Dissertations / Theses on the topic 'Cancer molecular targets'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 dissertations / theses for your research on the topic 'Cancer molecular targets.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.
Culp, W. David. "Identifying molecular targets for cancer therapy /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-188-3/.
Full textEhsanian, Reza. "Molecular targets in head and neck cancer." Thesis, University of Oxford, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.540135.
Full textQureishi, Ali Akhtar Siddique. "Molecular targets in head and neck cancer." Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/molecular-targets-in-head-and-neck-cancer(f4b44db3-7db7-4ed6-8b8d-77d3d446b116).html.
Full textCampbell, Paul Michael. "DNA methylation machinery as molecular targets for cancer therapeutics." Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=82836.
Full textTarrado, 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.
Full textWong, Ka-wing, and 王家穎. "Study of potential targets of miR-143 in cervical cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/206496.
Full textpublished_or_final_version
Pathology
Master
Master of Medical Sciences
Bachelor, Michael A. "Identification of molecular targets for the chemoprevention of non-melanoma skin cancer." Diss., The University of Arizona, 2004. http://hdl.handle.net/10150/280585.
Full textWhetstone, Jennifer Lynn. "Identification of synthetic benzopyranones as selective agents for molecular targets in breast cancer /." The Ohio State University, 2001. http://rave.ohiolink.edu/etdc/view?acc_num=osu1486401895209686.
Full textOng, Chee Wee. "Clinical and molecular characterisation of prognostic markers and therapeutic targets in prostate cancer." Thesis, Queen's University Belfast, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.709689.
Full textAlfarsi, Halema. "In silico mutagenesis and 3D culture appraoch to define molecular targets in ovarian cancer." Thesis, Université Paris-Saclay (ComUE), 2015. http://www.theses.fr/2015SACLS104.
Full textOvarian cancer causes more deaths in the United States than any other type of female reproductive tract cancer, with an estimated 21,980 new cases and 14,270 deaths in 2014. Approximately 70% of ovarian cancers are diagnosed at advanced stage and only 30% of women with such cancers can expect to survive 5 years. This low survival rate is due to the frequent diagnosis of epithelial ovarian cancer at an advanced stage, and to intrinsic and acquired resistance to platinum-based chemotherapy. Clinical and pathological classification methods, including tumor grade and the extent of surgical debulking, still fail to fully predict disease progression and patient outcome. Clinical profile of initial response to chemotherapy in the majority of patients followed by recurrence in high proportion of patients suggests the presence of a subpopulation of cells that survives and leads to chemoresistance. Only by treating this subpopulation we can achieve durable response rates.Genomic instability is a hallmark of malignant tumors, causing disturbed integrity of the genome, numerical alterations, and structural changes. For various cancer types greater genomic instability has been associated with poor prognosis, suggesting that genomic instability may confer growth advantage of cancer cells. With the recent development of next-generation sequencing (NGS) technology, the Cancer Genome Atlas (TCGA) researchers have identified molecular abnormalities related to the pathophysiology, clinical outcome, and potential therapeutic targets in high-grade serous ovarian cancer (HGSC). The TCGA study provides a large-scale integrative view of the aberration in HGSC with extensive heterogeneity between individual tumorsOur research protocols enabled us to combine computational biology approach and gene knock down in the first part to identify genes that play an important role in ovarian cancer biology. we carried out in silico mutagenesis of the human genome corresponding to the regions sequenced by publically available ovarian cancer sequencing data from the TCGA. We compared the simulated mutations to the observed mutations in the TCGA cohort. We found genes that were observed to be mutated less than expected from the simulation data.Our approach allowed us to identify therefore a set of genes that we think are selected and remain unmutated for their potential role in tumor progression. Silencing of un-mutated genes impacted growth, morphology, migration, invasion and chemotherapeutic. This is the first study depicting that inhibition of a specific non-mutated gene by its single targeting siRNA can be utilized to obtain improved therapeutic efficiency
Klossner, Daniel Patrick. "Improving cryosurgical ablation of advanced state prostate cancer through identification of molecular targets in a prostrate cancer cell model." Diss., Online access via UMI:, 2007.
Find full textVisser, Jacobus Albertus Koch. "Phytoestrogenic extracts of Cyclopia modulate molecular targets involved in the prevention and treatment of breast cancer." Thesis, Stellenbosch : Stellenbosch University, 2014. http://hdl.handle.net/10019.1/86718.
Full textENGLISH ABSTRACT: Phytoestrogen containing extracts of Cyclopia, an indigenous South African fynbos plant used to prepare honeybush tea, may serve as a source of new estrogen analogues. It would be of great benefit if these new analogues would not only prevent the development and progression of breast cancer which, globally, is responsible for the highest number of cancer associated deaths among females, but also have a reduced side-effect profile when compared to current treatments and, in addition, also alleviate menopause associated symptoms. In this study three extracts, P104, SM6Met, and cup-of-tea, from two species of Cyclopia, C. genistoides and C. subternata, were evaluated for their potential to modulate molecular targets involved in prevention and treatment of breast cancer. We show that the phytoestrogenic extracts of Cyclopia antagonise estrogen-induced cell proliferation both in vitro as well as in vivo. Furthermore, our study presents various molecular mechanisms whereby the Cyclopia extracts may be eliciting this effect. Importantly, we show, for the first time, that the Cyclopia extracts behave as ERα antagonists and ERβ agonists which, with respect to the known role of the ER subtypes in breast cancer, where the ERα subtype is associated with the stimulation of cell proliferation and the occurrence of breast cancer, while ERβ ameliorates the action of ERα in breast cancer and could act as an inhibitor of breast cancer development, may be beneficial for the prevention or treatment of breast cancer. In addition, we also show that the extracts of Cyclopia behave as selective estrogen receptor degraders by down-regulating ERα protein levels while stabilising ERβ protein levels, which not only provides a possible molecular explanation for the observed ERα antagonism and ERβ agonism, but, in addition, may be beneficial as higher ERα levels are associated with malignant breast cancer tumours, while higher ERβ levels are associated with benign tumours. Furthermore, we show that the Cyclopia extracts affect the nuclear localization and distribution of both ER subtypes in a manner that provides an additional molecular explanation for the observed ERα antagonism and ERβ agonism. Investigation of the molecular processes involved in the promotion and progression of breast cancer, such as the distribution of cells between the phases of the cell cycle, cancer cell invasion, and the regulation of genes governing these processes provides evidence that the Cyclopia extracts are not as proliferative as estrogen. In addition, Cyclopia extracts display anti-inflammatory properties, which may be beneficial as inflammation is an enabling characteristic in cancer development and progression. Furthermore, this study, for the first time, shows that the phytoestrogenic extracts of Cyclopia are absorbed, are not toxic, and display biological ERα antagonist activity in vivo by retarding uterine growth. Thus, we propose that the Cyclopia extracts act as selective estrogen receptor subtype modulators with potential to be developed as a nutraceutical for the treatment or prevention of breast cancer.
