Dissertations / Theses on the topic 'Cancer – Recherche – Thérapeutique'
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Gilabert, Marine. "Recherche de biomarqueurs pronostiques et prédictifs de la réponse thérapeutique des tumeurs pancréatiques : "le projet pacaomics"." Thesis, Aix-Marseille, 2014. http://www.theses.fr/2014AIXM5012/document.
Full textWe developed an efficient strategy in which PDAC samples from 17 consecutive patients were collected by Endoscopic Ultrasound-Guided Fine-Needle Aspiration (EUS-FNA) or surgery and preserved, by an original approach, as breathing tumors by xenografting and as a primary culture of epithelial cells. Transcriptomic analysis was performed from breathing tumors by an Affymetrix approach. We observed a significant heterogeneity in the RNA expression profile of tumors. However, the bioinformatic analysis of this data was able to discriminate between patients with long- and short-term survival corresponding to patients carrying poorly-differentiated PDAC tumors respectively. We identified 942 genes with statically different expression. Among these genes, 439 were under-expressed and 505 genes over-expressed (fold change ≥2) in short survivors. Primary culture of cells allowed us to analyze their relative sensitivity to anticancer drugs in vitro by a "Chemogram", by similarity with the antibiogram for microorganisms, establishing an individual profile of drug sensitivity. As expected, the response was patient-dependent. Interestingly, we also found that the transcriptome analysis predict the sensitivity of cells to the five anticancer drugs the most frequently used to treating patients with PDAC. In conclusion, using this approach, we found that the transcriptomic analysis could predict the sensitivity to anticancer drugs and the clinical outcome of patients with PDAC
Joly, Baptiste. "Optimisation de la résolution temporelle en tomographie par émission de positons dédiée au contrôle de dose en hadronthérapie." Clermont-Ferrand 2, 2010. http://www.theses.fr/2010CLF22018.
Full textGenevois, Anne-Laure. "Implication du récepteur à dépendance TRKC et de son ligand NT-3 en cancérogénèse : de la recherche fondamentale à la thérapeutique." Phd thesis, Université Claude Bernard - Lyon I, 2013. http://tel.archives-ouvertes.fr/tel-01067136.
Full textCorbel, Caroline. "Recherche de nouveaux agents anticancéreux agissant par inhibition d'interaction protéine/protéine : caractérisation de leurs effets cellulaire." Rennes 1, 2011. http://www.theses.fr/2011REN1S024.
Full textMisregulations of CDK5/p25 are implicated in neuronal diseases, as well as in the migration and the metastatic potential of cancer cells. Inhibitors of the CDK5/p25 complex, acting mainly via the ATP pocket of the kinase, have been described. However, this class of inhibitors is subjected to a selectivity problem because a lot of cellular proteins need ATP. We used the BRET (Bioluminescence Resonance Energy Transfer) method to discover new inhibitors of CDK5/p25 interaction. The originality of the assay developed lies in the cellular system used: the yeast Saccharomyces cerevisiae. Following the validation of the method developed, 5571 compounds have been screened. Three molecules were characterized and two of them were mainly studied, notably to understand their mode of inhibition, different from the ATP mimetic compounds
Jourdier, Hélène. "Recherche d'un effet centre et d'un effet temps dans la prise en charge des patients traites pour un cancer colorectal métastatique non resecable." Versailles-St Quentin en Yvelines, 2010. http://www.theses.fr/2010VERS001G.
Full textOBJECTIVES : In patients treated for colorectal cancer, in first metastatic line treatment, 1/ to bring to light an institutional impact in overcome, and 2/ to compare four plans of administration of oxaliplatine associated with 5 fluoro-uracile (FOLFOX). METHODS : Retrospective analysis of data from 1042 patients included in three prospective randomized, phase II-III trials. RESULTS : 1/ 23%-improvement in global survival was observed in both centers having included most patients compared with the other centers (24,5 months versus 19,9 months ; HR=1,31 [1,12-1,53], p=0,0006). It was not observed any difference in first line treatment efficiency ; on the other hand, rates of surgery, of R0-surgery and of reintroduction of oxaliplatine are statistically higher in these two centers than in the other centers. 2/ There was no differences of efficiency of the various plans of FOLFOX but a trend to better survival for the patients treated by FOLFOX 7m in first metastatic line of chemotherapy. CONCLUSION : Center experience, in terms of volume, impacts positive global survival in metastatic colorectal cancers, probably because of better multidisciplinary management. Because of a better tolerobility, the modification of the administration of FOLFOX could have an impact on global survival
Bouchikhi, Fadoua. "Synthèse de composés hétérocycliques aromatiques azotés, inhibiteurs potentiels de kinases." Phd thesis, Université Blaise Pascal - Clermont-Ferrand II, 2008. http://tel.archives-ouvertes.fr/tel-00731331.
Full textDerbez, Benjamin. "Entre cobaye et partenaires : l’expérience des patients dans l’économie morale de la recherche clinique en cancérologie." Paris, EHESS, 2014. http://www.theses.fr/2014EHES0097.
Full textBased on an ethnographic field work and a socio-historical investigation, this thesis challenge both the image of the "guinea pig" and that of "partner", frequently associated with patients who participate in clinical trials in oncology. Indeed, field data collected between 2008 and 2010 in clinical research services in medical oncology, indicate that, beyond the traditionnal issue of informed consent, patient participation in research relies on the production and the negociated circulation of moral feelings (hope / trust) and specific practices of care, in patients-investigators interactions, which constitute what might be called a "moral economy" of clinical research in oncology. Setting this local moral economy in the overall structure of power relations (economic, political, social) that characterizes the clinical cancer research at national and international level, by the mean of socio-historical research allows us, however, to also understand how the process of ethical normalization of the experimental activity observed in the field is based on a set of governmental techniques - on the professionals side - and subjectification - on the patients side. Centered on the contextualized analysis of daily practices of the actors and their experience, this thesis is thus a critical contribution to ethical reflection on human experimentation
Zaayter, Liliyana. "Recherche d'inhibiteurs d'UHRF1 : effets sur les aspects épigénétiques dans les cellules cancéreuses." Thesis, Strasbourg, 2018. http://www.theses.fr/2018STRAJ017.
Full textAbnormal DNA methylation is one of the major hallmarks of cancer. The dynamic and reversible nature of this epigenetic modification has made it a potential target for cancer treatment. UHRF1, a pivotal DNA methylation maintenance protein, is also strongly involved in tumorogenesis. It isoverexpressed in a wide array of cancers and leads to silencing of TSGs and tumor growth. In this context, the aim of the thesis is to develop potential UHRF1 inhibitors that may be clinically effective for anti-cancer therapy. To reach this objective, a diverse approach was adopted including virtual screening, biophysical and biological techniques that helped to characterize the inhibitory activity of active molecules and understand their mechanism of action. The tests revealed one positive compound from the anthraquinone family that inhibited UHRF1 by binding to its SRA domain and impairing its interaction with DNMT1, the enzyme responsible for DNA methylation maintenance. This compound showed an anti-proliferative activity in various cancer cells
Poiraudeau, Loïc. "Identification de nouvelles cibles thérapeutiques dans le cancer neuroendocrine de la prostate." Electronic Thesis or Diss., université Paris-Saclay, 2023. http://www.theses.fr/2023UPASL143.
Full textProstate cancer is the most common cancer in men and the second leading cause of cancer death in men in industrialized countries. The systemic treatment of these cancers is androgen deprivation therapy (ADT), which can be achieved through surgical or pharmacological castration. Metastatic castration-resistant prostate cancer (mCRPC) is treated with androgen receptor inhibitors (ARi). However, approximately one-third of patients are not responsive to these drugs and the others, who are initially responsive, unfortunately develop secondary resistance, which is acquired within approximately 1-2 years. The mechanisms that explain primary and secondary resistance are not well understood. Neuroendocrine differentiation (NE) of mCRPC is one of these mechanisms. In fact, between 15 and 20% of resistant tumors evolve into neuroendocrine prostate cancer (NEPC). The prognosis of these patients is very poor because the precise molecular mechanisms involved in neuroendocrine differentiation are not clearly elucidated and there is no therapeutic solution adapted to these tumors.The objective of this thesis was to study neuroendocrine differentiation in order to identify new therapeutic targets. We relied on the MATCH-R study, which aimed to study the mechanisms of resistance to targeted therapies (enzalutamide, abiraterone). Patient biopsies were characterized using high-throughput sequencing and immunohistochemistry methods. As part of this study, the laboratory also developed and characterized preclinical patient-derived xenograft (PDX) models. We show from WES and RNAseq performed on patient biopsies that neuroendocrine differentiation is likely the result of transcriptomic and epigenetic alterations. Moreover, our PDXs retain the genetic, molecular, and pharmacological characteristics of their original biopsies. RNAseq analysis identified a membrane protein, which is specifically expressed by NEPC. The expression of this protein is correlated with the expression of NE markers such as synaptophysin (SYP) and chromogranin A (CHGA), as well as a worse diagnosis. Treatment of our NEPC PDXs with a single intravenous injection of an antibody-drug conjugate targeting this protein, resulted in a significant decrease in tumor volume in the treated group compared to the untreated group. Finally, we identified an orphan nuclear receptor, NR0B2 that is overexpressed in NEPC and could be involved in resistance to ARi. NEPC are aggressive tumors with few therapeutic options. These tumors result from transcriptomic alterations and require the development of relevant models that recapitulate the complexity of the disease to identify potential targets for new targeted therapies. ADCs are promising therapies, especially in NEPC, and have shown anti-tumor efficacy in preclinical evaluation
Puyo, Stéphane. "Recherche d’alternatives thérapeutiques aux taxanes dans les cancers de la prostate de hauts grades : identification d’une signature prédictive de la réponse à l’oxaliplatine." Thesis, Bordeaux 2, 2011. http://www.theses.fr/2011BOR21842/document.
Full textProstate cancers are classified in two categories. High grade cancers are distinguished from low grade cancers by their higher agressivity and worse prognostic. When they become refractory to hormone therapy, high grade cancers are treated with a taxane-based chemotherapy. However, response rates remain low. Therefore, there is a real need for the discovery of new therapeutic alternatives which are specific for this type of tumors. For that purpose, our work aimed at proposing such an alternative with a strategy that took into account the high grade genetic background. We exploited a signature of 86 genes for which expression level could distinguish between low grade and high grade tumours. With an original in silico approach, we searched the NCI databases and identified 382 correlations between 50 genes and the sensitivity to 139 antiproliferative agents. Among these, a signature of 9 genes was able to specifically predict cell response to oxaliplatin. This signature was validated at the functional level in two prostate cancer cell lines, DU145 and LNCaP. We have thus provided the proof-of-concept that our approach allows the identification of new drugs that can be used alternatively to taxanes in order to specifically treat high grade prostate cancers. This strategy also allows the identification of new markers (genes) regulating the sensitivity to various drugs. Our results demonstrate for example the implication of SHMT genes, which are involved in the regulation of the one-carbon metabolism, in the specific sensitivity to oxaliplatin, by a mechanism which involves, at least in part, the deregulation of the global level of DNA methylation
Tourbez, Arthur. "Développement et caractérisation d'organoïdes de tumeurs cérébrales pédiatriques utilisés en recherche fondamentale et translationnelle." Electronic Thesis or Diss., Lyon 1, 2023. https://n2t.net/ark:/47881/m6416x50.
Full textPediatric high-grade gliomas (pHGG) and posterior fossa type A ependymomas (EPN-PFA) remain one of the biggest challenges in pediatric oncology. They exhibit vast inter- and intra-tumoral heterogeneity, complicating the development of effective therapeutic strategies. Then to improve their clinical outcome, we absolutely need pre-clinical models that recapitulate key features of their corresponding parental tumors. During my PhD, I developed an optimized protocol for the establishment and biobanking of pHGG organoids (pHGG_O) and EPN-PFA organoids (EPN-PFA_O). These models can be grown long-term and comprehensive histological and molecular analyses showed that they recapitulate inter- and intra-tumoral heterogeneity of their parental tumor even after several passages and cryopreservation as 3D cultures. I further showed that they can be employed to test responses to standard of care therapy as well as new therapeutic options, including drugs from clinical trials as they accurately capture the clinical phenotypes of their respective parental tumors. Moreover, these models led to the identification of the DRD2 inhibitor ONC201 as an unexpected potential therapeutic agent for H3K27M non-altered pediatric brain tumors and helped identify combination strategies to increase the therapeutic response to ONC201. Thus, those models are positioned to support powerful and innovative preclinical studies, particularly those related to personalized assessments of treatment response profiles and identification of novel efficient drug combinations
Pierson, Jean-Thomas. "Synthèses et études biologiques de nouveaux agents antimitotiques de type néoflavonoïde." Aix-Marseille 1, 2008. http://www.theses.fr/2008AIX11096.
Full textThe synthesis of neoflavonoid compounds is reported through a suzuki coupling method with good yields and excellent purity to consider a biological activity study. A screening of a large number of such compounds, structural analogs of combretastatin, displayed two major compounds with a potent cytotoxicity and anti-tubulin activity. They give important informations about the structural requirements in order to create new molecules with anti- carcinomic activity, binding at the colchicin site of the tubulin dimer. Those analogs were also tested for their anti-parasitic activity over Plasmodium falciparum, with acceptable dose- response level, and over Leishmania donovani. Although no mecanism of action could be pinpointed, an immunomodulation activity, were noticed, which is some known characteristic of the coumarin family
La, Rochère Philippe de. "La souris humanisée : modèle d'étude de l'immunothérapie anti-cancer A comprehensive analysis of humanized mouse models for the study of cancer immunotherapies Inhibition of PI3K increases immune infiltrate in muscle invasive bladder cancer." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCB068.
