Cancer Research - Europa

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