Genome scale validation of oncologic disease drug targets by in vivo functional analysis.

125 The sequencing of the human genome has provided an unprecedented opportunity to identify novel drug targets that can enable the discovery of new therapeutics. In order to accelerate drug development, reduce costs, and improve success rates, it is critical to identify the key targets that, when modulated, can produce therapeutic effects. Gene knockout (KO) mice can be used to identify promising drug targets through in-depth phenotypic analysis designed to detect desirable physiological profiles with potential therapeutic implications for medicine. By virtue of the inactivation of specific genes, knockout mice may be used to genetically model the actions of perfectly selective and potent chemical or biological antagonists. In fact, careful analysis of the phenotypes of KO mice can allow one to make predictions with regard to mechanism of action and potential on-target side effects of future drugs without having to first develop a candidate small molecule or biotherapeutic agent with which to validate the target. The power of this approach has been demonstrated by studies examining the targets of the best-selling drugs and current pharmaceutical pipelines. These analyses revealed that the therapeutic effect of established drugs show a strong correlation with the KO mouse phenotype of the corresponding target. We have implemented this target validation approach by developing systems and infrastructure to generate and comprehensively phenotype mutant mice at a rate of more than fifteen targets per week. The battery of tests encompassed by our analysis has been specifically selected to reveal those genes that encode key control points in mammalian physiology and behavior. Tests to detect potential oncology targets include: adult skin fibroblast proliferation assay, radiation sensitivity, gene expression profiling, developmental defects in the mammary gland, tissue-specific defects in the development of other organs, angiography, embryonic lethality, and matrigel plug assay. For targets found to be of interest, additional assays are performed to more thoroughly examine gene function. Data will be presented illustrating the process from knockout through an oncologic phenotypic analysis.