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Circulating biomarkers in colorectal cancer and their application in diagnosis and prognosis
Červená, Klára ; Vymetálková, Veronika (advisor) ; Boublíková, Ludmila (referee) ; Václavíková, Radka (referee)
Despite all the advances in the field of clinical and molecular oncology, the numbers related to the incidence and mortality of colorectal cancer (CRC) remain at unacceptable levels. In recent years, liquid biopsy consisting of circulating biomarkers has come to the forefront of research, offering many advantages over conventional biopsy, such as providing timely information on tumor heterogeneity and the ease of repeated sampling. This dissertation thesis aimed to identify novel candidate circulating biomarkers from microRNAs, long non-coding RNAs, and cell-free DNA that could be used for earlier diagnosis, better prognosis, or prediction of therapy response of CRC patients and thus further advance personalized medicine. The main results of this work are: 1) Circulating microRNAs in plasma (miR-122-5p and miR- 142-5p) can distinguish patients with rectal cancer and cancer-free individuals and could predict therapy response in patients (both in primary and metastatic CRC patients). 2) Gene amplification of the long non-coding RNA MALAT1 can represent an important step in the transition of healthy mucosa to adenoma tissue. Plasma MALAT1 is overexpressed in patients with colorectal adenomas and CRC patients compared to cancer-free individuals and has the potential as a predictive biomarker for CRC...
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Effect of the anticancer drug cabozantinib on cytochrome P450 activity
Slobodníková, Eva ; Dračínská, Helena (advisor) ; Václavíková, Radka (referee)
Cabozantinib is an anti-cancer drug used mainly for the treatment of thyroid and renal cell carcinoma. It is classified as a low molecular weight selective tyrosine kinase inhibitor. Tyrosine kinases play a key role in signal transduction and regulation of many cellular processes such as growth, differentiation, and proliferation. The changes in the tyrosine kinase pathways are associated with the formation and progression of tumors where their growth is uncontrolled. Tyrosine kinase inhibitors act on tyrosine kinase receptors, thereby preventing the spread of cancer cells and slowing down the progression of cancer. Because cabozantinib, like other clinically used drugs, is metabolized by cytochromes P450, adverse drug interactions may occur that result in altered pharmacokinetics of the administered drugs and a consequent decrease in the efficacy of these drugs. In this diploma thesis, the effect of cabozantinib on the activity of the main enzymes of phase I biotransformation of xenobiotics, cytochromes P450, was investigated in vitro. The effect on the activity of both rat and human cytochrome P450 isoforms involved in xenobiotic metabolism was studied. CYP isoforms were predominantly incubated with cabozantinib at two concentrations; 10 µM and a concentration corresponding to the substrate...
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Molecular Biomarkers of Anticancer Drugs Efficacy in Experimental Models and in Patients with Solid Tumors
Šeborová, Karolína ; Václavíková, Radka (advisor) ; Mohelníková Duchoňová, Beatrice (referee) ; Indra, Radek (referee)
Ovarian carcinoma is a heterogeneous group of diseases usually of epithelial origin. The vast majority of diagnosed cases are high-grade serous carcinomas, which account for over 80% of all cases. Ovarian carcinoma is one of the most common causes of death in women from gynecological malignancies. The main cause of high mortality is diagnosis of the disease in late stages due to the long-term asymptomatic course. The second important cause is the development of multidrug resistance to the administered treatment, which is in the case of ovarian carcinoma patients still mainly based on a combination of paclitaxel and platinum derivatives - cisplatin or carboplatin. These are some of the reasons that motivate scientists to search for new biomarkers, which could help detect the disease in early stages, or monitor the success of treatment, and predict the development of resistance. Molecular characterization of cancer in general may also reveal new therapeutic targets. The development of resistance to already existing drugs stimulates the direction of scientists to prepare new drugs that would be especially effective against already resistant tumors. The main aim of the presented theses was to expand information on the molecular profile of ovarian carcinoma, to reveal prognostic and predictive molecular...
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Identification of expression profile changes of resistance-associated genes in experimental in vivo model of ovarian carcinoma
Bryndová, Barbora ; Václavíková, Radka (advisor) ; Dračínská, Helena (referee)
Ovarian carcinoma is one of the most serious gynecological malignancies in the world. High mortality of this cancer is mainly due to the development of multiple drug resistance to conventional treatments involving taxanes. Therefore, current research is focused on the study of new taxane-based derivatives capable to overcome known mechanisms of drug resistance. At present, there are several promising Stony Brook taxane derivatives (SB-T-taxanes), investigated in frame of efficacy, toxicity and mechanism of action. The aim of this bachelor thesis was to study changes in the expression of genes involved in the development of resistance in tissues and tumor obtained from in vivo mo- dels after the administration of derivatives SB-T-121605 compared to conventional taxane paclitaxel and non-treated models. Expression of selected ABC transporter genes (ABCB1, ABCC1 and ABCG2), taxane metabolizing enzyme genes (CYP3A11, CYP3A13 and CYP2C29) and their mouse orthologs was estimated in liver, intestinal and tumor tissue samples taken from in vivo mouse xenograft models. Tumor tissue was derivated from the highly resistant NCI/ADR-RES ovarian cancer cell line. Gene expression was determined by real-time quantitative polymerase chain reaction. Administration of the SB-T-121605 derivative led to several...