AFRIKAANSE OPSOMMING: Fitoëstrogeen-bevattende ekstrakte van Cyclopia, ‘n inheemse Suid Afrikaanse fynbosplant wat gebruik word vir die voorbereiding van heuningbostee, mag as ‘n bron van nuwe estrogeen-analoë dien. Dit sal baie voordelig wees indien hierdie nuwe analoë nie net die ontwikkeling en progressie van borskanker sal voorkom nie, aangesien borskanker wêreldwyd verantwoordelik is vir die grootste getal kankerverwante sterftes onder vroue, maar ook ‘n verminderde newe-effek profiel vertoon in vergelyking met huidige behandelings en ook, boonop, simptome wat met menopouse geassosieer word, sal verlig. In hierdie studie is drie ekstrakte, P104, SM6Met, en cup-of-tea, vanaf twee spesies van Cyclopia, C. genistoides en C. subternata, geëvalueer vir hul potensiaal om die molekulêre teikens betrokke by die voorkoming en behandeling van borskanker te moduleer. Ons wys dat die fitoëstrogeniese ekstrakte van Cyclopia antagoniseer estrogeen-geïnduseerde selproliferasie beide in vitro as ook in vivo. Verder bied ons studie ook verkskeie molekulêre meganismes aan oor hoe die Cyclopia ekstrakte hierdie effek mag ontlok. ‘n Belangrike bevinding is dat ons vir die eerste keer wys dat die Cyclopia ekstrakte hulself as ERα -antagoniste en ERβ-agoniste gedra wat, met betrekking tot die erkende rol van die ER-subtipes in borskanker, waar die ERα-subtipe geassosieer word met die stimulasie van selproliferasie en die gebeurtenis van borskanker, terwyl ERβ die aksie van ERα onderdruk en as ‘n inhibeerder van borskankerontwikkeling kan dien, voordelig mag wees vir die voorkoming of behandeling van borskanker. Ons wys boonop ook dat die ekstrakte van Cyclopia hulself soos selektiewe estrogeen- reseptor-degradeerders gedra deurdat hul ERα-proteïnvlakke verlaag terwyl hul ERβ-proteïnvlakke stabiliseer. Dit verksaf nie net ‘n moontlike molekulêre verduideliking vir die waargeneemde ERα-antagonisme en ERβ-agonisme nie, maar mag ook voordelig wees in borskanker aangesien hoër ERα-vlakke geasosieer word met kwaadaardige borskankertumors en hoër ERβ-vlakke met nie-kwaadaardige tumors. Verder wys ons dat die Cyclopia ekstrakte die lokalisering en verspreiding van beide ER-subtipes in die selkern op so ‘n wyse beïnvloed dat dit ‘n addisionele molekulêre verduideliking bied vir die ERα-antagonisme en ERβ-agonisme wat waargeneem is. Verdere ondersoek van die molekulêre prosesse betrokke by die promosie en progressie van borskanker, soos die verspreiding van selle tussen die fases van die selsiklus, die beweging van kankerselle na omliggende weefsels, en die regulering van gene wat hierdie prosesse beheer, verskaf bewyse dat die Cyclopia-ekstrakte nie so proliferatief is soos estrogeen nie. Die ekstrakte van Cyclopia vertoon boonop ook anti-inflamatoriese eienskappe, wat voordelig mag wees aangesien inflammasie ‘n bydraende eienskap in kankerontwikkeling en -progressie is. Verder wys hierdie studie vir die eerste keer dat die fitoëstrogeniese ekstrakte van Cyclopia geabsorbeer word, nie toksies is nie, en dat hulle biologiese ERα-antagonis aktiwiteit vertoon deurdat hulle uterus-groei vertraag in vivo. Dus stel ons voor dat die Cyclopia-ekstrakte optree soos selektiewe-estrogeen-reseptor-subtipe-moduleerders met die potensiaal om ontwikkel te word as ‘n nutraseutiese middel vir die behandeling of voorkoming van borskanker.
Kauntz, Henriette. "Cellular and molecular targets of silibinin, a natural flavonoid, in colorectal cancer prevention and therapy." Thesis, Strasbourg, 2012. http://www.theses.fr/2012STRAJ052/document.
Full textColorectal cancer (CRC) is the second most common cause for cancer-related deaths in Europe and in the USA. Because of the limited efficacy and considerable toxicity of chemotherapeutic agents, new approaches are needed. The hepatoprotective flavonolignan silibinin is the major biologically active compound of the milk thistle (Silybum marianum).The molecular mechanisms of the anticancer properties of silibinin in CRC were studied in an in vitro model of cancer progression consisting of the adenocarcinoma cell line SW480 and its derived metastatic cell line SW620. Its chemopreventive effects were assessed in an in vivo model of azoxymethane-induced colon carcinogenesis in the rat. Silibinin induced apoptotic cell death with activation of caspase-3 in both cell lines. The expression of death receptors was upregulated, and caspase-8 was activated. The potential of the mitochondrial membrane was perturbed permitting the release of cytochrome c and the activation of caspase-9. Besides the activation of the extrinsic and the intrinsic apoptotic pathway, silibinin induced an autophagic response. Combination of silibinin and TRAIL, a promising anticancer agent selectively inducing apoptosis in cancer cells, induced synergistic cell death in both cell lines. Synergy in cell death induction was also observed by the combination of silibinin and the histone deacetylase (HDAC) inhibitors TSA and SAHA. In the preclinical model in the rat, silibinin administration was able to reduce by half the number of preneoplastic lesions present in the colon. In conclusion, silibinin is a promising natural agent for colon cancer chemoprevention and for combination therapy with TRAIL/HDAC inhibitors
Barry, Sayka. "Search for novel molecular targets in pancreatic cancer by comparative analysis of primary and metastic disease." Thesis, Queen Mary, University of London, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.515470.
Full textTong, Chiu-hung, and 唐朝虹. "MiR-143 and its downstream targets: possible biomarkers for cervical cancer and precursors." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B46579436.
Full textSchreiber, Melanie [Verfasser], and Guido [Akademischer Betreuer] Sauter. "Tissue microarray based identification of molecular cancer therapy targets in clinical routine / Melanie Schreiber. Betreuer: Guido Sauter." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2013. http://d-nb.info/1045024171/34.
