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Biochemical tools for targeting immunomodulatory receptor CD73
Poukarová, Magdalena ; Ormsby, Tereza (advisor) ; Hlouchová, Klára (referee)
New approaches to cancer treatment are investigated because cancer remains one of the most abundant causes of death. One of the promising fields of oncology is immunotherapy, which is based on the activation of immunity to eliminate malignant cells. Several immunotherapy drugs have already been approved and are being used; however, only a part of patients responds with the desired efficiency. In recent years, ecto-5'-nucleotidase CD73 emerged as a potential new target of immunotherapy. The expression of this GPI-anchored enzyme at the extracellular membrane is significantly up-regulated tumour cells and in immune cells of the tumour microenvironment. CD73 catalyses the hydrolysis of AMP to immunosuppressive adenosine, therefore contributing to the immunosuppressive environment in the tumour and participating in resistance to immunotherapy. CD73 appears to be a promising target for a combination treatment to improve the effect of other immunotherapy drugs. So far, several clinical trials of CD73 antibodies and small-molecule inhibitors have been conducted. This diploma thesis describes the development of new biochemical tools for CD73. DNA- linked Inhibitor ANtibody Assay (DIANA), a sensitive method that enables the measurement of the binding affinity of a small-molecule inhibitor to a protein, was...
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MTH1 protein, its role in cancer cells and targeting in anticancer therapy
Poukarová, Magdalena ; Ormsby, Tereza (advisor) ; Doubravská, Lenka (referee)
MTH1 is a protein belonging to the NUDIX hydrolase family. It helps cancer cells to cope with oxidative stress caused by tumor transformation. MTH1 hydrolases oxidized forms of deoxyribonucleotidetriphosphates (dNTPs), thus protects the cell from mutations, helps to maintain genomic integrity and prevents senescence and cell death. Unlike cancer cells, for which MTH1 activity is essential, its expression is very low in healthy cells. Therefore, MTH1 was considered as a potential therapeutic target for the cancer treatment. Several generations of MTH1 inhibitors have been developed. However, the results of testing their anticancer activity were often contradictory. The aim of this work will be to show the function of MTH1 protein, its role in cancer cells and to discuss the path that led to the development of successful inhibitors. Key words: MTH1, cancer, oxidative stress, 8-oxo-dGTP, MTH1 inhibitors
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