Full textImmunotherapy is revolutionizing cancer treatment by shifting the treatment strategy from targeting the tumor to targeting the immune system. The blockade of immune checkpoints with anti-CTLA-4, anti-PD1 and anti-PD-L1 antibodies shows impressive clinical results. However, the response rate remains low. It is therefore essential to better understand the mechanisms of action of these therapies, to identify biomarkers of response and toxicity, and to evaluate therapeutic combinations. Such mechanistic and preclinical studies require the optimization of adapted murine models. For these purposes, my PhD work has focused on the development of humanized mouse models, in which immunodeficient mice are grafted with human tumor (cell lines or patient derived xenografts) and immune cells to study different immunotherapy approaches. In humanized mouse models, the human immune cell compartment can be reconstituted from either hematopoietic stem cells (HSC) from umbilical cord blood or with mononuclear cells from human blood (PBMC). We have observed that the injection of HSCs generates several subpopulations of immune cells (myeloid cells, T and B lymphocytes, NK cells), detectable from 4 weeks; while the injection of PBMCs mainly generates T lymphocytes, detectable from 1 week. In the latter model, lymphocyte reconstitution is associated with an anti-tumor effect, but is also accompanied by the development of graft-versus-host disease. Both models have advantages and disadvantages for the evaluation of cancer immunotherapies, which are discussed in my thesis. Using these models, we evaluated the therapeutic effect of a clinically used anti-PD1 antibody on tumor cell lines or on patient derived xenografts of different types of tumors. We observed a heterogeneity in the response to treatment, reflecting the clinical observation of responder and non-responder patients. Finally, in order to evaluate the interest of humanized mice for the study of therapeutic combinations, we tested an anti-PD1 therapy associated with a targeted therapy in bladder cancer. Our results, identifying the strengths and limitations of humanized mice, demonstrate the relevance of these new models for the evaluation of immuno-oncology therapies and open perspectives in the study of therapeutic combinations
Segaoula, Zacharie. "Pertinence et validations préclinique et clinique du modèle spontané canin de mélanome dans le développement thérapeutique en oncologie." Thesis, Lille 2, 2017. http://www.theses.fr/2017LIL2S004/document.
Full textPharmaceutical development is a long and fastidious process. In fact, each drug candidate has to meet with a certain safety criteria list, pharmacokinetic and pharmacodynamics profiles need to be determined prior to first use in humans and market approval.For years, the pharmaceutical industry has been suffering from a lack of innovative molecules and thus despite the efforts and cost increases in R&D programs. And most novel drug candidates entering clinical trials fail to reach approval, largely because preclinical models used in development do not provide adequate information about their efficacy or toxicity. That’s why; more predictive models of efficiency in oncology, shaping more precisely the human pathology are needed.The study of novel drug candidates in dogs with naturally occurring tumors allows drug assessment in neoplasms sharing many fundamental features with its human counterparts, and thus provides an opportunity to answer questions guiding the cancer drug development path in ways not possible in more conventional models. Moreover, the strong homologies in clinical presentation, morphology, and overall biology between dogs and their human counterparts make companion animals a good model to investigate tumor process from ætiology to tailored treatments.The aim of this project was to validate the canine spontaneous tumor model, by combining preclinical and clinical approaches, in the comprehension of the underlying mechanisms of cancer from carcinogenesis to drug resistance and tumor dormancy and also the discovery of new tools essential for the prediction, diagnosis clinical follow-up and treatment.Metastatic melanoma is one of the most aggressive forms of cutaneous tumors in humans. It constitutes 4 to 11% of skin malignancies and only 2% of the cancers of the epidermis. These highly immunogenic tumors hold a severe prognosis when metastasized and contribute to an immune anti-tumor reaction which could potentially lead to immune escape and resistance to most standard treatment protocols. And even if the 5-year survival has been improved to 50 – 80% over the past decades, its incidence is still in the rise with 7000 cases and 75% related deaths reported every year in France.In dogs, melanomas are one of the most frequently diagnosed malignancies of the oral cavity. These cancers account for 7% of all malignant tumors in dogs and 160000 reported every year worldwide. It also constitutes one of the most aggressive metastasizing tumors with a median post-surgery survival rate of 173 days.We developed and characterized immunucytochemically, pharmacologically and genomically two canine melanoma cell lines from naturally occurring dog tumors with distinct clinical profiles. A list of genetic alterations of these two profiles has also been established and is in accordance with the published literature, presenting same features as human tumors. And because tumor heterogeneity is responsible of resistance to treatment and relapse, we isolated and investigated cancer stem cell populations in our cell line models in order to identify the linked biomarkers which may constitute future potential targets for the expansion of the oncological therapeutic panel.In conclusion, due to its intact immune system, tumor niche and also because it shares the same environment as we do, the canine patient represent a promising opportunity in the advancement of cancer research, the acceleration of translation process and the setting up of more effective and less toxic molecules with dual benefits for the human and veterinary medicine toward better patient care
Beck, Guillaume. "Recherche de nouveaux agents thérapeutiques dans le traitement des lymphomes à cellules B." Thesis, La Réunion, 2020. http://www.theses.fr/2020LARE0002.
Full textB cell lymphoma is a type of cancer that develops in the lymphatic system. Studies by Meadows et al have indicated that PI3Kδ may be a therapeutic target in this cancer. The aim of this study is to identify inhibitors of the ATP binding site of the protein kinase PI3Kδ. A virtual screening of 350 compounds targeting the PI3Kδ protein was carried out. The prior validation of a scoring protocol was carried out beforehand on our protein of interest PI3Kδ. This protocol contains different selection steps based on calculated affinities and known experimental affinities, such as a docking step, a complex relaxation step and a reevaluation of ligand affinities for the target protein. For the secondary scoring step, we tested different calculation methods: empirical (X-Score, ID-Score, Cyscore) and knowledged-based (IT-Score) functions as well as quantum chemistry calculation methods (FMO in GAMESS, PM6-D3H4X in MOPAC, and DFT-D in Terachem). We first applied this protocol to the MBL molecule. This chalconoid-like molecule appears to have an affinity for the PI3Kδ protein. The application of this protocol on the virtual chemistry library allowed us to obtain predictions of ligands with a high affinity for PI3Kδ. From these screening results, we will be able to send our results to the MEDCHEM team at Grenoble Alpes University, for experimental validation
Giraud, Sandrine. "Régulation de l'activité transcriptionnelle du facteur STAT3 : l'exemple du gène p21waf1." Angers, 2004. http://www.theses.fr/2004ANGE0015.
Full textSignal transducer and activator of STAT3 are activated in response to various cytokine. Following tyrosine phosphorylation, STAT3 proteins dimerize and translocate to the nucleus and activate specific target gene. In the present study, we have identified new cofactors of STAT3. SRC-1 interacts with STAT3 ant enhances transcriptional activation by STAT3 through its CBP interacting domain. As a next step, we have shown that BRG1, the ATPase subunit of the Swi/Snf chromatin-remodelling complexe interacts with STAT3 and is recruited to p21waf1 proximal promoter. BRG1 recruitment is associated with H3 acetylation and followed by increased accessibility of p21waf1 proximal promoter. Finally, STAT3 recruits cdk9 kinase to phosphorylate the C-terminal domain of RNA polymerase at serine 2. The elongating form of the polymerase then promotes the elongation phase of transcription. Therefore, STAT3 regulate transcription at different levels: initiation, chromatine remodelling and elongation
Folco-Lognos, Béatrice. "Rôle des pairs dans les trajectoires individuelles d’appropriation psychologique de la maladie : illustration dans le cancer du sein." Thesis, Montpellier 3, 2021. http://www.theses.fr/2021MON30002.