Full textOliveira, Mónica Catarina Castro. "Proteasome-proteins: are these putative targets for basal-like breast cancer therapy with AAV-vectors?" Master's thesis, Universidade de Aveiro, 2016. http://hdl.handle.net/10773/18553.
Full textO cancro da mama do tipo basal (BLBC) é um grupo de tumores muito agressivo associado a um mau prognóstico. De momento, não existe nenhum tratamento eficaz para o BLBC, uma vez que rapidamente adquirem resistência às terapias normalmente usadas. Assim, é urgente encontrar novas abordagens para tratar esta doença. Com base em dados anteriores, o objetivo geral deste estudo foi avaliar se o PSMA2, uma proteína do proteassoma, seria um alvo putativo para a inibição para terapia em BLBC. Desta forma, o primeiro objetivo específico foi avaliar o efeito anti-tumorigénico de vírus adeno-associados (AAV) capazes de entregar short hairpin RNAs (shRNA), anteriormente validados, capazes de inibir a expressão do PSMA2 em xenotransplantes de células BLBC em ratinho. Para atingir esse objetivo, foram testados in vivo, vetores AAV2 com shRNAs para os genes PLK1 e PSMA2 para diferentes concentrações de partículas virais (2x1010, 2x109, 2x108 partículas virais/tumor), em que células MDA-MB-468 BLBC foram injetadas na mama de ratinhos nude. Após cerca de um mês, foram realizadas injeções intratumorais com AAVs duas vezes por semana. A administração de AAV2-shPSMA2 resultou numa diminuição no crescimento do tumor sem toxicidade evidente, e este efeito foi mais significativo na concentração de 2x109 partículas virais/tumor. O segundo objetivo específico foi analisar a expressão de PSMA2 em amostras humanas de cancro da mama, o que indica que há também uma importância clínica na inibição deste gene, uma vez que se mostrou estar associado a características menos favoráveis relacionadas com tumores da mama do tipo basal. Em conclusão, embora ainda preliminar, os resultados obtidos abrem a possibilidade de direcionar uma terapia genética em BLBC usando vetores AAV recombinantes que entregam shRNAs para silenciar especificamente a expressão do gene PSMA2.
Basal-like breast cancer (BLBC) is an aggressive group of tumours associated to poor patient prognosis. Currently, there is no effective treatment for BLBC once they rapidly acquire resistance to standard therapies. For this reason, novel approaches to treat this disease are urgently needed. Based on previous data, the general goal of this study was to evaluate if PSMA2, a proteasome protein, was a putative target for inhibition in BLBC therapy. In this way, the first specific aim was to evaluate the anti-tumorigenic effect of adeno-associated virus (AAV)-based vectors, that were able to deliver validated short hairpin RNAs (shRNAs) that inhibit the expression of PSMA2 in BLBC mouse xenografts. To achieve that aim, we have tested, in vivo, AAV2 vectors with shRNAs for the genes PLK1 and PSMA2 for different concentrations of viral particles (2x1010, 2x109, 2x108 VP/tumour), MDA-MB-468 BLBC cells were injected into the mammary fat pad of nude mice and, after nearly one month, intratumoral injections with AAVs were performed twice a week. The delivery of AAV2-shPSMA2 resulted in a decrease in tumour growth with no obvious toxicity, and this effect was more significant at the concentration of 2x109 VP/mouse. The second specific aim was to analyse the expression of PSMA2 in human breast cancer samples, which indicated that there is also a clinical importance in inhibiting this gene, once it showed to be associated with less favourable features that are linked to basal-like breast tumours. In conclusion, although still preliminary, the results obtained open a possibility to direct a gene-based therapy in BLBC using recombinant AAVs that deliver shRNAs that specifically silence PSMA2 gene expression.
Webster, Rebecca. "Complementary investigations of the molecular biology of cancer : assessment of the role of Grb7 in the proliferation and migration of breast cancer cells; and prediction and validation of microRNA targets involved in cancer." University of Western Australia. School of Medicine and Pharmacology, 2008. http://theses.library.uwa.edu.au/adt-WU2008.0179.
Full textSilva, Evangelista Cláudia. "Molecular Characterization of Pediatric Brainstem Gliomas (DIPG) and Identification of New Therapeutic Targets." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS269.
Full textDIPG is one of the most severe paediatric brain tumours. No progress has been made in their management over the past 50 years and radiotherapy remains only transiently effective. Recently, a specific somatic mutation in the histone H3 (K27M) has been found in approximately 95% of DIPG patients and can be considered as the oncogenic driver of these tumours. Two major subgroup of patients with distinct oncogenic program and response to radiotherapy can be defined according to the gene in which the alteration occurs, encoding the H3.1 or H3.3 protein variants. We performed two synthetic lethality screens by RNA interference targeting the human kinome in order to identify the genes responsible for DIPG cell survival, as well as those sensitizing tumour cells to radiotherapy after inhibition. The dual purpose of this project was to better understand the biology underlying oncogenesis of DIPGs and to discover new therapeutic targets.We identified 41 genes required for DIPG cell survival with no major deleterious effect on normal control cells. Among them, we identified VRK3, a serine threonine kinase never involved in DIPG oncogenesis with functions remaining poorly described to date. We have shown that its inhibition leads to a complete arrest of DIPG cell proliferation and is additionally associated with important morphological changes, more particularly in H3.3-K27M mutated tumours. VRK3 is therefore a promising new therapeutic target for all patients in this fatal pathology.In parallel, a similar survival screen was performed in conjunction to cell radiation and very few interfering RNAs enhance H3.3-K27M cell radiosensitivity, in contrast to H3.1-K27M cells. These data highlighted a significant difference in radiosensitivity of the DMG in vitro models in H3.1- versus H3.3-K27M mutated tumours, in a concordant way with patient survival following radiotherapy. These unprecedented results suggest new opportunities for improving the current treatment of DIPG patients regardless of their genotype
Majmudar, Pooja M. "Investigating Molecular Targets of Phosphaplatins: A Class of Novel Non-DNA-Binding Platinum Anticancer Agents in the Treatment of Ovarian Cancer." Ohio University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1300373466.
Full textEl, Baba Chirine [Verfasser], and Regine [Akademischer Betreuer] Schneider-Stock. "Clinical potential of Thymoquinone in colorectal cancer: identification of molecular targets and efficacy in combination therapy / Chirine El Baba. Gutachter: Regine Schneider-Stock." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2014. http://d-nb.info/1054731772/34.
