Development of novel, integrative bioinformatics approaches to identify drug targets with genomic vulnerabilities and illuminate mechanism of action

Since the sequencing of the first human genome was completed in 2003 a ‘genomic revolution’ has generated vast amounts of data that has illuminated our understanding of how germline (hereditary) and somatic (spontaneous) molecular changes to our genomes drives disease. This in turn has led to development of ‘targeted therapeutic’ small molecule and biologic-based medicines that specifically target these molecular changes, whilst attempting to spare non-affected tissues, and is particularly relevant to disease settings such as oncology where traditional non-targeted treatments such as chemotherapy suffer from significant off-target side-effects and toxicity.

The relationship between efficacy and toxicity can be measured as Therapeutic Index (TI), or therapeutic window, defined as the toxic dose (TD) divided by the effective dose (ED) in a defined proportion of the population. In theory targeted therapies should have much larger therapeutic windows than chemotherapeutics, however the clinical trial failure rate is still unacceptably high and there remains significant limitations to the target selection and validation process.