One of the major challenges in cancer is how to selectively disrupt the cancer cell yet leave normal functioning cells intact. Novel strategies that result in synthetic (synergistic) cancer cell lethality (dependencies) that are specific for the cancer cell are thus most likely to have translational impact. The aim of this project is to evaluate mechanisms of synthetic lethality in cancers derived from mesenchyme (sarcoma), as these are rare cancers with defined genotype-phenotype correlation of unmet need. Molecular mechanisms of lethality target genes and their epistatic context that exist in all cell clones are preferred because of tumour evolutionary conservation. We have combined extensive analysis of NGS sequencing and CRISPR loss of function screens in contexts where there is loss of tumour suppressor genes and chromatin repressor functions. The novel validated targets we have observed require detailed mechanistic evaluation in sarcoma cells that may require additional methodology, for example using dual and multiple guide CRISPR enhanced Cas12a screens as well as CRISPR-prime manipulation of target gene functional domains. Importantly, genomic copy number context, paralogs and the epigenome are all factors that are likely to influence the context of synthetic lethality and the prospect for functional targets for therapeutic agents. By defining mechanistic validation, the targets will be incorporated into improved personalised diagnostics and therapeutics for sarcoma. The student will join an established multi-disciplinary laboratory with day-to-day post-doctoral supervision, gain first-hand experience in cancer biology, CRISPR based genome engineering, cancer genomics, cancer bioinformatics, pre-clinical target validation and directed development for clinical translation.