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Deconstructin oncogenesis and tumour suppression to find the best cancer drug targets

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Myc and p53 are pleiotropic transcription factors that, respectively, drive and suppress cancer. Myc levels are elevated and deregulated in most cancers, suggesting a pivotal role for Myc in oncogenic signaling. De-activation of Myc function in tumours driven by oncogenically activated Myc triggers their rapid regression through a variety of intracellular and extracellular mechanisms, including differentiation, apoptosis and vascular collapse. However, Myc mutations are relatively rare and the aberrant Myc in most tumours appears to be a consequence of aberrant upstream signals. The extent to which such endogenous Myc, acting as a client of upstream oncogenes, is a therapeutic target depends on the degree to which it coordinates functions essential for tumour maintenance and what those functions are, neither of which is known. To investigate the therapeutic potential of Myc inhibition we have constructed switchable genetic mouse models in which endogenous Myc can be systemically and reversibly inhibited in normal and tumour tissues in vivo. Our data indicate that inhibiting Myc has a remarkably efficacious and durable therapeutic impact on multiple cancer types, triggering widespread tumour cell apoptosis while eliciting only mild, reversible and non-cytotoxic side effects in normal tissues. The p53 tumor suppressor, or its attendant pathway, is functionally inactivated in almost all human cancers. However, the mechanism by which p53 suppresses tumorigenesis remains obscure. p53 mediates the cellular apoptotic and senescence response to DNA damage, and this is thought to be critical for both tumour suppression and for the progressive erosion of somatic regenerative capacity that characterizes aging. However, using a unique mouse model in which the endogenous p53 gene is replaced by one encoding a ligand-dependent, reversibly switchable variant of p53, we show that the p53-mediated DNA damage response is dispensable for tumour suppression. Hence, by selectively manipulating the DNA damage and tumour suppressor functions of p53 it may be possible to potentiate tumour suppression and cancer therapy whilst simultaneously extending life-span.

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