Dissertations / Theses: 'Cancer molecular targets'

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Culp, W. David. "Identifying molecular targets for cancer therapy /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-188-3/.

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Ehsanian, Reza. "Molecular targets in head and neck cancer." Thesis, University of Oxford, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.540135.

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Qureishi, 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.

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Background: Head and neck cancer (HNSCC) affects 650,000 people annually. Laryngeal cancer (LSCC) and oropharyngeal cancer (OPSCC) are amongst the commonest sub-types. For other cancers e.g. breast cancer, personalised treatments based on tumour markers have improved patient survival. With the exception of human papilloma virus (HPV); there are no clinically utilised biomarkers in HNSCC. Insulin growth factor receptor 1 (IGF-1R) and HPV are promising molecular markers in LSCC and OPSCC respectively. This thesis investigates the use of IGF-1R as a marker of radiotherapy resistance in LSCC and evaluates HPV detection in patients with OPSCC. Aims: • To assess IGF-1R as a marker of radiotherapy resistance in LSCC. • To determine the diagnostic accuracy of salivary PCR to detect HPV in patients with OPSCC. Methods: Immunohistochemistry (IHC) was used to compare IGF-1R levels between patients with LSCC achieving long-term remission and experiencing recurrence after radiotherapy. LSCC cells were used to create and interrogate an in vitro model of radiation resistance. Following the completion of a systematic review on HPV testing in OPSCC, a diagnostic accuracy study was performed to determine the sensitivity and specificity of saliva testing for HPV in OPSCC. Results: IGF-1R levels are higher in radioresistant LSCC and increase following radiotherapy. IGF-1R inhibition appears to be more effective at limiting cell survival in cells with IGF-1R overexpression. The sensitivity and specificity of saliva testing when compared to p16 IHC and HPV DNA in situ hybridisation is 72.2% and 90%. Conclusions: Elevated IGF-1R appears to associate with previous radiotherapy and radiotherapy resistance in LSCC. Treatments accounting for IGF-1R status, or molecular therapies targeting this receptor, may have merit in patients whose tumours overexpress IGF-1R. Saliva testing for HPV is a promising alternative to p16 IHC performed on tumour tissue. In selected patients, this might avoid the need for surgical biopsies and expedite treatment.

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Campbell, 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.

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One of the elements commonly seen in cancer is the change in methylation status of the genome. These aberrations in methylation appear to be critical for the neoplastic phenotype and manifest as changes to gene expression of oncogenes and tumour suppressors. In addition to epigenetic alterations, the proteins involved in maintaining the plastic methylation status of the genome, DNA methyltransferases and demethylases, also show methylation-independent protein-protein interactions that have effects on cell cycle progression and proliferation. As changes in gene expression and mitotic regulation are seminal elements of cancer, and because several methylated DNA binding proteins show differential expression in a wide variety of cancers, these proteins serve as prime targets for anticancer therapies. This thesis relates to exploring both current and forthcoming possibilities and mechanisms of utilizing the DNA methylation machinery for pharmacological intervention of cancer. Chapter two deals with an antisense drug, currently in clinical trials, targeted to reduction of DNA methyltransferase 1, the maintenance methylation enzyme in mammalian cells. Our data indicate that the existence of a common truncation mutation of the adenomatous polyposis coli gene seen in some forms of sporadic and familial colorectal cancer may lead to downstream upregulation of DNA methyltransferase 1, as reconstitution of the wildtype protein reduces DNA methyltransferase 1 mRNA and protein. Reduction of the transcripts of this methylation enzyme with an antisense oligonucleotide decreases the tumourigenicity of these colorectal cancer cells, and provides a rationale for use of this drug in colorectal cancer patients and prophylactic treatment of adenomatous polyposis coli mutation-bearing individuals. Chapter three describes the rationale, design, and in vitro and in vivo testing of antisense molecules against the methylated DNA binding protein MBD2. These drugs red

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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.

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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.

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Wong, 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.