Full textStudy1: Exploratory study of the lived experience of expert patients belonging to an association Objective: Collect and analyze verbatims to allow the emergence of categories in order to understand the work of the disease through interactions with peers Me Objective: Collect and analyze verbatim to allow the emergence of categories Method: Qualitative analysis pragmatic semio Study 2 : Non-Pharmacological Interventions in Patients with Breast Cancer: An Exploratory Study of Social Network Forums Data. Running title: Non-Pharmacological Interventions in Patient with Breast Cancer Abstract: Background: Patients and healthcare professionals are becoming increasingly interested in non-pharmacological interventions (NPI), which can also be called complementary and alternative medicine (CAM). In just a few years, this supportive care has gone from solutions aimed at improving the quality of life to solutions intended to reduce symptoms, supplement oncological treatments and prevent recurrences. Social networks are a major vector for disseminating these practices that are not always disclosed to doctors by patients. An exploration of the content of exchanges on social networks by patients suffering from breast cancer can help to better identify the extent and diversity of these practices. Objective: This study explores the interest of breast cancer patients in NPI-CAM from posts published in health forums and French-language [social media] groups. Methods: The retrospective study is based on a French database of 2 forums and 4 Facebook groups between June 3, 2006 and November 17, 2015
Dieli, Anna Maria. "La hiérarchie des individus biologiques : problèmes ontologiques et épistémologiques." Thesis, Paris 1, 2018. http://www.theses.fr/2018PA01H203/document.
Full textOne of the main problems related to the definition of individuality in biology is how to account for the hierarchical structure of nature, which has been prominently emphasized in evolutionary theory (Dobzhansky 1937; Eldredge 1985; Mayr 1963; Liebermann, Vrba 1995). Nowadays, works in several areas validate a hierarchical approach to the study of biological individuality: the debate on the units of selection, for example, springs from the idea that hierarchy is the product of evolution by natural selection. Moreover, studies on major evolutionary transitions inquiry why selection at lower levels does not disrupt integration at higher levels (Maynard Smith, Szathmary 1995). Finally, the hierarchy theory (Gould, Vrba 1986) proposes a new formulation of the Darwinian theory, ln order to overcome reductionism. Moreover, nowadays cancer, thanks to its analysis from a multi-level perspective, is increasingly considered as a pathology linked to the tissue organization more then to the cell regulation (Sonnenschein, Soto 1999). ln effect, cancer was originally considered to be a deregulation of the normal growing program of the cell. Exploring the notion of hierarchy and levels of individuals in biology has epistemological and ontological consequences. First of all, from an epistemological point of view we have to understand whether complexity is the necessary outcome of natural selection. Another problem is to understand why selection at lower levels does not disrupt integration at higher levels (Maynard Smith, Szathmary 1995, Calcott Sterelny 2011 ). A paradigmatic case in which integration between lower and higher levels is lost is cancer, in which selection acting on cells destroys tissue and organism organisation (Nowell 1976, Okasha 2006). This pathological case seems to show that biological individuals have a hierarchical organization ln which the identity of parts depends both on their interactions and on higher-level effects. Therefore, relations among levels are crucial: we need a relational ontology of levers· (Bertolaso 2013, 2016), which will allow understanding how each level ls the result of relations among underlying parts. Then, from an ontological point of view, the problem we face today in defining the most fundamental level in biological hierarchy is the same of the old metaphysical problem of defining parts and wholes. This is an ontological concern: asking what makes of an aggregate a real individual The aim of this dissertation ls to show that a definition of individual as functional unit gives reason of the hierarchical organization of living beings: it allows a contextual analysis of the individual (Goodnight). Through such a definition, we can overcome reductionism without supporting a naif pluralism
Calatayud, Anna-Line. "Développement et caractérisation de modèles précliniques de carcinomes hépatocellulaires pour l'évaluation de la réponse thérapeutique et l'étude des mécanismes de l'hépatocarcinogenèse." Thesis, Université de Paris (2019-....), 2020. https://theses.md.univ-paris-diderot.fr/CALATAYUD_Anna_Line_va2.pdf.
Full textHepatocellular carcinoma (HCC) is a very aggressive malignancy, which is resistant to current therapeutic options for advanced stages. In addition, most of recent phase 2 or 3 clinical trials failed due to the development of multiple resistance mechanisms. In this context, preclinical models are very useful to understand the molecular biology of HCC and looking for new therapeutic targets or specific biomarkers of treatment response. Thus, in this work, the study of HCC cell lines that represent a subgroup of aggressive tumors but recapitulate the molecular diversity of HCC enabled us to show associations between specific molecular contexts and response to treatments allowing to establish several new therapeutic hypotheses. Thanks to these cell lines we also understand that the overexpression of MET as a criterion for inclusion of patients in tivantinib clinical trials explained its failures and to propose the expression of Ki67 as a better biomarker predictive of its antitumor efficacy. Finally, by studying murine models of oncogenic cooperation, we highlighted for the first time the tumor suppressor role of RSK2 in hepatic carcinogenesis, in cooperation with the inactivation of AXIN1 or the activation of the Wnt/β-catenin pathway. Overall, this study shows that preclinical models are extremely informative, despite their various limitations, they allow to bring new therapeutic hypotheses. In particular we demonstrated the crucial role of the RAS-MAPK pathway activation in HCC development reinforcing the interest of the use of MEK1/2 inhibitors in future clinical trials in candidate subgroups
Hajmirza, Azadeh. "H3K9 trimethylation controls oncogenic signaling and the malignant state in mantle cell lymphoma." Thesis, Université Grenoble Alpes (ComUE), 2017. http://www.theses.fr/2017GREAV084.
Full textMantle cell lymphoma (MCL) is an aggressive lymphoid cancer characterised by iterative clinical relapses and short survival. MCL displays complex genetics and hallmarks of misregulated expression of lineage specific genes. We have hypothesized that the latter might result from corruption of H3 lysine 9 trimethylation signaling. By screening for H3K9me3 levels across a cohort of 120 MCL cases, we found global reductions in H3K9me3 in 1/3 of cases. H3K9me3 depletion was linked to underexpression / attenuated activity of SUV39H1 and SETDB1 histone methylases, respectively, and to differential expression of key cancer signatures relating to embryonic/hematopoietic stem cell function, B cell differentiation, and DNA damage response. Targeted deep sequencing did not reveal association to mutations in known epigenetic modifiers, indicating a new, previously-unsuspected role for H3K9me3 in MCL pathogenesis. In keeping with this, knockdown of SUV39H1 increased tumour growth in MCL xenografts while SETDB1 depletion induced G1/S arrest coincident to reprogramming to a pre-B cell phenotype. Taken together this identifies convergence of H3K9me3 signaling pathways to essential targets for MCL disease pathogenesis. These are currently under investigation by H3K9me3 ChIP-seq. Survival analyses in the setting of a prospective clinical trial will establish the prognostic impact of H3K9me3 in MCL
Motuhi, Sofia-Elena. "Valorisation de substances naturelles marines de Nouvelle-Calédonie d'intérêt en traitement anticancéreux." Thesis, Rennes 1, 2016. http://www.theses.fr/2016REN1B050.
