Дисертації з теми "Target therapies"
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1
Holt, Sandra. "Fatty acid amide hydrolase - A target for anti-inflammatory therapies?" Doctoral thesis, Umeå universitet, Farmakologi, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-504.
Анотація:
Anti-inflammatory drugs are a widely used class of therapeutic agents, but the use of non-steroidal anti-inflammatory drugs (NSAID) is hampered by their gastrointestinal side-effects. Recent reports that cyclooxygenase-2 inhibitors may cause cardiovascular events underline the importance of identifying new therapeutic strategies for the treatment of inflammation. One such target could be agents modifying the endogenous cannabinoid (endocannabinoid) system, since there is evidence that this system plays a role in our natural defence against inflammation. The levels of the endocannabinoid anandamide (arachidonoyl ethanolamide, AEA) are low under normal conditions, and stand under strict regulatory control of synthesising and degrading enzymes. Fatty acid amide hydrolase (FAAH) is the main enzyme degrading AEA, hydrolysing it to ethanolamine and arachidonic acid. The focus of this thesis lies in exploring the pharmacology of FAAH to evaluate its possibilities as a target for new anti-inflammatory drugs. In Papers I and II, the effects of the ambient pH on the properties of FAAH were investigated, since tissue pH is known to decrease under inflammatory conditions. In homogenates, it was found that the activity of FAAH decreased as the assay pH was decreased, consistent with the known pH profile of the enzyme. More importantly, the sensitivity of the enzyme to inhibition by FAAH inhibitors changed. In particular, the sensitivity of the enzyme to inhibition by the NSAID ibuprofen increased seventeen-fold as the assay pH decreased from 8.37 to 5.28. A similar pattern was found using intact C6 glioma cells when the extracellular, but not the intracellular pH was reduced. Thus, at an extracellular pH value of 6.2, (R)-ibuprofen, (S)-flurbiprofen and (R,S)-flurbiprofen inhibited the metabolism of AEA with IC50 values of 26, 14 and 15 µM, respectively. These values are in theory reachable upon normal dosing of the compounds. In Paper III, the effect of the selective FAAH inhibitor URB597 and the NSAID indomethacin were investigated in vivo upon the oedema response to carrageenan administration in the paw of anaesthetised mice. Both compounds reduced the oedema in a manner completely blocked by the CB2 receptor antagonist SR144528. In Paper IV, the effect of inflammation upon endocannabinoid synthesis was investigated in mice. Lipopolysaccharide-induced pulmonary inflammation was found not to affect the release of AEA to any obvious extent, and did not change the activities of the AEA synthesising enzymes N-acyl transferase or N-acyl phosphatidylethanolamine phospholipase D, or of FAAH in lung tissue. The results of this thesis would suggest that FAAH inhibitors can produce anti-inflammatory effects, and that the endocannabinoid system contributes to the actions of the NSAID indomethacin in the carrageenan model of inflammation, but that an increased endocannabinoid synthesis (a prerequisite for FAAH inhibition as a therapeutic strategy) is not an obligatory response to an inflammatory stimulus.
2
Di, Stefano Anna Luisa. "Molecular markers of gliomas : implications for diagnosis and new target therapies." Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066015.
Анотація:
Le travail de thèse est dédié à la caractérisation de fusions spécifiques oncogéniques entre les gènes FGFR et TACC dans les gliomes. Nous avons analysé 907 gliomes pour la présence du gène de fusion FGFR3-TACC3. Nous avons montré que les fusions FGFR3-TACC3 ne touchent que les gliomes IDH wild-type (3%), sont mutuellement exclusives avec l'amplification de EGFR et avec la forme tronquée EGFRvIII et inversement, sont associées à l'amplification de CDK4 et de MDM2 et à la délétion du 10q. Les fusions FGFR3-TACC3 sont associées à une expression intense et diffuse de FGFR3 en immunohistochimie (IHC) et l'IHC pour FGFR3 est un marqueur prédictif très sensible de la présence des fusions FGFR3-TACC3. Les patients porteurs d'une fusion FGFR3-TACC3 ont une survie globale significativement plus longue comparés aux patients avec gliome IDH wild-type. Nous avons traité deux patients porteurs d'un gène de fusion FGFR3-TACC3 avec un inhibiteur tyrosine-kinase (TK) spécifique pour FGFR et nous avons observé une stabilisation de maladie et une réponse mineur chez un patient. Dans la deuxième section nous avons optimisé une nouvelle séquence de spectroscopie différentielle-MEGA-PRESS-pour la détection de l'oncometabolite 2-hydroxyglutarate (2 HG) qui s'accumule de manière spécifique dans les gliomes IDH mutés. Nous avons analysé de façon prospective une cohorte de 25 patients avant chirurgie pour probable gliome de grade II et grade III. Nous avons trouvé que la MEGA-PRESS est hautement spécifique (100%) et sensible (80%) dans la prédiction de la présence de la mutation IDH. Son taux est corrélé aux concentrations de 2 HG mesurés sur tissu congelé par spectrométrie de masse (GC-MS/MS)This work is devoted to the characterization of a specific oncogenic fusion between FGFR and TACC genes in gliomas. Overall, we screened 907 gliomas for FGFR3-TACC3 fusions. We found that FGFR3-TACC3 fusions exclusively affect IDH wild-type gliomas (3%), and are mutually exclusive with the EGFR amplification and the EGFR vIII variant, whereas it co-occurs with CDK4 amplification, MDM2 amplification and 10q loss. FGFR3–TACC3 fusions were associated with strong and homogeneous FGFR3 immunostaining. We show that FGFR3 immunostaining is a sensitive predictor of the presence of FGFR3-TACC3 fusions. FGFR3-TACC3 glioma patients had a longer overall survival than those patients with IDH wild-type glioma. We treated two patients with FGFR3–TACC3 rearrangements with a specific FGFR-TK inhibitor and we observed a clinical improvement in both and a minor response in one patient. In the second section, we developed a non-invasive diagnostic tool by 1H-magnetic resonance spectroscopy in IDH mutant gliomas. We optimized a uniquely different spectroscopy sequence called MEGA-PRESS for the detection of the oncometabolite 2-hydroxyglutarate (2 HG) that specifically accumulates in IDH mutant gliomas. We analysed a prospective cohort of 25 patients before surgery for suspected grade II and grade III gliomas and we assessed specificity and sensitivity, correlation with 2 HG concentrations in the tumor and associations with grade and genomic background. We found that MEGA-PRESS is highly specific (100%) and sensitive (80%) for the prediction of IDH mutation and correlated with 2 HG levels measured by gas chromatography-tandem mass spectrometry (GC-MS/MS) in frozen tissue
3
Han, Yanyan. "Functional characterization of FMNL1 as potential target for novel anti-tumor therapies." Diss., lmu, 2010. http://nbn-resolving.de/urn:nbn:de:bvb:19-112968.
4
Zincke, Fabian. "Biomarker based therapies in high risk cancer patients - MACC1 as molecular target." Doctoral thesis, Humboldt-Universität zu Berlin, 2020. http://dx.doi.org/10.18452/21021.
Анотація:
Das metastasierende kolorektale Karzinom stellt eine große Herausforderung in der Krebstherapie dar. Verlässliche und effiziente Biomarker zur Prognose des Krankheitsverlaufes oder der Therapieantwort (Prädiktion) sind rar. Metastasis-associated in colon cancer 1 (MACC1) ist ein prognostischer, prädiktiver und kausaler Biomarker für verschiedene Tumorentitäten. Durch die Induzierung von Zielgenen, wie z.B. MET, beeinflusst es Signalwege wie MEK/ERK und AKT/β-catenin und fördert so Zellproliferation und -motilität sowie Tumorprogression und Metastasierung in vivo. Diese Arbeit sollte neue Strategien erforschen diese Prozesse durch die Inhibition von MACC1 auf Transkriptions- und Signaltransduktionsebene zu unterbinden.
Mit zwei verschiedenen Screeningmethoden konnten wir Statine als potente transkriptionelle Inhibitoren von MACC1 als auch phosphotyrosin (pY)-abhängige Interaktionen von MACC1 mit essentiellen Signalmolekülen identifizieren: SHP2, GRB2, SHC1, PLCG1 und STAT5B. Statine verringerten MACC1-spezifische Proliferation und Koloniebildung in vitro als auch Tumor Wachstum und Metastasierung in vivo bei Dosen äquivalent der humanen Standardtherapie zur Blutlipidsenkung. Mutation der pY-Bindungsstellen reduzierte die Aktivität des MACC1-induzierten ERK Signalwegs sowie Zellmigration und -proliferation. Anhand unserer Daten orchestriert MACC1, abhängig von MET und EGFR, neue SHP2/SRC/ERK und PKA/SRC/CREB Signalkaskaden zu einem malignen Phänotyp. Gezielte Intervention restringierte die MACC1-abhängige Koloniebildung, was neue therapeutische Interventionspunkte identifiziert und eine hervorragende Basis für Untersuchungen zur Kombinationstherapie darstellt.
Die weitere Erforschung der spatiotemporalen Organisation des MACC1 Signalosoms und assoziierter Signalkaskaden soll das volle therapeutische Potential von MACC1 ausschöpfen. Wir empfehlen zudem Statine in der Krebstherapie bzw. -prävention, besonders bei MACC1-stratifzierten Patienten, anzuwenden.Metastatic colorectal cancer still represents a major challenge in therapy. Reliable and efficient biomarkers for early prognosis of disease course or treatment response (prediction) remain scarce. Metastasis-associated in colon cancer 1 (MACC1) has been established as prognostic, predictive and causal biomarker for several tumor entities. Its induction of target genes such as MET affects several signaling pathways including MEK/ERK and AKT/β-catenin. Thus, it promotes cellular proliferation and motility as well as tumor progression and metastasis formation in vivo. This study intended to explore new strategies to inhibit these processes by targeting MACC1 on transcriptional and signaling level. By two distinct screening methods, we identified statins as potent MACC1 transcriptional inhibitors as well as phosphotyrosine (pY)-dependent interactions of MACC1 with crucial signaling molecules: SHP2, GRB2, SHC1, PLCG1 and STAT5B. Statins showed MACC1-specific reduction of proliferation and colony formation in vitro as well as restriction of tumor growth and metastasis formation in vivo at doses equivalent to human standard lipid reduction therapy. Mutation of the pY-interaction sites abrogated MACC1-dependent ERK signaling as well as cell migration and proliferation. Our data further suggest that MACC1 governs SHP2/SRC/ERK and PKA/SRC/CREB axes conferring a malignant phenotype in response to MET and EGFR. Targeted intervention restricted MACC1-dependent colony formation which indicates new drug intervention points for MACC1 signaling and provides an excellent baseline for further investigations of combinatorial treatments. Additional research about the spatiotemporal organization of MACC1 signalosome formation and downstream signaling will reveal the entire potential of MACC1 as therapeutic target, whereas statins should already be considered for cancer therapy or prevention, especially in patients stratified for MACC1 expression.
5
Kyle, Fiona. "LRH-1 as a target for the development of new breast cancer therapies." Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/55285.
