MUTP53 - Mutant p53 as target for improved cancer treatment (FP6-LIFESCIHEALTH) (2004-02-01 - 2009-01-31) (»add to infobox)

Klas WIMAN, Moshe OREN, Wolfgang DEPPERT, Pierre HAINAUT, Alan FERSHT, Ada SACCHI, Hein TE RIELE, Jiri BARTEK, Anne-Lise BORRESEN-DALE, Matthias THEOBALD, Emil PALACEK, Giannino DEL SAL, Thoomas STANISLAWSKI, Neeme TONISSON, N. N. APREA

KAROLINSKA INSTITUTET (SE010 - Stockholms län) (Sweden), WEIZMANN INSTITUTE OF SCIENCE (NoRegion - NoRegion) (Israel), HEINRICH-PETTE-INSTITUT FUER EXPERIMENTELLE VIROLOGIE UND IMMUNOLOGIE AN DER UNIVERSITAET HAMBURG (DE600 - Hamburg) (Germany), INTERNATIONAL AGENCY FOR RESEARCH ON CANCER (FR716 - Rhône) (France), MEDICAL RESEARCH COUNCIL (UKI11 - Inner London - West) (Great Britain), REGINA ELENA CANCER INSTITUTE (ITE43 - Roma) (Italy), HET NEDERLANDS KANKER INSTITUUT / ANTONI VAN LEEUWENHOEK HOSPITAL (NL326 - Groot-Amsterdam) (Netherlands), KRAEFTENS BEKAEMPELSE - DANISH CANCER SOCIETY (DK001 - København og Frederiksberg kommuner) (Denmark), DET NORSKE RADIUMHOSPITAL HF (NO011 - Oslo) (Norway), JOHANNES GUTENBERG UNIVERSITAET MAINZ (DEB35 - Mainz, Kreisfreie Stadt) (Germany), INSTITUTE OF BIOPHYSICS - ACADEMY OF SCIENCES OF THE CZECH REPUBLIC (CZ062 - Jihomoravsky kraj) (Czech Republic), CONSORZIO INTERUNIVERSITARIO BIOTECNOLOGIE (ITD44 - Trieste) (Italy), GANYMED PHARMACEUTICALS AG (DEB35 - Mainz, Kreisfreie Stadt) (Germany), AS ASPER BIOTECH (EE008 - Lõuna-Eesti) (Estonia), APREA (SE010 - Stockholms län) (Sweden)

Mutations in the p53 tumor suppressor gene are the most frequent genetic alteration in human cancer, occurring in over 40% of all cases of cancer. One well-studied outcome of these mutations is the loss of the tumor suppressor activity of the wild type (wt) p53. However, there is growing evidence that many of the mutations that occur in the p53 protein in fact generate mutant p53 proteins (mutp53) that have acquired new biochemical and biological properties. Through this gain of function (GOF), mutp53 is believed to contribute actively to the cancer process. We propose to explore mutp53 as a target for novel anti-cancer therapies. Such therapies should aim to either abrogate the GOF effects of mutp53, or restore wt-like properties to mutp53, so that it can now regain its tumor suppressor capabilities. To achieve these ambitious aims, we propose a multi- disciplinary approach to explore and exploit the contribution of mutp53 to cancer. One component of this project will investigate in depth the molecular properties of mutp53: structural studies will pinpoint the changes that particular mutations inflict on the structure of p53, and allow the classification of mutp53 into distinct subclasses. In parallel, biochemical studies will explore the mode of action of mutp53 within cells, including its impact on patterns of gene expression, identification of specific DNA sequences targeted by mutp53, and discovery of mutp53-interacting cellular proteins. Preclinical models for mutpS 3-driven cancer will also be developed, as a critical instrument for pre- clinical studies. The other component will aim at translating this wealth of information into better cancer therapy. One part ofthat effort will address the clinical relevance of particular p53 mutations in human cancer, and particularly its impact on the patient s response to chemotherapy. This should lead to guidelines for more effective use of conventional therapy.#

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