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Title: Treating paediatric gliomas by targeting distinctive epigenetic features
Author: Meier, Stefanie
ISNI:       0000 0004 7965 0603
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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Paediatric gliomas comprise a broad range of brain tumours that derived from glial cells. While high-grade gliomas are often resistant to therapy and associated with a poor outcome, patients with low-grade gliomas face a better prognosis. However, the treatment of low-grade gliomas is often associated with severe long-term adverse effects. In the past, most research was conducted on adult glioma; the paediatric form of the disease was considered as equivalent. Consequently, similar treatment approaches were and are still used in adult and paediatric glioma patients. However, recent studies indicate that substantial differences exist between the adult and the paediatric form of the disease. This shows that there is a strong need for a better understanding of paediatric glioma and for improved treatment approaches. The aim of this study was to investigate the role of MLL1 and MLL2, two methyltransferases implicated in aberrant gene regulation in cancer, and to test whether these proteins are suitable drug targets in paediatric glioma. I detected that MLL1 and MLL2 are involved in the regulation of multiple transcription factors, including Hox cluster genes and MYC, that were previously associated with tumourigenesis. The knockdown of the two methyltransferases led to a decrease in cell viability. For these reasons, I considered MLL1 and MLL2 suitable potential drug targets. Disulfiram is a clinically approved drug that reportedly targets MLL1 in leukaemic cells, and is active against cancer cells. In this study, I showed that disulfiram efficiently kills both paediatric low- and high-grade glioma cell lines and patient-derived stem cells. The treated cells showed a decrease in both MLL1 and MLL2 protein levels, and an MLL1/MLL2 signature; genes regulated by the two methyltransferases were found to be expressed at lower levels. Further, I detected that auranofin, a second clinically approved drug, enhances the killing efficacy and the MLL-targeting effect of disulfiram in a synergistic way. With my findings I contributed to the understanding of the role of MLL1 and MLL2 in paediatric glioma and the mechanism of action of disulfiram. New potential approaches to the treatment of paediatric glioma are highlighted in this study.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available