Full textMarine zones associated with coral reef systems of the New Caledonia archipelago have been investigated for almost forty years with respect to their plant and invertebrate biodiversity and chemodiversity. In particular, thanks to their unique subtropical position close to tectonically active zones and to the Australian subcontinent, the complex reef systems of New Caledonia’s lagoons are home to a highly diverse marine fauna that is relatively protected from climatic disturbances. This is reflected by the score of novel bioactive molecules that have been discovered and characterized, several of which have been actively investigated for their antineoplastic and antitumoral potential activities. We paid particular attention to macroalgal species that induce programmed cell death, as an approach to detecting original anticancer bioactivities. Seven species of red (Rhodophyceae) and brown (Phaeophyceae) macroalgae collected in the South lagoon of New Caledonia (decree N°197-2016/ARR/DENV) have demonstrated interesting in vitro anticancer activity. In particular, one red macroalgal species led to the characterization of two bioactive natural products, the structure of one of which has not been described to date. Biological tests have shown that these two compounds could be promising candidates as antimitotic kinase inhibitors agents for the development of targeted anticancer chemotherapies. Interesting biological activities have also been revealed from several molecular isolates from two species of brown macroalgae, showing high selectivity towards non-cancerous cells. In the continuing investigations of the therapeutic potential of natural products isolated from New Caledonian marine organisms, this doctoral thesis has highlighted the therapeutic potential of several species of Rhodophyceae and Phaeophyceae which has hitherto been largely unexplored
Ambrosetti, Damien. "Carcinomes rénaux : caractérisation moléculaire et des voies métaboliques dépendant des mécanismes hypoxiques." Electronic Thesis or Diss., Nice, 2015. http://theses.unice.fr/2015NICE4143.
Full textRenal carcinomas (RCC) are divided into several subtypes, defined by histological, genetic and phenotypic criteria. The differential diagnosis of these tumors is important with prognostic and therapeutic implications. Genetics and diagnosis: We studied the clinical, histological, immunohistochemical and genetic of papillary RCC (PRCC) type 1 and 2 cohort. An extensive genomic characterization completed by NGS has allowed us to classify type 2 PRCC in several groups of variable clinical evolution. Our results provide new information on the pathogenesis of PRCC that provide perspectives for personalized treatment. Metabolism, tumor grade and phenotype: In a series of clear cell RCC (ccRCC), we analyzed the characteristics of these tumors and the expression of proteins involved in the metabolism and isoforms of HIF. This study allowed us to demonstrate quantitative correlation between the expression of MCT1, GLUT1 and CA XII and Fuhrman grade, and qualitatively peripheral HIF2alpha localization and co-localization of proteins HIF2alpha and HAF. Theranostic strategies: In order to define the most appropriate treatment for patients with RCC, we made a parallel between sensitivity to targeted therapies of patients (in vivo), and cells derived from the original tumor (in vitro). We have demonstrated that the response in patients and in cells and was similar, thus in vitro assays are a way to define personalized treatment for ccRCC
Batisse, Lignier Marie. "Progression tumorale dans un modèle murin de carcinogénèse surrénalienne ciblée induite par antigène T de SV 40 : Recherche de cibles thérapeutiques pour le corticosurrénalome." Thesis, Clermont-Ferrand 1, 2016. http://www.theses.fr/2016CLF1MM07.
Full textAdrenocortical carcinoma (ACC) is a rare aggressive malignant tumor of adrenal cortex. 30% of patients have metastatic disease at diagnosis and the 5 year-survival rate is obtained inonly 20%. Unfortunately, the mechanisms of tumorigenesis are not well identified. Understanding these mechanisms could offer perspectives for new targeted therapies improving the survival in these patients. P53 inactivation in the adrenal cortex seems a good target to study its role in the tumorigenesis. Large T antigen of SV40 virus is an oncogene that fixes and inhibits P53 and RB. Our laboratory has mouse models expressing this antigen (AdTAg mouse model) in the adrenal cortex and developping progressive adrenal tumors. The initial objective was to characterize the ontogeny of these tumors, studying their molecular characteristics, especially β-catenin and IGF2/mTOR signaling, during the malignant progression. AdTAg mouse models develop adrenocortical tumors with characteristics that are identical to human ACC. They present pulmonary and liver metastases that lead to increased mortality rate from 22 weeks old. These tumors lead to hypercorticism that suggest their steroidogenic differentiation. Weiss score analyses indifferent ages show that these tumors progress from benign to malignant ones, associated with a precocious activation of mTOR pathway and tardive activation of Wnt/β-catenin pathway. These pathways are thus interesting therapeutic targets. The second part of this thesis was concentrated on the anti-cancer treatment trials. Rapamycin, an mTOR inhibitor inhibits cell proliferation and increases cell apoptosis in these tumors. After 3 months of treatment, the tumor burden was significantly reduced and corticosterone levels were normalized. We have also evaluated effects of Wnt/ β-catenininhibitors, Quercetin and PRI-742, in our mouse models. Quercetin inhibits tumor proliferation and progression and it extends the survival rate of AdTAg mice. Surprisingly, this effect was independent of Wnt/β-catenin activity and the molecular mechanisms remain to be elucidated. Inversely, PRI-724 seems to be a specific inhibitor of this pathway, blocking the interaction between CBP and β-catenin. A treatment of 2 months reduced significantly the tumor volume in AdTAg mice. This effect was through the inhibition of CBP and β-catenininteraction and signaling. These results encourage using the inhibitors of mTOR and Wnt/β-catenin pathway offering promising targets to improve the survival in patients with ACC
Thieury, Charlotte. "Recherche de composés cytotoxiques dans la biodiversité végétale de la Nouvelle-Calédonie." Thesis, Nouvelle Calédonie, 2016. http://www.theses.fr/2016NCAL0007.
Full textAs old as human consciousness, correspondence between plants and their healing properties is known. An analysis of our pharmacopoeia shows that even now humans seek these drugs in nature. This study on anticancer drugs has focused on valuing nature as a source of new substances named "leads", bioactive compounds that are at the base of drug development.The first part of this study focused on the pharmacomodulation of a natural anticancer molecule from a locally-known plant. 23 flavokawain derivatives (FKD) were synthesized to improve the understanding of the structural requirements necessary for optimal selectivity and cytotoxicity via an SAR study. Six molecules have shown significant improvements in terms of activity and selectivity. The study of their mechanisms of action revealed that FKD induced a variable cell cycle arrest depending on the p53 status of cancer cell lines as well as apoptosis. The action delays of FKD depended of Akt/mTor status of cancer cell lines. The second part of this study focused on the phytochemical exploration of new caledonian endemic plants to discover new sources of cytotoxic molecules. The ccreening of cytotoxic activities helped to highlight interesting activities in Diospyros olen, Meiogyne baillonii and several species of Soulamea. A phytochemistry work led to the isolation of many molecules including three news: sapranthine H and macrocarpasines A and B. Aristolactame BII and elliptinone exhibited strong cytotoxic activity. Aristolactame BII led to a cell cycle arrest depending on the p53 status of cancer cell lines.This valuation work is essential in an objective of protecting an endangered biodiversity like it’s the case in New Caledonia to allow the establishment of backup programs
Petrazzuolo, Adriana. "Pharmacological Inhibitors of Anaplastic Lymphoma Kinase (ALK) Induce Immunogenic Cell Death Through On-Target Effects." Thesis, université Paris-Saclay, 2021. http://www.theses.fr/2021UPASL018.
