Cancer is the second cause of death in Europe, after cardiovascular diseases. These lethal diseases are in desperate need of new therapeutic approaches: despite dramatic advances in the use of conventional chemo and radiotherapy and the growth of more “targeted” drugs, many cancers are still incurable.Cancers are difficult to treat not because they are so mechanistically diverse (indeed, we argue that cancers are not very diverse mechanistically) but because they evolve in response to any pharmacological elective pressure we impose upon them.To address this problem, we employ a novel class of genetically engineered mouse (GEM) in which individual tumour suppressor genes may be systemically toggled off and on, reversibly and at will, in vivo. In this way we can identify the most effective therapeutic targets. We hypothesize that targeting the functionally non-degenerate signaling nodes that link robust networks offers two unique advantages as a therapeutic strategy: a durable therapeutic response, and the possibility for treating many distinct cancer types. In this project, we will focus our attention to the non-redundant tumor suppressor p53, and investigate its relevance as a discrete or combined therapeutic target for the treatment of cancer and protection of individuals from radiological or chemotherapeutic injury. Furthermore we will also examine the potential tumour suppressor role of p73, with the same technical approach.Our overarching aim is to deliver to the pharmaceutical industry pre-clinical models of what drugs would do, both therapeutically and in terms of side effects, were we are able to target any intracellular effector of choice.