Анотація:
Estrogen drives the growth and development of estrogen receptor alpha (ERα) positive breast cancer and ERα is the target for hormonal therapies that inhibit its activity. A substantial proportion of patients become resistant to these therapies, demonstrating a need for new therapies. Gene expression microarray studies have been performed with a view to identifying potential novel therapeutic targets, biomarkers or forming the basis of identifying a molecular signature for endocrine resistance. These studies have identified candidate genes whose expression is altered in models of endocrine resistance. Investigation of the molecular pathways particularly highlights cell survival and regulation of apoptosis and indicates that these pathways play a key role in the development of resistance. Microarray analysis also identified the liver receptor homolog 1 (LRH-1, NR5A2), a member of the nuclear receptor superfamily of transcription factors, as an estrogen regulated gene in MCF7 cells. Functional analysis showed that LRH-1 regulates breast cancer cell growth, acting in part by regulating ERα expression. Gene expression profiling of MCF-7 cells following RNAi for LRH-1 identified LRH-1 regulated genes. LRH-1 is known to regulate expression of CYP19A1 (aromatase), responsible for estrogen biosynthesis through the aromatisation of aromatase. Together, our findings identify LRH-1 as a potential therapeutic target for breast cancer treatment. Results of screening for small molecule inhibitors of LRH-1 will be presented, together with analysis of gene expression profiling for LRH-1 regulated genes.
6
Cunniff, Brian. "Mitochondrial structure and function as a therapeutic target in malignant mesothelioma." ScholarWorks @ UVM, 2014. http://scholarworks.uvm.edu/graddis/249.
Анотація:
Malignant mesothelioma (MM) is a rare tumor associated with occupational exposure to asbestos with no effective treatment regime. Evaluation of mitochondrial function in human MM cell lines revealed a common tumor phenotype: in comparison to immortalized or primary human mesothelial cells, MM tumor cells displayed a more oxidized mitochondrial environment, increased expression of mitochondrial antioxidant enzymes, and altered mitochondrial metabolism. Earlier work by our laboratory indicated that increases in mitochondrial reactive oxygen species (mROS) in MM cell lines supports expression of FOXM1, an oncogenic transcription factor that contributes to increased cell proliferation and chemoresistance. These studies sought to investigate targeting of mitochondrial structure and function as a therapeutic avenue in MM.
MM cells have reduced mitochondrial reserve capacity, a redox vulnerability exploitable by pro-oxidant therapeutics. Targeting of the mitochondrial peroxidase peroxiredoxin 3 (PRX3) with the anti-cancer compound thiostrepton (TS) induces irreversible modifications to PRX3 protein, increased mROS, and selective MM cell death. Mass spectrometry showed TS targets conserved cysteine residues in PRX3. In vitro and in MM cells, TS failed to modify human PRX3 harboring mutations to Cys108, Cys127 or Cys229. Pre-incubation of MM cells with dimedone blocked cysteine adduction of PRX3 by TS, suggesting adduction requires an active PRX3 catalytic cycle. Studies with immortalized and primary human mesothelial cells showed adduction of PRX3 by TS occurred at a much lower rate in normal cells than MM cells, and this difference correlated with markedly decreased cytotoxicity. Moreover, MM cells transduced with shRNA to PRX3 grew more slowly and were less sensitive to TS than their wild type counterparts, indicating PRX3 is a major target of TS in MM cells. Studies with a xenoplant mouse model of MM showed TS alone or in combination with the TRX2 inhibitor gentian violet significantly reduced tumor volume.
Tumor cell mitochondria have an increased mitochondrial membrane potential, therefore numerous drugs have been developed that selectively accumulatte into energized mitochondria to enhance drug efficacy and specificity. Here two mitochondrial-targeted nitroxides, Mito-carboxy-proxyl (MCP) and Mito-TEMPOL (MT), were investigated for their anti-cancer effects. Treatment of MM cells with MCP or MT led to rapid disruption of the mitochondrial reticulum, increased oxidant levels, and reduced FOXM1 and PRX3 protein expression. Immunostaining revealed a pool of cytoplasmic FOXM1 associated with PRX3 in mitochondria, suggesting PRX3 participates in regulating FOXM1 expression. Combination of MCP or MT with TS led to synergistic effects on MM cell viability.
Upregulation of mitochondrial antioxidant enzymes is an adaptive response that ameliorates mitochondrial oxidative stress and supports tumor cell survival. Studies here indicate that enhanced dependency on the PRX3 catalytic cycle in tumor cells promotes inactivation of PRX3 by TS, providing a therapeutic window dependent on a mitochondrial phenotype common to many human tumor types. Therefore TS, alone or in combination with other agents, may prove useful in the management of intractable tumors such as MM.
7
Ruscito, Ilary [Verfasser]. "Harnessing tumor angiogenesis to explore ovarian cancer immune suppression and address target-therapies outcomes / Ilary Ruscito." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2021. http://d-nb.info/1235400476/34.
8
Semenchenko, Kostyantyn. "Development of tumour therapies : from target validation of TTLL12 to tests of a small molecule XRP44X in pre-clinical models of cancer." Thesis, Strasbourg, 2014. http://www.theses.fr/2014STRAJ107.
Анотація:
Les modifications post-traductionnelles de la tubuline sont des cibles attrayantes pour la thérapie du cancer. TTLL12 est impliqué dans la détyrosination de la tubuline, la triméthylation de l’histone H4K20 et le cancer de la prostate. La thèse porte sur les effets de la surexpression de TTLL12 sur ces modifications à différents stades du cycle cellulaire et sur la sensibilité à des agents ciblant les microtubules. Les résultats montrent que TTLL12 affecte ces modifications indépendant du cycle cellulaire et réduit la sensibilité des cellules à paclitaxel. XRP44X est un nouvel inhibiteur de la signalisation Ras-ERK-Elk3. Ses propriétés antitumorigène ont été montré in vitro et dans certaines études in vivo. Le projet de thèse était une continuation des études pré-cliniques sur XRP44X dans des modèles de cancer de la prostate de souris. Les résultats montrent que XRP44X est un inhibiteur efficace de la tumorigenèse et des métastases, ce qui peut être dû à son effet sur Elk3Tubulin posttranslational modifications are an attractive target for cancer therapy. TTLL12 isinvolved in tubulin detyrosination, histone H4K20 trimethylation and prostate cancer. The thesis addresses the effects of TTLL12 overexpression on these tubulin and histone modifications at different stages of the cell cycle and on sensitivity to microtubule-targeting agents. The results show that TTLL12 over expression affects tubulin detyrosination and H4K20 trimethylation independently of cell cycle phase and reduces cell sensitivity totaxanes.XRP44X is a novel inhibitor of Ras-ERK1/2-Elk3 signalling and tubulin-binding agent. Itsantitumorigenic properties had been shown in vitro and in initial in vivo studies. The thesis project was a continuation of pre-clinical studies on XRP44X in mouse prostate cancer models. The results show that XRP44X is an effective inhibitor of tumorigenesis and metastasis in prostate cancer, which may be due to its effect on Elk3
9
Zincke, Fabian [Verfasser], Ulrike [Gutachter] Stein, Edda [Gutachter] Klipp, and Stephan Michael [Gutachter] Feller. "Biomarker based therapies in high risk cancer patients - MACC1 as molecular target / Fabian Zincke ; Gutachter: Ulrike Stein, Edda Klipp, Stephan Michael Feller." Berlin : Humboldt-Universität zu Berlin, 2020. http://d-nb.info/1202775608/34.
10
Trouvilliez, Sarah. "Caractérisation des interactions entre TrkA, CD44 et les molécules de leur signalisation dans les cancers du sein triple négatifs." Thesis, Université de Lille (2022-....), 2022. http://www.theses.fr/2022ULILS104.
Анотація:
Le cancer du sein est la tumeur maligne la plus fréquente chez les femmes dans le monde (OMS). Le cancer du sein est une maladie hétérogène et le pronostic varie en fonction des caractéristiques moléculaires. En particulier, la prise en charge des cancers du sein triple négatifs (TNBC) reste un défi clinique en raison de l'absence de thérapie spécifique et efficace. Dans ce contexte, notre équipe a mis en évidence le rôle de TrkA dans les TNBC. Plus précisément, les travaux du Pr. Toillon montrent qu'il agit non seulement via sa phosphorylation mais aussi par le biais de plateforme de récepteurs membranaires. En particulier, le NGF induit une interaction de TrkA avec la glycoprotéine CD44. Le complexe TrkA/CD44 active une signalisation indépendante du phosphorylation de TrkA impliquée dans la résistance des inhibiteurs de la phosphorylation de TrkA. Afin de cibler ce mécanisme de résistance, les interactions entre TrkA, CD44 et leurs partenaires de signalisation ont été étudiées. Tout d'abord, j'ai déterminé que le complexe TrkA/CD44 implique uniquement le variant 3 de CD44. En déterminant les motifs moléculaires impliqués, un peptide bloquant l'association TrkA/CD44v3 a été synthétisé et un mutant H112A de TrkA. J’ai ainsi confirmé l'importance des acides aminés de CD44v3 (IDDDEDFISST) et de l'acide aminé H112 de TrkA dans cette interaction. De façon intéressante, ce peptide bloquant réduit la croissance tumorale et la métastase. De plus nous avons montré que l'inhibition de CD44 n'affecte pas la liaison d’une des molécules de la signalisation de TrkA/CD44. Nous avons décrypté ensuite décrypté l’interaction TrkA/molécule de la signalisation et montré qu’un inhibiteur de cette interaction bloque la migration de cellules cancèreuses triples négatives. En conclusion, nos études ont révélé le rôle des interactions TrkA/CD44/molécules de leur signalisation dans l'agressivité des cancers du sein et la résistance des inhibiteurs de TrkA. Ceci suggère que si les inhibiteurs de la phosphorylation de TrkA actuels ne sont pas efficaces dans le TNBC, de nouveaux inhibiteurs perturbant la signalisation TrkA/CD44 pourraient être de nouvelles stratégies thérapeutiques efficacesBreast cancer is the most common malignancy in women worldwide (WHO). Breast cancer is a heterogeneous disease and prognosis varies according to molecular characteristics. In particular, the management of triple-negative breast cancer (TNBC) remains a clinical challenge due to the lack of specific and effective therapy. In this context, our team has highlighted the role of TrkA in TNBC. More precisely, the work of Prof. Toillon shows that TrkA acts not only via its phosphorylation but also via the membrane receptor platform. In particular, NGF induces an interaction of TrkA with the glycoprotein CD44. The TrkA/CD44 complex activates a TrkA phospho-ndependent signaling involved in the resistance of TrkA inhibitors. To target this resistance mechanism, the interactions between TrkA, CD44 and their signaling partners were investigated. First, I determined that the TrkA/CD44 complex involves only CD44 variant 3. By determining the molecular motifs involved, a peptide blocking the TrkA/CD44v3 association was synthesized and an H112A mutant of TrkA. I thus confirmed the importance of the amino acids of CD44v3 (IDDDEDFISST) and of the amino acid H112 on TrkA in this interaction. Interestingly, this blocking peptide reduces tumor growth and metastasis. Furthermore, we showed that CD44 inhibition does not affect the binding of one of TrkA/CD44 signaling partners. We then deciphered the TrkA/signaling molecule interaction and showed that an inhibitor of this interaction blocks the migration of triple negative cancer cells. In conclusion, our studies revealed the role of TrkA/CD44/signaling molecule interactions in breast cancer aggressiveness and resistance to TrkA inhibitors. It suggests that if current TrkA inhibitors are not effective in TNBC, novel inhibitors disrupting TrkA/CD44 signaling could be a new therapeutic option
11
Tucker, Catherine Amanda. "Targeted therapies in mantle cell lymphoma." Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/922.
