Dissertations / Theses on the topic 'Preclinical tumor models'
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MINOLI, LUCIA. "TUMOR MICROENVIRONMENT IN EXPERIMENTAL PRECLINICAL MOUSE MODELS OF HUMAN CANCER: MORPHOLOGICAL APPROACH." Doctoral thesis, Università degli Studi di Milano, 2020. http://hdl.handle.net/2434/704551.
Chen, Liu Qi. "Development and Application of AcidoCEST MRI for Evaluating Tumor Acidosis in Pre-Clinical Cancer Models." Diss., The University of Arizona, 2014. http://hdl.handle.net/10150/323450.
Denton, Nicholas Lee Denton. "Modulation of tumor associated macrophages enhances oncolytic herpes virotherapy in preclinical models of Ewing sarcoma." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1523892800897524.
TOSCA, ELENA MARIA. "Dynamic energy budget based models of tumor-in-host growth inhibition and cachexia onset in preclinical settings." Doctoral thesis, Università degli studi di Pavia, 2019. http://hdl.handle.net/11571/1242427.
The anticancer drug development process is characterized by the highest attrition rates in the clinical setting, primarily due to adverse efficacy and safety results. Preclinical animal models slightly representative of the human condition and an inadequate predictive paradigm of preclinical to clinical translation may be likely causes of this. Pharmacometric models, able to extract, synthesize and integrate preclinical information, could support the transfer of the preclinical results to the clinical setting. Within the paradigm of the Model-Informed Drug Discovery and Development, my thesis deals with the development, implementation and analysis of new mathematical modeling approaches to exploit data routinely generated in the preclinical phases of anticancer drug development process. In all the described research activities it can be recognized the importance of PK/PD modeling in better characterizing, understanding and predicting PK/PD behaviour of oncology agents. The focus of this work is a mathematical modeling of interactions between tumor and host organism during anticancer drug treatments in preclinical experiments. To this aim, a tumor-in-host modeling approach is proposed on the basis of a set of tumor-host interaction rules taken from the Dynamic Energy Budget (DEB) theory. This framework, suitably adapted to several experimental contexts, is able to integrate the different aspects characterizing the in vivo tumor growth studies: the drug cytotoxic or cytostatic activity on the tumor, the eventually onset of cachexia due to the treatment, the effect of the tumor on the host and, viceversa, the influence of the host condition on tumor dynamics. In particular, a tumor-in-host DEB-based model describing the cachexia onset and tumor growth inhibition (TGI) after the administration of cell-killing agents has been developed, mathematically analysed and, subsequently, applied on a etoposide experiment in Wistar rats. The cytostatic anticancer effect of angiogenesis inhibitors in xenograft mice has been, also, modeled within the tumor-in-host DEB-based framework. This DEB-TGI anti-angiogenic model has proved to be extremely useful to describe and understand the complexities of an hypoxia-triggered resistance to bevacizumab. Finally, starting from the previous developed TGI models, a tumor-in-host approach to analyse combination experiments and assess possible drug-drug interaction between anti-angiogenic and chemotherapeutic agents is proposed.
Lahr, Christoph Alexander. "Tissue-engineering humanised bone sarcoma models in rodents-a preclinical study platform for orthopaedic research." Thesis, Queensland University of Technology, 2021. https://eprints.qut.edu.au/207759/1/Christoph%20Alexander_Lahr_Thesis.pdf.
Laranga, Roberta <1985>. "Development of Preclinical Models of Mammary Carcinogenesis: Functional Role of Her2 and its Isoforms in Tumor Progression and in Drug Resistance." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2017. http://amsdottorato.unibo.it/7832/1/Laranga_Roberta_Tesi.pdf.
Fuchs, Jeannette [Verfasser], and Thorsten [Akademischer Betreuer] Stiewe. "Establishment and characterization of preclinical mouse models for evaluation of oncogenic and tumor-suppressive properties of p53 family members / Jeannette Fuchs ; Betreuer: Thorsten Stiewe." Marburg : Philipps-Universität Marburg, 2017. http://d-nb.info/1131253272/34.
