Whole Genome Sequence-guided targeting of colorectal and oesophageal cancers

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The development of new medicines is a long term and high cost endeavor with exceptionally high failure rates. Across all major disease indications oncology consistently ranks as the most challenging. Current pharmaceutical costs and failure rates are not sustainable. Selection of the correct target is a major reason for these attrition rates. It is increasingly recognised that developing a medicine against a target that shows genetic association with the underlying disease state increases the likelihood of that medicine reaching the market by over 2-fold. Despite the emergence of CRISPR as a powerful genetic perturbation tool, high throughput target identification approaches have been constrained by the lack of in vitro cellular models that both faithfully recapitulate clinical tumour responses to perturbation and are amenable to high throughput screening approaches. The historical cost of whole genome sequencing ("WGS") has also limited the availability of large panels of highly characterised cellular models and therefore the ability to understand the genetic drivers of cancer at a granular level. Patient-derived tumour organoids are 3D advanced _in vitro_ cellular models. There is a growing appreciation that patient-derived tumour organoids are a more predictive _in vitro_ model for drug discovery than cancer cell lines whilst at the same time remaining amenable to high-throughput drug screening formats. Using deeply characterised patient-derived tumour organoids we will apply genome-wide synthetic lethal perturbation approaches and a proprietary data aggregation, analysis and visualisation platform to identify and prioritize novel synthetic lethal cancer targets. Synthetic lethality takes advantage of the fact that mutations in cancer cells which allow them to grow unrestricted often makes them dependent on "alternative" biological processes which healthy cells do not need. Targeting these alternative processes would allow selective destruction of cancer while leaving healthy cells unaffected. PARP inhibitors, which target cancers with defects in DNA damage repair, have proven this strategy for targeting cancers can work. Roadmaps to rapidly progress the most promising targets into drug discovery programmes will be developed in parallel.