Анотація:
Mantle cell lymphoma (MCL) is characterized by the presence of the
t(11 ;14)(g13 ;g32) translocation which results in cyclin Dl over-expression. MCL is one
of the most difficult lymphoproliferative disorders to manage with a median survival rate
of 43 months from diagnosis. The poor prognosis associated with MCL is due in large
part to its late classification as a separate clinical entity leading to a dearth in available
pre-clinical models. The specific objectives of the research described in this thesis were
(1) to establish MCL preclinical models of disease and (2) to evaluate deregulated cell
signaling pathways in MCL that can impact treatment response. Pre-clinical models of
MCL were established from pre-existing cell lines containing the t(11 ;14)(g13 ;g32).
These cell lines were previously misclassified because they were developed prior to the
classification of MCL as a distinct lymphoma subtype. With the establishment of MCL
models, deregulated cell signaling pathways in MCL and response to different treatment
strategies were investigated. These included an investigation of the cell signaling
pathways activated in bcl-2 over-expressing MCL cells that were treated with
oblimersen; a molecular gene silencing strategy that effectively suppresses bcl-2 in vitro
and in vivo. Silencing bcl-2 provided insight into which pathways were influenced by
bcl-2 over-expression in MCL. More specifically loss of cyclin D1, NF-KB, p53, bax and
p27 were observed following bcl-2 silencing. Additional studies investigated how
abnormal expression of CD40/CD40L and Fas/FasL along with bcl-2 family members
contributes to B cell clonal expansion and influences Rituximab-mediated cell death in
MCL models. Rituximab is a chimeric monoclonal antibody targeted against B cells and
both Rituximab-sensitive and insensitive MCL models were defined. An abnormally
high expression of bcl-2, bcl-x L, mcl-1, CD40/CD40L and Fas were observed in all MCL
cells, as well as high levels of soluble FasL, capable of blocking Fas-mediated apoptosis.
These deregulated pathways were associated with response to Rituximab treatment in a
sensitive MCL model. These studies demonstrated some of the key pathways associated
with treatment response in MCL, and the establishment of well characterized MCL
models enables us to continue to explore new treatment strategies currently being studied
in other lymphomas.
12
Yau, Chung-cheung, and 邱宗祥. "Molecular targeted therapies in advanced hepatocellular carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B48421145.
Анотація:
With the recent advances in the knowledge of hepato-carcinogenesis, there has been encouraging development in the molecular targeted therapy for patients with advanced hepatocellular carcinoma (HCC). Sorafenib, an anti-angiogenic multi-targeted receptor tyrosine kinase inhibitor, has become the standard of treatment in HCC patients with Child-Pugh A cirrhosis. Nevertheless, the benefits and safety profile of sorafenib in the majority of the unselected advanced HCC patients and other patient subgroups are still unclear. More importantly, the survival benefit associated with sorafenib use is generally modest in Asian population. Therefore, an unmet medical need remains for more effective therapeutic agents.
This thesis studied the impact of molecular targeted therapy in the treatment of advanced HCC patients and it contains 10 original studies divided into six sections. The first section provides a concise overview of the epidemiology, risk factors, and current treatment options for HCC patients. Also, the molecular biology and opportunity for the use of targeted therapy in advanced HCC were discussed.
The second section is about a new prognostic score system that we developed — Advanced Liver Cancer Prognostic System (ALCPS). Our study results showed that ALCPS was able to objectively estimate the 3-month survival probability of advanced HCC patients and thus could enhance patient selection for targeted therapy or clinical trials.
The third section is about the use of sorafenib in the treatment of advanced HCC patients. The results of our single centre phase II study showed that sorafenib had good efficacy and acceptable tolerability in treating advanced HCC patients in hepatitis B endemic area. Furthermore, our retrospective study results confirmed that the overall survival benefits and overall treatment-related adverse events of sorafenib were comparable in elderly and young advanced HCC patients. More importantly, our other retrospective analysis showed that Child-Pugh (CP) A and CP B patients tolerated sorafenib similarly and derived similar clinical and progression-free survival benefit. Among CP B patients, most benefits were observed in patients with score 7. Nevertheless, CP B patients were more susceptible to developing cirrhotic complications. Last but not least, our study also demonstrated that drop in serum alpha-fetoprotein level > 20% in the first 6 weeks of sorafenib treatment was a useful early surrogate endpoint for evaluating antitumor response and survival benefits. All these results are instrumental in guiding future rational use of sorafenib in advanced HCC population.
The fourth section is about the role of targeted therapies in treating sorafenib-refractory advanced HCC patients. In a single arm phase II study, we showed that bevacizumab and erlotinib combination was not effective in treating advanced HCC patients who had failed prior sorafenib treatment.
The fifth section of the thesis comprises results of four early phase novel clinical trials that may potentially improve the therapeutic outcomes in advanced HCC patients. First, our phase I/II study demonstrated that another anti-angiogenic agent — PTK787 had encouraging and possible synergistic activity when combined with intravenous doxorubicin in treating advanced HCC patients. Second, our multi-center phase II study results demonstrated promising activity with good tolerability of a novel combination — sorafenib together with capecitabine and oxaliplatin (SECOX) in the treatment of advanced HCC patients. Third, in a phase I study, we showed that pazopanib, a novel anti-angiogenic agent, had a manageable safety profile and preliminary activity in advanced HCC patients. Moreover, pazopanib reduced tumor vessel leakage, as shown by contrast-enhanced magnetic resonance imaging indicating a direct effect on HCC vasculature that might be associated with its antitumor activity. Lastly, in another phase I study, we evaluated safety, pharmacological parameters, and potential antitumor activity of pegylated recombinant human arginase 1 (peg-rhArg1) in advanced HCC patients. Our results illustrated that arginine depletion in humans can be achieved safely with peg-rhAgr1 in a dose-response manner and peg-rhArg1 had manageable safety profile and preliminary evidence of activity in advanced HCC patients.
In the last section, the future perspectives about the use of molecular targeted therapy in the treatment of advanced HCC patients were discussed.published_or_final_version
Medicine
Master
Doctor of Medicine
13
Galmbacher, Katharina Monika. "Caspase-1 as a target of bacterial tumor therapy." kostenfrei, 2008. http://www.opus-bayern.de/uni-wuerzburg/volltexte/2009/3350/.
14
Guerreiro-Lucas, Luciano Andre. "Longitudinal intravital evaluation of tumour vasculature targeted therapies." Thesis, University of Nottingham, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.495592.
Анотація:
Tumour growth and metastasis are dependent on the formation and maintenance of a dedicated microvascular network. Angiostatin4.5 (AS4.5) is a naturally occurring anti-angiogenic agent known to inhibit angiogenesis in vitro and tumour growth in vivo.
15
Leite, Diana Moreira. "Peptide nanomaterials as targeted endocrine therapies for glioblastoma." Thesis, University of Portsmouth, 2017. https://researchportal.port.ac.uk/portal/en/theses/peptide-nanomaterials-as-targeted-endocrine-therapies-for-glioblastoma(15707f91-4dd4-4220-bf7e-bb008a65b632).html.
16
Bolin, Sara. "Mechanisms of Medulloblastoma Dissemination and Novel Targeted Therapies." Doctoral thesis, Uppsala universitet, Neuroonkologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-300907.
Анотація:
Medulloblastomas are the most frequent malignant childhood brain tumors, arising in the posterior fossa of children. The overall 5-year survival is 70%, although children often suffer severe long-term side effects from standard medical care. To improve progression-free survival and quality of life for these children, finding new therapeutic targets in medulloblastoma is imperative. Medulloblastoma is divided in to four molecular subgroups (WNT, SHH, Group 3 and Group 4) based on key developmental pathways essential for the initiation and maintenance of tumor development. The MYC family of proto-oncogenes regulates cell proliferation and differentiation in normal brain. Aberrant expression of MYC proteins occurs commonly in medulloblastoma. Our studies on Group 3 medulloblastoma identify the transcription factor SOX9 as a novel target for the E3 ubiquitin ligase FBW7, and show that increased stability of SOX9 confers an increased metastatic potential in medulloblastoma. Moreover, SOX9-positive cells drive distant recurrences in medulloblastoma when combining two regulatable TetON/OFF systems. MYCN depletion leads to increased SOX9 expression in Group 3 medulloblastoma cells, and the recurring tumor cells are more migratory in vitro and in vivo. Segueing to treatment of medulloblastoma, we show that BET bromodomain inhibition specifically targets MYC-amplified medulloblastoma cells by downregulating MYC and MYC-transcriptional targets, and that combining BET bromodomain- and cyclin-dependent kinase- inhibition improves survival in mice compared to single therapy. Combination treatment results in decreased MYC levels and increased apoptosis, and RNA-seq confirms upregulation of apoptotic markers along with downregulated MYC target genes in medulloblastoma cells. This thesis addresses novel findings in transcription factor biology, recurrence and treatment in Group 3 medulloblastoma, the most malignant subgroup of the disease.
17
Romanus, Dorothy. "The Value of Targeted Therapies in Lung Cancer." Thesis, Harvard University, 2014. http://nrs.harvard.edu/urn-3:HUL.InstRepos:13070030.
Анотація:
The goal of this dissertation was to examine the realized value of targeted therapies in routine care and to identify opportunities for improving the return on medical spending for these technologies.
Chapter 1 investigated the value of targeted therapies in lung cancer patients who were treated in routine care. This observational, claims-based analysis used propensity score, and instrumental variable methods, combined with a Kaplan Meier Sample Average estimator to calculate lifetime costs and life expectancy. An incremental comparison showed that the realized value of targeted therapies in routine care was unfavorable relative to chemotherapy treatment. Subgroup analyses revealed that initial erlotinib therapy yielded effectiveness results that are substantially lower than efficacy survival outcomes in molecularly guided trials. Our results indicated that in routine care, chemotherapy was the most cost effective strategy. The unexpectedly low outcomes with first-line erlotinib suggested that some of the value of this treatment was not being realized in practice.
Chapter 2 examined the practice patterns of targeted therapies and utilization of predictive biomarker testing in routine care to better understand the observed gaps between trial-based and `real-world' outcomes with these agents. In our nationally representative cohort of lung cancer patients, we found that the vast majority of patients did not undergo molecular testing to inform first-line therapy. Our prediction models for biomarker screening and first-line treatment suggested that phenotypic enrichment criteria guided selection for testing and initiation of erlotinib therapy. Since clinical characteristics do not adequately discriminate between mutation positive and wild type tumors, these practices signal the need for wider dissemination of biomarker screening to accurately target patients towards improving therapeutic gains with erlotinib.
Chapter 3 assessed the cost-effectiveness of multiplexed predictive biomarker screening to inform treatment decisions in lung cancer patients. Using a micro-simulation model to evaluate the incremental value of molecularly guided therapy compared to chemotherapy in unselected patients, we found that personalized therapy is a cost effective strategy. Our results indicated that better value of targeted therapies in lung cancer is achievable through molecularly guided treatment.
