oxaliplatin cytotoxicity. It seems that p38 is involved in mechanism of action of anti-tumor agent. The aim of our project is to determine, in KRAS WT colorectal cells, if p38 MAPK is involved as well in the cetuximab effect. In this aim, experiments were done on two KRAS WT CRC cell lines but with different p53 status which respond differently to Cetuximab: Caco2 cells (30% of survival inhibition, TP53 mutated) and DiFi cells (80% of survival inhibition, TP53 wild-type). Cytotoxic experiments combining cetuximab treatment and inhibition of p38MAPK or p53 by transcriptional inhibition or using a pharmacological inhibitor of p38 (SB202190) were performed. We assessed apoptosis and inhibition of proliferation by FACS analysis of cell cycle and DNA synthesis. In addition, BIM, PUMA and p27 expression were analyzed by QPCR and Western Blot. Our results showed that inhibition of p38MAPK enhances Cetuximab cytotoxic effect in Caco2 cells but impairs it in DiFi cells as inhibition of p53. We also observed that inhibition of p38 MAPK and p53 decreases cetuximab induced apoptosis and inhibition of p38 decrease anti-proliferative effect in DiFi cells. The prevention of cell death by SB202190 in cetuximab treated DiFi cells could be explained by ERK pathway activation and the decrease of FOXO3a nuclear localization leading to p27 and BIM expression decrease, respectively involved in cellular proliferation and mitochondrial apoptosis. Our results have shown the same inhibiting effect of SB202190 on the cytotoxic effect of two tyrosine-kinase inhibitors targeting EGFR (lapatinib and erlotinib) in DiFi cells indicating that p38MAPK implication is linked to inhibition of EGFR kinase activity not to Cetuximab only. We have shown that p38MAPK is involved in response to the inhibition of EGFR activity via nuclear localization of FOXO3a. p53 protein has also a role in cetuximab response. Both seem to be predictive factors of response to cetuximab therapy

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Krämer, Alwin, Gerdt Hübner, Andreas Schneeweiss, Gunnar Folprecht e Kai Neben. "Carcinoma of Unknown Primary – an Orphan Disease?" Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-136631.

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Carcinoma of unknown primary (CUP) is an intriguing clinical finding that is defined as biopsy-proven metastasis from a malignancy in the absence of an identifiable primary site after a complete clinical work-up. CUP is a relatively common clinical entity, accounting for approximately 3–5% of all cancer diagnoses, and consists of a heterogeneous group of tumors that have acquired the capacity to metastasize before the development of a clinically evident primary lesion. Notable advances have been made over the past years in the treatment of well-defined clinical subgroups of CUP, such as women with peritoneal carcinomatosis and young adults with poorly differentiated carcinomas of midline distribution, but for the majority of patients, the prognosis still remains poor. In this review, we highlight recent advances in the diagnosis and treatment of patients with CUP syndrome, and emphasize the importance of identifying several favorable subsets of CUP, amenable to specific treatment options. In addition, we will point out novel diagnostic and therapeutic approaches which will hopefully improve both our understanding and the prognosis of this more or less neglected disease
Unter dem Cancer of Unknown Primary (CUP)-Syndrom werden diejenigen Tumorerkrankungen zusammengefasst, bei denen auch nach Abschluss der Diagnostik nur Metastasen, jedoch kein Primärtumor gefunden wird. Das CUP-Syndrom macht ca. 3–5% aller neu diagnostizierten Malignomfälle aus und umfasst eine heterogene Gruppe von Tumoren, die die Fähigkeit zur Metastasierung erlangt haben bevor sich ein klinisch manifester Primärtumor entwickelt hat. Obwohl bemerkenswerte Fortschritte in der Behandlung von Patienten mit bestimmten, gut definierten Erkrankungssubgruppen, wie beispielsweise Frauen mit isolierter Peritonealkarzinose oder jungen Erwachsenen mit gering differenzierten Karzinomen mit Mittellinienverteilung, erzielt werden konnten, ist die Prognose bei der Mehrzahl der Patienten nach wie vor schlecht. Wir berichten im weiteren Verlauf dieser Übersichtsarbeit über Fortschritte in der Diagnostik und Therapie von Patienten mit CUPSyndrom und weisen darauf hin, dass es trotz der immer noch sehr schlechten Prognose von großer Bedeutung ist, Patienten mit bestimmten Subtypen des CUP-Syndroms zu identifizieren, die spezifischen Therapien mit der Option auf Heilung zugeführt werden sollten. Darüber hinaus möchten wir auf neuere diagnostische und therapeutische Bestrebungen aufmerksam machen, die das Verständnis und die Prognose dieses auch in der Onkologie bisher stiefmütterlich behandelten Krankheitsbildes hoffentlich verbessern werden
Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich

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Schubert, Maik. "Entwicklung der targetspezifischen Komponente eines Tumor-Pretargeting Systems auf der Basis L-konfigurierter Oligonukleotide". Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-193974.

