Understanding how to target cell vulnerabilities induced by high Notch signalling as a potential anti-cancer strategy.

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Notch is a transmembrane localised signalling receptor utilised both in development and adult stem cell regulation and whose misregulation is frequently involved in different human cancers. Notch is activated by proteolytic removal of the extracellular domain (NECD) and subsequent gamma-secretase dependent intramembrane cleavage to release the Notch intracellular domain (NICD). Once in the nucleus NICD combines with a transcription factor Su(H)/CBF and the complex along with recruited coactivators activates gene-specific transcription. The outcomes are context-dependent and Notch plays many roles in development affecting different cell fate, proliferation and cell death/survival, decisions across many tissues. Notch signalling has been linked to cancer stem cell regulation and therefore it makes Notch an attractive target for therapies that control its signal activity. There are already some drugs which target high Notch signalling but a number of trials have not ben successful because there are unacceptable side effects. In this project the strategy is being developed ovecome this by using Notch instead as a biomarker to determine which tumours are sensitive to targeting other components that will kill the tumour cell but leave normal cells unaffected. Using a whole genome screen in a Drosophila cell culture model system we have identified candidate targets which would be useful to inhibit in conditions of aberrantly high Notch signalling and set of targets which would be useful to inhibit in conditions of aberrantly reduced Notch signalling. By studying cell culture and in vivo systems in the fly this project aims to understand the mechanisms by which Notch signalling at different levels sensitises the cells to knock down of different sets of target genes and identify a synthetic lethal combination, which may in the longer term be translated into a therapeutic approach. Proof of principle will then be obtained in human cancer cell lines.