Full textSouza, Ana Carolina Santos de. "Mecanismo da ação antineoplasica de substancias bioativas e alvos moleculares estrategicos para a indução de morte de celulas tumorais." [s.n.], 2007. http://repositorio.unicamp.br/jspui/handle/REPOSIP/314043.
Full textTese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
Made available in DSpace on 2018-08-08T07:42:49Z (GMT). No. of bitstreams: 1 Souza_AnaCarolinaSantosde_D.pdf: 3901394 bytes, checksum: ef9ac69de23f7f2b15590ee29a931c8f (MD5) Previous issue date: 2007
Resumo: Produtos naturais têm originado muitos dos compostos biologicamente ativos usados clinicamente, destacando-se como importantes fontes de novos agentes terapêuticos utilizados no tratamento das mais variadas patologias incluindo câncer, HIV/AIDS, Alzheimer e malária. O desenvolvimento de novos fármacos a partir de produtos naturais, especialmente os derivados de plantas, tem desempenhado importante papel na prevenção e tratamento do câncer sendo que, de todos os antitumorais disponíveis entre 1940 e 2002, aproximadamente 40% eram caracterizados como produtos naturais ou derivados destes, com outros 8% sendo considerados agentes mimetizantes de produtos naturais. No presente trabalho, fisetin (flavonóide de origem vegetal) e a vitamina riboflavina foram avaliados como potenciais agentes antitumorais. Para este propósito, as linhagens de células leucêmicas HL60 e de câncer prostático PC3 foram tratadas com riboflavina irradiada ou fisetin por 24 horas e seus efeitos sobre vias de transdução de sinais responsáveis pela sobrevivência e morte celular foram avaliados. Os resultados obtidos demonstram que riboflavina e fisetin apresentam expressiva atividade antiproliferativa, induzindo a morte das células tumorais em concentrações na ordem de µM. A investigação do mecanismo molecular da ação citotóxica da riboflavina demonstrou que o tratamento de HL60 e PC3 com a vitamina irradiada induz morte celular através da via extrínseca de indução de apoptose, mediada pela ativação do sistema Fas/FasL e aumento na síntese de ceramida. Como conseqüência da ativação do receptor de morte Fas, uma seqüência ordenada de eventos leva à modulação de cascatas de sinalização através da alteração da atividade/expressão de moléculas-chave associadas a proliferação, sobrevivência, migração e morte celular. Assim como a riboflavina, fisetin também mostra-se eficiente indutor de morte por apoptose em células HL60, modulando cascatas de proteínas quinases e fosfatases e levando a alterações na expressão de NF?B, atividade de MAPKs, níveis de fosfoproteínas e, também, à inibição de enzimas envolvidas na manutenção do estado redox. Os resultados obtidos neste trabalho contribuem para um maior conhecimento sobre a atividade/função biológica de algumas moléculas envolvidas na sobrevivência e morte de células leucêmicas e prostáticas, sugerindo potenciais alvos para o desenvolvimento de estratégias terapêuticas mais eficazes no combate a doenças neoplásicas. Além disso, os resultados obtidos demonstram que a riboflavina irradiada e fisetin são potentes indutores de apoptose e promissores agentes antitumorais, capazes de modular importantes vias de sinalização intracelular através de ação específica sobre moléculas-chaves relacionadas a proliferação, resistência e invasividade de células tumorais
Abstract: Natural products have been providing numerous clinically used medicines and remain as essential components in the search for new drugs against various pharmacological targets including cancer, HIV/AIDS, Alzheimer¿s, malaria, and pain. Drug discovery from natural products, especially from medicinal plants, has played an important role in the chemoprevention and treatment of cancer and, off all available anticancer drugs between 1940 and 2002, about 40% were natural products per se or natural product-derived, with another 8% considered natural product mimics. In the present work, the plant flavonoid fisetin and the vitamin riboflavin are evaluated as potential anticancer agents. For this purpose, the leukemic cell line HL60 and the human prostate cancer cell PC3 were treated for 24h with irradiated riboflavin or fisetin and their effects on signal transduction pathways related to the cell survival and proliferation were evaluated. The results obtained demonstrated that riboflavin and fisetin have strong anti-proliferative activity, inducing tumoral cell death at µM concentrations. The investigation of the molecular death mechanism triggered by riboflavin demonstrated that the treatment of HL60 and PC3 with the irradiated vitamin induces apoptotic cell death through induction of the extrinsic pathway mediated by the activation of Fas/FasL system via a ceramide-dependent pathway. As a consequence of the activation of the death receptor Fas, an orderly sequence of signaling events leads to the modulation of signaling cascades through alterations in the activity/expression of key targets molecules related to proliferation, survival, migration and cell death. As well as riboflavin, fisetin also showed strong apoptotic activity, inducing HL60 cell death through modulation of protein kinase and phosphatase signaling cascades, leading to alterations in the NF?B expression, MAPKs activities, phosphoprotein levels and also inhibition of enzymes involved in the redox status maintenance. The results obtained in this work bring out information about the biologic activity of some molecules involved in the survival and death of leukemic and prostate cancer cells, indicating among then potential targets for the development of rational therapeutic strategies. Moreover, the data obtained demonstrated that irradiated riboflavin and fisetin have potential proapoptotic activity, pointing out these bioactive compounds as promising antitumoral agents, since they can affect important molecular targets related to proliferation, resistance and invasibility of cancer cells
Doutorado
Bioquimica
Doutor em Biologia Funcional e Molecular
Fryknäs, Mårten. "Molecular Screening for Target Discovery in Cancer." Doctoral thesis, Uppsala universitet, Institutionen för genetik och patologi, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7086.
Full textFryknäs, Mårten. "Molecular screening for target discovery in cancer /." Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7086.
Full textHonarvar, Hadis. "Development of Affibody molecules for radionuclide molecular imaging and therapy of cancer." Doctoral thesis, Uppsala universitet, Medicinsk strålningsvetenskap, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-298740.
Full textBapat, Aditi Ajit. "Inhibition of Ape1's DNA repair activity as a target in cancer identification of novel small molecules that have translational potential for molecularly targeted cancer therapy /." Connect to resource online, 2009. http://hdl.handle.net/1805/2062.
Full textTitle from screen (viewed on February 2, 2010). Department of Biochemistry and Molecular Biology, Indiana University-Purdue University Indianapolis (IUPUI). Advisor(s): Mark R. Kelley, Millie M. Georgiadis, John J. Turchi, Martin L. Smith. Includes vitae. Includes bibliographical references (leaves 114-133).