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Zur Behandlung von Tumorerkrankungen sind radioaktiv markierte Antikörper als hochaffine und selektive Radioimmuntherapeutika von zunehmender Bedeutung. Allerdings ist der Einsatz solcher radioaktiv markierter Antikörper bei der Behandlung strahlenresistenter solider Tumore limitiert, weil infolge ihrer hohen Blutverweildauer und nur langsamen Anreicherung im Zielgewebe, bedingt durch ihre Molekülgröße, der gesamte Organismus einer hohen Strahlenbelastung ausgesetzt wird. Eine Alternative dazu stellt die Strategie des Pretargeting von Tumoren dar. Die Intention dieses Prinzips besteht darin, mittels einer mehrstufigen Applikationsfolge die Injektion eines targetspezifischen Antikörper-Konjugates und einer kleinen radioaktiv markierten Verbindung zu trennen, welche zueinander ein komplementäres System bilden. Eine Substanzklasse die erstmals von Wissenschaftlern des Helmholtz-Zentrums Dresden-Rossendorf (HZDR) als potentielles komplementäres System für Tumor-Pretargeting-Anwendungen untersucht wurden ist, sind spiegelbildliche bzw. L konfigurierte Oligonukleotide. Aufgrund ihrer hohen metabolischen Stabilität, geringen Immunogenität und sehr geringen Spezifität zu natürlich vorkommenden potentiellen Bindungspartnern sind L-Oligonukleotide, im speziellen L-DNA-Derivate, das ideale System bzgl. der In-vivo-Hybridisierung zwischen einem tumorspezifischen Antikörper und der radioaktiv markierten Chelateinheit. Das verwendete Pretargeting-System besteht aus den Radionuklid markierbaren Komponenten NOTA-L-DNA-(0-20kDa)-PEG 6a-e sowie DOTA-GA-L-DNA-10kDa-PEG 8d und aus der targetspezifischen Antikörper-Einheit, deren Entwicklung eines der Aufgabengebiete der vorliegenden Arbeit darstellte. Als Antikörper wurde dabei der klinisch zugelassene chimäre monoklonale Antikörper Cetuximab (Handelsname Erbitux®, C225) verwendet, welcher mit sehr hoher Affinität an das Oberflächenprotein „Epidermaler Wachstumsfaktor Rezeptor“ (Epidermal Growth Factor Receptor, EGFR) bindet. Die Zielstellung dieser Arbeit beinhaltete vor allem die In-vitro- und In-vivo-Charakterisierung des L-DNA basierenden Pretargeting-Systems im Hinblick darauf, ob das Internalisierungsverhalten von Cetuximab einen limitierenden Faktor für seine Anwendung in Pretargeting-Experimenten darstellt. Es konnten zwei mit der komplementären L-DNA (c-L-DNA) modifizierte Cetuximab-Derivate mit einem niedrigen (n = 1,5) und einem hohen (n = 5) Konjugationsgrad an c-L-DNA hergestellt werden. Zur radiopharmakologischen Charakterisierung wurden beide Konjugate zusätzlich mit NOTA funktionalisiert und entsprechende Verfahren zur Markierung mit dem Radiometallnuklid 64Cu erarbeitet. Die Reaktionsparameter sowohl bei der Synthese als auch bei der Radiomarkierung wurden hinsichtlich des pH-Wertes, der Temperatur und der mechanischen Beanspruchung so gewählt, dass einerseits der Affinitätsverlust in Bezug zum nativen Cetuximab möglichst gering gehalten wird und andererseits die erarbeiteten Protokolle sich perspektivisch auch auf andere Antikörper übertragen lassen. Die zentrale Fragestellung dieser Arbeit bestand darin, die Internalisierungsgeschwindigkeit der beiden Cetuximab-Konjugate NOTA3-C225-(c L DNA)1,5 und NOTA3-C225-(c-L-DNA)5 im Hinblick auf deren Eignung für In vivo-Pretargeting-Experimente zu bewerten. Dabei wurde festgestellt, dass bereits nach 24 h an A431- und FaDu-Zellen 50 - 70% des auf der Zelloberfläche gebundenen Antikörpers nicht mehr für die Bindung der radioaktiv markierten Komponente zur Verfügung stand. 72 h nach der Antikörperapplikation waren sogar 80 - 90% des extrazellulär gebundenen Antikörpers internalisiert. Besonders diese hohe Internalisierungsrate könnte im Hinblick auf In-vivo-Anwendungen problematisch sein und eine geringe Tumorakkumulation der radioaktiv markierten Komponente bewirken. Infolge der Konjugation von Cetuximab mit p-SCN-Bn-NOTA 3, GMBS 9 und 17mer-c-L-DNA 2 war eine Änderung der pharmakologischen Eigenschaften von Cetuximab nachweisbar. Insbesondere dadurch, dass die Antikörpermodifikation vorrangig an den Aminogruppen der Lysin-Einheiten erfolgte und durch das 17fach negativ geladene Phosphatrückgrat des Oligonukleotids, wurde eine starke Anionisierung der Oberflächenladung und damit eine Verringerung des isoelektrischen Punktes festgestellt. Dennoch bestätigten Kompetitionsbindungsstudien an A431- und FaDu-Gesamtzellhomogenat für alle untersuchten Antikörper-Derivate unabhängig vom Konjugationsgrad deren sehr hohe Affinität zum EGFR. Auch die an intakten Zellen berechneten KD-Werte unterstreichen dies. Einzig die Bindungskapazität weist dabei eine Abhängigkeit zum Konjugationsgrad auf, sodass trotz sehr guter Ki- und KD-Werte auf eine Verringerung der Affinität infolge der Antikörpermodifikation zu schließen ist. Interessant ist auch, dass nach einem Zeitraum > 4 h eine zweite Bindungsphase auftritt, welche möglicherweise durch eine Reexpression des EGFR aus intrazellulären Kompartimenten, infolge der Internalisierung des Rezeptor-Antikörperkomplexes, hervorgerufen wird. Außerdem wurde untersucht, inwieweit die unterschiedlichen und sterisch sehr anspruchsvollen PEG-Substituenten der 17mer-L-DNA die Hybridisierung am Antikörper sowie am Rezeptor-Antikörper-Komplex an A431- und FaDu-Zellen beeinflussen. Dabei stellte sich heraus, dass die Hybridisierung am Immunkomplex in Abhängigkeit des PEGylierungsgrades vom nicht PEGylierten Konjugat [64Cu]Cu6a zum 20kDa-PEG-Derivat [64Cu]Cu6e sukzessive abnimmt. Hingegen scheint der PEGylierungsgrad bei der Hybridisierung am im Phosphatpuffer und im humanen Vollblut inkubierten Antikörper keinen Einfluss zu haben. Weiterhin wurde im Zellversuch gezeigt, dass am hoch modifizierten Cetuximab-Konjugat NOTA3-C225-(c L-DNA)5 in Abhängigkeit des Konjugationsgradunterschiedes zum niedrig modifizierten Derivat NOTA3-C225-(c L-DNA)1,5 ca. dreimal mehr Ligand hybridisiert. Erste In-vivo-Pretargeting-Untersuchungen bestätigten, dass NOTA-L-DNA-10kDa-PEG 6d der ideale „Kandidat“ für das Pretargeting-Konzept basierend auf L-konfigurierten Oligonukleotiden ist. Besonders die wesentlich höhere Tumorakkumulation von [68Ga]Ga6d (10kDa-PEG) im Vergleich zu den anderen untersuchten L-DNA-Konjugaten [68Ga]Ga 6a-c (0, 2, 5kDa PEG) und [68Ga]Ga6e (20kDa-PEG) ist dabei von besonderer Bedeutung. Zukünftige Pretargeting-Studien sollten demnach ausschließlich mit der 10kDa-PEG modifizierten 17mer-L-DNA durchgeführt werden. Die Substitution des bifunktionalen Chelators p-SCN-Bn-NOTA 3 durch DOTA-GA-Mal 7 ermöglicht den Einsatz eines breiten Spektrums therapeutisch relevanter Radionuklide wie beispielsweise 90Y, 177Lu oder auch 67Cu. Dies konnte anhand eines ersten Pretargeting-Experimentes mit NOTA3-C225-(c L DNA)1,5 und [177Lu]Lu-DOTA-GA-L-DNA-10kDa-PEG [177Lu]Lu8d bestätigt werden. Zusammenfassend muss aber festgestellt werden, dass Cetuximab als Antikörper für das Pretargeting aufgrund seiner Internalisierungscharakteristik nicht geeignet ist. Es zeigte sich zwar, dass nach 24 h mittels Pretargeting eine verringerte Leberakkumulation im Vergleich zum direkt markierten Cetuximab-Derivat [64Cu]Cu-NOTA-C225-(c-L-DNA)1,5 erzielt werden kann, allerdings fällt die Tumorakkumulation ebenfalls um ca. 40 – 70% niedriger aus und demnach wird eine deutlich geringere Dosis im Tumor angereichert. Dies lässt den Rückschluss zu, dass in vivo eine ähnlich hohe Internalisierung auftritt wie im In-vitro-Zellversuch ermittelt. Das Pretargeting-Intervall musste demnach auf 24 h festgesetzt werden, auch wenn zum Zeitpunkt der Applikation der radioaktiv markierten Komponente der Antikörper immer noch im vaskulären System zirkulierte. Kleintier-PET-Aufnahmen lassen allerdings vermuten, dass eine Applikation der radioaktiv markierten Komponente 48 h nach der Antikörper-Gabe bessere Verteilungsverhältnisse ergeben hätte. Der eigentliche Vorteil des Pretargetings, innerhalb weniger Stunden eine ähnlich hohe Tumorakkumulation zu erzielen, wie sie direkt markierte Antikörper erst nach mehreren Tagen aufweisen, konnte mit Cetuximab nicht verwirklicht werden.

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Baro, Serrano Marta. "Estudio del efecto de dasatinib en combinación con cetuximab en un modelo animal de radioterapia experimental". Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/125003.