Ferreira, Luís Pedro Correia Pinto. "Development of multicelular 3D cancer testing platforms for evaluation of new anti-cancer therapies." Master's thesis, Universidade de Aveiro, 2017. http://hdl.handle.net/10773/22713.
O cancro do pulmão (CP) é um dos cancros mais diagnosticados a nível mundial e também um dos mais mortíferos. Atualmente, as terapias administradas a nível clínico para o tratamento do CP são ainda extremamente ineficazes e limitadas no que diz respeito ao aumento da taxa de sobrevivência dos pacientes oncológicos. Esta realidade demonstra a necessidade de investigar ativamente novas terapias para o tratamento desta neoplasia. No entanto a validação pré-clínica de terapias inovadoras para o CP tem-se revelado extremamente difícil devido à inexistência de plataformas que sejam adequadas para testes a nível laboratorial, uma vez que as culturas celulares in vitro bidimensionais (2D), recomendadas pelas agências regulatórias são incapazes de mimetizar as caraterísticas principais dos tumores humanos. Estas limitações têm originado uma fraca correlação entre a performance das terapias nos estudos in vitro e a obtida em ensaios clínicos controlados. Neste contexto, os modelos de tumores tridimensionais (3D) in vitro têm vindo a ser reconhecidos como uma solução para este problema, pois podem recapitular várias componentes do microambiente tumoral. Das várias plataformas 3D in vitro de CP investigadas atualmente muito poucas avaliaram o papel da inclusão de células estaminais mesenquimais (MSCs). Para colmatar esta lacuna, o trabalho de investigação desenvolvido no âmbito desta dissertação descreve a produção e otimização de novos modelos hétero-celulares 3D in vitro. Estas plataformas são compostas por células tumorais do CP (A549) e do seu estroma, nomeadamente fibroblastos da pele e células estaminais mesenquimais derivadas da medula óssea (BM-MSCs). Estes três tipos de células foram co-cultivadas em micropartículas poliméricas de policaprolactona revestidas por ácido hialurónico, com o objetivo de incluir este componente da matriz extracelular que se encontra presente no microambiente do CP. Esta abordagem permitiu formar a nível laboratorial microtecidos multicelulares 3D híbridos que melhor mimetizam a heterogeneidade celular das neoplasias pulmonares. Os resultados obtidos demonstraram que os microtumores formados através da técnica de sobreposição-líquida são reprodutíveis em termos de morfologia e tamanho, apresentaram núcleos necróticos, organização celular 3D e produziram proteínas do microambiente tumoral. Além destas caraterísticas, os dados obtidos através de microscopia de fluorescência revelaram que as BM-MSCs migram para o interior dos microtumores ao longo do tempo. A avaliação da citotoxicidade da Doxorubicina, um fármaco anti-tumoral rotineiramente utilizado a nível clínico, demonstrou que a inclusão de micropartículas aumenta a resistência das células tumorais em modelos homotípicos. Nos modelos tri-cultura heterotípicos a citotoxicidade foi comparável à obtida em microtumores sem micropartículas. Estes resultados evidenciam assim o papel importante dos fibroblastos e das BM-MSCs na resposta dos microtumores. Numa visão global, os modelos 3D formados recapitulam com mais exatidão o microambiente do cancro do pulmão e poderão servir no futuro como plataformas de teste para descobrir ou aperfeiçoar novas terapias, ou combinações de terapêuticas, para este tipo de neoplasia.
