The prevention of human cancer development depends on the integrity of the cellular defence mechanisms that respond to stress.A key player in this defence is the p53 tumor suppressor, which eliminates cancer cells by inhibiting their growth.These p53 functions often affect the efficacy of anti-cancer therapies.While p53 is often mutated in human cancers, it remain normal in about 50% of cases, notably in breast carcinoma. the non-mutated p53 could be activated to suppress tumor progression.Deregulation of p53 modulators, such as Mdm2 or p73, can hampered p53 tumor suppression activities by acting upstream and/or downstream of p53.It is crucial to understand how p53 modulators contribute to human malignancies.Based on this information, we propose to develop rational theraupetic approaches to manipulate p53 modulators,thereby wakening the sleeping tumor suppressive activities of p53, allowing it to eliminate cancer cells.A carefully structured consortium will interactively build a technology platform to comparatively identify,characterize and evaluate the regulatory roles of p53-modulators and define the mechanisms of their action.Large-scale gene functional analyses will be conducted to identify relevant signalling pathways that impair or mediate tumor suppression by p53.These analyses will include p53 activators and inhibitors, p53 homologues p73/p63,and dissection of p53 targets genes mediating apoptosis and growth arrest.Our links with highly profiled clinical partners and our access to large, well-characterized and clinically documented sample collections will enable the evaluation of diagnostic expression profiles, and their potential prognosis value in cancer.Particular emphasis will be directed towards translating basic knowledge of functional oncogenomics into cancer diagnoses, treatment and identification of new molecular targets for drug discovery and contributing to leadership in European health technology.
Keywords:
Cancer, tumor suppression, oncogenomics, new anti-cancer therapies.
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