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Cervical cancer is a common gynaecological malignancy worldwide, with more than 450,000 incidences every year. Its etiology has been well documented to be associated with persistent infection with high-risk genotypes of human papillomavirus (HPV). The carcinoma can be screened by convention Pap smear and liquid-based cytology. Although preventable, cervical cancer remains a primary cause of death from cancer in developing countries where cytological screening is not so available. In the past decades, many studies have been carried out to explore molecular screening or diagnosis of cervical cancer, such as HPV DNA testing, histological or cytological biomarkers. Micro RNAs, small non-coding RNA molecules of 18-25 nucleotides in length, areaberrantly expressed in various cancers. MiR-143 was reported consistently downregulated in cervical cancer tissues and cell lines, but its functional roles in cervical carcinogenesis has not been clearly illustrated. Ten miR-143 downstream target genes were chosen and their expression levels in five cervical cancer cell lines (HeLa, SiHa, CaSki, C4-I and C33A) were investigated. In general, the gene expressions of candidates are upregulated in our cell lines with lowmiR-143 level. To further identify specific miR-143 targets in cervical cancer for biomarkers, protein expressions of TARDBP, ERK5, KRAS and PHF6were significantly downregulated upon miR-143 overexpression. Hence, miR-143 level is inversely correlated with the mRNA and protein expressions of these target genes. Immunohistochemical study of ERK5 and TARDBP on FFPE samples including normal cervix, CINs and SCC cases showed that both ERK5 and TARDBP were positively stained in SCC samples, whereas weaker staining was found in CINs (both LSILs and HSILs) for both antigens. Thus, the intensity of positive staining ascended with the histological grading: LSIL, HSIL and SCC samples. Such differential expression pattern supports ERK5 and TARDBP as specific markers for high grade cancerous lesions. In summary, two targets of miR-143, ERK5 and TARDBP, could be specific markers for high-grade lesion of cervical cancer. This is supported by their transcript and protein expressions inversely associated with miR-143 level, and that their strong immunohistochemical positivity in SCC samples. Their underlying molecular mechanisms involved in carcinogenesis and possible future applications require more in-depth researches.
published_or_final_version
Pathology
Master
Master of Medical Sciences

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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.

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The ultraviolet (UV) component of sunlight has been identified as a major etiological factor in the development of non-melanoma skin cancer (NMSC). Upregulation of Activator Protein-1 (AP-1) and Cyclooxygenase-2 (COX-2) have clearly demonstrated a functional role in skin tumor promotion. The goal of this work was to contribute to the growing knowledge of UVA and UVB induced signaling events leading to increases in AP-1 and COX-2. We show that UVA induces COX-2 expression in the human keratinocyte cell line, HaCaT through a post-transcriptional mechanism involving the 3 ' untranslated region (3'UTR). Use of a pharmacological inhibitor of p38 MAPK, SB202190, decreased UVA-induced COX-2 steady-state mRNA and protein levels. The stability of COX-2 mRNA is increased in UVA-irradiated cells and dependent upon p38 MAPK activity. We further explored the role of UVA-induced p38 MAPK activity in apoptosis in both HaCaT cells and primary keratinocytes. Dramatic increases in apoptosis were observed in UVA-irradiated cells treated with SB202190 or through the use of a dominant-negative construct. UVA induced expression of Bcl-X L with abrogation of expression using SB202190. Overexpression of Bcl-X L prevented PARP (Poly ADP-ribose Polymerase) cleavage induced by the combination of UVA and p38 MAPK inhibition. We further demonstrated that UVA enhanced the stability of Bcl-XL mRNA through increases in p38 MAPK activity mediated through the 3' UTR. p38 MAPK and Bcl-XL expression play critical roles in the survival of UVA-irradiated keratinocytes. Previous investigations from the laboratory identified p38 MAPK and PI3-Kinase as the major mediators of UVB-induced AP-1 and COX-2 in the HaCaT cell line. To further validate p38 MAPK and PI3-Kinase as potential molecular targets we investigated whether an acute UVB dose activated the p38 MAPK and PI3-Kinase pathways in vivo. We observed rapid increases in both p38 MAPK and PI3-Kinase signaling in mouse epidermis. Activation of these pathways resulted in the phosphorylation of cyclic AMP response element binding protein (CREB). Topical treatment with SB202190 or LY294002 (a specific inhibitor of PI3-Kinase) significantly decreased UVB-induced COX-2 expression and AP-1 activation in vivo. Our data suggest that p38 MAPK and PI3-Kinase may serve as significant molecular targets for the chemoprevention of UVB-induced NMSC.

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Whetstone, 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.

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Ong, 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.

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The increasing advances in genomic technologies in the last decade have allowed us to understand the molecular mutational landscape of prostate cancer. However, validation of genomic profiles generated by high-throughput efforts is laborious and expensive. Therefore, there is a need for a systematic and streamlined assessment of high-throughput genomic data to prioritise genes for further detailed biological validation studies for which this thesis entailed. Through cluster analysis of a panel of carefully selected markers, such as AR, ERG, MYC, RB1, PTEN and TP53, we were able to align patients into individual subgroups based on their PTEN status. Subsequently, through an objective computer learning elastic net modelling, we identified a cluster of 35 genes that was defining the clusters in our cohort. The prognostic effect of this signature was conserved in three independent datasets, with prominent statistical power, in Gleason 7 prostate cancer. Notably, our study is the first to report a signature with prognostic value in Gleason 7 cases. Additionally, we were able to identify a putative actionable target, S1PR2, by overlapping PTEN-low expressing clinical cases with gene expression data available from a Pten-knockout mouse model. From our analysis, we have observed that the combined inhibition of S1PR2 and the S1P kinases, SPHK1/2 were able to reduce cell migration and viability. Through a series of molecular validation, we postulated that the inhibition of both S1PR2 and SPHK1/2 could decrease cell viability and migration essential for cancer cell survival. Collectively, our findings contributed to the better understanding of the genomic changes associated with the heterogeneity of prostate cancer. Furthermore, we have uncovered several possible avenues for novel therapeutic interventions for untreated Gleason 7 prostate cancer.