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.
Full textpublished_or_final_version
Medicine
Master
Doctor of Medicine
Yang, Ya-Ting. "Molecularly targeted therapy for ovarian cancer." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1149015359.
Full textLovato, Amanda. "Poly (ADP-ribose) glycohydrolase (PARG) is a new therapeutic target for breast cancer." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=119605.
Full textLe cancer du sein est une maladie hétérogène, invariablement associée à une perturbation de l'expression génique. Le silençage des gènes suppresseurs de tumeurs (GST) est l'un des phénomènes jouant un rôle lors de l'initiation du cancer. Si la réactivation de l'expression de ces gènes est une stratégie attractive sur le plan clinique, la mise au point de traitements efficaces a été entravée par la compréhension insuffisante des mécanismes responsables du silençage des GST. Récemment, de nouveaux mécanismes régulant le silençage des GST dans le contexte du cancer ont été décrit, ce qui pourrait conduire à l'identification de nouvelles cibles thérapeutiques. Un des exemples concerne la protéine CTCF, un facteur essentiel au maintien de l'organisation de la chromatine et de l'activité transcriptionnelle à de nombreux loci du génome. Dans des cellules où des GST sont « silencés », la capacité de liaison de CTCF proche de ces gènes est perdue. La perte de cette liaison est due à l'abrogation d'une modification post-traductionnelle sur CTCF : la poly-(ADP)-ribosylation (aussi appelée PARylation). Selon notre hypothèse, l'inhibition de la PARylation de CTCF par l'enzyme PARG, responsable de la déPARylation, perturbe les patrons de modification épigénétiques normaux des GST, ce qui aboutit au silençage de ces gènes. Nous nous proposons d'analyser l'impact de la surexpression de PARG dans le cadre du cancer du sein sur la programmation des modifications épigénétiques et l'expression de gènes cibles de CTCF, ainsi que sur la prolifération des cellules épithéliales mammaires.Dans un premier temps, nous avons recueilli des données de sources bio-informatiques et de nos propres expériences, et nous avons pu observer une surexpression de l'ARNm de PARG dans 30 à 50% des cas de cancer du sein (UCSC Cancer Genome Browser et Oncomine). De plus, les niveaux protéiques de PARG sont plus importants dans les lignées cellulaires de cancer du sein par rapport aux lignées cellulaires non transformées. Dans un deuxième temps, nous avons utilisé la lignée MCF10A (immortalisée mais non transformé) pour générer une lignée cellulaire surexprimant PARG afin d'évaluer le rôle de cette protéine dans la transformation cellulaire. Nous avons pu observer que les cellules surexprimant PARG étaient passées d'une morphologie épithéliale à une morphologie mésenchymateuse, et que leurs vitesses de prolifération avaient diminué. L'expression du transgène PARG a toutefois été rapidement perdue, ce qui laisse entrevoir le rôle significatif de PARG en biologie cellulaire.Dans un troisième temps, nous avons voulu observer les effets de la perte de PARG sur des lignées de cancer du sein en utilisant soit une drogue (acide tannique : TA) soit la technique des shARNs. Par ces deux méthodes, nous avons montré que la déplétion de PARG (ou inactivation) ralentie significativement la prolifération des cellules cancéreuses. De plus, le traitement avec l'acide tannique conduit d'une part à la formation de nombreux foyers de dommages à l'ADN, et d'autre part à la diminution de la marque répressive H3K27me3, ce qui pourrait conduire à la réexpression de GST. Enfin, ce travail permet de mettre en avant le potentiel de PARG comme cible thérapeutique dans le traitement du cancer du sein.
Andreyev, Hubert Jervoise Nicholas. "Kirsten ras mutation in colorectal adenocarcinoma : prognostic indicator and molecular target." Thesis, Institute of Cancer Research (University Of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266506.
Full textMartinez, 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.
Full textDoctorat en Sciences médicales (Médecine)
info:eu-repo/semantics/nonPublished
Rodilla, Martín Ananda Marina. "Anticancer Effect and Molecular Target Identification of Novel Anionophores in Lung Cancer." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/664165.
Full textEl cáncer de cavidad oral y de pulmón se engloban dentro de las enfermedades de vías respiratorias más comunes, siendo este último una de las principales causas de mortalidad en el mundo. A pesar de los nuevos avances en el diagnóstico y la atención clínica, el éxito de los tratamientos convencionales es todavía limitado, ya que los pacientes acaban desarrollando resistencias y presentando recidivas. Debido a las limitaciones terapéuticas para abordar estas patologías, es necesario identificar nuevos compuestos con diferentes mecanismos de acción y mayor eficacia para combatir este tipo de neoplasias. Las células cancerosas adquieren una serie de características durante la carcinogénesis, como un gradiente de pH invertido en comparación con las células normales, lo cual favorece la progresión del cáncer mediante el aumento de la proliferación y la evasión de la apoptosis. Recientemente se ha propuesto una nueva estrategia terapéutica contra el cáncer la cual implica la modulación del pH intracelular. Es por esto que nuestro grupo de investigación estudia el potencial de compuestos transportadores de aniones como nuevos agentes quimioterapéuticos, ya que poseen la capacidad de disminuir el pH intracelular selectivamente. En concreto, este trabajo de tesis se ha centrado en caracterizar el efecto anticanceroso de anionóforos, compuestos transportadores de aniones, derivados de moléculas naturales llamadas tambjaminas, tanto a nivel celular como molecular. En primer lugar, se ha determinado el efecto de los análogos sintéticos de tambjamina sobre la viabilidad celular en líneas de cáncer oral y pulmonar, así como en células madre cancerosas derivadas de tumores de pacientes, demostrando ser potentes agentes citotóxicos. A su vez, se ha estudiado qué implicación tiene la pérdida de la homeostasis iónica impulsada por estos compuestos a nivel celular. En este sentido, se ha caracterizado cómo los compuestos inducen la alcalinización de los lisosomas, y provocan una vacuolización masiva en el citoplasma que se corresponde con el hinchamiento de la mitocondrias. Estos dos fenómenos conllevan la pérdida de función de ambos orgánulos. Al mismo tiempo, se han estudiado en detalle los mecanismos de acción ligados al desequilibrio osmótico provocado por los compuestos. Por una parte, se ha observado cómo estos anionóforos estimulan un aumento en la actividad de proteínas relacionadas con respuesta a estrés celular, y cómo provocan la activación de la vía apoptótica, sin que ésta sea la responsable directa de la muerte de toda la población celular. Conjuntamente, se ha detectado una acumulación de autofagosomas, relacionado con el bloqueo de la autofagia, consecuencia del fallo lisosomal tras el tratamiento con estos compuestos. A su vez, se ha podido observar cómo las células tratadas con estos anionóforos pierden la integridad de la membrana plasmática, indicando que el proceso citotóxico culmina en necrosis en una gran mayoría de la población celular. Por otro lado, en esta tesis doctoral, mediante experimentos computacionales in silico, se ha identificado la proteína AKT como una posible diana molecular de uno de nuestros compuestos. A su vez, se ha corroborado por espectroscopia mediante resonancia de plasmones superficiales, que la afinidad de unión entre el análogo de tambjamina y AKT es elevada, situada en un rango micromolar. Asimismo, se ha detectado una disminución tanto de la fosforilación, como de la proteína total AKT tras el tratamiento con tambjamina. Igualmente, gracias al estudio de la modificación de los patrones de expresión de miRNA tras el tratamiento con el compuesto, se han dilucidado las principales rutas de señalización involucradas en el proceso citotóxico, siendo las más afectadas PI3K/AKT, apoptosis y autofagia. Por último, para completar los estudios preclínicos, se ha evaluado la toxicidad y eficacia de estos compuestos in vivo en modelos murinos de cáncer de pulmón en estudios preliminares, mostrando una potente capacidad antitumoral tanto en el modelo ectópico como ortotópico. Por todo esto, los análogos sintéticos de tambjamina pueden ser considerados una buena herramienta para inducir muerte en células cancerosas mediante una nueva estrategia terapéutica que modifica el pH intracelular y podrían llegar a ser buenos fármacos para abordar el tratamiento de tumores resistentes a la apoptosis.
