Download Active p53

Active p53
Manipulating tumour suppression:
a key to improve cancer treatment
Keywords
Tumour suppression, p53, p73,
p63, inhibitors, activators
Outline of
the consortium
Summary
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 tumour suppressor protein. By inducing efficient growth
inhibition, p53 eliminates cancer cells thereby
preventing 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
tumour progression. This situation is prevalent among a wide range of
cancers, notably breast carcinoma. However, p53 activity is hampered by
malfunction of its many modulators, such as Mdm2 or p73, which govern
p53 tumour 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 tumour suppression activities of p53, allowing it to eliminate cancer cells. This carefully structured
consortium comprising 19 academic research centres and SMEs (see
diagram) will interactively build a technology platform to comparatively
identify, characterise 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 tumour 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. Our links with highly profiled clinical partners and our access to
large, well-characterised 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 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.
Cancer research
44
Problem
Cancer is the second leading cause of death in European countries, and
one of the most imminent health problems in the developed world.The
p53 protein is generally recognised as the key determinant of tumour
suppression. It has been declared by the European Union that “a large
co-operative effort is needed to ensure that every European citizen will
rapidly profit from the revolution of knowledge in cancer management”
(Philippe Busquin). The presence of wild type p53 is particularly prevalent in breast cancer, the type of cancer that stands at the centre of the
European cancer policy. Since breast cancer affects mostly (though not
exclusively) women, breast cancer research is also an important task to
implement the gender dimension into basic research. For these reasons,
we will choose breast cancer as one of our focuses in this block of
work. Moreover, a non-mutated but inactive p53 is also found in a high
percentage of the most frequent intracranial tumour of children, neuroblastoma. Since paediatric tumours are particularly dramatic events
for patients and their families, it appears appropriate to put another
focus on this tumour species.
Aim
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 breast cancer and neuroblastoma. Overall, the integrated action of our consortium is
aiming at re-establishing tumour suppressor activity in cancer, thereby
translating basic knowledge of functional oncogenomics into cancer
diagnoses and treatment, and contributing to leadership in European
health technology.
The overall goals of this integrated effort are to understand:
1. which modulators determine the tumour-suppressive activities of
the p53 family members
2. by what mechanisms these modulators affect the tumour suppression activities
3. how the expression and activity of p53 modulators is regulated
4. whether p53 modulators affect the biological characteristics of
tumour cells
5. whether the status of p53 modulators correlates with the clinical
outcome and can be used to determine the individual prognosis
6. whether and how p53 modulators can be targeted by therapeutic
strategies, and be manipulated towards regaining tumour suppression
7. disseminate the knowledge that will be produced to practically all
the interested parties including medical doctors, and managerial staff
in the industries
8. familiarise SMEs with scientific research work and state-of-theart technology that will provide the necessary know-how for the
improvement of their services and competitiveness.
The four blocks are linked as outlined.These links are formed according
to the biological activities governing p53 and, therefore, the scheme simultaneously
depicts biological dependencies as well as the mode of collaboration within
the consortium. Activators of p53 frequently act by antagonising p53 inhibitors,
and vice versa; this will be taken into account by networking accordingly between
the blocks 1 and 2. Activators and inhibitors of p53 may act on p73 and p63 as
well and this was shown to be true in a number of cases.Therefore, each regulator
of p53 will be assessed regarding its impact on p53-homologues as well
by collaborative efforts between block of work 3 with blocks 1 and 2.
Finally, the assessment of p53 downstream activities, and the development of
cutting-edge technologies to analyse them, will be used throughout the consortium.
Therefore, block of work 4 forms a basis not only for reaching excellence on its own,
but also to effectively advance the progress of blocks 1, 2 and 3.
Potential applications
The members of our consortium have identified a number of p53-modulators
(stage 1), and in some cases have begun to understand their mechanisms of action.
We are now pursuing an integrated strategy to advance our knowledge
on the nature of these modulators through stages 2-5, and ultimately
to evaluate their potential as candidate drug targets (stage 6).
We are starting from the scenario outlined below.
The ultimate general objective of this research proposal is to provide
a basis for the re-activation of tumour suppression and the design
of novel therapeutic approaches to combat cancer. In particular, we
are aiming at modulating p53 family activities to decrease resistance
of tumour cells to anti-cancer treatments. Thus, the ultimate goal of
this research proposal is the identification of novel drug targets and
strategies for induction of p53-mediated apoptosis in therapy-resistant
cancer cells.The participation of the SMEs is expected to play a key role
to the practical application of the knowledge that will be produced.
Project website: www.europeire.it/Activep53/intro.htm
Acronym: Active p53
Project number: LSHC-CT-2004-503576
EC contribution: € 6 000 000
Duration: 60 months
Starting date: 01/12/2004
Instrument: IP
Projects funded under the
Sixth Framework Programme
45
Understanding
Expected results
Coordinator
Giovanni Blandino
Department of Experimental Oncology
Regina Elena Cancer Institute
Rome, Italy
E-mail: [email protected]
Partners
Matthias Dobbelstein
Centre of Medical Biotechnology
University of Southern Denmark
Odense, Denmark
Ygal Haupt
The Lautenberg Center for General and Tumour Immunology
The Hebrew University - Hadassah Medical School
Jeruslem, Israel
Guido Kroemer
Centre National de la Recherche Scientifique
Laboratoire de Génétique Oncologique – UMR8125 –
Institut Gustave Roussy
Villejuif, France
Xin Lu
Tumour Suppressor Group
Ludwig Institute for Cancer Research
London, United Kingdom
Karen Voudsen
The Beatson Institute for Cancer Research
Tumour Suppressor Laboratory
Glasgow, United Kingdom
Varda Rotter
Weizmann Institute of Science
Molecular Cell Biology / Biology
Rehovot, Israel
Nicholas B. La Thangue
University of Glasgow
Biochemistry and Molecular Biology
Institute of Biomedical and Life Sciences, Cathcart Lab
Glasgow, United Kingdom
Gerry Melino
Medical Research Council
Leicester, United Kingdom
Jiry Bartèk
Danish Cancer Society
Dept. of Cell Cycle and Cancer
Institute of Cancer Biology
Danish Cancer Society
Copenhagen, Denmark
Massimo Levrero
Fondazione Andrea Cesalpino
Laboratory of Gene Expression
Rome, Italy
Aart Gerrit Jochemsen
Dept. Molecular and Cell Biology, Tumour Suppressor Group
Leiden University Medical Center
Leiden, The Netherlands
Galina Selivanova
Karolinska Institute
Department of Laboratory Medicine,
Stockholm, Sweden
Gianni Del Sal
Università Degli Studi Di Trieste
Dipartimento di Biochimica
Biofisica E Chimica Delle Macromolecole
Trieste, Italy
Richard Iggo
Swiss Institute for Experimental Cancer Research
Oncogene Group
Epalinges, Switzerland
Wolfgang Deppert
Heinrich-Pette-Institut für Experimentelle Virologie
und Immunologie an der Universität Hamburg
Department of Tumour Virology
Hamburg, Germany
David Lane
University of Dundee
Department of Surgery and Molecular Oncology, Nethergate
Dundee, United Kingdom
Simona Greco
Biotecgen s.r.l.
Department of Biological Sciences
Institute of Physiology
Lecce, Italy
Ismail Moarefi
SiREEN AG
Martinsried, Germany
Cancer research
46