The prevention of human cancer development depends on the integrity of a complex network of defence

mechanisms that help cells to respond to various stress conditions. A key player in this network is the p53 tumor

suppressor protein.

By inducing efficient growth inhibition, p53 eliminates cancer cells thereby prevents the development of human

malignancies. These functions of p53 often determine the efficacy of anti-cancer therapies.

Although p53 is frequently mutated in some cancers, in about 50% of all human cancers, p53 is non-mutated and

could, in principle, be activated to prevent tumor progression. This situation is prevalent among a wide-range of

cancer, notably breast carcinoma. However, p53 activity is hampered by malfunction of its many modulators,

such as Mdm2 or p73, which govern p53 tumor suppressive activity by acting upstream and/or downstream of

p53. There is therefore a crucial need to understand how p53 modulators contribute to human malignancies.

Based on this information, we propose to develop rational therapeutic approaches to manipulate p53

modulators, thereby wakening the sleeping tumor suppressive activities of p53, allowing it to eliminate cancer

cells. A carefully structured consortium constitutes 19 academic research centers and SMEs (see diagram). It

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 target genes

mediating apoptosis and growth arrest (Fig.1, 2). 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 incancer.

Particular emphasis will be directed towards translating the information on p53 regulation into the development of

new anti-cancer therapies. p53 regulatory proteins will be used for the identification of new molecular targets for

drug discovery.

AIMS

The principal aim of this proposal is to ease both diagnosis and prognostic classification, as well as the efforts

towards novel therapy regimens to treat patients suffering from these diseases: breast cancer and

neuroblastoma. Overall, the integrated action of our consortium is aiming at re-establishing tumor suppressor

activity in cancer, thereby translating basic knowledge of functional oncogenomics into cancer diagnoses and

treatment, and contributing to leadership in European health technology