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Providing new recommendations to oncologists, allowing<br />
them to ‘individualise’ the chemotherapy course chosen<br />
for a given patient, will therefore meet the objective of<br />
better treatment with minimal side-eff ects, and will<br />
provide evidence-based guidelines for good clinical<br />
practice.<br />
• A major component of this project is aimed at developing<br />
novel therapies, based on mutp53 knowledge to be<br />
gained by the consortium. The increased selectivity and<br />
specifi city of such drugs is most likely to reduce sideeff<br />
ects on normal patient tissue, because such tissue<br />
does not express any mutp53, unlike the targeted tumour<br />
cells. Thus, any successful drug that comes out of this<br />
project is highly likely to lead to improved clinical practice<br />
and to better treatment, with reduced side-eff ects<br />
as compared to the presently available options. Moreover,<br />
the fact that close to half of all human tumours<br />
possess mutp53 in abundant amounts makes any new<br />
drug emanating from this endeavour potentially valuable<br />
to a very large number of cancer patients. Such drug,<br />
if successful, may thus have far-reaching impacts, not<br />
only on individual cancer patients, but also on European<br />
society as a whole.<br />
Expected results<br />
The proposed project will address the following main<br />
objectives:<br />
• elucidate the biochemical basis for mutp53 GOF (GOF),<br />
with special emphasis on genomics and proteomics<br />
approaches;<br />
• evaluate the contribution of mutp53 to the malignant<br />
properties of cancer cells;<br />
• explore in depth the structural properties of selected<br />
mutp53 proteins, in order to provide leads for structurebased<br />
rational drug design;<br />
• evaluate the impact of mutp53 status on the response of<br />
selected types of human tumours to chemotherapy, and<br />
use this information to formulate guidelines for more<br />
eff ective use of currently available anti-cancer therapies;<br />
• search for molecules and compounds that can selectively<br />
interfere with mutp53 GOF or restore wtp53 activity to<br />
mutp53, and explore them as potential anti-cancer drugs;<br />
• initiate clinical trials (Phase I) with one mutp53-selective<br />
drug that has already gone successfully through preclinical<br />
studies;<br />
• generate leads and new tools towards the development<br />
of mutp53- based immunotherapy.<br />
Potential applications<br />
<strong>Cancer</strong> represents one of the most severe health problems in<br />
the European community. Cases are growing with the age of the<br />
population. The economic and emotional burden is enormous.<br />
Mutp53 protein is expressed in about 50 % of all human<br />
tumours. In some categories with growing incidence, e.g. lung<br />
cancer, colon carcinoma and skin tumours, more than 60-70 %<br />
of the tumours are associated with mutated p53. This may be<br />
due to the induction of p53 mutations by dietary and environmental<br />
carcinogenic insults, which are encouraged by<br />
modern western society’s lifestyle (exposure to sun, very<br />
heavy smoking in most parts of Europe, high-fat diet).<br />
In some types of cancer, expression of mutp53 appears to<br />
be particularly highly correlated with the more aggressive<br />
tumour stages. Yet, in many cancers, mutation of p53<br />
appears to occur during the very early steps of carcinogenesis.<br />
This is particularly true for cancers of the lung,<br />
head-and-neck, bladder, skin and oesophagus. In these<br />
pathologies, mutp53 is amongst the earliest tumourigenic<br />
changes that can be detected in the patient, sometimes<br />
ahead of the clinical diagnosis of a cancer lesion. The expression<br />
of mutp53 is relatively easy to diagnose, employing<br />
immunohistochemical assays that are already available as<br />
commercial kits and are in use in many pathology laboratories<br />
throughout Europe. However, there is still a lack of rapid,<br />
low-cost and sensitive assays for mutation detection, and<br />
this is the key to the systematic implementation of mutp53based<br />
strategies for cancer diagnosis, prognosis, and<br />
treatment. This is why one of the activities of our consortium<br />
will be to support the validation and the transfer into<br />
production of a new type of micro-array developed by<br />
Asperbio, an SME partner of our consortium. Improved<br />
detection of p53 mutations may enable earlier cancer diagnosis,<br />
increased curability and reduction in the societal<br />
impact of cancer morbidity and mortality.<br />
An eff ective novel treatment of cancers expressing mutp53<br />
could help to prolong life expectancy and quality of life. Such<br />
a treatment may be applicable for eradicating small lesions in<br />
pathologies where mutation is an early event, thus providing<br />
low-cost, low-stress approaches for lesions that are currently<br />
managed through surgery and/or chemotherapy. On the other<br />
hand, mutp53-based therapies can be applied synergistically<br />
with conventional therapy regimens in patients with advanced<br />
cancers. The mutp53-based approach thus opens a whole<br />
range of possibilities that can be implemented in current<br />
medical practice without costly equipment, infrastructures or<br />
extensive training programmes.<br />
58 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
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