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Keywords | p53 tumour suppressor | mutations | gain-of-function | p53 status | clinical outcome |<br />
mutant p53-reactivating drugs | novel cancer therapy |<br />
Mutp53<br />
Mutant p53 as a target for improved<br />
cancer treatment<br />
Summary<br />
Mutations in the p53 tumour suppressor gene are the most<br />
frequent genetic alteration in human cancer, occurring in<br />
over 40 % of all cases of cancer. One well-studied outcome<br />
of these mutations is the loss of the tumour suppressor<br />
activity of the wild type (wt) p53. However, there is growing<br />
evidence that many of the mutations that occur in the p53<br />
protein generate mutant p53 proteins (mutp53) have<br />
acquired new biochemical and biological properties.<br />
Through this gain of function (GOF), mutp53 is believed to<br />
contribute actively to the cancer process.<br />
We propose to explore mutp53 as a target for novel anticancer<br />
therapies. Such therapies should aim to either<br />
abrogate the GOF eff ects of mutp53, or restore wt-like<br />
properties to mutp53, so that it can now regain its tumour<br />
suppressor capabilities. A multi-disciplinary approach will<br />
be undertaken to explore and exploit the contribution of<br />
mutp53 to cancer.<br />
One component of this project will investigate in depth the<br />
molecular properties of mutp53: structural studies will pinpoint<br />
the changes that particular mutations infl ict on the<br />
structure of p53, and allow the classifi cation of mutp53 into<br />
distinct subclasses. In parallel, biochemical studies will<br />
explore the mode of action of mutp53 within cells, including<br />
its impact on patterns of gene expression, identifi cation<br />
of specifi c DNA sequences targeted by mutp53, and discovery<br />
of mutp53-interacting cellular proteins. Preclinical<br />
models for mutp53-driven cancer will also be developed, as<br />
a critical instrument for pre-clinical studies.<br />
The other component will aim at translating this wealth of<br />
information into better cancer therapy. One avenue will<br />
address the clinical relevance of particular p53 mutations in<br />
human cancer, particularly its impact on the patient’s<br />
response to chemotherapy. This should lead to guidelines<br />
for more eff ective use of conventional therapy. The other<br />
avenue will explore novel therapies targeted at mutp53 and<br />
mutp53-expressing tumour cells. A major eff ort will focus<br />
on the discovery of small compounds that can restore<br />
wtp53-like activity to mutp53. An innovative approach to<br />
immunotherapy directed against mutp53-overexpressing<br />
cancer cells will also be explored. Owing to the extremely<br />
high frequency of p53 mutations, the success of this project<br />
will impact on a very large number of cancer patients in<br />
Europe and worldwide.<br />
BIOLOGY<br />
Problem<br />
<strong>Cancer</strong> is a major cause for human suff ering in Europe as<br />
well as elsewhere in the world. It causes immense eff ects on<br />
the cancer patients themselves, on their families, as well as<br />
on society at large. In addition to the severe human suff ering<br />
and their immediate societal impact, cancer treatment and<br />
management is also a major economic burden. The importance<br />
of this problem and the urgency of the need for novel<br />
approaches to cancer management and treatment have<br />
been recognised by the EC, as refl ected by the establishment<br />
of a specifi c call in the area of ‘Combating <strong>Cancer</strong>’.<br />
Mutations in the p53 tumour suppressor gene are the most<br />
frequent genetic alteration in human cancer, occurring in<br />
over 40 % of all cases of cancer. We propose to explore<br />
mutp53 as a target for novel anticancer therapies. Such<br />
therapies should aim to either abrogate the gain of function<br />
(GOF) eff ects of mutp53, or restore wt-like properties to<br />
mutp53, so that it can now regain its tumour suppressor<br />
capabilities. A multi-disciplinary approach will be undertaken<br />
to explore and exploit the contribution of mutp53<br />
to cancer.<br />
Aim<br />
In our proposed project, we introduce a multidisciplinary<br />
approach to explore mutp53 as a new target for innovative<br />
treatment.<br />
A primary objective of the ‘Combating <strong>Cancer</strong>’ initiative is<br />
‘to combat cancer by developing improved patient-oriented<br />
strategies… to better treatment with minimal side-eff ects’<br />
with a focus on ‘encouraging the development of evidencebased<br />
guidelines for good clinical practice’.<br />
Our project meets these requirements in at least two distinct<br />
ways:<br />
• We aim to improve the use of contemporary chemotherapy<br />
through providing better guidelines based on<br />
correlations between p53 genotype of the tumour and<br />
its response to particular types of anti-cancer drugs.<br />
It is important to keep in mind that, although novel therapeutic<br />
approaches are very exciting and promising,<br />
millions of cancer patients all over Europe are being<br />
treated every day with standard chemotherapy. Beyond<br />
its limited effi cacy, this is also associated with signifi cant<br />
toxicity and therefore often unjustifi ed patient suff ering.<br />
The ability to make better predictions as to which particular<br />
chemotherapeutic regimen is most likely to work<br />
for a particular patient thus has far-reaching implications,<br />
both in ensuring better and more eff ective<br />
treatment and, not less importantly, in preventing unnecessary<br />
suff ering from severe side-eff ects in cases where<br />
it is clear that a particular treatment is not going to work.<br />
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