You also want an ePaper? Increase the reach of your titles
YUMPU automatically turns print PDFs into web optimized ePapers that Google loves.
Active p53<br />
Manipulating tumour suppression:<br />
a key to improve cancer treatment<br />
Summary<br />
The prevention of human cancer development depends on<br />
the integrity of a complex network of defence mechanisms<br />
that help cells to respond to various stress conditions. A key<br />
player in this network is the p53 tumour suppressor protein.<br />
By inducing effi cient growth inhibition, p53 eliminates cancer<br />
cells thereby preventing the development of human<br />
malignancies. These functions of p53 often determine the<br />
effi cacy of anti-cancer therapies. Although p53 is frequently<br />
mutated in some cancers, in about 50 % of all human cancers<br />
p53 is non-mutated and could, in principle, be activated<br />
to prevent tumour progression. This situation is prevalent<br />
among a wide range of cancers, notably breast carcinoma.<br />
However, p53 activity is hampered by malfunction of its<br />
many modulators, such as Mdm2 or p73, which govern p53<br />
tumour suppressive activity by acting upstream and/or<br />
downstream of p53. There is therefore a crucial need to<br />
understand how p53 modulators contribute to human<br />
malignancies. Based on this information, we propose to<br />
develop rational therapeutic approaches to manipulate<br />
p53 modulators, thereby wakening the sleeping tumour<br />
suppression activities of p53, allowing it to eliminate cancer<br />
cells. This carefully structured consortium comprising<br />
20 academic research centres and SMEs (see diagram) will<br />
interactively build a technology platform to comparatively<br />
identify, characterise and evaluate the regulatory roles of<br />
p53 modulators and defi ne the mechanisms of their action.<br />
Large-scale gene functional analyses will be conducted to<br />
identify relevant signalling pathways that impair or mediate<br />
tumour suppression by p53. These analyses will include p53<br />
activators and inhibitors, p53 homologues p73/p63, and<br />
dissection of p53 target genes mediating apoptosis and<br />
growth arrest. Our links with highly profi led clinical partners<br />
and our access to large, well-characterised and clinically<br />
documented sample collections will enable the evaluation<br />
of diagnostic expression profi les, and their potential prognosis<br />
value in cancer. Particular emphasis will be directed<br />
towards translating the information on p53 regulation into<br />
the development of new anti-cancer therapies. p53 regulatory<br />
proteins will be used for the identifi cation of new<br />
molecular targets for drug discovery.<br />
10<br />
Keywords | Tumour suppression | p53 | p73 | p63 | inhibitors | activators |<br />
© C. AND M. KAGE<br />
Problem<br />
<strong>Cancer</strong> is the second leading cause of death in European<br />
countries, and one of the most imminent health problems in<br />
the developed world. The p53 protein is generally recognised<br />
as the key determinant of tumour suppression. It has<br />
been declared by the European Union that ‘a large cooperative<br />
eff ort is needed to ensure that every European<br />
citizen will rapidly profi t from the revolution of knowledge in<br />
cancer management’ (Philippe Busquin). The presence of<br />
wild type p53 is particularly prevalent in breast cancer, the<br />
type of cancer that stands at the centre of the European<br />
cancer policy. Since breast cancer aff ects mostly (though<br />
not exclusively) women, breast cancer research is also an<br />
important task to implement the gender dimension into<br />
basic research. For these reasons, we will choose breast<br />
cancer as one of our focuses in this block of work. Moreover,<br />
a non-mutated but inactive p53 is also found in a high percentage<br />
of the most frequent intracranial tumour of children,<br />
neuroblastoma. Since paediatric tumours are particularly<br />
dramatic events for patients and their families, it appears<br />
appropriate to put another focus on this tumour species.<br />
Activators<br />
WB1<br />
similarities to p53<br />
direct interference<br />
Homologues<br />
WB3<br />
p53<br />
p53 activity<br />
and<br />
technology<br />
WB4<br />
similarities to p53<br />
direct interference<br />
Activators<br />
WB2<br />
The four blocks are linked as outlined. These links are formed according to the biological<br />
activities governing p53 and, therefore, the scheme simultaneously depicts biological<br />
dependencies as well as the mode of collaboration within the consortium. Activators of p53<br />
frequently act by antagonising p53 inhibitors, and vice versa; this will be taken into account by<br />
networking accordingly between the blocks 1 and 2. Activators and inhibitors of p53 may act on<br />
p73 and p63 as well and this was shown to be true in a number of cases. Therefore, each<br />
regulator of p53 will be assessed regarding its impact on p53-homologues as well by<br />
collaborative eff orts between block of work 3 with blocks 1 and 2. Finally, the assessment of p53<br />
downstream activities, and the development of cutting-edge technologies to analyse them,<br />
will be used throughout the consortium. Therefore, block of work 4 forms a basis not only for<br />
reaching excellence on its own, but also to eff ectively advance the progress of blocks 1, 2 and 3.<br />
CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
Change language