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Synthetic lethality screening combined with methionine restriction for the treatment of DIPG

Cancer cells are less viable in methionine-deficient environments and thus exhibit a methionine dependency. Dietary methionine depletion has been demonstrated to induce suppress tumor growth and induce cell death in several preclinical tumour models. We have previously identified that methionine restriction leads to DIPG cell death in vitro and extends life in xenograft models of DIPG. We hypothesize that by identifying drugs that cooperate with methionine restriction to target H3K27M mutant cells we can further increase the efficacy of methionine restriction and accelerate its use in the clinical trial setting. To identify lethal combinations specific to DIPG and not harmful to normal cells we used the concept of synthetic lethality. Synthetic lethality arises when cells are killed through defective function of two or more genes or pathways, but not through defects in these targets individually. This phenomenon can be exploited by developing a treatment to kill tumour cells with a specific mutation or feature (for example histone mutations) while leaving normal cells that do not have the mutation unharmed. We are using drug libraries that are already FDA approved which reduces cost and most importantly, the time needed to reach patients and improve their outcomes. We aim to identify and develop pre-clinical data for the best drug/methionine restriction combination to take forward to prospective clinical trials.


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