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Alfarsi, 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.

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Le cancer de l’ovaire est la première cause de décès par cancer gynécologique chez la femme. La survie globale à 5 ans est inférieur à 40% due à un diagnostique tardif et une haute fréquence des récidives malgré une chimiosensibilité initiale. Les caractéristiques cliniques et anatomopathologiques ne prédisent pas de façon précise le pronostic des patients et il est urgent de trouver de nouvelles cibles moléculaires. Ces dernières années plusieurs nouvelles stratégies ont émergé. De nombreux consortium ont analysé de façon exhaustive le génome des cancers ovariens établissant ainsi une carte d ‘identité précise des cancers avancés. Par ailleurs plusieurs groupes ont montré le rôle primordial du stroma tumoral dans la progression des tumeurs ovariens.Dans ce travail de thèse nous avons d’abord mis en place un modèle de culture tridimensionnel des cancers de l’ovaire en utilisant la membrane amniotique comme substitut au péritoine. Nous avons pu ainsi quantifier les premières étapes de l’invasion tumorale et montrer le rôle primordial des MSCs via la sécrétion de l’Interleukin IL6. Notre deuxième travail a consisté en une analyse des données de génomiques du TCGA. Nous avons utilisé les concepts de Background mutation rate et mis en place un système de mutagenèse in silico avec des boucles de réitération (Bootstrap). Cette stratégie nous a permis d’obtenir une liste des gènes qui auraient du être retrouvé muté. En posant l ‘hypothèse que les gènes protégés des mutations étaient primordiales au développement tumoral nous avons mis en place une plateforme de screening basé sur l’inhibition par siRNA pour démontrer la validité de notre stratégie. Ainsi nous avons pu montrer le rôle primordial de gène dont la fonction n’était pas décrite dans le cancer de l’ovaire (ANKLE2, MAB1-Beta).Au total utilisant deux stratégies différentes de recherche nous avons pu mettre ne évidence le rôle d’IL6 dans l’invasion initiale du péritoine par les cellules tumorales ovariennes et déterminer le rôle de gènes non muté dans la progression tumorale
Ovarian 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

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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.

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Visser, 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.

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Thesis (PhD)--Stellenbosch University, 2014.
ENGLISH 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.

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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.

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Le cancer colorectal est la deuxième cause de mortalité due au cancer en Europe et aux États-Unis. Etant donné l’efficacité limitée et la toxicité élevée des agents de chimiothérapie, de nouvelles approches sont nécessaires. Le flavanolignane silybine représente le principal constituant actif du chardon-marie (Silybum marianum). Les mécanismes moléculaires des propriétés anticancéreuses de la silybine ont été étudiés dans un modèle cellulaire de progression du cancer colorectal humain : les cellules SW480 issues d’un adénocarcinome, et leurs dérivées métastatiques les cellules SW620. Les effets chimiopréventifs de la silybine ont été étudiés dans un modèle de cancérogenèse colique induite par l’azoxyméthane chez le rat. La silybine induit une mort apoptotique avec activation de la caspase-3 dans les deux lignées. L’expression des récepteurs de mort TRAIL est augmentée, et la caspase-8 activée. Le potentiel mitochondrial est perturbé provoquant une libération du cytochrome c et une activation de la caspase-9. En plus de l’activation des voies apoptotiques extrinsèque et intrinsèque la silybine induit une réponse autophagique. La combinaison de la silybine et de TRAIL, un agent anti-cancéreux prometteur, provoque une mort cellulaire synergique dans les deux lignées. Un effet synergique est aussi observé avec la combinaison de la silybine et des inhibiteurs des histones déacétylases (HDAC) : TSA et SAHA. Dans le modèle chez le rat, la silybine réduit de 50% le nombre des lésions prénéoplasiques. En conclusion, la silybine est un agent naturel intéressant pour la prévention du cancer colorectal et dans le cadre d’une combinaison avec TRAIL/des inhibiteurs d’HDACs
Colorectal 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

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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.

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Tong, 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.

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Schreiber, 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.

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Oliveira, 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.

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Mestrado em Biologia Molecular e Celular
O 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.

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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.