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La hiperactividad del EGFR (epidermal growth factor receptor) confiere mal pronóstico. El EGFR se encuentra sobreexpresado en distintos tipos de tumores, entre ellos el cáncer de colon, pulmón, páncreas y cabeza y cuello (HNSCC). Además la cooperación con otros miembros de la familia del EGFR podría ampliar esta lista a otras neoplasias. La inhibición del EGFR es una de las vías de investigación más activa contra el cáncer. La radioterapia consigue, en un elevado porcentaje de casos, una buena respuesta. Sin embargo, la existencia de células resistentes a la radiación reduce el control tumoral. Una de las causas de la radioresistencia es la hiperactividad del EGFR. En cáncer de cabeza y cuello, el bloqueo del EGFR con el anticuerpo monoclonal anti- EGFR cetuximab aumenta el control local y la supervivencia en pacientes tratados simultáneamente con radioterapia. Sin embargo, no todos los pacientes tratados con cetuximab y radiación se benefician del tratamiento, lo que sugiere que, independientemente de la expresión del EGFR, existen mecanismos de resistencia a la combinación. La ramificación de las vías de señalización que dependen del EGFR sugiere que la topografía de la resistencia puede ser variada y múltiple. Cuanto más arriba de la vía de transmisión de señales se sitúe el by-pass, mayor debería ser la resistencia debido a que un mayor número de funciones citoprotectoras se verían liberadas. Se han descrito distintas posibilidades de by-pass al bloqueo del EGFR. Una de las oncoproteínas que podría ejercer un by-pass proximal es SRC, cuya actividad se relaciona con la progresión tumoral tanto en fases avanzadas como en lesiones premalignas. Además, SRC y EGFR comparten vías de señalización que promueven la progresión de la célula tumoral. En conjunto estos hechos sugieren que la inhibición de SRC podría aumentar la potencia antitumoral de la combinación de radioterapia y cetuximab. En este proyecto se han evaluado los efectos del tratamiento concomitante con radioterapia, cetuximab y dasatinib, y mejorado los conocimientos de los mecanismos biológicos involucrados. También se ha determinado si el uso de inhibidores de SRC podía potenciar el efecto antitumoral de la combinación de radioterapia y cetuximab en tumores dependientes del EGFR. La adición de DST al cetuximab o al cetuximab y radioterapia tuvo un efecto contrario al esperado: produjo un mayor crecimiento de los tumores, un incremento de la angiogénesis y de la síntesis de ADN, un aumento de la fosforilación de las oncoproteínas RAS, ERK1/2, AKT y STAT3; una elevación de la secreción de VEGF, y una hiperactividad del metabolismo glucolítico. El tratamiento combinado con dasatinib e inhibidores de las quinasas JAK, HER2 y MET no inhibió el exceso de fosforilación de ERK inducido por dasatinib, una respuesta reactiva similar a la descrita con C225 y que sugiere la implicación de mecanismos de acción, comunes e independientes de JAK, HER2 y MET. Por el contrario el bloqueo de EGFR por el inhibidor tirosina quinasa AG1478 dio lugar a una inhibición completa de la fosforilación de ERK y AKT a pesar de la presencia de DST, indicando que la quinasa del EGFR está implicada en el efecto antagónico inducido por dasatinib. Por último, este trabajo contribuye a la idea que la combinación de terapias moleculares puede dar lugar a antagonismos, que pueden ponerse de manifiesto durante una investigación preclínica antes de ser evaluados en ensayos clínicos.
Aberrant epidermal growth factor receptor (EGFR) signalling drives oncogenesis in many carcinomas, including head and neck squamous cell cancer (HNSCC). Irrespective of the mechanism of activation, EGFR overexpression is a major origin of resistance to cancer cell death—and a relevant cause of local failures after radiotherapy. The blockage of EGFR by the monoclonal antibody cetuximab in combination with radiotherapy has been shown to improve survival and local control in head and neck cancers. However, major responses are limited in part due to the robustness of signalling networking, which grants alternative routes to avoid blockage of EGFR. SRC-family kinases occupy a central position within the cell signal networking, which makes SRC a potential target in cancer treatment. In this project we evaluated the effects of the concomitant treatment with radiotherapy, cetuximab and dasatinib, and improved the knowledge of the biological mechanisms involved; to determine whether SRC inhibitors could potentiate the antitumor effects of radiotherapy and cetuximab combination in EGFR-dependent tumours. Unexpectedly, the addition of dasatinib to cetuximab or cetuximab and radiotherapy resulted in an antagonistic effect which was characterized by increased tumour growth; an increase in the angiogenesis and DNA synthesis; association with the inhibition of SRC; an increase in cell signalling involving phosphorylation of RAS, ERK1/2, AKT and STAT3 oncoproteins; elevation of VEGF secretion and hyperactivity of glycolytic metabolism. Also, the simultaneous blockade of SRC and JAK kinases, HER2 or MET, induced a similar reaction to that described with cetuximab suggesting the involvement of mechanisms of action, common and independent, of JAK, HER2 and MET. Conversely, blocking EGFR with the tyrosine kinase inhibitor AG1478 resulted in a complete inhibition of ERK and AKT phosphorylation, despite the presence of dasatinib, indicating that the EGFR kinase is involved in the induced antagonistic effect of dasatinib. Finally, this project contributes to the idea that the combination of molecular therapies can result in antagonism, which may become perceptible during a preclinical research before being evaluated in clinical trials.

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Ziegler, Katharina Melanie [Verfasser], e Wolfgang [Akademischer Betreuer] Frieß. "Untersuchungen zur Stabilisierung und Interaktion von Cetuximab mit nicht-ionischen Tensiden / Katharina Melanie Ziegler. Betreuer: Wolfgang Frieß". München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2013. http://d-nb.info/1047062275/34.

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29

Maugeri, Marco. "Analysis of the involvement of exosomal miRNAs and proteins in the response of CRC cells to Cetuximab". Doctoral thesis, Università di Catania, 2014. http://hdl.handle.net/10761/1527.

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It has been demonstrated that intercellular communication via cell- released vesicles is very important both for normal and tumor cells, and specifically to determine tumor development and progression as well as invasion and angiogenesis. Cell communication could involve the exosomes, small vescicles of endocytic origin, which are released from different kinds of donor cells; they can transfer molecular signals as proteins and RNAs through the extracellular environment to specific recipient cells in a autocrine, paracrine or endocrine way. Exosomes can strongly influence the recipient cells phenotype by transferring oncogenes that could influence the response of cells to drugs or immune reactions. Recently, it has been demonstrated the presence of miRNAs inside the exosomes and their potential involvement in cancer development. Considering the important role of miRNAs in colorectal cancer, one of the most diffused and studied tumor, it was considered interesting to investigate the role of exosomal miRNAs and associated proteins in the response of CRC cells to Cetuximab (an anti-EGFR therapeutic antibody). The EGFR signaling pathway is very importantly in relationship both to CRC and miRNA biogenesis and expression, and recently also to the exosomal communication system. Therefore, one of the major aims of this thesis was to analyze the possible involvement of exosomes in the response to Cetuximab of two CRC cell lines (wild-type KRAS Caco-2 cells and KRAS mutated HCT-116 cells) through the transfer of specific miRNAs and proteins to recipient cells. To carry out this analysis, we performed cellular and exosomal miRNA profiling after Cetuximab treatment, for 745 miRNAs by using Real-Time PCR. The results of the analysis showed that exosomal miRNA profiles globally reflect those of whole cells at steady-state, but there exists an important quantitative asymmetrical distribution. After Cetuximab treatment, Caco-2 sensitive cells showed several exosomal differentially expressed (DE) miRNAs in comparison to HCT-116 cells. Many DE miRNAs are involved in cancer and immunity. These data could be explained by considering that the EGFR pathway can regulate miRNA biogenesis via the MAPK/ERK cascade. Exosomal proteins analysis was performed for 741 cancer-related proteins through a specific antibody microarrays platform. Also the profile of exosomal proteins from Caco-2 cells showed important alterations after Cetuximab treatment. Globally, several DE miRNAs and proteins from Caco-2 exosomes were related to cancer, stimulation of immunity and inflammation. Interestingly, exosomes transfection experiments between Caco-2 and HCT-116 cell lines (performed to investigate their effect on cell viability) showed that the transfection of steady state Caco-2 exosomes in the HCT-116 cell line determined a decrease of cell viability of recipient cells, while Cetuximab-treated Caco-2 cells exosomes, transfected in HCT-116 cells, increased their viability. These data could be explained considering that exosomes from Cetuximab-treated cells are enriched in oncogenic- and immune stimulation-related miRNAs. Finally, DE proteins were searched to find potential RNA-binding proteins. Globally, the results of this thesis could be useful to: (1) verify the existence of horizontal transfer of genetic informations in eukaryotes; (2) search for potential miRNAs and proteins biomarkers of Cetuximab response in CRC in vivo. Eventually, it will be interesting to perform the characterization of exosomal miRNAs and proteins expression profiles of plasma from CRC patients after Cetuximab treatment. Moreover, the characterization of the asymmetrical distribution of miRNAs between cells and exosomes could be important to further investigate the potential and specific mechanism of miRNA sorting within exosomes.

