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Mutant p53 as target for improved cancer treatment

Final Report Summary - MUTP53 (Mutant p53 as target for improved cancer treatment)

The p53 tumour suppressor gene is mutated in almost 50 % of all human tumours, including most tumour types. A majority of these mutations are point mutations that give rise to single amino acid substitutions in the so called core domain, i.e. the central domain of p53 that binds to DNA in a sequence-specific manner. Mutant p53-carrying tumours often show poor response to conventional anti-cancer therapy such as radiotherapy and chemotherapy. Therefore, novel therapeutic strategies that target mutant p53-carrying tumours could significantly improve clinical outcome in cancer patients. p53 mutations do not only serve to inactivate normal (wild type) p53, but may also endow the mutant protein with novel properties, so called Gain-of-function (GOF) activities, that could contribute to tumour development.

This project focused on exploring mutant p53 as a target for novel anti-cancer therapies. Such therapies aim at restoring wild type p53 tumour suppressor capabilities in mutant p53-carrying tumours by either abrogating the GOF effects of mutant p53, or reactivating wild type properties of mutant p53. A multi-disciplinary approach was undertaken to explore and exploit the contribution of mutant p53 to cancer.

Overall, the project has been very successful. There has been substantial progress over the project period and all partners have made significant contributions. One major goal was to identify and explore small molecules targeting mutant p53 and to test such a molecule in cancer patients as a new anti-cancer therapy. Indeed, a first-in-man phase I clinical study with one of these molecules, APR-246 (i.e. PRIMA-1-Met) has been initiated within the frame of this project.

The project has been unique in bringing together most of the p53 research community in Europe. By doing so, it has put European p53 research at the forefront of cancer research worldwide. Within the MUTP53 project, novel therapies based on mutant p53 have been developed, and p53 has been explored as an important clinical marker. This will allow more effective diagnosis and improved treatment of cancer. Thus, the project should provide major clinical benefit for cancer patients and people in Europe.

Work within the project has produced a wealth of information about biochemical properties of mutant p53, p53 as a clinical marker, and ways to target mutant p53 in tumours. More specifically, the main exploitable results include a mouse model with mutant p53, a p53 mutation detection array, methods for safe and efficient gene transfer, and several small molecules that restore wild type function to mutant p53. The information obtained on the prognostic and predictive value of p53 mutations in tumours should be of great value for clinical oncologists in the treatment of cancer patients.

The consortium has organised several international p53 conferences. Results from the consortium have been published in high-impact scientific journals such as Nature Genetics, Science, Cancer Cell, Cancer Research and PNAS. Members of the consortium have presented their data and numerous scientific meetings, and also commented on their work in newspapers and on radio and TV.

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