Söderström, Torbjörn. "Molecular endocrinology of target enzymes in androgen metabolism : implications for prostate cancer /." Stockholm : Karolinska Univ. Press, 2001. http://diss.kib.ki.se/2001/91-89428-12-9/.
Full textZincke, 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.
Full textMetastatic 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.
Soares, Eliana Janine de Paiva. "CD44-glicoprofilling: establishing the molecular basis for target therapeutics in bladder cancer." Master's thesis, Universidade de Aveiro, 2017. http://hdl.handle.net/10773/22766.
Full textO cancro da bexiga (BC) apresenta uma das maiores taxas de recorrência entre os tumoures sólidos e é a segunda causa de morte, relativamente a doenças do trato geniturinário. A introdução de modelos moleculares para um melhor prognóstico e desenvolvimento de terapias dirigidas efetivas, continua a ser um aspeto desafiador devido à significativa heterogeneidade molecular inter e intratumoral. No entanto, a CD44, uma proteína de membrana fortemente O-glicosilada e envolvida nas interações célula-célula, adesão celular e migração, parece desempenhar um papel crítico na progressão e disseminação do cancro da bexiga, abrindo portas para potenciais terapêuticas dirigidas. No entanto, o gene que codifica esta proteína geralmente sofre splicing alterativo, o que resulta em diversas isoformas funcionalmente distintas, de pesos moleculares variáveis e com vários locais de glicosilação. No entanto, a natureza dessas isoformas no contexto do cancro da bexiga ainda não está bem esclarecida. Com base nestas ideias, este trabalho tem como objetivo determinar as isoformas da CD44 mais clinicamente relevantes e com potencial de direcionar para clones mais agressivos. É dado particular ênfase à identificação de O-glicanos associados ao cancro, que visam aumentar o entendimento molecular para o desenho de ligandos altamente específicos. Consequentemente observou-se que a CD44 está aumentada na urina de doentes com cancro de bexiga, comparativamente com urinas controlo de indivíduos saudáveis. Esse efeito é mais pronunciado em estadios avançados da doença, particularmente após a invasão muscular, o mesmo se verifica com expressão da CD44 nos tumores de bexiga. Além disso, uma abordagem direcionada por RT-PCR demonstrou que o modelo celular de tumores superficiais de cancro da bexiga, a linha celular 5637 e os tumores de bexiga não invasivos sobre-expressam isoformas da CD44 de alto peso molecular (CD44v3-10high, CD44v8-10high, CD44slow). Por outro lado, as linhas celulares T24 e HT1376 derivadas de tumores musculo-invasivos e estes mesmos tumores sobre-expressam predominantemente CD44s, uma isoforma de menor peso molecular (CD44v3-10low, CD44v8-10low, CD44shigh). Além disso, os clones quimiorresistentes das células T24, tratadas com cisplatina, também sobre-expressam CD44s. Da mesma forma, os tumores invasores apresentaram um fenótipo semelhante, apoiando a associação da CD44 com fenótipos mais agressivos. Os estudos de glicómica e glicoproteómica envolvendo a linha celular T24 demonstraram ainda a expressão de CD44 glicosilado com antigénios sialil-Tn (CD44-STn) e di-sialil-T (dST), anteriormente associados a um pior prognóstico. Em paralelo, ensaios de imuno-histoquímica e de ligação de proximidade in situ confirmaram a existência de CD44-STn e CD44-dST em tumores musculo-invasivos. Em conclusão, CD44s, possivelmente modificada com STn e dST, tem o potencial de direcionar selectivamente para células mais agressivas de tumores de bexiga e clones quimiorresistentes, estabelecendo assim as bases moleculares para o desenho de ligandos. Estudos futuros devem-se concentrar em avaliar o impacto funcional da remodelação da CD44 para isoformas de menor peso molecular, acompanhando a transição de tumores superficiais para invasores.