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30

Krämer, Alwin, Gerdt Hübner, Andreas Schneeweiss, Gunnar Folprecht e Kai Neben. "Carcinoma of Unknown Primary – an Orphan Disease?" Karger, 2008. https://tud.qucosa.de/id/qucosa%3A27719.

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Carcinoma of unknown primary (CUP) is an intriguing clinical finding that is defined as biopsy-proven metastasis from a malignancy in the absence of an identifiable primary site after a complete clinical work-up. CUP is a relatively common clinical entity, accounting for approximately 3–5% of all cancer diagnoses, and consists of a heterogeneous group of tumors that have acquired the capacity to metastasize before the development of a clinically evident primary lesion. Notable advances have been made over the past years in the treatment of well-defined clinical subgroups of CUP, such as women with peritoneal carcinomatosis and young adults with poorly differentiated carcinomas of midline distribution, but for the majority of patients, the prognosis still remains poor. In this review, we highlight recent advances in the diagnosis and treatment of patients with CUP syndrome, and emphasize the importance of identifying several favorable subsets of CUP, amenable to specific treatment options. In addition, we will point out novel diagnostic and therapeutic approaches which will hopefully improve both our understanding and the prognosis of this more or less neglected disease.
Unter dem Cancer of Unknown Primary (CUP)-Syndrom werden diejenigen Tumorerkrankungen zusammengefasst, bei denen auch nach Abschluss der Diagnostik nur Metastasen, jedoch kein Primärtumor gefunden wird. Das CUP-Syndrom macht ca. 3–5% aller neu diagnostizierten Malignomfälle aus und umfasst eine heterogene Gruppe von Tumoren, die die Fähigkeit zur Metastasierung erlangt haben bevor sich ein klinisch manifester Primärtumor entwickelt hat. Obwohl bemerkenswerte Fortschritte in der Behandlung von Patienten mit bestimmten, gut definierten Erkrankungssubgruppen, wie beispielsweise Frauen mit isolierter Peritonealkarzinose oder jungen Erwachsenen mit gering differenzierten Karzinomen mit Mittellinienverteilung, erzielt werden konnten, ist die Prognose bei der Mehrzahl der Patienten nach wie vor schlecht. Wir berichten im weiteren Verlauf dieser Übersichtsarbeit über Fortschritte in der Diagnostik und Therapie von Patienten mit CUPSyndrom und weisen darauf hin, dass es trotz der immer noch sehr schlechten Prognose von großer Bedeutung ist, Patienten mit bestimmten Subtypen des CUP-Syndroms zu identifizieren, die spezifischen Therapien mit der Option auf Heilung zugeführt werden sollten. Darüber hinaus möchten wir auf neuere diagnostische und therapeutische Bestrebungen aufmerksam machen, die das Verständnis und die Prognose dieses auch in der Onkologie bisher stiefmütterlich behandelten Krankheitsbildes hoffentlich verbessern werden.
Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

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31

Fischhaber, Doris [Verfasser], e Volker [Akademischer Betreuer] Heinemann. "Verlauf von Magnesium- und Calciumwerten unter einer Therapie mit Cetuximab : eine erweiterte Toxizitätsanalyse / Doris Fischhaber. Betreuer: Volker Heinemann". München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2015. http://d-nb.info/1077986777/34.

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32

Majorana, Alessandra. "Alterazioni specifiche del trascrittoma dei microrna e struttura globale del network in carcinoma colorettale dopo trattamento con Cetuximab". Thesis, American Association for Cancer Research, 2011. http://hdl.handle.net/10761/129.

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Il carcinoma del colon-retto (CRC) e' una delle neoplasie piu' frequenti nel mondo occidentale e rappresenta un problema socio-sanitario di notevole rilievo. E' noto che non tutti i pazienti affetti da CRC rispondono in modo positivo alla terapia con i piu' comuni agenti antitumorali (es. Cetuximab): vi sono infatti dei fattori genetici predittivi della risposta, tra i quali sicuramente uno dei piu' noti e' lo stato mutazionale di KRAS. Tuttavia, questo approccio diagnostico molecolare e' comunque invasivo, poiche' presuppone un prelievo bioptico. Per questa ragione, diversi gruppi di ricercatori stanno cercando di individuare biomarcatori che, oltre ad essere specifici, siano identificabili con procedure non invasive. Indubbiamente, tra i possibili marcatori, i microRNA (miRNA) rivestono un ruolo particolarmente rilevante. I miRNA sono piccole molecole di RNA non codificante che svolgono un ruolo critico nella regolazione dell ' espressione genica in tutti i processi cellulari. Ad oggi, sono stati pubblicati diversi dati che suggeriscono come il profilo di espressione dei miRNA vari in modo specifico nei diversi tipi di cellule neoplastiche, in correlazione con il fenotipo del tumore e con la sua evoluzione. L' oggetto di questa tesi e' stato lo studio della relazione tra risposta terapeutica e modifiche del trascrittoma dei miRNA nel tumore colorettale (CRC), che ad oggi rimane sconosciuta. Per raggiungere questo obiettivo abbiamo effettuato il profiling dell'espressione di 667 miRNA in due linee cellulari umane CRC, una sensibile e l'altra resistente al Cetuximab (Caco-2 e HCT-116, rispettivamente) mediante RT-PCR con sonde TaqMan. Le Caco-2 e le HCT-116 esprimono diversi set di miRNA dopo il trattamento: in particolare, mentre nelle Caco-2 sono differenzialmente espressi 21 miRNA (DE miRNA), nelle HCT-116 i DE miRNA sono 22 (t-test, p <0.01). Testando l'espressione dei DE miRNA in campioni paraffinati di pazienti affetti da CRC, abbiamo scoperto che il miR-146b-3p e il miR-486-5p sono piu' abbondanti nei campioni con il gene KRAS mutato rispetto a quelli wild-type (test di Wilcoxon, p <0.05). Dall' analisi dei cluster e delle famiglie geniche dei DE miRNA e' emerso che miRNA localizzati in stretta prossimita' genomica o appartenenti alla stessa famiglia mantengono spesso lo stesso trend di espressione in seguito al trattamento. Secondo dati di letteratura, il 67% dei DE miRNA e' coinvolto nel cancro, incluso il CRC, mentre 19 targets dei DE miRNA sono stati precedentemente associati alla pathway del Cetuximab e del CRC, come ad esempio KRAS (targets dei DE miRNA let-7b e let-7e), PTEN e PIK3R1 (entrambi targets del miR-486-5p). Abbiamo identificato 25 fattori di trascrizione che putativamente controllerebbero questi DE miRNA; 11 di questi sono gia' stati individuati per essere coinvolti nella patogenesi del CRC, come ad esempio MYC, che controlla positivamente l ' espressione del miR-17* (un marcatore del CRC i cui livelli sono abbondanti in biopsie e plasma di pazienti). Sulla base di questi dati, suggeriamo che la sottoespressione di let-7b e let-7e e la sovraespressione del miR-17* potrebbero far considerare questi miRNA come marcatori molecolari candidati per la resistenza al Cetuximab. L'analisi funzionale globale delle network dei targets dei DE miRNA ha mostrato una significativa sovra-rappresentazione di processi biologici correlati al cancro, all' angiogenesi e alla risposta immunitaria, e di moduli centrati sui nodi critici coinvolti nell' internalizzazione di EGFR e sua degradazione ubiquitina-mediata. L'identificazione di miRNA la cui espressione e' legata all' efficacia della terapia, dovrebbe quindi consentire di predire la risposta dei pazienti al trattamento e potrebbe condurre ad una migliore comprensione dei meccanismi molecolari della risposta farmacologica. Il lavoro esposto in questa tesi e' stato pubblicato nel 2010 su Molecular Cancer Therapeutics (E-pub 29 Settembre).
The relationship between therapeutic response and modifications of miRNA transcriptome in Colorectal Cancer (CRC) remains unknown. We investigated this issue by profiling the expression of 667 miRNAs in two human CRC cell lines, one sensitive and the other resistant to cetuximab(Caco-2 and HCT-116, respectively) through TaqMan RT-PCR. Caco-2 and HCT-116 expressed different sets of miRNAs after treatment: specifically, 21 and 22 miRNAs were differentially expressed (DE) in Caco-2 or HCT-116, respectively (t-test, p<0.01). By testing the expression of DE miRNAs in CRC patients, we found that miR-146b-3p and miR-486-5p are more abundant in KRAS mutated samples respect to wild-type ones (Wilcoxon test, p<0.05). 67% of DE miRNAs were involved in cancer, including CRC, while 19 miRNA targets had been previously reported to be involved in the cetuximab pathway and CRC. We identified 25 TFs putatively controlling these miRNAs, 11 of which already reported to be involved in CRC. Based on these data, we suggest that the down regulation of let-7b and let-7e (targeting KRAS) and the up regulation of miR-17* (a CRC marker) could be considered as candidate molecular markers of cetuximab resistance. Global network functional analysis, based on miRNA targets, showed a significant overrepresentation of cancer-related biological processes and networks centered on critical nodes involved in EGFR internalization and ubiquitin-mediated degradation. The identification of miRNAs, whose expression is linked to the efficacy of therapy, should allow to predict the response of patients to treatment and possibly lead to a better understanding of the molecular mechanisms of drug response.

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33

Azzopardi, Nicolas. "Apport de la modélisation pharmacocinétique à l'étude de la variabilité de réponse aux anticorps monoclonaux antitumoraux : application au cetuximab". Thesis, Tours, 2011. http://www.theses.fr/2011TOUR3309/document.

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Les anticorps monoclonaux ont révolutionné le traitement de nombreuses pathologies. Cependant, leur pharmacocinétique (PK) et l’influence de leur concentration sur la réponse clinique restent mal connues. Nous avons étudié les sources de variabilité interindividuelle de la PK du cetuximab, un anticorps anti- EGFR, ainsi que l’influence de l’exposition à cet anticorps sur la réponse. Nous avons validé une méthode ELISA de dosage du cetuximab. Dans un modèle murin, nous avons étudié l’absorption pulmonaire du cetuximab. Nous avons étudié la PK du cetuximab chez un patient hémodialysé. Nous avons décrit la PK du cetuximab chez des patients traités pour cancer colorectal métastatique, à l’aide d’un modèle combinant des éliminations d’ordre 0 et 1. Enfin, nous avons identifié la clairance globale du cetuximab, paramètre pouvant être estimé précocement par la concentration résiduelle à J14, comme un facteur influençant la survie sans progression des patients. Nos travaux montrent qu’une description de la PK d’un anticorps par approche compartimentale permet d’identifier les sources de variabilité et d’étudier l’impact de la PK sur la réponse clinique
Monoclonal antibodies have profoundly modified the treatment of many diseases. However, their pharmacokinetics (PK) and the influence of their concentrations on the clinical response are poorly known. We studied the sources of the interindividual variability of PK of cetuximab, an anti-EGFR, and the influence of the exposure to this antibody on the response. We validated an ELISA technique to measure cetuximab concentrations. We studied the pulmonary absorption of cetuximab in a murine model. We studied cetuximab PK in a hemodialysed patient. In metastatic colorectal cancer patients, we described cetuximab PK with the help of a model combining zero- and first-order eliminations. Finally, we identified the global clearance of cetuximab, a parameter which can be estimated by residual concentration on day 14, as a factor influencing progression-free survival of the patients. Our work shows that the description of the PK of an antibody by compartmental approach allows to identify sources of variability and to study the impact of PK on the clinical response

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34

Tashiro, Takahiro. "In vivo and ex vivo cetuximab sensitivity assay using three-dimensional primary culture system to stratify KRAS mutant colorectal cancer". Kyoto University, 2018. http://hdl.handle.net/2433/232473.

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35

Morsbach, Fabian [Verfasser], e Jochen [Akademischer Betreuer] Dahm-Daphi. "The Role of p53 in Cetuximab Induced Radiosensitization of A549 Cells and the Mechanisms Involved / Fabian Morsbach. Betreuer: Jochen Dahm-Daphi". Hamburg : Staats- und Universitätsbibliothek Hamburg, 2014. http://d-nb.info/1046460285/34.

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36

Rebucci, Magali. "Mécanismes de résistance au cetuximab et influence des associations de traitement dans des lignées cellulaires de cancers de voies aérodigestives supérieures". Phd thesis, Université du Droit et de la Santé - Lille II, 2010. http://tel.archives-ouvertes.fr/tel-00576444.

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Abstract (sommario):

Dans le traitement des cancers des voies aérodigestives supérieures (VADS), une approche biologique par des anti-EGFR (Epidermal Growth Factor Receptor) comme le cetuximab (Erbitux®) a récemment été proposée. Le cetuximab est un anticorps monoclonal chimérique qui se lie spécifiquement au domaine extracellulaire de l'EGFR, régulateur central de la prolifération et de la différenciation dans les cancers. Par cette liaison, le cetuximab entre en compétition avec les ligands du récepteur et empêche son activation, induit son internalisation et bloque la transduction du signal vers les voies de signalisation en aval. Même si cette approche thérapeutique est rationnelle puisque l'EGFR est surexprimé dans la plupart des cancers et notamment dans les cancers des VADS, certains types de cancers présentent une résistance à cet anticorps. Parmi les molécules qui ciblent EGFR il existe également des inhibiteurs de l'activité tyrosine kinase intracellulaire de l'EGFR comme le gefitinib (Iressa®), mais ce dernier n'est actuellement pas prescrit dans le traitement des cancers des VADS.Le but de notre travail a été d'étudier les mécanismes de résistance au cetuximab dans des lignées cellulaires de cancers des VADS puis de proposer des associations thérapeutiques pouvant pallier à cette résistance.Nous avons choisi deux lignées cellulaires de cancers des VADS, CAL33 et SQ20B en comparaison à la lignée épidermoïde A431 sur exprimant EGFR et sensible au cetuximab. Nous avons pu mettre en évidence que CAL33 et SQ20B étaient résistantes au cetuximab mais de manière surprenante sensibles au gefitinib. Nous avons montré que l'absence d'inhibition de phosphorylation d'AKT et qu'une altération de l'internalisation de l'EGFR par le cetuximab étaient responsables en partie de la résistance au cetuximab dans ces modèles cellulaires.Afin de pallier à cette résistance nous avons alors étudié les conséquences biologiques de l'association du cetuximab avec (i) des inhibiteurs de la voie PI3K/AKT par différentes approches et avec (ii) les radiations ionisantes. Dans un premier temps, nous avons étudié l'influence de l'inhibition de la voie AKT par un inhibiteur de PI3K ou un siRNA ciblant AKT. Nous avons démontré que l'inhibition de la phosphorylation d'AKT par l'inhibiteur LY294002 sensibilisait au cetuximab la lignée CAL33 porteuse d'une mutation activatrice du gène PIK3CA codant pour la sous-unité catalytique p110 de la protéine PI3K. Nous avons montré que la persistance de l'activation d'AKT dans la lignée CAL33 prévenait l'effet anti tumoral du cetuximab, tandis que la résistance au cetuximab dans la lignée SQ20B ne semblait pas dépendante de la voie AKT.Une association de traitement du cetuximab avec les radiations ionisantes est déjà proposée en clinique dans le traitement des cancers des VADS. Nous avons donc dans un second temps déterminé les effets de cette association de traitement dans les lignées SQ20B et CAL33 respectivement sauvage et mutée dans la voie de signalisation AKT et dans la lignée contrôle A431. Nous avons montré que l'association du cetuximab aux radiations ionisantes potentialisait l'effet du cetuximab sur l'inhibition de prolifération de la lignée A431 alors que nous n'avons observé aucune potentialisation de l'effet du cetuximab sur la prolifération dans les lignées résistantes CAL33 et SQ20B. Dans ce travail, nous montrons que la voie AKT apparaît donc comme un élément central dans la réponse au cetuximab dans la lignée CAL33 et que l'association du cetuximab avec un inhibiteur de la voie PI3K/AKT pourrait être une bonne option thérapeutique dans le traitement des cancers des VADS mutés pour PIK3CA.

