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Precision Medicine


arduous and associated with significant cost in the process of characterising ‘gene-to-function’12. Increasing attrition in pharmaceutical pipelines and rising costs in bringing new drugs and diag- nostics to market have resulted in a relentless focus on improving the speed and efficacy of target iden- tification and development processes (eg, first to market) in the hope of attaining fast financial returns. Sophisticated large-scale methods are now available to profile diseases through genomics, transcriptomics, proteomics and metabolomics and identify biomarkers that define disease in terms of combined clinical, physiological and patho-biolog- ical abnormalities. The aspiration is that these approaches will bring more rapid and cost-effec- tive results in biomarker discovery and validation, with a ‘screen-to-gene’ approach to improve diag- nosis, facilitate the monitoring of disease and ther- apies and unravel underlying molecular pathways (Figure 1)12. Two of the most developed omics technologies


are cancer genomics and transcriptomics. Tumour whole genome, whole exome and transcriptome sequencing are now feasible assays with high sam- ple throughput, price tags in the order of $500- $1,500 per sample and comprehensive databases such as TCGA, COSMIC and ICGC being publicly available13. Genomics and transcriptomics have consequently become affordable and clinically fea- sible analytical techniques. This has led to a shift in the industry towards pharmacogenomics, which seeks to define genetic markers that predict indi- vidual responses to drugs to inform precision medicine. Competitors within this space are collab- orating with governments and other agencies to enhance patient accessibility to diagnostic tests and products. Many genomic screening tests are now available to optimise disease treatment, particular- ly for cancer. These include Foundation Medicine’s FDA-approved FoundationOne companion diag- nostic screen for solid tumours. Performed on for- malin-fixed paraffin embedded tumour tissue sec- tions this Next Generation Sequencing (NGS)- based test offers a broad screen of microsatellite instability and tumour mutational burden, includ- ing BRCA1/2 analysis for ovarian cancer treatment with Lynparza® (olaparib) or Rubraca® (ruca- parib); KRAS analysis for colorectal cancer treat- ment with Erbitux (cetuximab) and BRAF analysis for melanoma and non-small cell lung cancer treat- ment with Tafinlar® (dabrafenib); in addition to PD-L1 immunohistochemistry testing to inform therapy decisions14. Patient tissue biopsy is associated with limita- tions of cost, hospital time, patient trauma and


Drug Discovery World Winter 2019/20


inaccuracies of sampling from heterogenous tumour tissue. To overcome some of these issues there is an increasing interest in genomic analysis of liquid biopsy-based biomarkers. Liquid biopsy is a non-invasive method that combined with -omic approaches could be extremely useful in clinics to identify relevant biomarkers. In 2014, Guardant Health launched its NGS-based 70 gene screen for common cancer mutations, Guardant360, which has since become one of the most frequently-used liquid biopsy screens to direct cancer treatment within the US15. The ability to multiplex using genomic tests and target a plethora of different biomarkers within one screen increases the diag- nostic capability, applicability and value of such assays. Guardant Health further launched GuardantOMNI in 2017, an NGS-based assay for use in patient stratification of clinical trials and monitoring response to therapeutics during clinical development of biopharmaceutical drugs and is developing additional screening assays for early cancer diagnosis and detection of cancer recur- rence using this technology. With investment of more than $1.5 billion since


201616, GRAIL is exploring genomic screening via NGS with the aim of identifying blood-based biomarkers for the early detection of cancer from circulating free DNA (cfDNA). It aims to generate an atlas of the circulating cell-free genome through analysis of more than 15,000 individuals with var- ious cancer states to allow the simple and rapid early diagnosis of cancers based on cfDNA biomarkers11,17. Others pursuing genomic and transcriptomic routes to biomarker identification and clinical implementation using liquid biopsies are Freenome and Thrive, both of which are utilis- ing genomic techniques alongside traditional pro- tein analysis via immunoassay, and the Swiss-based Novigenix, which is investigating immune-based transcriptomic biomarkers for cancer diagnosis and prognosis and has launched a transcriptomic- based assay for the early detection of colorectal cancer from blood biopsies18. Despite considerable progress in large-scale pro-


teomic methods, including improved detection limits and sensitivity, such methods have not yet been adopted into routine clinical practice. The main limitations that prevent integration into the clinic are the high cost of equipment, the need for highly-trained personnel and last, but not least, the establishment of reliable and accurate protein biomarkers or panels of protein biomarkers for disease detection. Compared to the genome and transcriptome, the proteome is far more complex and dynamic, being comprised of the basic protein


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