Genome-Scale CRISPR Screens: Strategies to Prioritise and Validate Potential Targets

Initial excitement associated with the completion of genome-scale CRISPR screens can quickly turn to dismay as the realisation of the sheer quantity of data generated becomes apparent. Extracting the most relevant biological data from such studies can seem daunting, but with the correct strategy, can be incredibly rewarding.

Drug discovery is a challenging process that is often hindered by inefficient target identification. Functional genomics has the potential to advance target identification strategies that are crucial to overcoming current limitations in oncology drug development processes. Wellcome Sanger Institute researchers have performed genome-scale CRISPR-Cas9 screening in 204 human cancer cell lines from 12 cancer-types and developed a data-driven framework to prioritise cancer therapeutic candidates. This webinar will describe the logic behind this framework including criteria used and also describe alternative metrics that could be included. Using published datasets, they assessed the current tractability of the target and included this in the candidate selection process.

Following the identification of the top candidate targets, key experimental verification and validation steps are required. In this webinar, our featured speaker will describe strategies to use published data to verify true positive hits, as well as experimental approaches. Selection of appropriate cellular models to carry out verification and validation experiments is an important factor to consider. The speaker will highlight cell models that are available and discuss the advantages and disadvantages of each system. Key factors to consider include verification of the target using independent reagents or technologies. Understanding the mechanism of action or functionality of the target in a model system is integral to assessing the suitability of a target to enter a drug development program. Revealing the cellular processes altered by perturbation of the target will indicate if cell death is induced, or if a reduction in cellular fitness reduces or halts cell growth.

Speaker

Fiona Behan, Post-Doctoral Fellow, Wellcome Sanger Institute

Fiona Behan is a post-doctoral research fellow at the Wellcome Trust Sanger Institute. Following the completion of her PhD implementing siRNA screens to identify novel drug targets in oesophageal adenocarcinoma, Fiona spent 1 year at the Department of Veterinary Medicine, University of Cambridge. This project involved investigating the use of miRNA profiling to discriminate subsets of soft tissue sarcomas. Her current postdoctoral position with Mathew Garnett at the Sanger Institute utilises whole genome CRISPR drop-out screens in a panel of cancer cell lines to identify novel oncology drug targets.

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