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37

Wolff, Christian [Verfasser]. "Radioaktiv markierter Epidermal-Growth-Factor-Rezeptor-Antikörper Cetuximab in der multimodalen Krebstherapie : Stabilität und synergistische Effekte mit der Strahlentherapie / Christian Wolff". Lübeck : Zentrale Hochschulbibliothek Lübeck, 2010. http://d-nb.info/1008506923/34.

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38

McMichael, Elizabeth L. "Role of Interleukin-21 and the Interleukin-21 Receptor in Natural Killer Cell Activation". The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1460726334.

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39

Streif, Matthias [Verfasser], e Christian [Akademischer Betreuer] Stroszczynski. "Prädiktive radiologische Faktoren für die Resektabilität von Lebermetastasen des kolorektalen Karzinoms nach neoadjuvanter FOLFOX/FOLFIRI + Cetuximab-Therapie / Matthias Streif. Betreuer: Christian Stroszczynski". Regensburg : Universitätsbibliothek Regensburg, 2014. http://d-nb.info/1054191638/34.

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40

Ritter, Matthias Johannes Christian [Verfasser]. "Überlebensvorteil des Lübecker Cetuximab-Taxol-Schemas in Kombination mit interstitieller Brachytherapie bei Patienten mit rezidivierten Kopf-Hals-Tumoren / Matthias Johannes Christian Ritter". Lübeck : Zentrale Hochschulbibliothek Lübeck, 2016. http://d-nb.info/1101974656/34.

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41

Pointreau, Yoann. "Etude des sources de variabilité de l'efficacité et des effets indésirables du cetuximab chez les patients traités pour un carcinome épidermoïde de la tête et du cou". Thesis, Tours, 2015. http://www.theses.fr/2015TOUR3311/document.

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Abstract (sommario):

Le cetuximab (CTX) est un anticorps monoclonal anti-EGFR indiqué dans les cancers ORL dont les modalités de prescription pourraient être améliorées. Après chimiothérapie d’induction (étude Tremplin), en comparaison au cisplatine, il était moins toxique mais sans améliorer la préservation laryngée. À la première injection, le CTX peut déclencher un choc anaphylactique lié à la préexistence d’IgE anti-αGal. Des tests prédictifs détectant ces IgE ont été développés et réalisés chez 41 patients avec une sensibilité et une valeur prédictive négative de 100%. La relation entre concentrations sériques et efficacité/toxicité a été étudiée chez 34 patients. La pharmacocinétique a été décrite à l’aide d’un modèle combinant des mécanismes d’élimination non saturable (CL) et saturable (k0). La clairance globale du CTX, reflet de l’exposition des patients, était reliée aux survies sans progression et globale (SG). Le grade de radiodermite était associé à la SG. Une simulation pharmacocinétique suggère, qu’en comparaison à l’injection standard de CTX, une injection toutes les trois semaines entrainera des AUC proches mais des concentrations résiduelles différentes
Cetuximab (CTX) is an anti-EGFR monoclonal antibody approved in head and neck cancer, which prescription modalities may be improved. After induction chemotherapy (Tremplin study), compared to cisplatin, CTX was less toxic but did not improve larynx preservation. During first infusion, CTX can induce an anaphylaxis reaction due to the presence of preexisting anti-αGal IgE. Predictive assays detecting these IgE were developed and tested in 41 patients, with sensitivity and negative predictive values of 100%. Relationship between serum concentrations and efficacy/toxicity was studied in 34 patients. CTX pharmacokinetics was described using a model combining non-saturable (CL) and saturable (k0) eliminations. Global clearance, which reflects patient exposure, was related to progression free and overall (OS) survivals. Severe radiation dermatitis was also associated with OS. A pharmacokinetic simulation suggests that, in comparison to standard CTX infusion, an infusion every three weeks will lead to similar AUC but to different residual concentrations

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42

Biscotti, Tommasina. "analisi immunoistochimica e molecolare (CISH/FISH) dei fattori predittivi di risposta alla terapia irinotecan-cetuximab nel carcinoma del colon-retto in stadio avanzato". Doctoral thesis, Università Politecnica delle Marche, 2008. http://hdl.handle.net/11566/242432.

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43

ARDIZZONE, MICHELE. "A PRECLINICAL INVESTIGATIVE PLATFORM SETUP, AS A TOOL FOR EVALUATING THE EFFICACY OF CETUXIMAB IN ADDITION TO THE STANDARD HUMAN MALIGNANT MESOTHELIOMA CHEMOTHERAPY PROTOCOL". Doctoral thesis, Università degli Studi di Milano, 2013. http://hdl.handle.net/2434/216308.

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Mesothelioma is a malignant tumour that arises from mesothelial cells lining the serosal cavities; in most cases it originates in the pleura and in very few cases in the peritoneum; other sites of origin (pericardium and tunica vaginalis of the testis) are extremely rare. The tumour itself is rare with regard to spontaneous occurrence, however it is universally recognized that exposure to asbestos fibres is harmful to human health, since as well as causing an occupational illness known for many years, asbestosis, it also causes malignant pleural and peritoneal mesothelioma as well pulmonary carcinoma, as proven in many epidemiological studies published since the early 1960s. The purposes of the overall PhD program were on the one hand 1) to set up a preclinical investigative platform screening the efficacy of anticancer drugs in human malignant mesothelioma cell lines, based on the integration of data from in vitro and in vivo activities, and on the other hand 2) to adopt this platform investigating the potential benefit of an anticancer monoclonal antibody (cetuximab) in the treatment of human malignant mesothelioma, both as single agent or in adjunct to the standard first line chemotherapy protocol with folate antimetabolite (pemetrexed) and platinum (cisplatin) compounds. At the end of the entire PhD program, it is important to acknowledge the value of having set up a preclinical diagnostic platform to use in screening molecules potentially effective against tumours (i.e. human malignant mesothelioma) strictly connected with the possibility of carrying out experimental preclinical investigations based on a step-wise approach, with a well-defined rationale that brings together the information obtained at different times, from early studies that can be conducted quickly and tend to be less costly in less complex cell systems, to studies in more complex animal models, with consequent time-saving and use of fewer animals.

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44

Semidey, Raven María Eugenia. "Evaluación de factores moleculares asociados a la respuesta a cetuximab: integración con tratamientos de radioterapia y quimioterapia en carcinoma escamoso de cabeza y cuello". Doctoral thesis, Universitat Autònoma de Barcelona, 2016. http://hdl.handle.net/10803/386551.