18
Stephen, Renu M. "Magnetic Resonance Imaging Biomarkers For Targeted Cancer Therapies." Diss., The University of Arizona, 2008. http://hdl.handle.net/10150/194845.
Анотація:
In 2007, there will be an estimated 178,480 new cases of breast cancer diagnosed in women in the United States. The elucidation of the vast heterogeneity of individual tumors has led to a paradigm shift from a one-size fits all treatment strategy to more individualized treatment based on the molecular profile of the tumor. Identifying biomarkers that respond to or predict the action of drugs is important in identifying efficacious targets and drugs that will improve clinical outcome. To examine this, we first identified two breast cancer cell lines (ACC-3199 and ACC-3171) from a panel of low passage breast cells lines that were capable of growing serially as tumor xenografts. This was followed by the in vivo molecular characterization of these two cell lines. In ACC-3199 tumors, we identified a gain of pAKT expression compared to cultured cells. Based on this finding, we investigated the role of diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) as potential imaging biomarkers in identifying early response to PX-866, a PI3K inhibitor, in ACC-3199 tumors as represented by changes in tumor cellularity and hemodynamic parameters, respectively. Our results indicated that DW-MRI was able to identify an early response to PX-886 in ACC-3199 tumors as defined by an increase in the apparent diffusion coefficient (ADC) value of the tumors prior to changes in tumor volumes. Using DCE-MRI, we were able to conclude that PX-866 was not an effective anti-angiogenic agent as indicated by an increase in tumor permeability following therapy. Based on the VEGFR2 expression observed in ACC-3171 tumor xenografts, we examined the response of MDA-MB-231/GFP and ACC-3171 tumor xenografts to the anti-angiogenic agent, sunitinib, using the same imaging modalities. DW-MRI was able to detect increases in ADC values as early as 12 h post-treatment in both MDA-MB-231/GFP and ACC-3171 tumors. Thus, it appears that DW-MRI may be a useful clinical test in predicting the early response to PI3K and anti-angiogenic inhibitors. These imaging approaches, in addition to the further molecular characterization of breast tumors may lead to the improvement and development of medical therapies for breast cancer patients.
19
Caissie, Amanda L. "Cyclooxygenase-2 and other targets of adjuvant therapies for uveal melanoma." Thesis, McGill University, 2005. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=85893.
Анотація:
Uveal melanoma has a high mortality rate, with approximately 45% of patients dying due to liver metastasis within 15 years of initial diagnosis and local treatment. As the eye lacks lymphatics, there is no staging of uveal melanoma according to lymph node metastasis. The search for new prognostic factors and therapeutic targets is therefore crucial to the advancement of uveal melanoma research. The expression of cyclooxygenase-2 (COX-2) has been investigated in human malignancies such as cutaneous melanoma. Immunohistochemical studies were therefore used to show that uveal melanomas do express COX-2 and that this expression is associated with various histopathological markers of poor prognosis. A novel sub-classification of mixed-cell-type tumours was devised, according to COX-2 expression.The numerous studies of COX-2 expression in human malignancies have focused on COX-2 expression in tumour cells. This work shows COX-2 to be expressed in uveal melanoma tumour cells and tumour-associated macrophages (TAM), with a higher amount of COX-2 expression associated with a higher amount of TAM infiltration. These results may help explain the poor prognosis previously attributed to a high amount of TAM infiltration in uveal melanoma.
This thesis also investigated the co-expression of COX-2, insulin-like growth factor 1 receptor (IGF-IR) and phosphorylated-Akt (p-Akt). A recent paper had shown IGF-1R expression to be associated with a higher risk of uveat melanoma metastasis. IGF-1R expression, present to different degrees in almost all uveal melanoma cases, represents the presence of the receptor, whereas p-Akt expression represents an activated downstream pathway. This thesis showed that p-Akt is expressed in uveal melanoma. While some uveal melanoma cases co-expressed COX-2, IGF-1R and p-Akt, all cases were positive for at least one of the three markers.
Studies in human malignancies, including uveal melanoma, have shown COX-2 inhibitors to have effects on both COX-2 positive and negative tumour cells. The effects of COX-2 inhibitors on IGF-1R and p-Akt have been postulated as possible mechanisms behind these COX-2 independent effects. This work has provided a rationale for the study of COX-2 inhibitors, alone or in combination with IGF-1R inhibitors, as systemic adjuvant treatment of this life-threatening intra-ocular malignancy.
20
Esteve, Arenys Anna. "Innovative targeted therapies for chemorefractory B-cell non-Hodgkin lymphomas." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/565937.
Анотація:
Lymphomas are a heterogeneous group of tumors characterized by the proliferation of lymphocytes predominantly in lymphoid structures but also in extranodal tissues. More than 90% of patients are afflicted by lymphomas of B-cell origin.
The current World Health Organization (WHO) classification of hematopoietic and lymphoid tumors categorizes B-cell neoplasms in more than 40 distinct disease entities, according to a combination of the morphology, immunophenotype, genetic, molecular and clinical features. Each entity has its own clinical course and requires specific treatments.
The characterization of activated signaling pathways involved in survival and proliferation, together with the development of a wide pharmacological armamentarium against cancer, have facilitated the bench-to-bedside translation of new targeted therapies in B-cell non-Hodgkin lymphomas (B-NHL). These novel therapies include two of the most relevant drugs lately approved: the anti-apoptotic agent venetoclax and the BTK inhibitor ibrutinib.
One major hurdle to their successful application is the rise of drug resistance. Resistance to therapy is observed in many cases of B-cell malignancies. This phenomenon significantly limits the utility of the current therapeutic strategies, and remains a substantial challenge for the clinical management of patients with advanced cancers. Resistance comes in two flavors: intrinsic resistance (also known as innate or de novo resistance) and acquired resistance, resulting from the clonal evolution of resistant variants.
With this concept in mind, in this thesis we have explored new approaches to overcome the development of drug resistance.
Venetoclax (ABT-199) is a first-in-class BH3 mimetic, FDA-approved for use in patients with R/R del17p chronic lymphocytic leukemia. In the clinical setting, it has demonstrated high response rates and good toxicity profiles in other subtypes of relapsed/refractory non-Hodgkin lymphoma.
We proposed a model of double hit lymphoma (DHL) resistance to ABT-199 in which the capacity of CPI203 to regulate the transcriptome of the cells could help to circumvent this problem. In ABT-199 sensitive cells, the BH3 mimetic acts by displacing BIM from BCL-2 complexes, allowing the de-repression and/or direct activation of BAX and leading to an activation of mitochondrial outer membrane permeabilization. In DHL cells, a compensatory upregulation of BFL-1 would bind and inactivate the pool of BIM proteins released from BCL-2 by ABT-199, avoiding MOMP and preserving cell survival. CPI203 primes cells to death by decreasing BFL-1 and
increasing BIM protein levels, and its combination with ABT-199 allows to tip the balance between pro- and anti-apoptotic signaling toward induction of cell death. This concept provides a new insight in the proposed mechanisms of resistance to BH3- mimetics in NHL cell lines, where MCL-1 and BCL-XL have been proposed as the major determinants of drug sensitivity and acquired resistance.
On the other hand, ibrutinib is a BTK inhibitor approved for first-line therapy in patients with chronic lymphocytic leukemia, as well as for the treatment of some relapsed/refractory B-NHL. Despite its high level of clinical activity, acquiring of mutations or re-wiring of the BCR pathway to retain the downstream signaling appears to be a common mechanism of resistance.
The inhibition of more than one BCR kinase might be useful in B-NHL cases that are resistant to the sole inhibition of BTK. We describe the compound IQS019 as a new BCR kinase inhibitor able to counteract both constitutive and ligand-dependent activation of the BCR pathway. Its capacity to inhibit the three upstream BCR kinases, BTK, SYK and LYN, confer an advantage over the inhibition of BTK alone by ibrutinib, in in vitro and in vivo models of B-NHL, being of special importance for the treatment of those patients with non-canonical NF-κB activation, who are low responders to ibrutinib.
Therefore, the development of innovative therapeutic approaches that permit to overcome drug resistance opens a window to important therapeutic advances in the treatment of B-NHL.Las neoplasias linfoides de célula B constituyen un grupo heterogéneo de tumores caracterizados por la proliferación de linfocitos B. Cada entidad clínica posee unas características particulares y requiere de un tratamiento específico. A pesar de los importantes avances terapéuticos, la supervivencia a largo plazo sigue siendo baja y precisa de un desarrollo constante de nuevas aproximaciones terapéuticas. Uno de los mayores problemas asociados a la respuesta a fármacos son las resistencias. En muchos casos estas resistencias se deben a cambios en proteínas diana o a la modulación compensatoria de otras proteínas o vías de señalización. El conocimiento de estos cambios será de gran importancia para poder encontrar aproximaciones terapéuticas que permitan eliminar estas resistencias. El linfoma doble-hit es un linfoma agresivo caracterizado por su baja respuesta a la quimioterapia estándar. Entre los múltiples agentes terapéuticos específicos actualmente en desarrollo encontramos el inhibidor de BCL-2, venetoclax. El venetoclax ha demostrado ser efectivo en varios subtipos de linfoma pero su uso conlleva el problema de la aparición de resistencias. Varios estudios han destacado el papel de proteínas de la familia BCL-2 en este proceso. Nuestros resultados indican que la regulación positiva de BFL-1 es uno de los factores clave en el desarrollo de resistencias al fármaco. Su regulación mediante el CPI203, un modulador epigenético, resulta en una sensibilización al venetoclax, tanto in vitro como in vivo. Por otro lado, la señalización de los receptores de células B (BCR) contribuye a la patogénesis de las neoplasias malignas de células B y ha surgido como una nueva diana terapéutica en varios tipos de linfoma. Así, los inhibidores de quinasas de la vía del BCR constituyen una estrategia terapéutica prometedora. Dentro de este grupo de fármacos destaca el inhibidor de Btk ibrutinib, que ha conseguido esperanzadoras tasas de respuesta pero que también se ve afectado por la aparición de resistencias. Nuestro trabajo muestra que el compuesto IQS019, inhibidor de varias quinasas de la vía del BCR (Btk, Syk y Lyn), posee un potente efecto antitumoral y permite escapar a las resistencias observadas al ibrutinib. Así, supone un buen tratamiento para varios subtipos de linfomas de células B, incluyendo aquellos poco sensibles a los inhibidores de quinasa de BCR actuales.
21
Serna, Romero Naroa. "Development of self-assembling protein only nanoparticles for targeted therapies." Doctoral thesis, Universitat Autònoma de Barcelona, 2018. http://hdl.handle.net/10803/662777.
Анотація:
Las medicinas innovadoras demandan con urgencia nuevos vehículos funcionales para la entrega dirigida de fármacos convencionales y novedosos, preferentemente en forma de nanopartículas. Los materiales nanoestructurados mejoran la biodistribución y la penetración celular, lo que les convierten en transportadores eficaces de fármacos, que con un rango de tamaño entre 6 y 100 nm escapan al filtrado renal. La arquitectura de estos nanoconjugados vehículo-fármaco debe ser lo suficientemente estable para permitir la circulación sistémica y la entrega específica en los tejidos diana, reduciendo así al mínimo la potencial toxicidad y efectos secundarios del fármaco. El propio vehículo debe ser no inmunogénico y no tóxico. De hecho, la toxicidad de los materiales explorados para la fabricación de nanopartículas es un tema crítico. Los nanotubos de carbono, dendrímeros, diferentes tipos de polímeros, materiales cerámicos y metales, a pesar de que poseen propiedades fisicoquímicas atractivas, exhiben efectos adversos, citotoxicidad y acumulación en el cuerpo y en el medio ambiente. Estos materiales deben ser funcionalizados para poder asociarse con el fármaco y para adquirir propiedades de unión específica a receptor.
Alternativamente, las proteínas son totalmente biocompatibles y funcionales, adecuadas para su bioproducción a gran escala. Alrededor de 400 proteínas terapéuticas han sido aprobadas por la FDA y EMA para su uso humano, lo que demuestra la viabilidad industrial de la producción biológica. Las proteínas pueden ser modificadas por ingeniería genética convencional para reclutar funciones deseadas, como unión a receptor, internalización, escape endosomal, entrega nuclear, autoensamblaje y unión a fármaco.
En este contexto, hemos desarrollado previamente una plataforma metodológica para generar partículas proteicas que se autoensamblan en forma de nanopartículas de alrededor de 20 nm que mimetizan las características arquitectónicas de los virus, incluyendo biodistribución, reconocimiento celular y penetración celular. Hemos demostrado previamente que estas nanopartículas muestran una biodistribución selectiva y acumulación en tumor tras ser administradas de forma intravenosa in vivo.
En esta tesis, hemos estudiado por un lado mas profundamente la plataforma de autoensamblaje y hemos desarrolado un principio de ingeniería para obtener nanopartículas de tamaño definido. Además, hemos analizado si la presentación en forma de nanopartículas de proteínas multifuncionales favorece su paso a través de la barrera hematoencefálica para su posible aplicación en enfermedades neurológicas.
Por otro lado, hemos seleccionado diferentes dominios citotóxicos proteicos (Bak, Puma, GWH1) y hemos generado nanopartículas estables con capacidad de acumularse en las células diana y que además, muestran actividad citotóxica intrínseca para su aplicación en cáncer y enfermedades infecciosas.
En resumen, la generación de partículas proteicas no immunogénicas, libres de vehículo, que escapen al filtrado renal, con capacidad de unión celular selectiva y con actividad citotóxica es un concepto totalmente nuevo en Nanomedicina, que se espera que tenga un profundo impacto social, científico y metodológico en la medicina innovadora del cáncer y, potencialmente, de otras enfermedades humanas.Innovative medicines urgently demand novel cell-targeted functional vehicles for the controlled delivery of conventional and novel drugs, desirably within the nanoscale. Nanostructured materials show high tissue and cell penetrability that make them very appealing in medicine, while escaping both renal clearance and aggregation in lung when sizing between 6 nm and 100 nm. The architecture of such vehicle-drug conjugates should be tight enough to allow stable systemic circulation and delivery into target tissues, thus minimizing the potential toxicity/side-effects of the cargo due to generic exposition of healthy organs. Importantly, the vehicle itself must be non-immunogenic and non-toxic. In fact, toxicity of the materials currently under exploration for nanoparticle fabrication is a major matter of concern. Carbon nanotubes, dendrimers, different types of polymers, ceramics and metals, despite possessing appealing physicochemical properties exhibit adverse effects concerning cytotoxicity and accumulation in the body and in the environment. All these materials need to be functionalized upon fabrication to associate with the cargo drug and to acquire receptor-based targeting properties. Alternatively, proteins are fully biocompatible and functional biomaterials suitable for scaled-up bioproduction, and about 400 protein therapeutics have been approved for used in humans by the FDA and EMA, proving the industrial feasibility of biological production for human therapies. Proteins can be conveniently modified by conventional genetic engineering to recruit desired functions such as cell receptor binding, internalization, endosomal escape, nuclear delivery, self-assembling and cross-molecular interactions for drug loading. In this context, we have previously developed a methodological platform to generate self-organizing, protein-only building blocks based on modular schemes, which once self-assembled as nanoparticles of around 20 nm, mimic the viral functions relevant to architectonic stability, proper biodistribution, cell targeting and cell internalization. We have previously demonstrated that these nanoparticles show selective biodistribution and accumulation into the tumor upon intravenous administration in vivo. In this thesis, on one hand, we have deeply studied this self-assembly platform and developed an engineering principle that allows obtaining nanoparticles of a defined size. In addition, we have analyzed whether the nanoparticulate presentation of multifunctional proteins favours their delivery through the blood-brain barrier for their possible application in neurological diseases. On the other hand, we have selected different cytotoxic protein domains (BAKBH3, PUMA, GWH1…) and generated stable nanoparticles with the capacity to accumulate in the target cells and that also, show intrinsic cytotoxic activities for their application in cancer and infectious diseases. In summary, the generation of fully functional, non immunogenic, vehicle-free protein-only nanoparticles escaping renal filtration and showing cytotoxic activity is a totally new concept in Nanomedicine that is expected to have a deep social, scientific and methodological impact in emerging medicines of cancer and potentially, of other relevant human diseases.
22
Giménez, Carabaza Neus. "Targeted therapies in CLL. New drugs against CLL recurrent mutations." Doctoral thesis, Universitat de Barcelona, 2019. http://hdl.handle.net/10803/668219.
Анотація:
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western countries. It is currently an incurable disease. CLL is a B-lymphoid neoplasm in which the microenvironment plays a key role in the development and evolution of the disease. The complete sequencing of 500 CLL patients described the presence of recurrent mutations, the study of which could improve clinical interventions in the management of this neoplasm and design specific treatments for each patient.
In this dissertation we have studied two of the most frequently mutated pathways in CLL: RAS-BRAF-MAPK-ERK and TLR-MYD88, as potential therapeutic targets.
The results obtained during this thesis, described below, have been published in two articles published in the journals Haematologica (PMID: 30262568) and Leukemia (PMID: 31197259) in 2019.
Patients with mutations in these pathways have differential clinical and biological characteristics. Mutated RAS-BRAF-MAPK-ERKs have higher levels of lactate dehydrogenase, ZAP-70, CD49d, CD38, Trisomy 12 and non-mutated immunoglobulin heavy chain region genes. High percentage of this mutated patients are treated before 5 years after the diagnosis. On the other hand, cases with TLR-MYD88 mutations have a better prognosis.
Stimulation of the RAS-BRAF-MAPK-ERK pathway induces an increase in ERK phosphorylation, indicative of increased proliferation and survival.
Stimulation of TLR-MYD88 also increases proliferation and survival, but also increases cell migration and cytokine secretion. Thus, the inhibition of these pathways, could be a possible therapeutic strategy for the CLL management.
Inhibition of the RAS-BRAF-MAPK-ERK pathway with the BRAF inhibitors already available in the clinic (vemurafenib and dabrafenib) was not possible in cases with mutations in the pathway. In contrast, ulixertinib, a pan-ERK inhibitor, did show positive results, but more studies should be done.
Inhibition of the TLR-MYD88 pathway was performed with the IRAK4 (key kinase for the pathway) inhibitor ND2158. Our results demonstrate that ND2158, with a dose-dependent effect, has a preferential effect on CLL cells over B cells from healthy donors. ND2158 treatment in primary cells of CLL shows a reduction in: NF-kB and STAT3-mediated signaling, cytokine secretion, proliferation and migration. We validated its effect in vivo on the Eμ-TCL1 transgenic mouse model, the most widely accepted for the study of CLL and its microenvironment. It has been observed that ND2158 is capable of reducing tumor progression as well as reducing mediated support by the myeloid tumor microenvironment. In contrast, ND2158 inhibits the expansion of effector CD8+ T cells and induces an exhaustion cell phenotype, an unwanted phenomenon for a good efficacy of the drug. To overcome this negative impact we propose a combination with immunotherapy, to improve the function of T lymphocytes and thus preserve the tumor control that the immune system function. We have also shown that ND2158 enhances the effect of two of the currently approved CLL clinical treatments, venetoclax and ibrutinib, thereby opening the door for possible clinical studies based on our data.
On the other hand, an in vitro validation project of compounds selected by system biology has also been started. As a result, we have concluded that statins, in combination with current venetoclax or ibrutinib treatments, could also be a new therapeutic strategy for CLL control.
23
Miniotis, Maria Falck. "Evaluation of MRS detectable metabolic markers of MEK1/" targeted therapies." Thesis, University of London, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.533141.
24
Martinez, Chanza Maria. "CYTOTOXIC AGENTS AND MOLECULAR TARGETED THERAPIES IN GENITOURINARY TRACT TUMORS." Doctoral thesis, Universite Libre de Bruxelles, 2021. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/323785.
Анотація:
Les agents cytotoxiques et les thérapies moléculaires ciblées sont l’un des piliers du traitement des patients atteints de tumeurs génito-urinaires. Cependant, il existe de nombreuses situations médicales pour lesquelles l’on manque d’options thérapeutiques standards dans la pratique clinique. Ce travail de recherche clinique vise à identifier et comprendre de telles situations ainsi qu'à essayer d'améliorer les résultats cliniques de ces sous-groupes de patients. Afin d'atteindre cet objectif, différents projets cliniques ont été développés.La première partie de cette thèse est consacrée à l'évaluation de l'efficacité et de l'innocuité du cabozantinib, un puissant multi-inhibiteur de la tyrosine kinase approuvé dans le carcinome rénal avancé, ceci dans deux entités cliniques associes aux besoins médicaux non satisfaits :les patients avec un diagnostic de carcinome rénal pas à cellules claires métastatique et les patients avec un cancer du rein et métastases cérébrales.La deuxième partie de la thèse est consacrée au cancer de la vessie musculo invasif non métastatique pour lequel un traitement néoadjuvant et une résection chirurgicale sont recommandés. Nos projets évaluent les facteurs prédictifs potentiels de réponse à la chimiothérapie néoadjuvant standard à base de platine, l'efficacité et l'innocuité de l'ajout d'un agent immunothérapeutique à la chimiothérapie néoadjuvante ainsi que le rôle de l’ajout d’une chimiothérapie adjuvante chez les patients présentant une maladie résiduelle malgré une chimiothérapie néoadjuvante.Doctorat en Sciences médicales (Médecine)
info:eu-repo/semantics/nonPublished
25
Tavallai, Mehrad. "INTRODUCING NOVEL COMBINATORIAL TARGETED THERAPIES IN MULTIPLE TYPES OF CANCER." VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4088.
Анотація:
The cancers of liver, colon and breast are amongst the top five most prevalent and most fatal worldwide. As the Raf/MEK/ERK pathway is frequently deregulated in hepatocellular carcinoma (HCC), sorafenib, a Raf kinase inhibitor, became the first systemic therapy approved for the treatment of patients with HCC. However, sorafenib only produced modest effects with low response rates in the clinic. Similarly, regorafenib, which was approved for the treatment of metastatic colorectal cancer (CRC), has had a poor response rate in the clinic. Since phosphodiesterase type 5 has been reported to be overexpressed in HCC and CRC, we hypothesized that sildenafil, a phosphodiesterase type 5 inhibitor, could enhance the toxicities of sorafenib and regorafenib in HCC and CRC cells, respectively. Our in vitro data indicated that the drugs interacted strongly to kill cancer cells via induction of ER stress, autophagy and apoptosis. In accordance with these findings, our in vivo data demonstrated a significant reduction in tumor growth.