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Re-analysis of suspected patients with FAP disease (Familial adenomatous polyposis)
Slavíková, Petra ; Urbanová, Markéta (advisor) ; Václavíková, Radka (referee)
Familial adenomatous polyposis (FAP) is a condition caused by germline mutations in tumor suppressor gene APC, inherited in autosomal dominant manner. Patients with FAP develop hundreds to thousands of adenomatous colorectal polyps with extremely high risk of malignant reversal into adenocarcinoma of colon and/or rectum. The aim of this thesis is to re-analyze a cohort of highly suspected FAP probands from years 1993-2004 whose diagnosis previously failed to be confirmed by at that time commonly used methods of molecular diagnostics. Next generation sequencing on MiSeq and NextSeq platforms (Illumina®) was performed on 78 samples of probands' DNA, isolated from peripheral blood, using gene panel CZECANCA version 1.2 (Czech Cancer Panel for Clinical Application). The panel enables sequencing of exons and exon-intron junctions of 226 genes linked to hereditary cancer predispositions, newly also including the diagnostically important promoter 1B region of APC. Pathogenic variant in the APC gene was detected in 18 % of re-analyzed probands, 11 % of probands carry pathogenic variants in other genes associated with colorectal polyps. Additional 13 % of probands are carriers of a variants of unknown clinical significance. NGS gene panel CZECANCA enabled diagnosis confirmation or re-evaluation of 22 FAP...
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New molecular biomarkers and therapeuticak targets in solid tumors
Voleská, Iveta ; Václavíková, Radka (advisor) ; Moulisová, Vladimíra (referee)
Breast and ovarian cancers are the most serious cancers among women. Relatively high mortality at advanced stages of the disease is often associated with the development of resistance to the cytotoxic agents. Chemoresistance usually develops on the base of different adaptive mechanisms that significantly decrease therapy efficiency. Currently TRIP6, ABCC3 and CPS1 enzyme has been identified based on high-capacity expression profile monitoring in tumor cell and tissue profiles as one such candidate playing a role in taxane resistance. The main goal of this thesis was to clarify the role or possible association of the ABCC3, CPS1 and TRIP6 genes with the development of tumor cell resistance to taxanes in models of sensitive and paclitaxel-resistant ovarian cancer cells and in the cohorts of patients with ovarian and breast cancer. The in vitro part compares the efficacy of paclitaxel and taxane derivatives in the sensitive and resistant ovarian cancer cell lines and clarifies the association between the different structure of taxane derivatives and the change in CPS1 expression after their application. The study in patient's cohorts with ovarian cancer reveals a relationship between higher levels of the CPS1 gene and shorter progression-free survival. The achieved results may serve as a base for data...
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Role of genetic factors responsible for development of pancreatic cancer
Borecká, Marianna ; Janatová, Markéta (advisor) ; Václavíková, Radka (referee) ; Živný, Jan (referee)
Cancer is a major health problem, worldwide, and is the second-most frequent cause of death (www.uzis.cz). Research is urgently necessary to reduce cancer incidence and the costs associated with cancer management, to develop more efficient and effective risk prediction strategies and personalised patient treatment. Germinal mutations in genes that predispose individuals to hereditary cancer syndromes are clinically important and can be used to classify carriers being at high risk of cancer development. Identification of these mutations can influence the prognosis and treatment of probands and can be used to include their family members into high-risk groups with corresponding preventive strategies. This study is focused on the currently underestimated description of newly identified genetic factors among the Czech population that predispose individuals to develop pancreatic ductal adenocarcinoma (PDAC). In 2017, the incidence of PDAC in the Czech Republic was 21 cases per 100,000 persons, and PDAC was the fourth-most frequent cause of death among all cancer diseases (www.svod.cz). Using a variety of screening techniques, which included high-resolution melting (HRM) analysis, Sanger sequencing of whole genes, and next-generation sequencing (NGS), with a CZECANCA panel that was generated in our...
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Molecular biomarkers of solid tumors and their use in prognosis and prevention of cancer
Elsnerová, Kateřina ; Václavíková, Radka (advisor) ; Fiala, Ondřej (referee) ; Vymetálková, Veronika (referee)
Molecular biomarkers of solid tumors and their use in prognosis and prevention of cancer Molekulární biomarkery solidních nádorů a jejich využití v prognóze a prevenci nádorových onemocnění Mgr. Kateřina Elsnerová Summary Malignant tumors of ovary and breast are among the most widespread cancers in women. Despite improvements in diagnostics and in therapy, mortality is still very high. An important tool for early cancer detection, as well as for monitoring prognosis and preventing progression, are molecular biomarkers; biomarkers were the topic of this work. The aim of this work was to find out (i) whether there are differences in gene expression between tumor and non-tumor tissues, and among controls (C), primary tumors (pT) and intraperitoneal metastases (iM), respectively; (ii) whether gene expression or genetic variants (single nucleotide polymorphisms, DNA methylation, germline mutations) associate with clinical data of patients, thus being potentially relevant for prognosis. In epithelial ovarian cancer (EOC), 50 of 94 genes were deregulated in controls compared to tumors. Fifteen of 66 genes were deregulated in intraperitoneal metastases compared to primary tumors. Gene expression of ABCA7, ABCB2, ABCC3, ESR2, NH1H4 and NR1I1 was deregulated either in comparison of primary tumors and metastases, or...
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