Full textGenetic aberrations hitting oncogenes or oncosuppressors drive tumor transformation and proliferation and yet contribute to hide tumor cells from immune recognition and elimination. For instance, oncogene abnormal activation guides immune escape recruiting immunosuppressive macrophages or myeloid-derived suppressor cells or hiding tumor cells from recognition by T lymphocytes (downregulating class I major histocompatibility complex). Accordingly, targeting oncogenic pathways contribute to harness the immune system against tumor cells reverting these immunosuppressive mechanisms. Over the past decades, many researches demonstrated that several anticancer chemotherapeutics, commonly used in clinic, do not only kill neoplastic cells but rather succeed in inducing potent and clinically relevant antitumor immune responses. Often, such effects are obtained through the induction of immunogenic cell death (ICD), a cell death modality characterized by a series of distinctive changes that increase the immunogenicity of dying cells: (i) exposure of calreticulin on the cell surface, (ii) release of ATP and (iii) high mobility group box 1, as well as a (iv) Type-I interferon response. This project examined the possibility that inhibition of an oncogenic kinase, anaplastic lymphoma kinase (ALK), might promote the immune-mediated elimination of cancer cells, triggering ICD. We used anaplastic large cell lymphoma (ALCL) as model, where ALK is expressed and activated following a translocation between chromosomes 2 and 5.We demonstrated that two different ALK pharmacological inhibitors, crizotinib and ceritinib, elicited ICD markers in vitro. The immunogenic phenotype of crizotinib- and ceritinib-induced cell death relied strictly on ALK inhibition. Multiple lines of evidences pointed into this direction: (i) crizotinib and ceritinib induced ICD hallmarks at pharmacologically relevant, low concentrations; (ii) ICD-inducing effects could be mimicked by ALK genetic knockdown; and (iii) signs of ICD were reduced when crizotinib binding was impaired due to a point mutation in ALK kinase domain. In addition, we dissected ALK downstream pathways to identify PI3K as the main ICD-repressing pathway. Finally, we confirmed the immunogenicity of ceritinib in vivo, using murine ALK-driven lymphoma cells. If such cells were treated in vitro with ceritinib and then injected into syngeneic mice, they induced an immune response that slowed down growth of live cells injected two weeks later. In lymphoma bearing mice, ceritinib induced the regression of tumors followed by relapses. Such relapses occurred more frequently and more quickly in immunodeficient hosts as compared to immunocompetent mice. Only in the latter, complete cure would be obtained in 30% of the cases. Altogether, our results provided the scientific basis to combine ALK inhibitors with immunotherapeutic agents including programmed cell death protein 1 (PD1) blockade. Indeed, combination of ceritinib with anti-PD1 blocking antibody increased the percentage of complete cures to 55%.ICD inducers have been identified in the past decades in cytotoxic agents that non-specifically target general cellular functions such as DNA-to-RNA transcription or microtubular polymerization. The present work characterized two ALK tyrosine kinase inhibitors for their ICD-inducing effects, evaluating their effects on ALK+ ALCL (which depends on ALK as a major oncogenic and trophic factor). Moreover, it demonstrates that ALK specific inhibition accounts for their ICD-inducing effects. These effects are also reflected by ceritinib-induced anti-lymphoma immune response in a preclinical model. Hence, the successful treatment of ALCL most likely relies, at least in part, on improved immunosurveillance, opening up to the possibility of combining ALK inhibitors with immunotherapeutic strategies. Future studies must explore the clinical utility of these combinations for the definitive cure of ALK-dependent tumors
Maherzi-Mechalikh, Chahrazed. "Optimisation des vaccins thérapeutiques induisant des réponses T CD8+ spécifiques d’antigènes tumoraux : étude de l’induction des lymphocytes T régulateurs après vaccination." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCB035.
Full textThe presence of tumor-infiltrating CD8+ T lymphocytes (TIL) is generally associated with a good prognosis in cancer patients. Conversely, the infiltration of tumors by CD4+ regulators T cells (Treg), is often associated with poor prognosis. Several "therapeutic" vaccines able to induce tumor-specific CD8+ T cell responses have been developed. However, to date, the clinical results of these vaccines remain insufficient. In a first work, we developed and analyzed the immunogenicity and therapeutic efficacy of a new survivin vaccine (SVX) composed of three long synthetic peptides (LSP) containing several CD4 and CD8 T-cell epitopes. Survivin is over-expressed by most human cancers, but absent in healthy adult tissues, making it an interesting therapeutic target for cancer vaccines. We demonstrated the high therapeutic efficacy of SVX vaccine against various established murine tumor models, associated with its capacity to generate both specific cytotoxic CD8+ and multifunctional Th1 CD4+ T-cell responses but also effective memory T-cell responses for long-term protection against relapses. Treatment with SVX vaccine was also found to strongly increase the tumor infiltration of both CD4+ and CD8+ T cells over Treg cells therefore tipping the balance toward a highly efficient immune response. Finally, a preliminary study in patients with different types of cancer revealed the presence of high levels of SVX-specific spontaneous T-cell precursors. This suggests that SVX can potentially stimulate the activation of these specific precursors. Altogether, our results strongly suggest that SVX is a promising cancer vaccine and warrants its further clinical development. In order to study the kinetics of tumor-specific immune responses associated with LSP vaccines, we studied the efficacy of a LSP vaccine derived from the Ovalbumin (OVA) protein. We showed in two tumor models that the combination of LSP-OVA with a suitable adjuvant induced a strong tumor regression, an important expansion of both OVA-specific CD4+ and CD8+ T cells in the lymphoid organs, as well as their migration to the tumor. In addition, the vaccine induced functional specific T cells, as shown by the high levels of cytotoxic cytokines. Interestingly, the vaccine did not induce either OVA-specific or polyclonal Treg, despite the presence of the tumor. Finally, when LSP-OVA failed to induce a complete depletion of the tumor, we observed an important expression of inhibitory receptors (PD-1, TIM-3 and TIGIT) on conventional CD4+ and CD8+ TIL. Our results suggest that to optimize this LSP vaccine, a combination with one or more immune checkpoint blockade agents should be considered
Lindner, Véronique. "Recherche de nouveaux facteurs pronostiques et thérapeutiques dans le carcinome à cellules rénales humain." Université Louis Pasteur (Strasbourg) (1971-2008), 2008. http://www.theses.fr/2008STR15802.
Full textIncidence of renal cell carcinoma (RCC) is increasing with a pejorative prognosis. It accounts for more than 90% of adult renal neoplasms. Despite the recent major improvements in the treatment of metastatic RCC (anti-angiogenic drugs), ones needs to precise prognostic factors and to develop more specific and combined targeted therapies. The aim of our project was to determine the implication of parathyroid hormone-related protein (PTHrP), expressed in 90% of RCC and its interaction with the other known signaling pathways involved in carcinogenesis. We identified the role of PTHrP in controlling tumor cell survival in vitro and in vivo. PTHrP acts through the PI3K/Akt pathway leading to the specific activation of Nuclear Factor kappaB (NFκB). The NFκB pathway is involved in the intrinsic resistance of RCC to apoptosis, with no influence of von Hippel-Lindau (VHL) tumor suppressor gene expression. , often inactivated in RCC. We built up a tissue-microarray containing 249 human RCC with 12 to 22 years of clinical follow-up. Clear cell RCC showed increased pAkt and pNFB (phosphorylated) immunoreactivity. Increased expression of pAkt was significantly associated with Fuhrman grade and reduced survival. Increased expression of pNFB was correlated with small and localized tumor with best recurrence free survival. These two prognostic factors were not found to be independent for patient survival. This report provides the strong implication of PTHrP/PI3K/Akt and NFB pathways in renal growth and survival of RCC, as promising prognostic and therapeutic
Audran, Emilie. "Recherche de biomarqueurs des cellules propagatrices de glioblastome : étude de la signalisation calcique et du protéome membranaire." Phd thesis, Université de Strasbourg, 2012. http://tel.archives-ouvertes.fr/tel-00767650.