Lung cancer (LC) is one the most commonly diagnosed cancers worldwide, being also one of the deadliest. Currently, clinically administered therapies for treatment of LC are still extremely ineffective and limited in increasing oncologic patients survival rates. This reality evidences the necessity of actively investigating novel therapies for the treatment of LC. However, preclinical validation of novel therapies as revealed itself as an extremely arduous process, due to the lack of suitable laboratory testing platforms since the recommend in vitro bi-dimensional (2D) cell cultures are unable to fully mimic the main hallmarks of human tumors. In this context, in vitro tridimensional (3D) tumor models are being increasingly recognized as a solution due to their ability to correctly recapitulate several characteristics of the tumor microenvironment (TME). Amongst currently developed 3D in vitro platforms for the study of LC, few have included or studied the role of mesenchymal stem cells (MSCs). To provide further insights into this hypothesis, the research work developed in this thesis describes the production and optimization of novel heterotypic in vitro 3D models, comprised by non-small-cell lung cancer cells (A549) and stromal cells, namely skin fibroblasts (HFs), and bone-marrow derived mesenchymal stem cells (BM-MSCs). These three diverse cell populations were co-cultured in hyaluronic acid coated polymeric polycaprolactone microparticles (LbL-MPs) as to include this key extracellular matrix component of LC TME. This approach allowed the formation of 3D multicellular heterotypic microtissues (3D-MCTS) that better recapitulate the cellular heterogeneity of LC TME in the laboratory. The obtained findings demonstrate that these models formed via the liquid-overlay technique were reproducible in terms of morphology and size, presented necrotic core formation, 3D cellular organization, and deposited matrix proteins in a similar manner as in the TME. Besides this, fluorescence microscopy data revealed that BM-MSCs migrated overtime into the microtumors core . Performed doxorubicin in vitro cytotoxicity assays revealed that the inclusion of LbL-MPs lead to an increased resistance of homotypic A549 monoculture models against this anti-cancer drug commonly used in clinical treatments. Alongside, the cytotoxicity obtained in triculture heterotypic models was comparable to that of microtumors without LbL-MPs inclusion, showcasing the role of HFs and BM-MSCs in microtumors response to therapy. Globally, the herein bioengineered 3D models were able to recapitulate with an increased precision the TME of LC, making them suitable test platforms for development or improvement of standalone or combinatorial therapies for this type of neoplasia.
Wolska-Krawczyk, Malgorzata [Verfasser], and Arno [Akademischer Betreuer] Bücker. "Evaluation of liver tumor perfusion by intraarterial transcatheder magnetic resonance angiography during transarterial chemoembolization in patients with hepatocellular carcinoma : Preclinical instrument validation in vascular models and clinical study / Malgorzata Wolska-Krawczyk. Betreuer: Arno Bücker." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2014. http://d-nb.info/1056906979/34.
Dobosz, Michael [Verfasser], Vasilis [Akademischer Betreuer] Ntziachristos, and Hans-Jürgen [Akademischer Betreuer] Wester. "The application of in vivo and ex vivo multispectral epi-fluorescence imaging for the preclinical discovery and development of monoclonal antibodies in tumor xenograft models / Michael Dobosz. Betreuer: Vasilis Ntziachristos. Gutachter: Hans-Jürgen Wester ; Vasilis Ntziachristos." München : Universitätsbibliothek der TU München, 2014. http://d-nb.info/1080903682/34.
Dobosz, Michael Verfasser], Vasilis [Akademischer Betreuer] Ntziachristos, and Hans-Jürgen [Akademischer Betreuer] [Wester. "The application of in vivo and ex vivo multispectral epi-fluorescence imaging for the preclinical discovery and development of monoclonal antibodies in tumor xenograft models / Michael Dobosz. Betreuer: Vasilis Ntziachristos. Gutachter: Hans-Jürgen Wester ; Vasilis Ntziachristos." München : Universitätsbibliothek der TU München, 2014. http://d-nb.info/1080903682/34.
Delgado, San Martin Juan A. "Mathematical models for preclinical heterogeneous cancers." Thesis, University of Aberdeen, 2016. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=230139.
PEDERZOLI, FILIPPO. "Microbiome and bladder cancer." Doctoral thesis, Università Vita-Salute San Raffaele, 2021. http://hdl.handle.net/20.500.11768/121778.
