Cancer Research - Europa

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Aim
Drop-Top has two major objectives, one technological and
one scientifi c. Regarding the former, we propose to develop
a tool for multiparametric analyses (mRNA levels, large
genetic rearrangements, genetic mutations, genetic polymorphisms,
protein levels and post-translational modifi cations)
of biological samples, to better predict tumour progression
and recurrence (see Figure 1). The evaluation of such heterogeneous
parameters will be performed on a single microarray:
the triple microarray, an oligonucleotide microarray for
simultaneous DNA, RNA and protein assessment). The triple
microarray constitutes the test surface of a workstation that
integrates technology for the hybridization, scanning and
detection of biomarkers. Its simplicity should facilitate a wide
implementation of this tool in the clinic.
As scientifi c objective, we propose to identify a set of
biomarkers with power for the prediction of clinical behaviour
of bladder cancer. Selection of such set of biomarkers
will be the end point of a fi ve-phase endeavour:
• identifi cation of candidate biomarkers for bladder cancer
progression and recurrence from the scientifi c
literature and from existing data generated by two
Drop-Top partners specialized in bladder cancer;
• pre-selection of biomarkers on the basis of the strength
of their association to tumour behaviour and on the scientifi
c and technical quality of the study;
• measurement and validation of said candidate biomarkers
in a set of samples from patients with a detailed
clinical record and follow-up;
• application of bioinformatics and biostatistics tools for
the identifi cation of a set of biomarkers with a strong
association to tumour behaviour.
Figure 1 | Triple microarray and Integrated station for improved multiparametric
analyses of biological sample.
The DroP-ToP strategy should be applicable to the study of
any tumour type, and more generally to any disease with
a genetic or gene-expression component. However, and as
a proof of concept, we propose to apply it to bladder carcinoma
because it represents a paradigm of the need for
useful biomarkers in the clinical setting:
• it is one of the best models of tumour progression;
• its incidence ranks fi fth among all cancer types (the
fourth most common in males and the ninth in females);
• despite widely variable outcome, the diagnosis and
prognosis tools used in the clinic are few and the same,
and they are invasive even for asymptomatic patients
(cystoscopy);
• it is the most expensive cancer type, as it can recur many
times after treatment;
• its evolution is very diffi cult to predict, whereas the therapeutic
approach for its two forms is completely diff erent:
when invasive at the time of diagnosis, it has a poor
prognosis and requires aggressive surgery (cystectomy);
when non-invasive, prognosis is favourable and it only
requires conservative surgery (resection);
• its recurrence is also diffi cult to predict, which leads to
unnecessary visits and cystoscopies for about 50 % of
patients, whose tumours will never recur;
• a number of highly promising biomarker candidates have
already been identifi ed and reported in the literature.
Expected results
Cancer is the second leading cause of death worldwide. In
the year 2002 there were 10 million new cases of cancer in
the world, 6 million deaths and approximately 22 million
people living with cancer worldwide. It is estimated that by
year 2020 there will be 15 million new cases per year, and
10 millions deaths. Bladder cancer is a highly common neoplasia,
mainly among men, and its incidence is rising in several
countries in Europe. Approximately 125 000 new cases with
bladder cancer are diagnosed each year in the EU.
Despite continued interest in the development of novel tests
to better predict bladder cancer prognosis, there has been
very limited progress. This is in part due to the fact that all
tests developed until present are based on the detection of
only one type of biomolecule (i.e. RNA, DNA or protein). Our
approach is radically diff erent: from a systematic review of
current knowledge on biomarkers of bladder cancer and
existing research results of the participating academic partners,
we propose to develop a microarray that can detect
the 3 major types of molecules in human biological samples.
This should provide a much more solid basis to identify
molecular predictors of the disease.
CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME