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  • (2023) Michniewicz, Filip
    Diffuse Intrinsic Pontine Glioma (DIPG) is an incurable paediatric brain cancer, characterised by aggressive diffuse growth in the pontine region of the brain, preventing surgical resection and requiring targeted therapeutic intervention. Over 80% of DIPG patients possess epigenetic alteration H3 K27M, which substitutes a lysine for a methionine in the n-terminus tail of Histone H3, preventing the binding of methyl groups and therefore induces H3 K27 hypomethylation. This alteration partners with other mutations, notably TP53, PIK3CA, PDGFRα and other receptor tyrosine kinase associated alterations and ACVR1, complicating the application of targeted therapies. Over 200 clinical trials investigating various combinations of therapies have thus far failed to improve survival, with the majority of patients passing within a year of diagnosis. Copper is an essential metal ion which is widely incorporated into proteins and enzymes, which take advantage of its redox activity to catalyse reactions. Interestingly, copper is highly accumulated within the brain, is upregulated in several cancers, including brain cancers and is increasingly targeted by therapeutics. In particular, copper is known to influence RTK signalling in cancer, and in Wilson’s Disease has been linked to epigenetic alterations. A recent study also highlighted the redox ability of the H3-H4 tetramer. Upon this basis, it was hypothesised that reducing copper may represent a viable therapeutic strategy for DIPG. Interrogation of patient transcriptomic data revealed correlation between copper chaperones and epigenetic genes, and increased expression of copper chaperone MT1X. Copper reduction through copper chelator tetraethylenepentamine (TEPA) induced apoptosis in 3 DIPG cell lines and dose-dependently reduced phosphorylation of RTK associated proteins. Transcriptomic, proteomic and metabolomic analyses further revealed copper chelation activated inflammasome, impacted cell cycle proteins, impacted citric acid, cysteine and methionine, fatty acid, lipid, purine and pyrimidine metabolism, and dysregulated epigenetic mechanisms. Copper chelation also improved survival in an orthotopically injected PDX model of DIPG, and completely cleared the tumour in 25% of treated mice. This thesis outlines that copper chelation is a potential therapeutic strategy for DIPG, however further work is required to find combinations and more clearly define its cellular effects.