The microbiome has gained increasing momentum in cancer research, as it has become clear that microorganisms residing within our body are involved in mediating the cellular and tissue metabolism in health and disease. In bladder cancer research, there are different microbial communities that may mediate cancer pathobiology and response to therapy: the gut microbiome, the urinary microbiome, the urothelium-bound microbiome. These bacterial communities may mediate the processes of carcinogenesis or recurrence, modify the response to local intravesical therapies or influence the activity of systemic anticancer protocols. Based on these premises, my research project aimed to unveil the urinary and urothelium-bound microbiome in therapy-naïve bladder cancer patients, describing the differently enriched bacterial communities using a sex-based stratification. Compared to healthy controls, I found that the urine of men affected by bladder cancer were enriched in the order Opitutales and subordinate family Opitutaceae, together with the isolated class Acidobacteria-6, while in female patients I found enriched the genus Klebsiella. Notably, the bladder cancer tissue was enriched in the genus Burkholderia in both men and women, when compared to non-neoplastic, paired urothelium biopsies. Then, I also characterized the gut microbiome of bladder cancer patients undergoing neoadjuvant pembrolizumab to understand if the intestinal bacteria may influence the immune-mediated anticancer activity. In this set, I have reported that antibiotic therapy has a negative effect on immunotherapy efficacy. Second, the gut microbiome of patients not responding to neoadjuvant pembrolizumab was characterized by a higher abundance of Ruminococcus bromii, while patients who showed a response were enriched in the genus Sutterella. Lastly, I started the implementation of in vivo and in vitro systems to test the mechanistic role of the bacteria identified in human samples. This thesis work reported innovative data on the role of different microbial communities (urinary/urothelium-bound/fecal) in bladder cancer and bladder cancer therapy, and provided novel in vivo and in vitro models to validate those finding and uncover the complex microbiome-host cells crosstalk in bladder cancer patients.
George, Courtney M. "Medulloblastoma: New animal models, preclinical drug testing, and characterising immune infiltrates." Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2022. https://ro.ecu.edu.au/theses/2575.
Pan, Jie. "Molecularly targeted therapy on a new preclinical mouse model for gastric neuroendocrine tumors." Diss., Ludwig-Maximilians-Universität München, 2013. http://nbn-resolving.de/urn:nbn:de:bvb:19-159343.
Neuroendokrine Tumore stellen heterogene Tumore mit ansteigender Prävalenz dar. Da es nur geringe Verbesserungen in der Therapie gibt, besteht ein Bedarf an neuen Modellsystemen. In unserer Arbeitsgruppe wurde das CEA424-SV40-T-Antigen transgene Mausmodell entwickelt, in welchem sich spontan Tumore im Bereich des Magenantrums bilden. Gleichzeitig wurden Zelllinien aus diesem Tumor etabliert. Die Analyse der Genexpression im Tumor und in den Zelllinien ergaben Hinweise auf einen neuroendokrinen Tumortyp. Deshalb wurde der Phänotyp des Tumors auch mit Blick auf den Ursprung der Tumore analysiert und für die Testung von Therapieoptionen eingesetzt. Die Analyse der CEA-424-SV40-TAg-Mäuse sowie der Tumorlinien wurden mittels Immunhistochemie, Immunfluoreszenz, Westernblot und ELISA untersucht. Dazu wurden Antikörper gegen das SV40-T-Antigen, den Proliferationsmarker Ki-67, Chromogranin A, Chromogranin B, Sekretin, die H-K-ATPase, Glukagon und die Transkriptionsfaktoren NeuroD und Nkx2.2 eingesetzt. Die Plasma Hormonkonzentrationen von Serotonin und Sekretin wurden mittels ELISA bestimmt. Die Färbung für das SV40-T-Antigen und Ki-67 zeigte einen hoch proliferierenden Tumor. Dieser war hoch positiv für die neuroendokrinen Marker Chromogranin A, Chromogranin B, Sekretin und Glukagon. Sowohl der Tumor als auch die Tumorzelllinien exprimierten die Transkriptionsfaktoren NeuroD und Nkx2.2, welche an der Differenzierung von neuroendokrinen Zellen beteiligt sind. Die Hormonkonzentrationen von Serotonin und Sekretin waren im Plasma der transgenen Mäuse deutlich erhöht. Dies ergab das Gesamtbild eines neuroendokrinen Karzinoms. In diesem Modell wurden nun verschiedene molekular begründete Therapien in vitro und in vivo getestet. So wurde an den Zelllinien die Empfindlichkeit von mTOR Inhibitoren (RAD001, NVP-BEZ235), Paclitaxel, E2F -Inhibitor, Hsp90-Inhibitor und dem p53 Inhibitor Nutlin3 getestet. Alle verwendeten Substanzen konnten die Proliferation der Tumorzellen dosisabhängig hemmen. Von diesen wurde dann der mTOR Inhibitor RAD001 für die in vivo Anwendung ausgewählt. RAD001 konnte dabei