The second study in this manuscript was conducted based on the growing body of evidence about the significant contribution of EGFR and JAK/STAT signaling to the breast tumorigenesis. Our preliminary in vitro data demonstrated that the concurrent inhibition of these two pathways by lapatinib, a dual ERBB1/2 inhibitor, and ruxolitinib, a JAK1/2 inhibitor, synergistically killed breast cancer cells of all types, including the resistant triple negative subtype. Our mechanistic studies showed that the combination of ruxolitinib and lapatinib triggered cytotoxic mitophagy, and autophagy-dependent activation of BAX and BAK leading to the mitochondrial dysfunction.
26
Dawson, Jesse. "Prevention of stroke risk stratification and targeted and novel therapies /." Thesis, Connect to e-thesis, 2009. http://theses.gla.ac.uk/851/.
Анотація:
Thesis (MD.) - University of Glasgow, 2009.MD. thesis submitted to Division of Cardiovascular and Medical Sciences, University of Glasgow, 2009. Includes bibliographical references. Print version also available.
27
Heisey, Daniel A. R. "TARGETED THERAPIES FOR EWSR1-FLI1 TRANSLOCATED EWING FAMILY OF TUMORS." VCU Scholars Compass, 2019. https://scholarscompass.vcu.edu/etd/5950.
Анотація:
The EWSR1-FLI1 t(11;22)(q24;q12) translocation is the pathognomonic genomic alteration in 85% of the Ewing Family of Tumors (EWFT) a malignancy of the bone and the surrounding tissue, predominantly affecting children and adolescents. This translocation results in the formation of a chimeric oncoprotein which acts as an aberrant transcription factor that is currently not pharmaceutically druggable, driving the need for more effective targeted therapies. The EWSR1-FLI1 translocation induces a variety of changes including dysregulation of the epigenome and altered gene expression to drive tumorigenesis, and consequently contributes to the hypersensitivity of EWFT to several classes of chemotherapeutics. We sought to exploit these intrinsic sensitivities by employing a matched pair of cell lines derived from the same patient with Ewing sarcoma prior to and following chemotherapy, a panel of Ewing sarcoma cell lines, and several patient-derived xenografts (PDX) collected at the time of relapse or autopsy, which led us to the development of two novel combination targeted therapies for EWFT.
In our matched pair of EWFT cell lines, we found sensitivity to the Poly(ADP-ribose Polymerase (PARP) inhibitor olaparib was diminished following chemotherapy, despite a predicted sensitivity. In addition, we discovered increased expression of the antiapoptotic protein BCL-2 in the chemotherapy-resistant cells, conferring apoptotic resistance to olaparib. We found that EWS-FLI1 increases BCL-2 expression; however, inhibition of BCL-2 alone is insufficient to sensitize EWFT cells to olaparib, revealing a dual necessity for BCL-2 and BCL-XL (BCL2L1) in EWFT survival. These data reveal BCL-2 and BCL-XL act together to drive olaparib mediated apoptotic resistance in Ewing sarcoma and identify a novel, rational combination therapy using olaparib and the BCL-2/BCL-XL inhibitor navitoclax.
In addition, using high throughput drug screening we have identified a novel epigenetic susceptibility in EWFT to GSK-J4 (GlaxoSmithKline), an inhibitor of lysine 27 of histone 3 (H3K27) demethylases: ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX) and Jumonji D3 (JMJD3). Treatment with GSK-J4 leads to a decrease in H3K27 acetylation (H3K27ac) and ultimately, the silencing of EWS-FLI1 gene targets.
We sought to sensitize GSK-J4-mediated inhibition of EWS-FLI1 targets by blocking RNA polymerase II activity using the Cyclin Dependent Kinase 7 (CDK7) inhibitor THZ1. By targeting CDK7-mediated transcription we were able to sensitize EWFTs to H3K27 demethylase inhibition. We therefore propose co-targeting of H3K27 demethylases and CDK7 acts as a surrogate EWS-FLI1 inhibitor. Given the difficulties targeting EWS-FLI1, these strategies may present viable clinical therapies.
28
Hing, Zachary Andrew. "Targeting Nuclear Export in Chronic Lymphocytic Leukemia." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1523543484958313.
29
Pavlik, Aaron, Phillip Schneider, and Cheryl Cropp. "Proposing Molecularly Targeted Therapies Using an Annotated Drug Database Querying Algorithm in Cutaneous Melanoma." The University of Arizona, 2015. http://hdl.handle.net/10150/614155.
Анотація:
Class of 2015 AbstractObjectives: The aim of this study was to develop a computational process capable of hypothesizing potential chemotherapeutic agents for the treatment of skin cutaneous melanoma given an annotated chemotherapy molecular target database and patient-specific genetic tumor profiles. Methods: Aberrational profiles for a total of 246 melanoma patients indexed by the Cancer Genome Atlas (TCGA) for whom complete somatic mutational, mRNA expression, and protein expression data was available were queried against an annotated targeted therapy database using Visual Basic for Applications and Python in conjunction with Microsoft Excel. Identities of positively and negatively associated therapy-profile matches were collected and ranked. Results: Subjects included in the analysis were predominantly Caucasian (93%), non-Hispanic (95.9%), female (59%), and characterized as having stage III clinical disease (37.4%). The most frequently occurring positive and negative therapy associations were determined to be 17-AAG (tanespimycin; 42.3%) and sorafenib (41.9%), respectively. Mean total therapy hypotheses per patient did not differ significantly with regard to either positive or negative associations (p=0.1951 and 0.4739 by one-way ANOVA, respectively) when stratified by clinical melanoma stage. Conclusions: The developed process does not appear to offer discernably different therapy hypotheses amongst clinical stages of cutaneous melanoma based upon genetic data alone. The therapy-matching algorithm may be useful in quickly retrieving potential therapy hypotheses based upon the genetic characteristics of one or many subjects specified by the user.
30
Malric, Laure. "Rôle de l'intégrine bêta 8 dans le maintien de l'état souche et la radiorésistance des cellules souches de glioblastomes : vers une nouvelle thérapie ciblée." Thesis, Toulouse 3, 2018. http://www.theses.fr/2018TOU30109/document.
Анотація:
Les glioblastomes (GB) sont des tumeurs cérébrales invasives, résistantes et qui récidivent systématiquement malgré un traitement associant chirurgie, radio- et chimiothérapie. Ces tumeurs de très mauvais pronostic, se caractérisent par une survie médiane de 15 mois. L'agressivité des GB est notamment due à la présence d'une sous-population de cellules souches (GSC). Les GSC sont caractérisées par leurs capacités d'auto-renouvellement, d'expression de différents marqueurs souches, de multipotence et de tumorigenèse. Elles sont fortement impliquées dans la résistance et la récidive tumorale et leur ciblage pourrait améliorer le traitement des GB. Au vu de la littérature et de résultats obtenus au laboratoire, l'intégrine ß8 est apparue comme une nouvelle cible potentielle de ces GSC. Cette intégrine est décrite comme possédant un rôle majeur dans la survie et l'auto-renouvellement des cellules progénitrices neurales saines et sa surexpression est associée à une diminution de la survie des patients. Nous avons alors émis l'hypothèse que l'intégrine ß8 pourrait être impliquée dans le maintien de l'état souche des GSC. J'ai démontré au cours de ma thèse que cette intégrine est surexprimée dans des primocultures de GSC issues de résections de GB ainsi que dans des coupes de tumeurs de patients. De plus, j'ai mis en évidence que ß8 est associée à l'état souche et à des fonctionnalités propres à ces cellules, notamment leur auto-renouvellement, leur viabilité, leur migration et leur radiorésistance. En inhibant sélectivement ß8 dans nos primocultures de GSC par si/shRNA, j'ai en effet observé in vitro une diminution de la formation de neurosphères et de la migration cellulaire ainsi qu'une augmentation de la différentiation et de la mort cellulaire, cette dernière étant potentialisée après irradiation. Enfin, in vivo, j'ai mis en évidence que l'inhibition de ß8 se traduit par une diminution de la tumorigenèse et une augmentation de la survie des souris. En conclusion, mes résultats de thèse permettent d'identifier l'intégrine ß8 comme une protéine membranaire nécessaire au maintien de l'état souche dans les GSC mais surtout comme une potentielle cible thérapeutique radiosensibilisante dans les GBGlioblastomas (GB) are invasive, resistant and recurrent brain tumors (median overall survival of 15 months) despite standard treatment including surgical resection, radio- and chemotherapy. This tumor aggressiveness could partly be explained by the presence into the tumor of Glioblastoma-Stem like Cells (GSC), characterized by their ability to self-renew, their higher expression of specific GSC markers, their multipotent aptitude and their high tumorigenic potential. They are strongly involved in tumor resistance and recurrence and their targeting could improve GB treatment. Regarding current literature but also transcriptomic results obtained in our lab, a specific ß8 integrin emerged as a potential selective target in GSC. We then hypothesized that ß8 integrin could be involved in stemness maintenance of GSC. I first demonstrated, during my doctoral thesis, that ß8 is overexpressed in primocultures of GSC isolated from patients resections and also in human GB samples. Moreover, I showed that this integrin could be associated with stemness and features unique to these cells, including self-renewal ability, viability, migration and radioresistance. Indeed, the selective inhibition of ß8 in GSC by si/shRNA resulted in vitro in a decrease of neurosphere formation and migration, associated with an increase of differentiation patterns and cell death, this one being potentiated after irradiation. Finally, in vivo, I showed that ß8 inhibition decreased tumorigenesis and increased mice survival. In conclusion, my doctoral results allow to identify ß8 integrin as a membrane protein essential for stemness maintenance of GSC but mostly as a new potential radiosensitizing therapeutic target for GB
31
Gracia-Maldonado, Gabriel. "Exploiting the MLL-rearranged leukemia gene signature to identify molecular targets for novel therapies." University of Cincinnati / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1573570752309466.
32
Sánchez, García Laura. "Engineering all-in-one protein-based nanoparticles for targeted cancer therapies." Doctoral thesis, Universitat Autònoma de Barcelona, 2019. http://hdl.handle.net/10803/667195.
Анотація:
Actualmente, las terapias convencionales contra el cáncer están lejos de ser ideales en cuanto a eficacia. Los fármacos actuales, formados por pequeños compuestos químicos se distribuyen indistintamente por todo el organismo, generando elevada toxicidad sistémica y dando lugar a efectos secundarios en tejidos sanos. En este contexto, la nanomedicina es una disciplina emergente que ofrece alternativas prometedoras para el desarrollo de terapias innovadoras y mejoradas contra el cáncer.