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[Truncated abstract] For this thesis, the molecular biology of cancer was approached from two directions. Firstly, an investigation was conducted on the role of growth factor receptor-bound protein 7 (Grb7) in breast cancer. Grb7 is an adapter molecule that binds to a variety of proteins, including the growth factor receptor and proto-oncogene, ErbB2, and mediates signalling to downstream pathways. It has been linked to cell migration and an invasive phenotype, and is of interest as a therapeutic target. To investigate the role of Grb7 in breast cancer, preliminary experiments were performed that, firstly, determined the expression of wild-type Grb7 and a splice variant, Grb7V, in a range of cell lines, and secondly, aided the development of a protocol for treating cells with short interfering RNA (siRNA) against Grb7 and the ErbB ligand, heregulin (HRG), in a cell system appropriate for measuring the functional outcomes. Using this protocol in conjunction with CellTitre (CT) proliferation assays, it was demonstrated that Grb7 does not play a role in the proliferation of either unstimulated or HRG-stimulated SK-BR-3 breast cancer cells. Furthermore, using the protocol in conjunction with Boyden chamber migration assays, it was shown that inhibition of Grb7 expression has a slight stimulatory effect on HRG-stimulated SK-BR-3 cell migration. Thus, Grb7 was found to play only a minor role in the migration of SK-BR-3 cells, suggesting that it is not an ideal anti-cancer target for breast cancers modelled by this cell system. Concurrently, a second investigation was conducted, which similarly sought insight into the molecular biology of cancer, but adopted a more strategic approach. ... These results provide evidence for a biologically significant role for the miR-7-mediated regulation of EGFR expression. A microarray experiment was also performed to identify genes that were down-regulated following treatment with miR-7 compared to NS precursor. Of 248 down-regulated genes, including EGFR, 37 promising new miR-7 target candidates were identified. Functional clustering of down-regulated genes and promising target candidates suggested that miR-7 may have functionally-related targets involved in processes including cell motility and brain-associated functions. This investigation thus yielded a program capable of accurately predicting a miRNA target not predicted by any other target prediction program, verified a previously unknown miRNA:target interaction with functional consequences in cancer cells and provided the first steps towards investigating miR-7-mediated regulation in greater depth. Furthermore, EGFR was, to our knowledge, the first example of a verified miRNA target with target sites that are not conserved across mammals, an observation with important implications for computational target prediction and the evolution of miRNA regulatory systems. In addition, the demonstrated growth inhibitory and cytotoxic effects of miR-7 on lung cancer cells raise the possibility of a miR-7-based therapeutic for the treatment of EGFR-overexpressing tumours.

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Silva, 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.

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Les DIPG représentent les tumeurs cérébrales pédiatriques les plus sévères. Aucun progrès dans leur prise en charge n’a été accompli au cours des 50 dernières années et la radiothérapie ne demeure que transitoirement efficace. Récemment, une mutation somatique de l’histone H3 (K27M) spécifique des DIPG a été trouvée chez environ 95% des patients. Elle est aujourd’hui considérée comme l'événement oncogénique initiateur de ces tumeurs. Deux sous-groupes majeurs de patients présentant des programmes oncogéniques et une réponse à la radiothérapie distincts peuvent être définis en fonction du gène dans lequel l’altération survient, codant les variantes protéiques H3.1 ou H3.3. Nous avons réalisé deux cribles de létalité synthétique par ARN interférence ciblant le kinome humain afin d'identifier d’une part les gènes nécessaires à la survie des DIPG et d’autre part les gènes dont l’inhibition sensibilise ces tumeurs à la radiothérapie. Le double objectif de ce projet était de mieux comprendre la biologie sous-jacente à l’oncogenèse des DIPG et de découvrir de nouvelles cibles thérapeutiques.Nous avons mis en évidence 41 gènes requis pour la survie des DIPG sans effet délétère majeur sur des cellules contrôles normales. Parmi eux, nous avons identifié VRK3 codant une serine thréonine kinase dont les fonctions restent peu décrites à ce jour et qui n'avait jamais été associée préalablement à l'oncogenèse de DIPG. Nous avons pu confirmer par la suite que son inhibition conduit à un arrêt total de la prolifération des cellules de DIPG associé à d’importants changements morphologiques, plus particulièrement dans les tumeurs mutées pour H3.3-K27M. VRK3 constitue par conséquent une nouvelle cible thérapeutique prometteuse dans cette pathologie à l’issue fatale pour la totalité des patients.En parallèle, un crible de survie similaire a été réalisé en conjonction avec l’irradiation des cellules. Très peu d’ARN interférents ont permis de sensibiliser les cellules H3.3-K27M à la radiothérapie contrairement aux cellules H3.1-K27M. Ce travail nous a permis de mettre en évidence une différence significative de radiosensibilité des modèles vitro de DMG en fonction du sous-groupe de tumeurs considéré, H3.1- ou H3.3-K27M muté, conformément à la survie des patients observée suite à la radiothérapie. Ces résultats inédits laissent entrevoir des perspectives d’amélioration du traitement de référence des patients atteints de DIPG actuellement identique quelle que soit leur génotype
DIPG 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

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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.

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El, 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.

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Souza, 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.

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Orientadores: Carmen Verissima Ferreira, Hiroshi Aoyama
Tese (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

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23

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.