die Entwicklung der Tumore signifikant hemmen und verlängerte das Überleben der Tiere dramatisch. Der Effekt der mTOR Inhibition bestand dabei vor allem in der Hemmung des mTOR-p70S6K und mTOR-4EBP1 Pathways, was im Westernblot und der Immunhistochemie gezeigt werden konnte. Trotzdem muss festgehalten werden, dass einige Tumorzellen der Therapie entkommen konnten. Um nun Informationen über den Transformations- und den Escape-Mechanismus zu bekommen, wurde versucht die Tumorursprungszelle zu beschreiben. Mögliche Kandidaten dafür sind sowohl die jüngst beschriebenen intestinalen Epithelstammzellen als auch mesenchymale Stammzellen. Dazu wurden Marker-Gene an den etablierten Zelllinien und den Tumoren mit Hilfe von RT-PCR, Immunhistochemie, Immunfluoreszenz, Westernblot und Microarray untersucht. Dabei fand sich in den Tumorzellen eine hohe Expression des möglichen epithelialen Stammzellmarkers Bmi1. Dies konnte auch im Westernblot und in der Immunfärbung bestätigt werden. Folgerichtig fand sich dieser Marker auch in den wachsenden Tumoren. Experimente, in denen mit siRNA die Expression des SV40-T- Antigen blockiert wurde, ergaben eine Reduktion der Bmi1-Expression und weisen damit auf einen engen Zusammenhang hin. Gleichzeitig fand sich allerdings auch eine hohe Expression des mesenchymalen Stammzell-Markergenes Etv1 im Tumor und in den etablierten Zelllinien. Etv1 stieg dabei im Verlauf der Tumorentwicklung im Gewebe deutlich an. Deshalb könnte es sich bei der ursprünglich transformierten Zelle auch um eine mesenchymale Stammzelle handeln. Da der CEA Promotor, der die Expression des SV40-T-Antigens in den transgenen Mäusen regulieren soll, einige Bindungsstellen für den Transkriptionsfaktor Etv1 hat, liegt die Möglichkeit der Induktion des T-Antigens über Etv1 nahe. Dazu stehen aber noch weitere Experimente aus. Zusammenfassend zeigen die hier präsentierten Daten, dass es sich bei dem CEA424-SV40 Tag-Mausmodell um ein klinisch relevantes Modell für einen neuroendokrinen Tumor handelt. Zusammen mit den etablierten Tumorzelllinien können daran neue Therapieansätze getestet werden. Damit bietet es die Möglichkeit sowohl den Zusammenhang zwischen dem T-Antigen und der Entwicklung des neuroendokrinen Phänotyps als auch neue Therapieformen zu untersuchen.
Baka, Zakaria. "Élaboration de cancers sur puce pour des applications en thérapies anticancéreuses." Electronic Thesis or Diss., Université de Lorraine, 2023. http://www.theses.fr/2023LORR0175.
Ovarian cancer is a major public health issue. Moreover, new treatments still face very high failure rates. This is mainly due to the unreliability of conventional preclinical models such as 2D cell culture. Thus, new tools based on 3D cell culture have emerged such as spheroids and organoids. However, these models have their own limitations (cost, difficulty of application). 3D bioprinting is a new approach to create tunable and reproducible tumor models. However, very few bioprinted tumor models have been reported so far. Besides the “third dimension”, it is important to consider the dynamic conditions of the tumor environment. This has been possible for some years now thanks to microfluidics-based cancer-on-a-chip technology. However, this technology currently does not simulate the drug vascular transport before its interaction with the tumor cells. In this PhD project, we set out to create a dynamic, three-dimensional model of ovarian cancer by combining 3D bioprinting and microfluidics. First, 3D bioprinting was used to create the tumor structure itself. For that, we formulated a bio-ink comprising SKOV-3 ovarian cancer cells and MeWo cancer fibroblasts embedded in a gelatin – alginate hydrogel. The bioprinted tumor structures were then characterized by various techniques to demonstrate their viability and biological relevance. Their response to anticancer drug cisplatin was also assessed. In the second step, we integrated the bioprinted tumor model into a microfluidic support for culture under physiological flow. This support was also intended to simulate the drug's vascular transport prior to interaction with the tumor tissue. We then used computational fluid dynamics to design an improved version of the first system. The aim of this improved version was to simultaneously assess multiple drug concentrations. This PhD project demonstrated the ability of 3D bioprinting to create viable and functional ovarian tumor models. It has also brought interesting research prospects with regard to the possibilities of combining 3D bioprinting and microfluidics to improve preclinical modeling of ovarian tumors
Piggott, Luke. "Investigating the therapeutic potential of cellular FLICE-like inhibitory protein and TRAIL in preclinical models of breast cancer." Thesis, Cardiff University, 2012. http://orca.cf.ac.uk/44561/.