Siendo materiales especialmente versátiles, las proteínas recombinantes están ganando mucho interés en el área de la biomedicina, con más de 400 fármacos recombinantes aprobados por agencias médicas. Las nanopartículas modulares y multifuncionales con naturaleza proteica son grandes candidatos para la entrega de fármacos ya que presentan gran estabilidad, biocompatibilidad y biodegradabilidad en el torrente sanguíneo. A la hora de diseñar sistemas para la administración de fármacos, el tamaño es una de las características más relevantes. Partículas dentro de la nanoescala (alrededor de los ~8 – 100 nm) poseen una mayor estabilidad ya que pueden escapar de la filtración renal y por tanto tienen un mayor tiempo de circulación y mejor biodistribución (comparado con los compuestos químicos de menor tamaño). Por eso en nuestro grupo se ha desarrollado un principio nanoarquitectónico para el desarrollo de ensamblajes proteicos comprendidos en la nanoescala. Este principio se fundamenta en el uso de péptidos terminales catiónicos, para la oligomerización de monómeros en nanopartículas auto-ensambladas. Estas nanoestructuras proteicas modulares pueden ser empleadas como vehículos dirigidos a células si el péptido catiónico situado en el extremo N-terminal es además un ligando especifico de tumor. Sin embargo, la conjugación química de estos vehículos a un fármaco convencional conlleva riesgos debido a posibles liberaciones del mismo y posteriores efectos secundarios. Por todo ello, el principal objetivo de esta tesis ha sido explorar la aplicabilidad de este principio para el desarrollo de nanomedicinas proteicas multifuncionales y libres de vehículos adicionales. Este propósito se ha llevado a cabo mediante el diseño racional de novo de proteínas intrínsecamente citotóxicas como entidades terapéuticas para desarrollar fármacos antitumorales proteicos dirigidos a tumor.
A partir de ahora, a raíz de los prometedores resultados discutidos en esta tesis, consideramos que es necesario seguir estudiando en profundidad la potencial aplicación de esta plataforma proteica multifuncional para el tratamiento de muchas otras enfermedades.Nowadays, conventional cancer therapies are far from being optimal in terms of efficacy. Current drugs are small chemical entities that equally distribute all over the organism, presenting high systemic toxicity and leading to undesired side effects on healthy tissues. In this context, nanomedicine is an emerging area that offers promising alternatives for the development of innovative and improved oncotherapies. Being extremely versatile materials, recombinant proteins are gaining interest in the biomedical area, with more than 400 recombinant pharmaceuticals approved by medical agencies. Modular and multifunctional protein-based nanoparticles are appealing candidates for drug delivery as they show high stability, biocompatibility and biodegradability in the blood stream. When designing drug delivery systems, size is one of the most relevant properties. Particles in the nanoscale (around ~8 – 100 nm) benefit from enhanced stability as they escape from renal filtration and thus present extended circulation time and improved biodistribution (compared to smaller chemical drugs). For that, in our group has been developed a nanoarchitectonic principle for the generation of protein-based assemblies ranged in the nanoscale. The principle relies on the use of cationic end-terminal peptides as pleiotropic tags for the oligomerization of monomers into self-assembled nanoparticles. Such modular protein-based nanostructures can be widely used as cell-targeted nanocarriers if the cationic N-terminal peptide is simultaneously a tumour-specific ligand. However, chemical conjugation of nanocarriers to conventional drugs is extremely risky due to the associated drug leakage and subsequent side effects. In this context, the main purpose in this PhD thesis was to explore the translational applicability of this principle for the development of all-in-one vehicle-free protein nanomedicines. This goal has been addressed through de novo rational design of diverse intrinsically cytotoxic proteins as therapeutic building blocks to develop protein-only tumour-targeted antitumoral drugs. From now on, encouraged by the promising results discussed in this thesis, we consider it is imperative to keep on studying in detail the potential application of this all-in-one protein-based platform for the treatment of any unrelated diseases.
33
Thangavelu, Amudha. "Targeted therapies in endomental cancer - in vitro and in vivo models." Thesis, University of Leeds, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.531515.
34
Bodey, Rachel Kay. "The combination of dosimetry for targeted radionuclide and external beam therapies." Thesis, Institute of Cancer Research (University Of London), 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.417601.
35
Rodrigues, Tiago André Moura. "Current options in breast cancer targeted therapies: life after HER-2." Master's thesis, Instituto de Ciências Biomédicas Abel Salazar, 2009. http://hdl.handle.net/10216/53412.
36
Rodrigues, Tiago André Moura. "Current options in breast cancer targeted therapies: life after HER-2." Dissertação, Instituto de Ciências Biomédicas Abel Salazar, 2009. http://hdl.handle.net/10216/53412.
37
Hewing, Bernd [Verfasser]. "Monozyten und Makrophagen – Targets für eine antiinflammatorische Therapie kardiovaskulärer Erkrankungen / Bernd Hewing." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2018. http://d-nb.info/1156901561/34.
38
Sallaberry, Pinto Júlia. "Novel markers and targets of collective tumor cell invasion before and after anti-angiogenic therapies." Doctoral thesis, Universitat de Barcelona, 2019. http://hdl.handle.net/10803/666666.
Анотація:
Local invasion is a key cell-biological event in the metastatic cascade. In response to a changing microenvironment, cancer cells may act using two main strategies of invasion: single cell invasion and collective invasion. Determining how tumor cells initiate and sustain local invasive behavior might help to improve patient diagnosis and lead to the development of new intervention modalities. Therefore, the aim of this thesis is to elucidate which molecular mechanisms are involved in PanNETs invasion before and after anti-angiogenic therapies.
Results from our group have demonstrated an irreversible increase in the incidence of invasive tumors during anti-angiogenic treatment in the RIP1-Tag2 mouse model. The RIP1-Tag2 mouse model is a valuable prototype of stepwise progression of tumorigenesis, and for this reason represents an appropriate choice for studying invasion in PanNETs. In addition, three dimensional models were developed with the aim of verifying the collective cell invasion process in βTC4 spheroids from RIP1-Tag2 tumors.
First, the morphology of RIP1-Tag2 tumors was described as collective tumor cell invasion, both before and after anti-angiogenic treatment. In detail, CLDN4 expression was associated with a high invasion capacity, reflected in the barrier function stability and adhesion union between cells. Cells and spheroid βTC4 models, in turn, demonstrated the functional implication of CLDN1 in the invasion of cancer cells. Finally, in clinical samples of PanNETs patients, CLDN1 was directly associated with tumor progression.
In summary, we identified a new link between barrier claudins, specifically 1 and 4, and the collective cell invasion process. In the future, through further validations, these markers could be used as tumor progression biomarkers for PanNETs tumors, as well as potential targets to intervene in collective invasion.La invasión local es un evento biológico celular clave en la cascada metastásica. En respuesta al microambiente tumoral, las células pueden actuar utilizando dos estrategias principales de invasión: la invasión de células individuales y la invasión colectiva. Determinar cómo las células tumorales inician y mantienen el comportamiento invasivo local podría contribuir en la mejora del diagnóstico del paciente y conducir al desarrollo de nuevas modalidades de intervención. Por lo tanto, el objetivo de esta tesis es determinar cuáles son los mecanismos moleculares involucrados en la invasión de PanNETs antes y después de las terapias anti angiogénicas. Resultados previos de nuestro grupo demostraron un aumento irreversible en la incidencia de tumores invasivos durante el tratamiento anti angiogénico en RIP1-Tag2. Los ratones transgénicos RIP1-Tag2 son un prototipo detallado de la progresión gradual en la tumorigénesis, por ello representan un modelo animal ideal para estudiar el proceso de invasión in vivo. Además, se desarrollaron modelos tridimensionales buscando verificar el proceso de invasión colectiva en esferoides βTC4 derivados de tumores RIP1-Tag2. En primer lugar, la morfología de los tumores RIP1-Tag2 se ha descrito como colectiva tanto antes y como después de la inhibición farmacológica de la angiogénesis. En detalle, la expresión de CLDN4 ha sido asociada a la capacidad de invasión colectiva, reflejada en la estabilidad de la función barrera y la integridad de la adhesión entre las células. Las células y esferoides βTC4, por su parte han demostrado la implicación funcional de CLDN1 en la invasión de células cancerosas. Finalmente, una asociación directa entre la expresión de CLDN1 y la progresión tumoral ha sido observada en las muestras clínicas de pacientes PanNETs. En resumen, hemos descrito una nueva conexión entre las claudinas de barrera, especialmente las CLDN1/4 y el movimiento colectivo de invasión tumoral. En el futuro, a través de validaciones adicionales, estos marcadores podrían ser aplicados como biomarcadores de progresión tumoral de PanNETs, así como potenciales dianas para la modulación de la invasión colectiva.
39
Mao, Yicheng. "Monoclonal Antibody and Liposomal Nanoparticle-based Targeting Therapies for Chronic Lymphocytic Leukemia." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1354299911.
40
Feustel, Dania Anuschka. "Untersuchungen zur Expression und Regulation der CML-spezifischen Hybridkinase p210bcr/abl als Target einer potentiellen tumorspezifischen Therapie." Giessen VVB Laufersweiler, 2008. http://d-nb.info/992934605/04.
41
Campbell, Lynn Rachel. "The role of her-targeted therapies on chemosensization in gastro-oesphageal cancer cells." Thesis, Queen's University Belfast, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.534707.
42
Randall, Adrian Joseph. "A systems approach to uncovering the adaptive response of cancer to targeted therapies." Thesis, Massachusetts Institute of Technology, 2012. http://hdl.handle.net/1721.1/72967.
Анотація:
Thesis (S.M.)--Massachusetts Institute of Technology, Computational and Systems Biology Program, 2012.Cataloged from PDF version of thesis.
Includes bibliographical references (p. 47-53).
Tyrosine kinase inhibitors have significant promise in the fight to develop agents that can target cancer in a tumor-specific manner. A number of drugs have been and are currently in development to inhibit specific kinases that can mediate uncontrolled proliferation; however, an unfortunate eventuality for most patients receiving these treatments is the development of resistance that renders these drugs almost completely ineffective. While a number of mechanisms can evolve within a tumor to mitigate effects of kinase inhibitors, we sought to uncover what changes are occurring in the tyrosine phosphorylation network at both short timescales (minutes to 72 hours) and long timescales (120 hours+) that can be playing a role in helping a tumor become resistant to driver-kinase inhibition. It is our hypothesis that specific feedback networks are able to detect and overcome driver kinase inhibition through activation of potential other pathways, which can go on to mediate a longer term resistance phenotype. In order to probe dynamics in the tyrosine phosphorylation network, we employed mass spectrometry to analyze peptides derived from six non-small cell lung cancer cell lines that we classify as either EGFR+ or EML4-ALK+. From both mass spectrometry data and growth assays, we identified an unintuitive boost in signaling and growth in response to low inhibitor concentrations, suggestive of a cellular mechanism that is adaptive to driver kinase inhibition. Studies of EML4-ALK driven H3122 cells showed that this short-term response is not the same as the known long-term resistance mechanism to ALK inhibition, leading support to the notion that the short-term "adaptive response" may be a novel type of mechanism to aid tumor adaptation to targeted therapies. In an effort to better probe signaling events occurring downstream of the phosphotyrosine network, a new pull down technique for mass spectrometry using 14-3-3 protein against phosphoserine and phosphothreonine peptides is described. The results of these studies open up many potential avenues for further exploration into the immediate and long-term signaling response of cancer to targeted therapies.
by Adrian Joseph Randall.
S.M.
43
Tarrado, Castellarnau Miriam. "Targeting metabolic reprogramming associated to cancer cells: search of novel targets and combined therapies in cancer treatment." Doctoral thesis, Universitat de Barcelona, 2015. http://hdl.handle.net/10803/385425.
