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Genomics


From genotype to phenotype: leveraging functional genomics in oncology


A challenge in drug discovery is that, at best, only around one in five drug candidates will lead to the launch of a medicine. In 2011, AstraZeneca initiated a strategic ‘5R Framework’ focusing on identifying drug projects in consideration of the right target, right tissue, right safety profile, right patient and right commercial potential1.


A


lthough we have significantly enhanced the quality of our pipeline since bringing in the 5R model and our success rate is


markedly higher than the industry average, the reality is that around 80% of our projects still fail before candidate selection, often resulting from a poor understanding of the relationship between target biology and disease. Therefore, understanding exactly what is going on at a fun- damental biological level, so-called target valida- tion, is essential if we are to boost the quality of our drug discovery pipeline and the chances of commercial success. The advent of next-generation DNA sequencing


has led to the creation of vast quantities of genom- ic data from individuals, tissues and tumours. Through AstraZeneca’s Genomics Initiative2 and the work of many other researchers around the world, we now have access to an enormous num- ber of DNA sequences that we can use to inform the development of molecularly-targeted therapies, support patient selection for clinical trials and


Drug Discovery World Spring 2019


match patients to the therapies most likely to ben- efit them. Drug discovery is increasingly informed by


genomics, which can significantly boost the chances of a novel therapy successfully navigating the lengthy journey from bench to bedside3. But despite the rapid proliferation of genomic information, we still have a limited understanding of how specific genes and genetic variations drive tumour growth and therapeutic resistance. In turn, this limits our ability to identify and validate novel targets that are truly informed by biology and make an impact on disease progression – arguably the most crucial step in the whole drug discovery pathway. In search of answers, we have established a


major collaboration with Cancer Research UK to launch the Functional Genomics Centre in Cambridge, UK4. Using the power of gene editing technology, we are investigating the connections between the information encoded within the genes (genotype) and its functional output (phenotype), systematically altering every single gene in the


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By Dr Ultan McDermott, Dr Steve Rees, Dr Susan Galbraith, Dr Mike Snowden and Dr Mene Pangalos


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