Pan, Jie [Verfasser], and Georg [Akademischer Betreuer] Enders. "Molecularly targeted therapy on a new preclinical mouse model for gastric neuroendocrine tumors / Jie Pan. Betreuer: Georg Enders." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2013. http://d-nb.info/1038152062/34.
FROECHLICH, GUENDALINA. "DISSECTING THE STING-DEPENDENT MOLECULAR MECHANISMS IN A PRECLINICAL MODEL OF COMBINED TREATMENT WITH TUMOUR-TARGETED HERPES SIMPLEX VIRUS AND IMMUNE CHECKPOINT BLOCKADE." Doctoral thesis, Università degli Studi di Milano, 2021. http://hdl.handle.net/2434/883382.
Alshammari, Fatemah O. F. O. "An immunohistopathological and functional investigation of β3 integrin antagonism as a therapeutic strategy in cancer : characterisation, development, and utilisation of preclinical cancer models to investigate novel β3 integrin anatgonists." Thesis, University of Bradford, 2013. http://hdl.handle.net/10454/6327.
O'Farrell, Alice C. "Development of in vivo tumour models for non-invasive proof-of-principle investigation of novel therapeutic agents. Engineering and characterisation of bioluminescent cell reporter systems for in vivo analysis of anti-cancer therapy pharmacodynamics." Thesis, University of Bradford, 2011. http://hdl.handle.net/10454/5391.
Dwiri, Fatima azzahra. "Impacts de l'irradiation ciblée sur le tissu cérébral et les déficits cognitifs : études multiparamétriques et longitudinales chez le rat." Electronic Thesis or Diss., Normandie, 2023. http://www.theses.fr/2023NORMC411.
Although radiotherapy, an essential treatment in neuro-oncology, improves the survival of patients, it significantly affects the surrounding healthy brain tissue, leading to cognitive deficits found in 50 to 90% of patients. Technological advancements made in the last decade have allowed the development of new irradiation techniques with promising ballistic properties. However, their potential for preventing cerebral radiotoxicity remains to be demonstrated, relying mainly on preclinical research, for which the use of these radiotherapy techniques is currently fragmented. The objective of this thesis work was to characterize the effects of targeted brain irradiation on tissue integrity and cognitive deficits in healthy adult rats and rats bearing brain tumor. This characterization was done through multiparametric imaging using MRI, various behavioral tests, as well as immunohistological analyses. Furthermore, a longitudinal approach was employed, with the animals being monitored up to 6 months after irradiation. Collectively, our data demonstrate, as expected and in accordance with the literature, that whole-brain irradiation leads to deficits in learning, memory, and emotion processes, both during acute and chronic phases. Similarly, this irradiation paradigm is associated with alterations in brain tissue. However, somewhat surprisingly compared to our initial hypothesis, irradiation of a single hemisphere did not significantly modify the evaluated cognitive performances or compromise tissue integrity. In the brain tumor model, cognitive deficits were observed following whole-brain irradiation, which were also present with hemispheric irradiation but with lesser effects. Unfortunately, due to low sample sizes within the experimental groups, it is difficult to conclude whether the observed radio-induced cognitive deficits are exacerbated in the presence of a tumor
O'Farrell, Alice Claire. "Development of in vivo tumour models for non-invasive proof-of-principle investigation of novel therapeutic agents : engineering and characterisation of bioluminescent cell reporter systems for in vivo analysis of anti-cancer therapy pharmacodynamics." Thesis, University of Bradford, 2011. http://hdl.handle.net/10454/5391.