Анотація:
Cancer is characterised by the lost of physiological control and the malignant transformation of cells that acquire functional and genetic abnormalities, leading to tumour development and progression. Colon and lung cancer are two of the most common cancers worldwide. In early stages of the disease, surgery is the common choice while chemotherapy is the main treatment for advanced stage cancer. However, the currently available chemotherapeutic treatments exhibit modest efficacy due to their side effects and drug resistance. Therefore, the search for combined chemotherapies with low systemic toxicity and high efficiency holds great promise to decrease the morbidity and mortality of cancer.
Tumour cells present common biological capabilities sequentially acquired during the development of cancer that are considered essential to drive malignancy. In particular, tumour cells switch their core metabolism to meet the increased requirements of cell growth and division. Indeed, oncogenic signals converge to reprogram tumour metabolism by enhancing key metabolic pathways such as glycolysis, pentose phosphate pathway (PPP), glutaminolysis and lipid, nucleic acid and amino acid metabolism. Several oncogenes including c-MYC, hypoxia inducible factor 1 (HIF1), phosphoinositide-3-kinase (PI3K), protein kinase B (PBK or Akt) and the mechanistic target of rapamycin (mTOR), have been known to be involved in the regulation of tumour metabolic reprogramming. Then, the study of the tumour metabolic reprogramming and its connection with oncogenic signalling is an essential strategy to identify new targets for cancer therapy.
Thus, the main objective of this thesis was to explore new possibilities for cancer treatment and diagnosis. To this end, we have analysed the links between metabolism and tumour progression, the tumour metabolic reprogramming associated to the dysregulation of cell cycle, and the use of combination therapies for cancer treatment. In order to accomplish our main objective, the results of this thesis are divided in three chapters:
1. We have identified glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a potential predictive biomarker for tumour staging and prognosis of human colorectal cancer. In addition, our results clearly discourage the use of GAPDH as a housekeeping marker in colorectal cancer.
2. We have characterised the metabolic reprogramming associated to the inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) in colon cancer cells. CDK4/6 inhibition causes a shift towards enhanced metabolism of glucose, glutamine and amino acids by increasing mitochondrial metabolism and function as well as glycolytic flux. Fluxomics and transcriptomics integrated data analysis revealed that this metabolic reprogramming is directed by MYC, which is accumulated when CDK4/6 are inhibited. In fact, the identification of the tumour metabolic adaptations associated to CDK4/6 inhibition reveals potential metabolic vulnerabilities that can be exploited in combination therapies with CDK4/6 inhibitors. Accordingly, we have obtained synergistic and selective antiproliferative effects in vitro by inhibiting mTOR, PI3K/Akt axis or MYC target genes in combination with CDK4/6 inhibitors. Therefore, we propose new combination therapies that simultaneously target cell cycle and metabolism of cancer cells.
3. We have determined the molecular mechanism of action of the selenium compound methylseleninic acid (MSA) in cancer cells. MSA effects are associated with the inhibition of the Akt pathway, leading to dephosphorylation of FOXO transcription factors and their nuclear translocation which, in turn, activate the expression of FOXO target genes. By targeting the PI3K/Akt/FOXO pathway, MSA synergises with cisplatin in combination therapies to reduce the commonly observed toxicity and overcome the resistance of cisplatin-based chemotherapy.
The completion of these objectives has shed new light on the understanding of tumour metabolic reprogramming as well as the mechanisms of action of compounds potentially useful as antitumour agents. We have used this information to develop new strategies complementing conventional and existing chemotherapies, providing new approaches for cancer treatment and diagnosis.
44
Fryer, Rosemary Ann. "Development of new drug therapies and the identification of cell signalling targets for treatment of pancreatic cancer." Thesis, St George's, University of London, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.546780.
45
Kouadio, Ange S. "Exploring the therapeutic potential of novel molecular targeted therapies in treating human ovarian cancer." Click here for download, 2008. http://proquest.umi.com/pqdweb?did=1650501211&sid=2&Fmt=2&clientId=3260&RQT=309&VName=PQD.
46
Seckl, Michael Julian. "Neuropeptide receptors and cell signals as targets in the development of novel therapies for small cell lung cancer." Thesis, University College London (University of London), 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.281770.
47
Jolly, Simmi. "Pharmacological characterisation of selective Y4 and dual Y2/Y4 receptor agonists : novel targets for putative anti-obesity therapies." Thesis, King's College London (University of London), 2013. https://kclpure.kcl.ac.uk/portal/en/theses/pharmacological-characterisation-of-selective-y4-and-dual-y2y4-receptor-agonists(b9e837b1-e9ca-4bc6-9b85-5b93a7357819).html.
Анотація:
The GIPIO (Gastrointestinal Peptides in Obesity) collaboration was set up with EU (FP7) funding in 2008, with the aim to develop a series of peptide analogues for the treatment of obesity. Based on the dual Y2/Y4 agonist, Obinepitide ([Q34]hPP), and the Y4 agonist, TM30339 (hPP2-36), novel peptides were developed and subsequently modified by either PEGylation or lipidation to improve their relatively short half-life and pharmacokinetic profile. This thesis presents a detailed study of the in vitro pharmacological data performed to aid the progression of the most promising peptide candidates. An assessment of Y2Y4 potency and activity was made, using optimised Y4 (human colonic epithelial monolayers) and Y2Y4 (human colon mucosae) bioassays, where preparations were mounted in Ussing chambers and changes in short-circuit current (Isc) recorded. In addition, receptor specificity of the most promising agonists was dissected using Y1 and Y2 antagonists. Furthermore, an assessment of Y4 receptor desensitisation was made by application of a subsequent addition of the native hormone, hPP. With a lysine linker at position 30 or 22, chemical modification of Obinepitide with either PEGylation or Palmitoylation resulted in prolonged reductions in Isc in both preparations compared with the transient response seen with their respective predecessors. Increasing the PEG size resulted in greater reductions in Isc, though a PEG22 modification resulted in a loss of functional activity. Mid to long chain lipidation of TM30339 (lauric acid and palmitic acid) also resulted in sustained reductions in Isc. Interestingly, lipidation with a short chain fatty acid (caprylic acid) caused a biphasic response, with an initial transient drop in Isc followed by a sustained anti-secretory response. Importantly, PEG and lipid side chains had no effect upon Isc. Pre-treatment of either human mucosa or epithelial monolayers with PEG2-, or 5-ylated Obinepitide did not cause significant subsequent Y4 desensitisation, an effect that was greater with the larger PEGylated peptide. Contrary to this, long chain lipidated peptides seemed to facilitate rapid and sustained desensitisation, revealed by the loss of further Y4 signalling even after nM lipidated agonist. This divergence in receptor signalling was also observed in fluorescent imaging studies performed by our collaborators. The data presented herein provides the first functional evidence of prolonged activity at the Y2 and Y4 receptors and these modified peptides have the potential to act for longer in vivo as anti-obesity treatments.
48
Fenton, Audrey C. "The role of oncogenic kras as a determinant of response to EGER?HER2 targeted therapies." Thesis, Queen's University Belfast, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.534743.
49
Cartaxo, Ana L. "Tumor microenvironment models: ex vivo, in vitro and in silico approaches to address targeted therapies." Doctoral thesis, Universidade Nova de Lisboa, Instituto de Tecnologia Química e Biológica António Xavier, 2020. http://hdl.handle.net/10362/105645.
Анотація:
"Cancer is the second leading cause of mortality worldwide, despite the extraordinary advances in the last two decades due to the development of targeted therapies. These target particular molecules required for cell growth and tumorigenesis; nonetheless, de novo or acquired resistance to therapy often lead to patient relapse and disease progression. There is cumulating evidence supporting the importance of tumor microenvironment (TME)-driven mechanisms in cancer progression and drug resistance. Therefore, there is a need for cancer models in which critical components of the TME, such as the non-malignant cell types and the extracellular matrix (ECM), are represented and tissue architecture is maintained. (...)"N/A
50
Hansom, Donald. "The effects of nanopattern surface technology and targeted metabolic therapies on orthopaedic implant related infections." Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/7917/.
Анотація:
Bacterial biofilm infections cause significant morbidity in orthopaedic joint replacement. One of the most common bacteria in orthopaedic prosthetic infections is Staphylococcus aureus. Infection causes implant failure due to bacterial adherence and subsequent biofilm production. Nanotopography refers to the topography of a surface at the nanometre level and has major effects on cell behaviour. Studies suggest that surface nanotopography impacts the differential ability of staphylococci species to adhere, and may reduce orthopaedic implant infection rate. This research thesis focuses on bacterial adhesion on nanofabricated materials, and investigates the related metabolic changes and possible interventions. Staphylococcus aureus growth and quantification methods were optimised, with regard to growth media, incubation time and lysozyme incubation time. Both polystyrene and titanium (Ti) nanosurfaces were studied. Adhesion analysis was performed using fluorescence imaging, quantitative PCR, and bacterial percentage coverage. Metabolomic analysis was conducted by substitution with ‘heavy’ labelled glucose into growth medium, thus allowing for bacterial metabolomic analysis and identification of up-regulated, labelled metabolites and pathways. Bacterial growth was optimal using DMEM + supplement media, with adhesion occurring after 1hr bacterial incubation. Optimal lysozyme incubation for bacterial quantification using qPCR was 2hr. These parameters were used for all subsequent experimentation. Surface topography affects cell behaviour, bacterial adhesion and long term implant survival can be affected. This study found reduced bacterial adhesion on the SQ and HEX polystyrene patterns. While not found to be significant, this trend was supported by a lower average percentage bacterial coverage on both the SQ and HEX patterns (P=0.05 and P=0.01, respectively). It may be that the SQ and HEX nanopatterns are the optimal nanopit orientation required to prevent bacteria microcolony formation, keeping the bacteria in small, isolated clusters. In addition, this series of investigations showed an increase in bacterial concentrations on both the 2.5Hr and 3Hr treated Ti nanowire discs when compared to the polished Ti control disc, suggesting nanoroughness increases are associated with elevated bacterial adhesion. This theory was further supported by average percentage coverage, being significantly higher on the 2.5Hr and 3Hr treated discs. If, however, a disordered NC Ti nanopattern, hexagonal in nature, is used bacterial adhesion is significantly reduced when compared to a polished, control surface. The bacterial percentage coverage was also noted to be significantly lower on the NC surfaces, with over a 10-fold reduction when compared to the control surface. It is postulated that this reduction is through similar mechanisms to those described by Ivanova et al, and primarily related to altered surface interactions. Metabolomic analysis demonstrated increased intensity counts for key metabolites (pyruvate, aspartate, alanine and carbamoyl aspartate) involved in bacterial aggregation, proteoglycan and DNA synthesis. These pathways are also known to be important in bacterial biofilm production. Therapeutic targeting of these pathways was found to result in significantly reduced bacterial adhesion. This study shows that by altering nanotopography bacterial adhesion, and therefore, biofilm formation can be affected. Specific nanopatterned surfaces may reduce implant infection associated morbidity and mortality. The identification of metabolic pathways involved in adhesion allows for a targeted approach to biofilm eradication in S. aureus. This is of significant benefit to the patient, the surgeon and the NHS, and may well extend far beyond the realms of orthopaedics.