Targeting epigenetic changes in cancer using synthetic lethality

Project Code: 

Human cancers are genetically unstable, exhibiting chromosomal rearrangements, which can result in tumour suppressor loss and oncogene activation. As such, cancer cells become dependent on secondary pathways for cell survival. Disrupting these secondary pathways can lead to cell death, termed synthetic lethality, and provides a powerful approach towards specifically targeting cancer cells.

We have focused on the role of epigenetic marks in maintaining genome stability, and which are frequently mutated in human cancers. We identified a role for histone H3 lysine 36 trimethylation (H3K36me3) in efficient DSB repair and DNA replication (Pai et al., Nature Communications 2014; Pfister et al., Cell Reports, 2014; Cell Reports, 2017). Further, we have exploited a conserved synthetic lethal relationship to target cancers deficient in this epigenetic mark (Pfister et al., Cancer Cell 2015), which has now entered clinical trials to specifically target H3K36me3-deficient cancers.   

The aim of this DPhil project is to extend these studies to identify and characterise synthetic lethal interactions with cancer-specific epigenetic changes using both yeast and mammalian systems. Novel genetic interactions identified in this way will be explored as possible therapeutic targets or biomarkers. Techniques will include yeast and mammalian genetics, CRISPR, molecular biology and biochemistry.

Secondary supervision will be provided by David Clynes.

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