Pérez, lanzón María. "Modeling Hormone Receptor Positive Breast Cancer in Immunocompetent Mice Blocking tumor-educated MSC paracrine activity halts osteosarcoma progression Organoids for Modeling Genetic Diseases. In: International Review of Cell and Molecular Biology A preclinical mouse model of osteosarcoma to define the extracellular vesicle-mediated communication between tumor and mesenchymal stem cells Failure of immunosurveillance accelerates aging The metabolomic signature of extreme longevity: Naked mole rats versus mice Lurbinectedin synergizes with immune checkpoint blockade to generate anticancer immunity Laminin-binding integrins are essential for the maintenance of functional mammary secretory epithelium in lactation Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer." Thesis, université Paris-Saclay, 2021. http://www.theses.fr/2021UPASL019.
Progress in breast cancer research relies on the availability of suitable cell lines that can be implanted in immunocompetent laboratory mice. The best explored mouse strain, C57Bl/6, is also the only one for which multiple genetic variants are available. Driven by the fact that no hormone receptor-positive C57Bl/6-derived mammary carcinoma cell lines are available, we decided to establish such cell lines. Breast cancers were induced in female C57BL/6 mice using a synthetic progesterone analogue combined with a DNA damaging agent. Cell lines were established from these tumors and selected for dual (estrogen + progesterone) receptor positivity, as well as transplantability into C57BL/6 females. One cell line, which we called MD5,fulfilled these criteria and allowed for the establishment of poorly differentiated, highly proliferative, immune cold tumors. Such tumors reduced their growth (though did not regress) upon treatment with estrogen receptor antagonists, as well as with anthracyline-based chemotherapy. However, the latter effect was not influenced by T cell depletion and MD tumors failed to respond to PD-1 blockade, suggesting that they are immunologically cold. In conclusion, C57BL/6-derived MD5 cells constitute a model of poor prognosis hormone receptor-positive breast cancer
Monteiro, Maria Vinhas. "Development of biomimetic pancreatic cancer 3D in vitro models for preclinical drug screening." Master's thesis, 2020. http://hdl.handle.net/10773/30418.
O adenocarcinoma ductal pancreático (ADP) é uma doença com uma das maiores taxas de mortalidade e com uma incidência crescente a nível mundial. Atualmente, as terapias administradas na clínica para o tratamento do ADP são ainda extremamente ineficazes e de acesso limitado. Perante este cenário torna-se urgente a investigação e validação de novas terapias para o tratamento desta neoplasia. O ADP é um cancro com uma bioarquitetura estratificada única e caracterizado por uma exacerbada reação desmoplásica envolvendo fibroblastos associados ao cancro, células imunes e proteínas da matriz extracelular (MEC), que desempenham um papel significativo na progressão tumoral e na resistência às terapias utilizadas atualmente em contexto clínico. A ausência de modelos de celulares capazes de reproduzir in vitro o microambiente desmoplásico e a histo-morfologia do ADP origina uma baixa correlação entre a performance de novas terapias obtida em ensaios pré-clínicos e aquela observada em ensaios clínicos controlados. Neste sentido, os modelos de tumores tridimensionais (3D) in vitro surgem como uma solução mais adequada para a avaliação pré-clínica quando comparados com as recomendadas culturas celulares bidimensionais 2D. Os modelos 3D representam modelos mais biomiméticos pois permitem recapitular de uma forma mais robusta e realista o microambiente tumoral, contribuindo para a descoberta de novos biomarcadores e para a avaliação pré-clínica de novos fármacos de uma forma mais precisa. Das plataformas 3D in vitro de ADP desenvolvidas atualmente, poucas são as que recapitulam de forma precisa a heterogeneidade celular, a arquitetura tumoral e o estroma fibrótico. Com o objetivo de colmatar estas limitações, a presente dissertação foca na bioengenharia e caracterização de um novo modelo 3D de ADP, consistindo numa co-cultura biomimética de células cancerígenas pancreáticas (PANC-1) e fibroblastos associados ao cancro (FACs). Este modelo 3D demonstrou recapitular os componentes celulares, a sua distribuição espacial e a resistência a terapias farmacológicas de uma forma semelhante à encontrada nos tumores humanos.