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Cancer is one of the major causes of death in the western world. Resistance to anti-cancer drugs and diagnostic difficulties are major obstacles to successful treatment. This thesis describes studies based on microarray expression analysis and high-throughput compound screening for identification of resistance mechanisms, drug targets and diagnostic markers. In paper I-IV, we applied global expression analysis and measurements of drug response in a human tumor cell line panel to identify drug targets and resistance mechanisms. In paper I, we identified gene transcript levels that correlate with drug resistance and sensitivity. Both well known and new potential markers and mechanisms were identified. In paper II, we showed that STAT1 activity is associated with cross-resistance to both doxorubicin and radiation in vitro and that fludarabine can counteract STAT1 activity and reduce resistance. In Paper III-IV, cell lines were exposed to a compound library consisting of more than thousand different substances in a high-throughput screening effort. These studies revealed that cell line models of squamous cell carcinoma (Paper III) and drug resistant myeloma (Paper IV) are sensitive to phosphodiesterase inhibitors and glucocorticoids respectively. The target molecules for these drugs were over-expressed at the mRNA level and constitute likely explanations for the observed drug potency. In paper V, we identified mRNA markers for the distinction between two types of thyroid tumors, thyroid follicular adenomas and thyroid follicular carcinomas, by means of microarray expression analysis. Our results indicated that distinction between the two tumor types is possible with a small number of markers.

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Fryknäs, 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.

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25

Honarvar, 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.

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Affibody molecules are a promising class of scaffold-based targeting proteins for radionuclide-based imaging and therapy of cancer. This thesis work is based on 5 original research articles (papers I-V), which focus on optimization of molecular design of HER2-binding Affibody variants for high contrast imaging of this predictive biomarker as well as development of Affibody molecules suitable for radionuclide-based targeted therapies. Papers I and II were dedicated to evaluation of the influence of the macrocyclic chelator DOTA positioning at N-terminus, in the middle of helix-3 and at C terminus of a synthetic Affibody molecule, ZHER2:S1. These synthetic variants were labelled with different radionuclides i.e. 111In and 68Ga to study also the effect of different labels on their biodistribution properties. In paper III a 2-helix variant, Z342min, was developed using native ligation cyclization to cross-link helices one and two resulting in a stable 2-helix scaffold and characterized in vivo. This study was performed with the aim to obtain structure-properties relationship for development of smaller Affibody molecules. Papers IV and V were devoted to development of therapeutic strategies. In paper IV, a series of peptide based chelators was investigated for labelling of Affibody molecules with 188Re to provide low renal retention. In paper V, a pretargeting approach using peptide nucleic acid was investigated. These studies were performed with the aim to overcome the high renal retention of Affibody molecules when labelled with residualizing therapeutic radionuclides. Otherwise, the particle emitting radiometals could damage the kidneys more than the tumours. The results obtained for anti-HER2 Affibody molecules summarized in this thesis might be of importance for the development of other scaffold protein based targeting agents.

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Bapat, 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.

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Thesis (Ph.D.)--Indiana University, 2009.
Title 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).

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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.

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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

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Yang, Ya-Ting. "Molecularly targeted therapy for ovarian cancer." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1149015359.

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Lovato, 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.

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Breast cancer is a heterogeneous disease, but is invariably associated with genome wide deregulation of transcription. The silencing of tumor suppressor genes (TSGs) in particular is thought to be an early, initiating event in many cancers. While re-expressing these genes is a clinically relevant goal, the development of therapeutics targeting the reactivation of TSGs has been hampered by a lack of understanding of the mechanisms responsible for TSG silencing. Recently, however, we have described a novel means through which several TSGs become silenced in cancer, which may highlight new therapeutic targets. This involves the epigenetic regulatory factor Ctcf which is critical for maintaining transcriptional activation and organizing chromatin at several TSG loci. In cells where these TSGs are silenced, the DNA binding of Ctcf to these TSGs is lost. This lack of DNA binding is associated with a loss of the post-translational modification by poly(ADP)ribosylation (known as PARylation). Aberrant dePARylation of Ctcf is associated with breast cancer progression, underscoring the importance of this Ctcf post-translational modification. We have novel data indicating that the dePARylating enzyme Parg is overexpressed in cancer. We hypothesize that inhibition of Ctcf PARylation by Parg disrupts normal epigenetic patterns at TSGs leading to subsequent gene silencing. We propose to examine the impact of Parg overexpression on the epigenetic programming and expression of Ctcf target genes, as well as the proliferation of breast epithelial cells. To determine the relevance of Parg in breast cancer, we have accumulated evidence from bioinformatics sources and through our own experimentation revealing an enrichment of Parg in a significant proportion of breast cancers. For instance, we have evidence from the Oncomine database and the UCSC Cancer Genome Browser that Parg is overexpressed at the mRNA level in 30-50% of breast cancers. Likewise, at the protein level, higher Parg expression is found in breast cancer cell lines compared to untransformed cell lines and is found to be enriched in more aggressive stages of a mouse tumor model. This is complemented with clinical breast tissue samples showing overexpression of Parg protein in breast cancer.In support of clinical data, we have generated Parg-overexpressing Mcf10a cells to assess the role of this protein in mediating cellular transformation. Interestingly, Parg overexpression induced cells to shift from an epithelial morphology to a mesenchymal one. This was met with a decrease in the rate of proliferation in vitro. The expression of the Parg transgene, however, was quickly lost and alludes to a significant role for Parg in cellular biology. Overexpression studies were complemented with drug and knockdown studies. This work illustrated that a shRNA knockdown of Parg was met with a significant decrease in cell growth. Similar results were obtained for cells treated with the Parg inhibitor, tannic acid. Use of this drug caused a decrease in the repressive histone mark H3K27me3 which we believe may restore the expression of silenced TSGs. Likewise, tannic acid induced DNA damage foci over the course of long treatments with the drug, suggesting that DNA damage, too, may contribute to the decrease in cellular proliferation observed. Ultimately, this work provides evidence for a therapeutic benefit of targeting Parg in breast cancer.
Le 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.

