Cancers are difficult pathologies to cure because tumor cells adapt and evolve in response to target inhibition. Hence, the major issue confounding efficacy of cancer drugs is the extent of functional redundancy (either innate, adaptive or acquired through mutation and selection) of the target. For this reason, we have developed novel, switchable genetic mouse models that allow us to regulate the activities of (currently) untargetable intracellular effector nodes that are functionally non-redundant: Ras, Myc, and E2F. In this way, we model, in pre-clinical mouse cancer models in vivo, the therapeutic index of inhibiting these specific effectors in various tumor models. The Myc oncoprotein is functionally deregulated in almost all human cancers, even though the gene is frequently not, of itself, mutated. Using switchable genetic mouse models in which endogenous Myc function can be systemically and reversibly inhibited in normal and tumour tissues in vivo, we demonstrate that inhibiting Myc has a remarkably efficacious and durable therapeutic impact on multiple cancer types while eliciting only mild, reversible and non-cytotoxic side effects in normal tissues. Moreover, in keeping with the non-redundant nature of Myc in proliferation, we never see the emergence of resistant clones since the requirement for Myc cannot be circumvented. Using a different switchable technology, we have also investigated the therapeutic potential of inhibiting mitogenic E2F activity. The p53 tumor suppressor is functionally inactivated in many tumor types, suggesting that p53 restoration might be therapeutically effective. Using a mouse in which endogenous p53 can be systemically and reversibly switched between inactive and active states in vivo, similarly, we use switchable genetics to model the therapeutic efficacy of restoring p53 in various cancer types and at various stages of their evolution. Our studies indicate unexpected ways in which p53`s chequered evolutionary legacy has compromised its efficacy as a tumour suppressor and indicate inherent limits in the efficacy of p53-restoration as a cancer therapy.

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