Mestrado em Biotecnologia
BAZZICHETTO, CHIARA. "Tumor-stroma interactions influence the response to PI3K targeted agents in preclinical models of colorectal cancer (CRC)." Doctoral thesis, 2019. http://hdl.handle.net/11573/1244565.
Simões, Rui Vasco Portas Ferreira. "Towards molecular imaging of preclinical brain tumor models by MRS : monitoring and analysis of mouse brain glioma MR spectral pattern changes during acute hyperglycemic challenges in vivo." Doctoral thesis, 2010. http://hdl.handle.net/10316/13879.
Hussain, Nosheen, David Connah, Hassan Ugail, Patricia A. Cooper, Robert A. Falconer, Laurence H. Patterson, and Steven D. Shnyder. "The use of thermographic imaging to evaluate therapeutic response in human tumour xenograft models." 2016. http://hdl.handle.net/10454/8781.
Non-invasive methods to monitor tumour growth are an important goal in cancer drug development. Thermographic imaging systems offer potential in this area, since a change in temperature is known to be induced due to changes within the tumour microenvironment. This study demonstrates that this imaging modality can be applied to a broad range of tumour xenografts and also, for the first time, the methodology’s suitability to assess anti-cancer agent efficacy. Mice bearing subcutaneously implanted H460 lung cancer xenografts were treated with a novel vascular disrupting agent, ICT-2552, and the cytotoxin doxorubicin. The effects on tumour temperature were assessed using thermographic imaging over the first 6 hours post-administration and subsequently a further 7 days. For ICT-2552 a significant initial temperature drop was observed, whilst for both agents a significant temperature drop was seen compared to controls over the longer time period. Thus thermographic imaging can detect functional differences (manifesting as temperature reductions) in the tumour response to these anti-cancer agents compared to controls. Importantly, these effects can be detected in the first few hours following treatment and therefore the tumour is observable non-invasively. As discussed, this technique will have considerable 3Rs benefits in terms of reduction and refinement of animal use.
University of Bradford
Tsoi, Mayra. "Anti-VEGFA therapy reduces tumor growth and extends survival in a murine model of ovarian granulosa cell tumor." Thèse, 2012. http://hdl.handle.net/1866/9608.
Ovarian granulosa cell tumors (GCTs) are potentially malignant tumors that have a tendency for late recurrence and cause death in 80% of women with advanced GCT due to recurrent disease. Although GCTs represent 5% of ovarian tumors in women, few studies have evaluated adjuvant treatment protocols for advanced or recurrent disease. Our goal was to determine the potential of targeting the vascular endothelial growth factor A (VEGFA) signaling pathway for the treatment of GCT. We used a genetically engineered mouse model, Ptentm1Hwu/tm1Hwu; Ctnnb1tm1Mmt/+; Amhr2tm3(cre)Bhr/+ (PCA), which imitates the advanced human disease. A monoclonal anti-VEGFA antibody was administered by intra-peritoneal injection once a week beginning at 3 weeks of age. Anti-VEGFA therapy significantly decreased tumor weights by 6 weeks of age (p<0.05) and increased survival in treated animals in comparison to controls. Significant decreases in tumor cell proliferation (p<0.05) and microvessel density (p<0.01), but no significant difference in apoptosis was found in PCA tumors. p44/p42 MAPK, a VEGFA receptor 2 (VEGFR2) signaling effector associated with cell proliferation, was significantly less activated in anti-VEGFA-treated tumors (p<0.05). In contrast, AKT activation, a VEGFR2 signaling effector associated with cell survival was similar among all groups. These results suggest that anti-VEGFA therapy effectively reduces cell proliferation and microvessel density in PCA mice by inhibition of the VEGFR2-MAPK pathway, resulting in inhibition of GCT growth. We conclude that anti-VEGFA therapy merits further investigation in the form of controlled randomized trials for the treatment of human GCT.
Belardinilli, Tamascia. "Innovative 3D model for the establishment of primary paediatric brain tumour cultures: new platform for the preclinical study of immunotherapeutic approaches." Doctoral thesis, 2020. http://hdl.handle.net/11573/1349215.