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30

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.

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31

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.

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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

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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.

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Oral and lung cancer are included in the most prevalent respiratory diseases, being the latter one of the main causes of mortality worldwide. Despite new advances in diagnosis and clinical care, success of conventional treatments is still limited since patients end up developing resistances and presenting recurrences. Due to the therapeutic limitations to address these pathologies, it is necessary to identify new compounds, with different mechanisms of action and greater efficiency to overcome these neoplasms. Cancer cells acquire a series of characteristics during carcinogenesis, as a reversed pH gradient compared to normal cells, which favors cancer progression promoting proliferation and evasion of apoptosis. Recently, a new therapeutic strategy against cancer, which involves the modulation of intracellular pH has been proposed. Accordingly, our research group is focused on analyzing the potential of anion transporter compounds as new chemotherapeutic agents, since they possess the ability to selectively lower the intracellular pH. In particular, this doctoral thesis is focused on the anticancer effect characterization, at the cellular and molecular level, of novel anionophores, derived from natural compounds known as tambjamines. Firstly, the effect of the synthetic analogues on cell viability in oral and pulmonary cancer cell lines, as well as in cancer stem cells derived from patients’ tumors, has been determined, proving to be potent cytotoxic agents. Likewise, the implication of ion homeostasis disruption driven by these compounds has been studied at the cellular level. In this regard, it has been characterized how the compounds induce lysosomal alkalization and cause a massive vacuolization in the cytoplasm, which is consistent with mitochondrial swelling. These two phenomena led to the loss of function of both organelles. At the same time, the mechanisms of action linked to the osmotic imbalance caused by the compounds have been studied in detail. On one hand, it has been observed how these anionophores increase the activity of proteins related to cellular stress response, and how the apoptotic pathway is triggered, although this is not directly responsible for the death of the entire cell population. Likewise, an accumulation of autophagosomes, has been detected after treatment with these compounds, which might be related to the blockade of autophagy, consequence of the lysosomal failure after treatment with these compounds. Moreover, it has also been observed how the cells treated with these anionophores lose the integrity of the plasma membrane, indicating that the cytotoxic process culminates in necrosis in the vast majority of the cell population. Besides this, in this doctoral thesis, AKT protein has been identified as a potential molecular target of one of our compounds, using in silico docking experiments. In turn, it has been corroborated by surface plasmon resonance that the binding affinity between the selected tambjamine analogue and AKT is high, in the micromolar range. Likewise, a decrease in protein activity and in the total amount of AKT protein has been detected after treatment. Furthermore, the main signaling pathways involved in the cytotoxic process have been elucidated studying the modifications of miRNA expression patterns after the treatment with tambjamine, being the most affected PI3K / AKT, apoptosis and autophagy. Finally, to complete the preclinical studies, the toxicity and efficacy of these compounds in murine models of lung cancer have been evaluated in in vivo preliminary studies, showing a potent antitumor capacity in both ectopic and orthotopic models. Overall, these synthetic analogues of tambjamine may be considered a good tool to induce death in cancer cells through a new therapeutic strategy that modifies the intracellular pH and these compounds may become a good therapeutic option for apoptosis-resistant tumors.
El 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.

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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/.

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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.

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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.

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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.

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Mestrado em Bioquímica - Bioquímica Clínica
O 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.

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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.

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This research study investigated the association of microRNA related single nucleotide polymorphisms (miRSNPs) with breast cancer susceptibility in Australian Caucasian women. The thesis then progressed with developing an in silico methodology for miRNA-target identification followed by the validation of miRNA-target relationships regarding the distinctive molecular subtypes of human breast cancers.

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Phadke, 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.

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Pharmaceutical Sciences
Ph.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

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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.

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Prostate cancer is the second most diagnosed and cause of cancer-related death in Australian men. Resistance to treatment and non-specificity of the drugs is a major bottleneck for prostate cancer. Recently, nano-formulated drugs are being developed for targeted drug delivery into the cancer cells. Prostate cancer cells use aerobic glycolysis promoted by the pyruvate dehydrogenase kinase-1 (PDK1) gene for energy production. We targeted PDK1 using nano-formulations selective for prostate cancer cells and tested these using in vitro and in vivo models. Nano-conjugated Radicicol was identified as most promising drug and potential useful co-therapy agent with inhibitory effect on tumour development.

