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STRATEGIC IMPACT ON EUROPEAN COMPETITIVENESS
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It is of strategic importance for the European biomedical research to coordinate
its resources at enabling discovery of new candidate cancer-related genes and developing
experimental approaches for their systematic functional and clinical validation.
To keep up with advances in genomic sequence and expression data generation, the
US and Japan are now hugely accelerating gene functional characterization. TRANSFOG
intends to bring momentum to a core of highly strategic functional genomics activities
that are critical for acquiring molecular medicine and new drug development capability
at the European level.
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TRANSFOG will initially focus on basic biological processes involved in cancer progression,
for two reasons: (a) progression towards the metastatic phenotype is the actual
cause of most cancer-related deaths, and there's no effective way to combat cancer
when multiple molecular lesions have altered basic biological functions; (b) most
of the participating RUs are world-recognized leaders in this field, for which integration
at the European level will provide a structuring effect and allow to achieve the
critical mass required for a world-competitive functional genomics project. Indeed,
Europe hosts a strong community of top-level researchers studying various aspects
of tumour invasive growth, which already share research projects under collaborative
grants, and their results in meetings like the EMBO Workshop: "The Invasive Growth
Program: Signals and Effectors", which was held at the IRCC (Partner 2) in February
2002. Other RUs provide complementary, top-level competences crucial for integration
and technological enabling of the outlined research activities.
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A crucial issue in genomics is to develop enabling technologies. TRANSFOG will tackle
this issue by developing a series of technologies here briefly outlined.
- Tools and standards for genomic data sharing will allow merging the results of cancer-oriented
genomic screenings carried out by the Consortium or available in databases and generating
a prioritized list of candidate cancer genes.
- Generation/assembly of plasmid collections carrying FL-cDNAs or siRNAs to achieve
gain- or loss-of-functions of the identified candidates. Within few years, competitive
research will rely on the availability of genome-wide collections enabling systematic
gene gain- or loss-of-function and protein-protein interaction studies. Similarly,
only high-throughput biochemical and biological assays will take full advantage
of such collections, together with bioinformatic resources to handle and mine the
data. A great advantage of a smaller collection focussed on cancer gene discovery,
like the one proposed here, is that it will enable functional analysis at a mid-throughput
level, with a higher probability of success in the timeframe of the project. The
know-how developed in the process of generating and employing such collection will
provide the basis for competitive, larger-scale studies to be carried out later
on at the European level.
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SOCIAL IMPACT: HEALTH SYSTEM, QOL
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The willingness to understand and cure cancer will be the driving force for generating
functional genomics technologies specifically aimed at improving management of the
oncological patient. Indeed, a more precise evaluation of the tendency of a tumour
to give rise to metastases will have a great social impact, in particular to help
reduce mortality and, at the same time, reduce overtreatment of patients that would
not require aggressive anticancer therapy, and promote direct, early exploration
of alternative therapeutic strategies in patients with diagnostic signatures that
predict poor prognosis
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INNOVATION ASPECTS, SCIENTIFIC AND TECHNOLOGICAL IMPACT
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The Human Genome Project, currently in the phase of sequence assembly and annotation,
is tremendously accelerating the description and inventory of the genes potentially
involved in physiological and pathological processes. However, a similar turning
point is still lacking for highly parallel functional validation of genes identified
by genomic exploration. Systematic loss-of-function screenings are currently ongoing
on model organisms, including the mouse. Yet, functional redundancy or subtle phenotypes
may impair characterization of a consistent number of genes. Moreover, such screenings
allow exploration of gene function in the context of the organism, but are hard
to direct at defining basic biochemical and biological properties.
Biomedical research is currently facing a historical change in the perspectives
and modality of gathering information about gene functions and biological processes.
The completion of the human genome sequencing reversed the conventional approach
to biomedical discovery, in which understanding a certain biological function required
identification of one or more genes involved in that function. The current situation
is that thousands of genes have been sequenced but still wait for any functional
information to be assigned to them. The fact that genes of unknown function represent
over 70% of all genes suggests that current comprehension of most biological and
pathological processes, and therefore of cancer, is by far incomplete. In this perspective,
systematic exploration of gene function is likely to yield a huge amount of information
in the next years. To this aim, new technological platforms have to be developed
to increase the throughput of established procedures for functional gene characterization.
The TRANSFOG project will deliver a consistent and integrated amount of functional
data on genes of as yet unknown activity and biological role. In the process of
reaching this objective, the participating Units will be enabled to set-up truly
post-genomic efforts toward systematic gene functional characterization. New technologies
will be developed that will allow exploration of gene regulatory networks, protein-protein
interactions and high-throughput cell-based evaluation of basic biological functions
such as motility, growth, apoptosis, invasion, adhesion, polarization and more complex
processes as in vitro epithelial morphogenesis and angiogenesis. The technologies
for systematic gene functional characterization developed here will be useful for
functional studies involving a variety of physiological and pathological processes,
and will be made available to the scientific community in the frame of a collaborative
research network. The bioinformatic networking endowed with the project will enable
participating Units to share tools for data handling, database exploration and functional
gene annotation. It will also facilitate integration of the present network with
other EC-funded networks and with the European and global post-genomic community.
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