Full textDa, Silva Pierre. "Une histoire de la recherche de substances naturelles à activités thérapeutiques." Phd thesis, Université Sciences et Technologies - Bordeaux I, 2013. http://tel.archives-ouvertes.fr/tel-01038036.
Full textLaplane, Lucie. "Cellules souches cancéreuses : ontologie et thérapies." Thesis, Paris 10, 2013. http://www.theses.fr/2013PA100119/document.
Full textA new theory of cancer has recently gained importance in the scientific community. According to this theory, cancers develop from a particular sub-population of cancer cells, named “cancer stem cells” (CSCs). The proponents of the CSC theory argue that relapses are caused by CSCs because they escape classical therapies. Consequently, they claim that eliminating all the CSCs of a given cancer is a necessary and sufficient condition to cure the patient. In this dissertation, I scrutinize this therapeutic strategy and I argue that its ability to cure cancers will depend on our understanding of the nature of stemness. Indeed, cancer stem cells are characterized by this property, that is, the capacity to self-renew and to differentiate. However, the nature of stemness is rather obscure. Is it a categorical property or a disposition? Can a non-stem cell (cancerous or not) acquire stemness, and under which conditions? On the basis of analysis survey of the scientific literature, I distinguish four possible concepts of the nature of stemness. I contend that if the CSC theory is true, determining the exact nature of stemness is essential for cancers treatments
Boehler, Christian. "Rôles de la poly (ADP-ribose) polymérase-3 (PARP-3) dans la réponse cellulaire aux dommages dans l'ADN et la progression mitotique." Thesis, Strasbourg, 2012. http://www.theses.fr/2012STRAJ113/document.
Full textPoly(ADP-ribosyl)ation is a post-translational modification of proteins mediated by poly(ADP-ribose) polymerases (PARPs), a family of 17 members. We started the functional characterization of a new member of this family : the Poly(ADP-Ribose) Polymerase-3 (PARP-3). This protein was poorly studied. The human Parp3 gene displays two splicing variants giving rise to two proteins. Whereas the full length hPARP-3 has been identified as a core component of the centrosome throughout the cell cycle, the shorter splice variant accumulates within the nucleus. Of note, only the shorter nuclear variant is found in mice. We generated PARP-3 depletion in human lung cell line (MRC5) using RNA interference to analyse functional consequences of PARP-3 absence. We identified PARP-3 as a new specific actor of Double-Strand Breaks (DSB) repair mechanism. We also identified a new protein partner of PARP-3, NuMA, which is an essential regulator of mitotic division. These cells also showed problems in mitosis entry, in mitotic spindle formation, an increased mitosis duration and chromosomes aberrations. Performing protein interaction studies and using biochemical approaches, we highlighted a protein complex composed of PARP-3, NuMA and Tankyrase 1 (PARP-5a), involved in mitotic mechanisms. PARP-3 has a key role in the regulation of this complex. It plays essential role in mitotic progression and in mitotic spindle integrity maintenance and in telomere stability. The roles of PARP-3 in both DSB repair mechanisms and in mitotic progression indicate PARP-3 as a possible promising therapeutic target in cancer therapy
Gloulou, Olfa. "Identification de nouvelles structures inhibitrices de kinases : conception synthèse et évaluation biologique." Thesis, Paris 5, 2013. http://www.theses.fr/2013PA05P637/document.
Full textIn the introduction, the main functions of cyclin dependent kinases are detailed. Whenever it was possible the link with pathologies where these kinases are overexpressed is presented. This is followed by the description of the inhibitors which are actually undergoing clinical testing. Most of these clinical studies are targeting cancer and leukemia. Impressive clinical results have been disclosed for Dinaciclib, Palbociclib and Roscovitine. The synthesis of two series of compounds is then envisioned. The first series of products are purine derivatives bearing a hydroxybiarylmethyl group on the 6 position of the purine scaffold. Two approaches were compared in the synthesis of the hydroxylbiarylmethylamino group. In both approaches the key step was the orthoformylation of phenols using magnesium chloride as catalyst. The prepared compounds were evaluated against kinases and a tumor cell line. They were found more potent than homologous products without hydroxyls. The second families of products are thieno[3,2-d]pyrimidines. A new general route to these products based on the preparation of 7-bromo-2,4-dichloro-thieno[3,2-d]pyrimidine which can allow the synthesis of a large diversity of trisubstituted derivatives
Bourmaud, Aurélie. "La non-adhésion aux traitements oraux dans les situations adjuvantes et métastatiques des cancers." Thesis, Lyon 1, 2014. http://www.theses.fr/2014LYO10267/document.
Full textNon-adherence to oral chemotherapies can lead to lowered efficacy and increased risk of adverse events. The objective of this PhD work was twofold : i) to identify dis-adherence risk factors ii) to develop and test the feasibility of a validated, tailored therapeutic educational program with the aim of improving adherence to oral endocrine adjuvant chemotherapy in breast cancer. A survey was carried out to collect information on drug prescription, administration and surveillance, in order to identify non- adherence risk factors related to health professional behaviors : the majority of prescribers followed no standards in prescription writing, safety monitoring, toxicity prevention and patient education. A cohort study was carried out to identify adherence profiles among patients treated with capecitabine, using a mixed method. A profile of low adherence appeared (highly educated patients, with an irregular active life, with occupied relatives) and absolutely all patients showed an over-adherence profile (with a high risk of toxicity). The pilot study assessing the development and the feasibility of an educational program tailored to patients’ needs led to the improvement of the program : an extra session dealing with anxiety was built, and a new recruitment method was developed. Otherwise, the program succeeded in improving knowledge and trust in the treatment. This PhD work succeeded in identifying new dis-adherence risk factors, thanks to qualitative-quantitative methods. Those risk factors were incorporate in the development process of an educational program, in order to tailor it to the targeted population. This method should guarantee the efficacy of the program on patient’s adherence
Taillandier, Luc. "Un modèle de xénogreffes de gliomes humains et son utilisation en recherches pré-cliniques biologique et thérapeutique." Nancy 1, 2003. http://www.theses.fr/2003NAN11309.
Full textDiaz, Herrero Alba. "Characterization of Tumor Immune Microenvironment in Human Diffuse Large B-cell Lymphoma." Electronic Thesis or Diss., université Paris-Saclay, 2024. http://www.theses.fr/2024UPASL057.