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Carbary, 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.

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Advances in optical imaging have provided methods for visualizing molecular expression in tumors in vivo, allowing the opportunity to study the complexity of the tumor microenvironment. The development of fluorescent contrast agents targeted to molecules expressed in cancer cells is critical for in vivo imaging of the tumors. Contrast agents emitting in the near infrared (NIR) allow for an increased depth of penetration in tissue due to decreased absorption and scattering. There is also significantly less autofluorescence from tissue in the NIR. Quantum dots are nanoscopic particles of semiconductors whose fluorescent emission wavelength is tunable by the size of the particle with desirable fluorescent qualities such as a wide range of excitation wavelengths, a narrow emission band, high quantum efficiency, high photostablility, and they can be produced to emit throughout the NIR imaging window. It has been shown that vascular endothelial growth factor receptor 2 (VEGFR2) is upregulated in many cancers, including colorectal, as it is important in tumor angiogenesis and is considered a predictor for clinical outcome and, in some instances, is used for targeted therapy with anti-angiogenic drugs. For these reasons, quantum dots bioconjugated to VEGFR2 antibodies have the potential to provide contrast between normal tissue and cancer, as well as a mechanism for evaluating the molecular changes associated with cancer in vivo. In this dissertation, we present on the design of two contrast agents using quantum dots targeted to VEGFR2 for use in the molecular imaging of colon cancer, both ex vivo and in vivo. First, as a preliminary ex vivo investigation into their efficacy, Qdot655® (655nm emission) were bioconjugated to anti-VEGFR2 antibodies through streptavidin/biotin linking. The resulting QD655-VEGFR2 contrast agent was used to label colon adenoma in vivo and imaged ex vivo with significant increase in contrast between diseased and undiseased tissue, allowing for fluorescence based visualization of the VEGFR2 expressing diseased areas of the colon with high sensitivity and specificity. Then, QD655-VEGFR2 was used in a longitudinal in vivo study to investigate ability to correlate fluorescence signal to tumor development over time using optical coherence tomography and laser induced fluorescence spectroscopy (OCT/LIF) dual-modality imaging. The contrast agent was able to target VGEFR2 expressing diseased areas of colon; however, challenges in fully flushing the unbound contrast agent from the colon before imaging arise when moving from ex vivo imaging to in vivo image. Lastly, lead sulfide (PbS) quantum dots were made by colloidal synthesis to emit at a 940 nm (QD940) and conjugated to anti-VEGFR2 primary antibodies through streptavidin/biotin linking. The resulting QD940-VEGFR2 contrast agent was then used to label cells in vitro. The QD940-VEGFR2 molecules were able to positively label VEGFR2 expressing cells and did not label VEGFR2 negative cells. Very low photoluminescence and large amounts of aggregation after conjugation of the quantum dot to streptavidin was detected. Improvements to the quantum dot stability through synthesis, capping and conjugation techniques must be made for this contrast agent to be effective as a contrast agent for cancer imaging.

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supsavhad, wachiraphan. "Novel Molecular Targets for Feline Oral Squamous Cell Carcinoma." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1471628009.

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Seedhouse, 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.

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Every 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.

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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.

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Thesis (M.S.)--Biomedical Engineering, Georgia Institute of Technology, 2009.
Committee Chair: Bao, Gang; Committee Member: Merrill, Alfred; Committee Member: Santangelo, Philip. Part of the SMARTech Electronic Thesis and Dissertation Collection.

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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.

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Wiench, 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.

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McIver, 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.

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Premnauth, 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.

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Lynch, 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.

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Garoub, Mohannad. "The Effect of Target-Specific Biomolecules in Breast Cancer." FIU Digital Commons, 2017. http://digitalcommons.fiu.edu/etd/3374.