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El carcinoma de cabeza y cuello (CCC) es una patología frecuente y de difícil manejo terapéutico que ocupa la sexta posición de incidencia nacional (4,3%), con una mortalidad del 37%. El tratamiento de los casos localmente avanzados está basado en la combinación de radioterapia (RT) y quimioterapia (QT) con anticuerpos monoclonales anti-EGFR como el cetuximab. Las alteraciones en los factores que participan en las vías de carcinogénesis dependientes de EGFR como PI3K/AKT/mTOR y RAS/RAF/MAPK pueden conllevar a sensibilidad o resistencia al tratamiento, afectando el pronóstico de la enfermedad. En este estudio se evaluó la relación existente entre la expresión de las proteínas de las vías de señalización de EGFR y sus mutaciones, y la respuesta al tratamiento con quimioterapia o radioterapia en combinación con cetuximab en los tumores de cabeza y cuello. Se estudiaron las proteínas mTOR, 4EBP1 y eIF4E y sus formas fosforiladas, PTEN, pS6, pMAPK y HER3 por inmunohistoquímica, así como los factores supresores p53, p16 y el índice de proliferación celular Ki67. De la misma manera, se detectaron mutaciones de proteínas implicadas en la tumorigénesis (PI3K, B-RAF, KRAS y H-RAS) y la presencia de VPH, especificando los serotipos observados. El análisis estadístico incluyó la realización de curvas de Roc para determinar el punto de mayor sensibilidad y especificidad para peor pronóstico sobre cada una de las proteínas estudiadas. Adicionalmente se realizaron análisis de supervivencia, mediante curvas de Kaplan-Meier, y modelos de regresión logística de Cox para determinar las variables asociadas a peor pronóstico. Se incluyeron 90 pacientes diagnosticados de CCC con una edad media de 59,7 ± 10,9 años, de los cuales el 86,67% era del sexo masculino. Se crearon tres grupos de pacientes según el tratamiento recibido: con RT asociado a cetuximab (23,33%), QT asociado a cetuximab (27,78%) y QT/RT (48,89%). La mediana de supervivencia libre de enfermedad fue de 48,5 (30-95,75) semanas y la supervivencia global fue de 88 (51-135,75) semanas. Se observó una menor supervivencia libre de enfermedad en aquellos tumores que expresaban mTOR >125 (HR 2,05; p=<0,01) y eIF4E >115 (HR 1,67; p=0,04), siendo factores independientes de peor pronóstico la expresión de mTOR, pmTOR y las metástasis ganglionares. En cuanto a la supervivencia global se observó un peor pronóstico en aquellos tumores que expresaron mTOR>125 (HR: 1,88; p=0,01), pMAPK (HR 1,50; p=0,008) y que presentaban metástasis ganglionares (92 vs 215 sem, p=0,004), siendo factores independientes de peor pronóstico la expresión de mTOR y las metástasis ganglionares. Se observó una peor supervivencia global y menor tiempo libre de enfermedad en aquellos pacientes cuyos tumores expresaban pMAPK, con HR 7,15 (2,20-23,18) y HR 3,42 (1,15-10,15), respectivamente, en el grupo que recibió QT combinado con cetuximab. Se observó una mayor supervivencia libre de enfermedad en los casos p16 positivos (HR 0,53; 0,23-1,24) y mejor supervivencia global (HR 0,37; 0,13-1,04), siendo un factor independiente asociado a mejor pronóstico. En conclusión, la combinación de inhibidores de mTOR puede tener un efecto sinérgico con el cetuximab en el tratamiento de CCC. Los mecanismos de resistencia a cetuximab se encuentran en relación con la persistencia de la activación de mTOR y MAPK como proteínas dependientes de EGFR.
Head and neck squamous cell carcinoma (HNSCC) is a frequent disease of difficult therapeutic management. It occupies the sixth position in national cancer incidence (4,3%) with 37% of mortality. The treatment of the locally advanced cases is based in the combination of radiotherapy (RT) and chemotherapy (CT) with anti-EGFR monoclonal antibodies like Cetuximab. The alterations in the factors that participate in the EGFR dependent cancer pathways like PI3K/AKT/mTOR and RAS/RAF/MAPK can lead to increased sensibility or resistance to the treatment, affecting the prognosis of the disease. In our study, we determined the relationship between the expression of the proteins of the EGFR signalling pathways and its mutations, and the response to the treatment with chemotherapy or radiotherapy in combination with cetuximab in HNSCC. We studied the proteins mTOR, 4EBP1 y eIF4E and its phosphorylated counterparts, PTEN, pS6, pMAPK and HER3 by immunohistochemistry, the suppresor factors p53, p16 and the Ki67 cellular proliferation index. Likewise, the mutations of the proteins involved in carcinogenesis (PI3K, B-RAF , KRAS y H-RAS) were detected as well as the presence of HPV. In the statistical analysis Roc curves were done to determine the point with more sensitivity and specificity to a worse prognosis in all the proteins studied. Global and disease-free survivals were analyzed through Kaplan-Meier curves. Multivariate logistic regression analysis was done to determine the variables associated, independently, with a worse prognosis. We included 90 patients diagnosed with HNSCC with a median age of 59,7 ± 10,9 years and more frequency of males (86,67%). Three branches were stablished according to the treatment received either RT associated with Cetuximab (23,33%), CT associated with Cetuximab (27,78%) and CT/RT (48,89%). The disease-free survival median was of 48,5 weeks (30-95,75) and global survival was 88 (51-135,75) weeks. We observed a lower disease-free survival in those tumors expressing mTOR >125 (HR 2,05;p=<0,01) and eIF4E >115 (HR 1,67;p=0,04), being independent factors of worse prognosis the expression of mTOR, pmTOR and the presence of lymph nodes metastases. On the other hand, there was a lower global survival in those tumors expressing mTOR>125 (HR: 1,88,p=0,01), pMAPK (HR 1,50;p=0,008) and patients with lymph node metastases 92 vs 215w, p=0.004, being independent factors of worse prognosis the expression of mTOR and the presence of lymph node metastases. We observed a lower global and disease-free survival time in those patients with tumors expressing pMAPK with HR 7,15 (2,20-23,18) and HR 3,42 (1,15-10,15), respectively, in the branch who received CT plus cetuximab. There was a better disease-free survival in the cases p16 positives (HR 0,53; 0,23-1,24) and a better global survival (HR 0,37; 0,13-1,04), being an independent factor of better prognosis. In conclusion, the combination of inhibitors of mTOR may have a sinergistic effect with the anti-EGFR treatment in HNSCC. The resistance mechanisms towards cetuximab are in relation with the persistance in the activation of the different proteins constitutives of the carcinogenesis pathways like mTOR and pMAPK, both EGFR dependents.

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45

Kapaun, Christine. "Analyse molekularpathologischer Faktoren des EGFR-Signalwegs und ihre Bedeutung als prädiktive Faktoren in der Behandlung des metastasierten kolorektalen Karzinoms mit dem EGFR-Antikörper Cetuximab". Diss., lmu, 2013. http://nbn-resolving.de/urn:nbn:de:bvb:19-155446.

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46

Neckel, Norbert Bruno [Verfasser], e Urs [Gutachter] Müller-Richter. "In vitro-Untersuchungen zur Wirksamkeit von Erlotinib, Gefitinib und Cetuximab bei der Behandlung des Kopf-Hals-Karzinoms / Norbert Bruno Neckel ; Gutachter: Urs Müller-Richter". Würzburg : Universität Würzburg, 2018. http://d-nb.info/1151128627/34.

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47

Coliat, Pierre. "Stratégie de sensibilisation des tumeurs des voies aérodigestives supérieures aux anti-EGFR et résistance induite : induction de HIF-2 et opportunité thérapeutique". Thesis, Strasbourg, 2015. http://www.theses.fr/2015STRAJ067/document.

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Abstract (sommario):

Les traitements des cancers des VADS reposent sur la chirurgie, la radiothérapie, et la chimiothérapie. Malgré ces traitements, la survie globale des patients à 5 ans est de l’ordre de 50%. Les causes d’échec thérapeutique sont dues au profil de résistance des tumeurs. Le ciblage de l’axe EGFR/mTOR/HIF-1 par une combinaison de rapalogues et d’anti-EGFR a montré son efficacité sur certaines tumeurs solides. L’objet de ce travail de thèse a été de caractériser l’impact d’une combinaison de drogues à faibles doses sur des lignées cellulaires des VADS au moyen d’une approche pharmacologique et moléculaires. Nos résultats montrent que la combinaison de la rapamycine (5nM) au cetuximab (2,5μg/ml) diminue la survie clonogénique des cellules et permet une inhibition du facteur de transcription HIF-1α. Cette combinaison de drogue améliore l’efficacité de la radiothérapie. En revanche, l’induction de HIF-2a induite par le traitement provoque la résistance des cellules aux traitements par, et une rechute rapide des tumeurs in vivo. L’inhibition de HIF-2 permet une inhibition de la survie cellulaire d’environ 100% dans un modèle résistant
Management of HNSCC relies on surgery, radiotherapy, and chemotherapy. Despite these treatments, the 5 years overall survival of patient is lower than 50%. Main causes of therapeutic failure are due to the profile of resistance of tumors. The efficacy of a combination rapalogues and anti-EGFR therapies in targeting the EGFR/mTOR/HIF-1 axis in solid tumors was shown previously. In this PhD work, we have evaluated the impact of a low-dose drug combination on head and neck cancer cells lines with a pharmacological and molecular approach. We show that the combination of rapamycine (5nM) and cetuximab (2,5μg/ml) efficiently inhibits the HIF-1 transcription factor and impairs cell clonogenic survival. The efficacy of radiation therapy is improved by this drug combination. However, cell resistance to the treatment is acquired via the induction of HIF-2 in our resistant model cell line. This induction is associated with more tumor relapse in tumors mice xenograft. The inhibition of HIF-2 achieves a dramatic drop of cell clonogenic survival to < 1%

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48

Capitain, Olivier. "Intensification thérapeutique dans les cancers colorectaux par des études pharmacogénétiques et pharmacogénomiques". Phd thesis, Université d'Angers, 2010. http://tel.archives-ouvertes.fr/tel-00536079.