Bladder Cancer (BC) presents one of the highest recurrence rates amongst solid tumours, and constitutes the second deadliest disease of the genitourinary track. The introduction of molecular models for disease management and effective targeted therapeutics remains a challenging aspect due to significant inter and intra-tumour molecular heterogeneity. Nevertheless, CD44, a heavily O-glycosylated membrane protein involved in cell-cell interactions, cell adhesion and migration has been suggested to play a critical role in bladder cancer progression and dissemination, holding potential for targeted therapeutics. However, the gene encoding for CD44 generally undergoes significant alterative splicing, which results in many functionally distinct isoforms of variable molecular weights and glycosylation sites. Nevertheless, the nature of these isoforms in bladder cancer are yet to be fully disclosed. Building on these insights, this work aims to highlight clinically relevant CD44 isoforms with potential for targeting more aggressive clones. Particular emphasis is also given to the identification of cancer-associated O-glycans envisaging the molecular rational for designing highly specific cancer ligands. Accordingly, it was observed that CD44 is increased in the urine of bladder cancer patients in relation to healthy controls. This effect is more pronounced for advanced stages of the disease, particularly upon muscle invasion, mimicking CD44 expression in bladder tumours. Moreover, a targeted approach by RT-PCR demonstrated that superficial bladder cancer cell model 5637 and non-invasive bladder tumours overexpress high molecular weight CD44 isoforms (CD44v3-10high, CD44v8-10high, CD44slow phenotype). Conversely, T24 and HT1376 cell lines derived from muscle invasive tumours and invasive lesions predominantly overexpress lower molecular weight isoform CD44s (CD44v3-10low, CD44v8-10low, CD44shigh phenotype). In addition, chemoresistant clones from T24 cells challenged with cisplatin also overexpressed CD44s. Likewise, bladder tumours from patients with invasive tumours presented a similar phenotype, supporting CD44s association with more aggressive phenotypes. Glycomics and glycoproteomics studies involving T24 cell line further demonstrated the expression of CD44 glycosylated with sialyl-Tn (CD44-STn) and di-sialyl-T (dST) antigens, previously associated with poor prognosis. In parallel, immunohistochemistry and in situ proximity ligation assays confirmed the existence of CD44-STn and CD44-dST in muscle invasive tumours. In conclusion, CD44s, possibly modified with cancer-associated STn and dST glycans, holds potential to selectively target more aggressive bladder cancer lesions and chemoresistant clones, setting the molecular rational for ligands design. Future studies should now focus on disclosing the functional impact of CD44 remodelling towards lower molecular weight isoforms, accompanying transition from superficial to invasive lesions.
Arif, Km Taufiqul. "Functional association of Micrornas with molecular subtypes of breast cancer." Thesis, Queensland University of Technology, 2021. https://eprints.qut.edu.au/213110/1/Km%20Taufiqul_Arif_Thesis.pdf.
Full textPhadke, Manali. "GLYCERALDEHYDE 3-PHOSPHATE DEHYDROGENASE: A NEW MOLECULAR TARGET IN CHEMOTHERAPY." Diss., Temple University Libraries, 2012. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/214810.
Full textPh.D.
Cancer therapy traditionally seeks to achieve complete tumor eradication via induction of cancer cell death by chemotherapeutic agents or radiation. An alternative strategy is to induce cytostasis, i.e. to arrest proliferation of cancer cells, perhaps in parallel with conventional chemotherapy. Such an alternative strategy could provide prolonged survival with less severe consequences of cytotoxic agents. To be truly effective, a chemotherapeutic drug should exert its action on biochemical targets specific for neoplastic cells while leaving the normal cells unaffected. Therefore, the knowledge of tumor cell-specific biochemical and signaling pathways is a pre-requisite for development of new, prospective anticancer drugs. In this study, we concentrated on the energy metabolism which is remarkably different in tumor and healthy cells. Cancer cells generate ATP mainly through the glycolytic pathway, and depend far less on oxidative phosphorylation (the Warburg effect). The way cancer cells generate energy reflects their need for energy as well as building blocks required for fast biosynthesis. Glycolysis, in contrast to oxidative phosphorylation, enhances biosynthetic pathways thus accelerating progression of tumor cells through the cell cycle. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) occupies a central position in the glycolytic pathway thus playing a critical role in the energy metabolism of cancer cells. Along with its enzymatic activity, GAPDH is a multifunctional protein which acts as a signaling and regulatory molecule in several cellular mechanisms. Based on the fact that glycolysis plays a pivotal role in survival of cancer cells, we hypothesized that down-regulation of GAPDH protein would alter the cancer cell proliferation, and cellular sensitivity of cancer cells to chemotherapy. The goal of this study was to evaluate GAPDH as a potential molecular target for treatment of cancer. In this project, our aims were: 1) To determine the effect of GAPDH level on cell proliferation and cell cycle progression of human carcinoma cells; 2) To elucidate the molecular mechanism(s) causing proliferation arrest in GAPDH-depleted cells; 3) To identify the chemotherapeutic agents exhibiting cytotoxic effect against non-dividing, senescent cells; 4) To analyze molecular dynamics of nuclear GAPDH and its mutant variants in the context of chemotherapy-induced stress. Towards these aims, we developed an experimental model where the level of GAPDH in human carcinoma cells was modulated by RNA interference (RNAi) technology. In vitro experiments were performed in this model system to evaluate the energy status, and signaling pathways in cancer cells after GAPDH depletion. Human carcinoma isogenic cell lines with different levels of GAPDH protein were analyzed for the sensitivity to various chemotherapeutic agents. Using site-mutagenesis, we prepared mutated variants of GAPDH and estimated their enzymatic activity. We also prepared constructs where GAPDH cDNA was fused with green fluorescent protein (EGFP) cDNA, and transiently expressed them in human cancer cells, to assess GAPDH localization and biological effects. We analyzed intranuclear localization and dynamic characteristics of GAPDH and its variants in the live cells using image confocal technologies (e.g. FRAP). In our study, we demonstrated that GAPDH is a molecular target with clinical potential for senescence-based tumor suppression. Our experiments revealed that depletion of GAPDH induces energy crisis and proliferation arrest in human carcinoma cells. We elucidated the molecular mechanisms initiated by GAPDH depletion, and demonstrated that GAPDH-depleted cells acquire the accelerated senescence phenotype. Moreover, we found chemotherapeutic agents cytotoxic to the senescent cells, a finding that opens a way to combination chemotherapy with therapy-induced senescence agents. Our results on dynamic characteristics of intranuclear GAPDH and its mutant forms indicate that in the nucleus, GAPDH interacts with biomolecules yet to be identified. The results of this study suggest a novel, prospective molecular target for pharmacotherapeutic intervention in cancer management.
Temple University--Theses
Kooshan, Zeinab. "Nanoparticle assisted small molecule delivery to target prostate cancer metabolism." Thesis, Queensland University of Technology, 2022. https://eprints.qut.edu.au/228736/1/Zeinab_Kooshan_Thesis.pdf.
Full textCarbary, Jordan Leslie. "Quantum Dots Targeted to VEGFR2 for Molecular Imaging of Colorectal Cancer." Diss., The University of Arizona, 2015. http://hdl.handle.net/10150/565917.
Full textsupsavhad, wachiraphan. "Novel Molecular Targets for Feline Oral Squamous Cell Carcinoma." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1471628009.
Full textSeedhouse, Steven James. "Investigating the serotonin 2C receptor as a candidate oncogene and drug target in advanced prostate cancer." Thesis, State University of New York at Buffalo, 2015. http://pqdtopen.proquest.com/#viewpdf?dispub=3725989.