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Cancer is the second leading cause of mortality in the United States and the World, therefore, early effective prevention, diagnosis, and therapy is needed. Estrogens play a major role in the initiation and progression of breast cancer. Elevated lifetime exposure to estrogens is associated with an increased risk of developing breast cancer. Estrogens through influencing mitochondria contribute to estrogen induced breast carcinogenesis; however, the exact mitochondrial mechanisms underlying the estrogen carcinogenic effect in breast tissue are not clearly understood. For this dissertation, the mitotoxic and cytotoxic effects of triphenylphosphonium cation (TPP) and Origanum majorana organic extract (OME) as well as PEGylated bioconjugate of OME with TPP (P-OME-TPP) against human breast epithelial and cancer cell lines was investigated. Initially, TPP, a lipophilic cation, was used to check whether an imbalance in mitochondrial bioenergetics, in part, may be responsible for estrogen induced growth of breast cancer. The results showed that exposure of estrogen-dependent MCF-7 cells to 17 β-estradiol (E2) induced the metabolic activity, proliferation, mitochondrial bioenergetics, DNA damage, and formation of cellular and mitochondrial reactive oxidant species (ROS). These E2-induced endpoints were inhibited by co-treatment with TPP, indicating mitochondrial mechanisms, in part, may contribute to the development of breast cancer. Furthermore, O. majorana, widely used in the Middle East as a culinary aromatic medicinal herb, has been shown to possess an extensive range of biological activity including antioxidant, anti-inflammatory, and anti-tumor growth effects. Interestingly, the anticancer potential of O. majorana against breast cancer remains largely unexplored; therefore, the anticancer effect of O. majorana on breast cell lines was investigated. The results showed that E2-induced metabolic activity and growth were inhibited by OME in MCF-7 cells. The results also demonstrated that synthesized P-OME-TPP conjugate, compared to OME, was far more effective in exerting its cytotoxic effect through the inhibition of growth and mitochondrial metabolic activity in both highly metastatic, triple negative MDA-MB-231 and estrogen-dependent MCF-7 breast cancer cells. Altogether, these findings offer a new perspective on the utility of mitochondria-targeted lipophilic TPP cation and the potential of O. majorana extract to be developed as a new therapy against breast tumors.

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Almqvist, 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.

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Targeted 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.

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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.

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Cancer is a disease in which cellular control over growth and differentiation has been lost. Targeted therapies for the treatment of cancer are becoming an increasing area of focus within the pharmaceutical industry and academia, due to the increasing understanding of the biology behind tumourgenesis. There are 518 protein kinases within the human genome and they play a significant role within cellular signalling. Aberrant signalling of kinases can contribute to the development of cancer, and inhibition of kinase targets can result in either a cytostatic or cytotoxic effort. Kinases have a discrete ATP-binding domain, which presents an ideal target for small- molecule inhibitors. mTOR (mammalian target of rapamycin) is a serine/threonine protein kinase, which forms two complexes, mTORC1 and mTORC2, as part of the PI 3-K/Akt pathway, a growth/survival pathway which has aberrant signalling in a number of cancers. The development of ATP-competitive inhibitors of mTOR has been based on a series of 2,6- diaminosubstituted pyrimidines, with modest activity against mTOR, as exemplified by NU6027 and NU6227 originally designed as CDK2 inhibitors. Structure-activity relationships for inhibition of mTOR have been explored. The 4-substituent was either modified to a smaller alkoxy group or completely removed, giving reduced activity. At the 5- position compounds with other substituents were then synthesised. Modifications of the 2- and 6-amino groups were also investigated. The pyrimidine heterocycle was also replaced with two pyridine regioisomers. None of the synthesised compounds showed improved mTOR inhibitory activity over NU6227 and NU6027. The tumour suppressor p53 is activated as a response to DNA-damage, oncogene activation and cellular stress. Once activated p53 acts as a transcription initiator, inducing thetranscription of a number of genes, including those involved in halting the cell cycle, repairing DNA-damage and initiating apoptosis. A further transcriptional target of p53 is MDM2, a negative regulator of p53. Inhibitors of the MDM2-p53 interaction have been reported including the isoindolinones e.g. NCL-00008406. Structure-activity relationships (SAR) studies for the identification of replacement of the 4- nitro group showed that a 4-ethynyl substituent had a similar level of potency, along with the 4-bromo, 3-fluoro substituents. SARs around the isoindolinone A-ring identified the 6-tert- butyl substituent as equipotent to the parent. Synthesis of an oxetane derivative such as NCL- 00018327 has demonstrated that replacing the cyclopropyl group with a 3,3-oxetane substituent either maintained or improved activity against MDM2. Synthetic efforts have identified highly potent, low nanomolar, isoindolinone-based inhibitors of the MDM2-p53 protein-protein interaction. Optimal substituents for the benzyl group have been identified, avoiding the use of a nitro group which is toxic within drugs. Synthesis of an oxetane derivative has been shown to be either equi- or more potent than cyclopropyl derivatives, and this modification is predicted to improved the aqueous solubility by reducing the clogP. Synthesis of a tert-butyl analogues using an alternative synthetic route has developed the SAR around the A-ring and resulted in an improved synthetic scheme. Purification of a range of MDM2 mutant proteins has identified a crystallisable form of MDM2 and the recently solved crystal structure of an isoindolinone bound to MDM2 should guide further improvements to potency and aid the incorporation of groups to improve physical properties. Cancer is a disease in which control over cellular growth is deregulated. Synthetic efforts have been directed toward the development of two targeted anti-cancer agents; the kinase mTOR and the protein-protein interaction MDM2/p53. 2,6-diaminopyrimidine were identified as most inhibitors of mTOR, but demonstrated a flat SAR and no increase in potency was observed. Isoindolinones have been identified as a valuable scaffold to inhibit the protein-protein interaction and have demonstrated excellent potencies.

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Dissertations / Theses on the topic 'Cancer molecular targets'

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