Full textDiffuse Large B-cell Lymphoma (DLBCL) is the most prevalent subtype of non-Hodgkin's Lymphoma worldwide, characterized by an abnormal proliferation of mature B cells. It is an aggressive B-cell malignancy for which the current therapeutic strategies are still insufficient. The tumor microenvironment (TME) is the dynamic network of cells and all elements surrounding and interacting with the tumor. It plays an important role in cancer development, treatment response, and patient survival. Consequently, investigating the TME in DLBCL patients is crucial to discover the mechanisms leading to relapse and identify prognostic biomarkers. However, its diffuse tissue structure presents a challenge in elucidating the cellular organization and communication within the TME. The objective of my Ph.D. thesis is to conduct a comprehensive multimodal characterization of the immune cells within the DLBCL tumor microenvironment.To facilitate access to human samples, I developed and implemented an ethically approved clinical research protocol and a circuit of tissue and blood samples from patients with DLBCL treated at Saint Louis hospital, ensuring that the patient cohort reflects the heterogeneity of the disease.First, I performed a deep characterization of T lymphocytes, with special focus on describing their role within the DLBCL tissue. Indeed, Tumor-infiltrating T-cells (TILS) are key players in the NHL TME, presenting different subtypes and cell states. I apply multiparametric flow cytometry and high-dimensional spectral cytometry to investigate the complex landscape of T diversity in DLBCL biopsies, as well as their communication patterns with other immune cells in the tissue. The unsupervised analysis approach identified unexpected T-cell subtypes at a protein level, compared to tissue control and other lymphoproliferative disorders. Furthermore, the ligand-receptor expression analysis enabled the cell-cell communication study of those T-cell subpopulations within the TME context. Second, I aimed to characterize transcriptomic immune landscapes at a large scale within DLBCL tissue. However, RNA sequencing technologies characterize isolated cells from dissociated tissues with a loss of spatial context. I applied spatial transcriptomics, a cutting-edge technology that enables gene expression mapping in formalin-fixed paraffin-embedded samples of DLBCL biopsies, thus preserving their morphological information. I identified distinct anatomically restricted gene expression profiles in DLBCL samples, defying the historical notion of DLBCL diffuse architecture. These profiles can be classified into ecosystems that differ in cellular composition, functional patterns, and neighborhood characteristics. Moreover, their spatially resolved signatures classify patients with different overall survival revealing the prognostic potential of these spatial identities.Third, I evaluated the effects of altering the communication between NK cells and malignant B cells in DLBCL. I performed a functional in vitro assessment of a blocking antibody developed by the pharmaceutical company Servier. The functional assays demonstrated the effect of the molecular candidate in co-culture settings by improving cytotoxic functions of NK cells against tumor cells. These findings highlight the importance of targeting the interaction between effector cells and malignant B cells to develop effective therapies for DLBCL.This multidisciplinary project carried out on human samples provides a deep understanding of the heterogeneity of immune cells in DLBCL microenvironment at a protein and transcriptomic level while considering their spatial organization. Hence, this project holds significant therapeutic potential, by gaining insights into the disease heterogeneity and its impact on clinical outcome. This project could eventually lead to the discovery of new potential biomarkers and effective therapeutic strategies for DLBCL patients
Ambrosetti, Damien. "Carcinomes rénaux : caractérisation moléculaire et des voies métaboliques dépendant des mécanismes hypoxiques." Thesis, Nice, 2015. http://www.theses.fr/2015NICE4143/document.
Full textRenal carcinomas (RCC) are divided into several subtypes, defined by histological, genetic and phenotypic criteria. The differential diagnosis of these tumors is important with prognostic and therapeutic implications. Genetics and diagnosis: We studied the clinical, histological, immunohistochemical and genetic of papillary RCC (PRCC) type 1 and 2 cohort. An extensive genomic characterization completed by NGS has allowed us to classify type 2 PRCC in several groups of variable clinical evolution. Our results provide new information on the pathogenesis of PRCC that provide perspectives for personalized treatment. Metabolism, tumor grade and phenotype: In a series of clear cell RCC (ccRCC), we analyzed the characteristics of these tumors and the expression of proteins involved in the metabolism and isoforms of HIF. This study allowed us to demonstrate quantitative correlation between the expression of MCT1, GLUT1 and CA XII and Fuhrman grade, and qualitatively peripheral HIF2alpha localization and co-localization of proteins HIF2alpha and HAF. Theranostic strategies: In order to define the most appropriate treatment for patients with RCC, we made a parallel between sensitivity to targeted therapies of patients (in vivo), and cells derived from the original tumor (in vitro). We have demonstrated that the response in patients and in cells and was similar, thus in vitro assays are a way to define personalized treatment for ccRCC
Kammerer-Jacquet, Solène-Florence. "Carcinome à cellules claires du rein : phénotype métastatique et résistance aux thérapies ciblées." Thesis, Rennes 1, 2016. http://www.theses.fr/2016REN1B038.
Full textClear cell renal cell carcinoma (ccRCC) is the most common kidney cancer. It is characterized by frequent inactivation of the tumor suppressor gene VHL found in 70% of tumors leading to the transcription of HIF transcription factor target genes such as VEGF. This is an aggressive tumor with 50% of metastatic patients. Sunitinib, an inhibitor of receptor tyrosine kinase antiangiogenic, is currently the most used in 1st line despite 30% of patients who progress quickly. The advent of a new anti-angiogenic targeting MET (cabozantinib) and immunomodulators (anti-PD-1 antibody, nivolumab) makes crucial discovery of predictors of response to treatment. In the first part, we studied a retrospective study of 98 consecutive ccRCC. We assessed complete VHL status and correlated it with the expression of PD-L1. Moreover, while the prognosis is different between ccRCC synchronous metastatic and metachronous, their phenotype have never been compared. In this purpose, we performed an analysis of the main pathological prognostic factors, immunohistochemical markers (CAIX, VEGF, PAR3, PD-1 and PD-L1) and molecular (VHL status: deletion, mutation and promoter methylation) correlated with specific survival. We demonstrated that non-inactivated VHL tumors (niVHL) were associated with the presence of synchronous metastases, sarcomatoid component, a dense lymphocytic infiltrate, an overexpression of VEGF, an expression of PD-L1 and a poor prognosis. We also compared the phenotypes of metachronous and synchronous metastatic ccRCC. The first ones were associated with sarcomatoid component, cytoplasmic expression of PAR-3 overexpression VEGFA and niVHL status and a poor prognosis even from the diagnosis of metastases. In the second part, we studied a retrospective study of 90 consecutive metastatic ccRCC treated with first line sunitinib to identify predictors of response or resistance. We used the same techniques as above plus the MET status (mutation in Next-Generation sequencing and expression by IHC). Patients were classified as primary-refractory, intermediate and long-term responders depending on the duration of their response as assessed by radiological criteria (RECIST). We also characterized the genetic profile of 73 ccRCC of this series by CGH array for which we had frozen tumor. Primary refractory patients often had poor prognosis (Heng criteria), liver metastases, infiltration of the hilar fat. Cytogenetically, their tumors had many more genetic alterations, both gains as losses. These recurrent alterations were gains of 5p, 7p, 8q22.1-qter and loss of 6q21-q25.3 region. The multivariate Cox model highlighted four independent factors: the score of Heng, liver metastases, infiltration of the hilar fat and gain of 8q which integrated into a prognostic nomogram had a c-index of 0.74 for survival progression-free survival and 0.77 for overall survival. In conclusion, our study identified a subtype of ccRCC with a poor prognosis with niVHL status that should be explored at the genomic level. Furthermore, we showed a phenotype difference between ccRCC synchronous and metachronous metastatic patients whereas their care is currently the same. Finally we have identified a prognostic nomogram in metastatic ccRCC treated with sunitinib in the first line. This nomogram if confirmed by a larger prospective study could have a significant clinical impact in the selection of patients most likely to benefit from anti-angiogenic therapy