Final Report Summary - ONCOSWITCH (Switchable in vivo genetic models to identify cancer drug targets)
Deducing the role of individual genes in the maintenance of normal and disease tissue function is difficult because classical germ line gene manipulations are often embryonically lethal (precluding their study in adult tissues) or partially or completely concealed by adaptive compensation during development and neonatal growth. We have developed several strategies with which to toggle, on and off, reversibly, the functions of specific genes in adult mice – either systemically in all tissues or tissue-by-tissue. The acute denial or preternatural activation of endogenous genes in adult tissues – normal and neoplastic – exposes completely novel phenotypes and gene properties. Most importantly and uniquely, our capacity to reversibly downregulate specific target endogenous oncogenes like myc, Kras and e2f demonstrates that, unlike irreversible deletion, transient downregulation is not disastrously or irrevocably toxic to normal tissues – so identifying novel temporal therapeutic windows for inhibiting these ubiquitous cancer targets.