Full textEvery year in the US, over 200,000 men are diagnosed with prostate cancer (PCa) and annual mortality in the US exceeds 30,000. PCa is treated surgically, and post-surgical recurrent tumors treated through targeted inhibition of the androgen receptor (AR) and AR signaling through disruption of androgen synthesis. If tumors resist antiandrogen therapy, castration recurrent (CR) tumors are treated with second line therapies that currently involve more potent inhibition of AR. Since the advent of these newer therapies, alternative, AR-independent resistance mechanisms have begun to become more prevalent. Thus, there is a need to explore and discover novel pathways, drug targets, and mechanisms driving aggressive and atypical subtypes of PCa.
Non-coding RNAs (ncRNAs) are known to play critical roles in normal cell behavior, as well as various diseases including cancer. Small nucleolar RNAs (snoRNAs) are one class of ncRNAs that are primarily involved in guiding specific enzymatic modifications (e.g. 2’O-methylation, pseudouridylation) of ribosomal RNAs (rRNAs) and thereby allowing fidelity of ribosome biogenesis. HBII-52 is an orphan C/D box snoRNA encoded in tandem repeat copies at chromosomal locus 15q11-13. HBII-52 has no predicted or reported rRNA targets, however, it has both predicted and validated messenger RNA (mRNA) targets, including the serotonin 2c receptor (5-HT2cR, encoded by the gene HTR2C). 5-HT2cR is a G-Protein Coupled Receptor (GPCR) predominantly expressed in brain, and it controls appetite and signaling via cognate ligand, serotonin (5-HT) binding. The pre-mRNA encoding 5-HT2cR is subject to complex alternative processing including alternative pre-mRNA splicing and Adenosine-to-Inosine (A-to-I) RNA editing. HBII-52 promotes processing to, highly active isoforms of 5-HT2cR, thus potentiating its signaling axis. A variety of inhibitors of 5-HT2cR exist including potent and selective inhibitors like SB242,084 that have already undergone preclinical evaluation for neurologic disorders.
Herein, we report that the expression levels of HBII-52 (MBII-52 in mouse) and 5-HT2cR are deregulated in PCa including both mouse and human preclinical models, and human clinical specimens. Furthermore, mechanistic studies of the HBII-52/5-HT2cR pathway in PCa cells indicated this pathway drives transition to an aggressive and invasive phenotype, specifically by a highly active, less edited isoform of 5-HT2cR. Finally, we evaluated the feasibility and efficacy of targeting 5-HT2cR using small molecules in PCa and arrived at a lead drug candidate, SB242,084. In conclusion, active edit-isoforms of 5-HT2cR promote aggressiveness and invasiveness of PCa cells. One potential mode of activation includes upregulation of HBII-52. HBII-52/5-HT2cR-positive cancer cells can be effectively targeted through selective inhibition of 5-HT2cR with small molecules.
Glick, Cindy Jennifer. "Development of androgen receptor messenger RNA targeted molecular beacons for use in the study of prostate cancer progression." Thesis, Atlanta, Ga. : Georgia Institute of Technology, 2008. http://hdl.handle.net/1853/26630.
Full textCommittee Chair: Bao, Gang; Committee Member: Merrill, Alfred; Committee Member: Santangelo, Philip. Part of the SMARTech Electronic Thesis and Dissertation Collection.
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.
Full textWiench, Benjamin [Verfasser]. "Molecular biology, pharmacogenomics and pharmacoproteomics of shikonin for target oriented cancer therapy / Benjamin Wiench." Mainz : Universitätsbibliothek Mainz, 2014. http://d-nb.info/1046482254/34.
Full textMcIver, Andrew. "Design and synthesis of DNA minor groove methylating compounds that target pancreatic ß-cells /." Electronic version (PDF), 2006. http://dl.uncw.edu/etd/2006/mcivera/andrewmciver.pdf.
Full textPremnauth, Gurdat. "Design, Synthesis and Biological Evaluation of New Molecules to Selectively Target Specific Cancers." University of Cincinnati / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1613744938434214.
Full textLynch, Tera L. "Design and synthesis of DNA minor groove methylating compounds that target estrogen receptor positive cells /." Electronic version (PDF), 2006. http://dl.uncw.edu/etd/2006/lyncht/teralynch.pdf.
Full textGaroub, Mohannad. "The Effect of Target-Specific Biomolecules in Breast Cancer." FIU Digital Commons, 2017. http://digitalcommons.fiu.edu/etd/3374.
Full textAlmqvist, Ylva. "Targeted Therapy of Colorectal Cancer : Preclinical Evaluation of a Radiolabelled Antibody." Doctoral thesis, Uppsala University, Radiology, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8657.
Full textTargeted radiotherapy (TRT) of cancer is a promising approach that enables selective treatment of tumour cells, while sparing normal tissue. The humanized monoclonal antibody A33 (huA33) is a potential targeting agent for TRT of colorectal cancer, since its antigen is expressed in more than 95 % of all colorectal carcinomas. The aim of this thesis was to evaluate the therapeutic potential of the two huA33-based TRT-conjugates, 177Lu-huA33, and 211At-huA33.
The conjugates 177Lu-huA33, and 211At-huA33, bound specifically to colorectal cancer cells, both in vitro and in vivo. A dose dependent cytotoxic effect of 211At-huA33 was also demonstrated in vitro. From a therapeutic perspective, both conjugates had a favourable biodistribution in tumour-bearing nude mice, with high tumour uptake and a low uptake in normal organs (with the exception of an expected thyroid uptake of 211At). After injection of 211At-huA33, the blood absorbed a slightly higher dose than the tumour, but for 177Lu-huA33, the tumour received a 12 times higher dose than blood. Two days after intravenous injection of 177Lu-huA33 in tumour-bearing mice, the tumours could be clearly visualised by gamma camera imaging, with very low interference from normal tissue radioactivity. In an experimental therapy study, also performed in tumour-bearing mice, there was an excellent therapeutic effect of 177Lu-huA33. About 50 % of the treated animals were tumour free 140 days after injection of 177Lu-huA33, while none of the non-radioactive controls survived beyond 20 days after injection of treatment substances.
In conclusion, this thesis demonstrates that the therapeutic conjugates 177Lu-huA33, and 211At-huA33, are promising targeting agents that might help improve therapy of colorectal cancer.
Revill, Charlotte Holly. "Design and synthesis of small-molecule inhibitors of two cancer targets : mTor and MDM2/p53." Thesis, University of Newcastle upon Tyne, 2012. http://hdl.handle.net/10443/2636.
Full text