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Le cancer colorectal représente un défi thérapeutique compte tenu de sa fréquence (38 000 nouveaux cas annuels dans notre pays), et de sa gravité (moins de 10 % de survie à 5 ans en situation métastatique). Sa prise en charge adéquate est avant tout multidisciplinaire associant les nouvelles techniques de chirurgie et de radiologie à la chimiothérapie. Celle-ci est représentée par trois cytotoxiques majeurs : le 5-Fluorouracile, pierre angulaire du traitement, l'oxaliplatine (L-OHP) et enfin l'irinotecan (CPT-11), auxquels se sont ajoutées ces dernières années les biothérapies ciblant le facteur angiogénique VEGF (bevacizumab) ou le récepteur épithélial de surface EGFR (cetuximab, panitumumab). Notre travail de Thèse d'Université a cherché à explorer, chez des patients atteints d'un cancer colorectal métastatique, le retentissement sur les taux de réponses, les survies et les toxicités, de génotypes enzymatiques impliqués dans les métabolismes des trois cytotoxiques principalement utilisés dans cette indication. Nos études translationnelles montrent l'optimisation des traitements à base de 5-FU par l'approche pharmacocinétique associée au dépistage préthérapeutique d'une population à haut risque de toxicité (DPYD mutés et/ou rapport UH2/U abaissé). Par ailleurs apparaissent de mauvais pronostic sur la survie globale et en cas de monochimiothérapie par 5-FU, les patients 3R/3R pour TYMS et homozygote sauvage pour MTHFR 1298 A>C ou 677 C>T, facteurs de risques génotypiques disparaissant avec l'adjonction de CPT-11. Concernant ce dernier, un schéma de traitement adapté au statut UGT 1A1, et combiné au cetuximab, aboutit à des taux de maladie contrôlée et de survie sans progression inégalés en deuxième ligne de traitement. Enfin, les patients homozygotes T/T pour ERCC1 118 C>T et C/C XPD 751 A>C apparaissent à risque de neurotoxicité chroniques à l'oxaliplatine. Considérant le génome tumoral, outre Kras et Braf, PI3KCA muté apparaît pour la première fois comme un facteur possible de résistance aux traitements anti-EGFR. En conclusion, la prise en compte des facteurs pharmacogénétiques et pharmacogénomiques devrait permettre à l'avenir une meilleure rationalisation des traitements de chimiothérapies en optimisant leurs efficacités tout en limitant leurs toxicités.

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Privitera, Giovanna. "Studio di nuovi approcci farmacologici in grado di inibire l'attivazione dei recettori del fattore di crescita epidermico (EGF) in linee cellulari di carcinoma polmonare non a piccole cellule (NSCLC)". Doctoral thesis, Università di Catania, 2013. http://hdl.handle.net/10761/1436.

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Il carcinoma del polmone rappresenta attualmente la neoplasia più frequentemente diagnosticata e costituisce la principale causa di morte per tumore solido al mondo. E una malattia multifattoriale che riconosce nella cancerogenesi cause ambientali e cause genetiche. L istotipo più frequente è il carcinoma non a piccole cellule (NSCLC) che rappresenta circa il 75-80% delle diagnosi. Il principale approccio terapeutico consiste nella resezione chirurgica (eventualmente preceduta e/o seguita da chemioterapia) limitata però ai soli stadi iniziali. Studi precedenti hanno dimostrato che l iper-espressione o l attivazione costitutiva dei recettori del fattore di crescita epidermico (EGF) è coinvolta nella crescita dei carcinomi umani, incluso quello polmonare. In questo lavoro sperimentale è stato studiato l effetto del blocco di due recettori dell EGF, EGFR e HER-2, sulla proliferazione delle cellule A549 e NCI-H226 di carcinoma polmonare. Sono stati utilizzati, a tale scopo, cetuximab, anticorpo monoclonale diretto contro l EGFR e trastuzumab, anticorpo monoclonale diretto contro l HER-2, a diverse concentrazioni per 72 h. Mediante il saggio di proliferazione MTT (3,(4,5-dimethylthiazol-2)2,5 difeniltetrazolium bromide) è stato osservato il 91,4% di inibizione della proliferazione delle cellule A549 trattate con una combinazione di cetuximab e trastuzumab alla concentrazione di 40 ug/ml, mentre le cellule NCI-H226 hanno mostrato una resistenza allo stesso trattamento combinato. Sono state successivamente valutate le eventuali variazioni di espressione dei livelli di mRNA dei recettori EGFR e HER-2 di entrambe le linee cellulari. Nelle cellule A549 è stato osservato un significativo incremento dei livelli di mRNA di EGFR dopo 30 h dal trattamento farmacologico, spiegabile considerando il meccanismo di azione del cetuximab, che determina internalizzazione e degradazione del recettore in tempi brevi. A questa segue quindi nuova sintesi di proteine recettoriali. Questi livelli di mRNA diminuiscono dopo 48 h e 72 h dal trattamento per avvicinarsi poi ai valori normali. Un comportamento analogo è stato osservato nei livelli di mRNA del recettore HER-2, in cui l internalizzazione del recettore, conseguente all interazione con il trastuzumab, determina già a 18 h di trattamento un incremento dell espressione di tale recettore. Le cellule NCI-H226 hanno mostrato invece un aumento di circa 3,5 volte dei livelli di mRNA dell EGFR dopo 48 h dal trattamento e il mantenimento di alti livelli anche dopo 72 h. Il recettore HER-2 non sembra essere invece influenzato dal trattamento farmacologico e, almeno nei primi tempi della somministrazione, i livelli di mRNA non vengono alterati. Solo dopo 72 h di trattamento è stato osservato un aumento di tali livelli, che vengono circa raddoppiati, ad indicare un possibile coinvolgimento tardivo di tale recettore nella risposta al trattamento combinato. L iniziale scarso coinvolgimento del recettore HER-2 potrebbe quindi essere responsabile della resistenza delle cellule NCI-H226. E pertanto nostro obiettivo futuro prolungare il tempo di trattamento delle cellule NCI-H226 con cetuximab e trastuzumab allo scopo di valutare un effetto antiproliferativo più tardivo. La differenza di sensibilità al cetuximab e al trastuzumab, nelle due linee cellulari prese in esame, non dipende invece dal numero di copie del gene, in quanto, mediante la tecnica di ibridazione in situ fluorescente (FISH), abbiamo osservato lo stesso incremento del numero di copie dei geni EGFR e HER-2 e quindi una condizione di polisomia, in entrambe le linee cellulari. La strategia di agire su entrambi i recettori potrebbe quindi migliorare il trattamento del carcinoma polmonare, aumentare la sopravvivenza e ridurre gli effetti collaterali della terapia, garantendo così al paziente un sensibile miglioramento della qualità di vita.

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Miller-Phillips, Lisa [Verfasser], e Volker [Akademischer Betreuer] Heinemann. "Molekulare Prädiktion des Ansprechens auf Cetuximab im Rahmen der FIRE-3 Studie : Untersuchungen am EGFR („Epidermal Growth Factor Receptor")-Signaltransduktionsweg / Lisa Miller-Phillips ; Betreuer: Volker Heinemann". München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/1190563681/34.

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