Cancer Research - Europa

INTACT
Identifi cation of novel targets
for cancer therapy
Summary
Despite intensive worldwide research eff orts, cancer remains
a devastating, often poorly treatable disease. We propose to
develop and apply new functional genomic technologies
that will provide unique approaches to the design of new
pathway-specifi c cancer therapies. To reach the objectives
outlined below, we have formed a multidisciplinary research
consortium, including top scientists with extensive experience
in developing innovative genomics technologies and
with an excellent track-record in identifying key signalling
molecules involved in cancer, as well as SMEs with experience
in identifying cancer-relevant genes and in screening
chemical compound libraries. The location of most of the
partners at leading European cancer centres will ensure
optimal conditions for the development of novel cancerspecifi
c treatments. This proposal provides new possibilities
of ‘translating basic knowledge of functional oncogenomics
into cancer diagnosis and treatment’ in compliance with the
main goal in the LifeSciHealth call in the Sixth Framework
Programme.
Problem
The availability of the complete human genome sequence
has provided unparalleled opportunities to examine changes
in both DNA sequence and gene expression in normal and
cancer cells. Several major projects are underway to identify
cancer specifi c mutations by largescale sequencing or cancer
specifi c alterations in gene expression by micro-array technology
and providing important information. However, these
technologies have severe limitations in that they provide only
an inventory of cancer-associated alterations without shedding
light on the functional implications of these changes.
Delineating how, or even whether, the alterations identifi ed
through these methodologies play a real role in malignant
development will be a massive task. We are therefore proposing
to make use of the most advanced technology developed
within the groups of the programme to move a step further
and apply new high-throughput functional screens for the
swift identifi cation of new targets that are critical for survival
of tumour cells carrying distinct, frequently occurring gene
defects. Building on the expertise of other members of the
programme we will be able to validate these targets in in vivo
mouse and human xenograft models, which closely mimic
the human disease condition and form the basis for new
experimental intervention-intervention strategies.
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Keywords | Cancer biology, high-throughput screening | RNA interference screening | knowl-
Keywords | Cancer biology edge-based | high-throughput | cancer therapy screening | RNA interference screening | knowledge-based cancer therapy |
Aim
The scientifi c and technological objectives are:
• use large-scale functional genomics, in particular genomewide
lossof-function screens, to identify novel mechanisms,
including novel oncogenes and tumour suppressor genes,
involved in the development of human cancer;
• to generate novel tools in the form of RNAi retroviral libraries
(mouse and human), cell-based assays, mouse models
and reagents that will be distributed on a non-profi t
cost-charge to academic researchers in the European
Community;
• to develop novel technologies for target validation in
mouse and to develop mouse models to validate the role
of the identifi ed genes in the development of cancer;
• to develop cell-based assays for cancer-relevant genes
that will serve as a starting point for the identifi cation
of anti-cancer agents through the screening of chemical
compound libraries. At the end of the four-year
programme, collaboration with large pharmaceutical
compa nies will lead to further refi nement of lead-compounds
and the possible introduction of novel anti-cancer
agents into clinical trials;
• to develop novel technologies to study gene function
in vitro and vivo, and to distribute these technologies
within the consortium and subsequently to researchers
in the European Community.
Expected results
Translating basic knowledge of functional oncogenomics
into cancer diagnosis and treatment. Until now, genomic
information has been used mainly to develop expression
array technologies. Such technologies have been commercialised
and are being applied in many laboratories; indeed,
members of this consortium have published key profi ling
papers on several human tumours. The central weakness
of this approach is that expression profi ling gives no indication
of gene function and is, therefore, not suited for the
functional annotation of the human genome. As such,
expression arrays have been useful in defi ning prognostic
profi les for multiple forms of cancer: however, they have
rarely given insight into potential therapeutic strategies
for disease.
In contrast, the technology platforms developed by this
consortium aim immediately at the determination of gene
function on a genomewide scale. Two key technological
developments form the basis of this consortium. First,
scientists in this consortium have developed retroviral
screening technologies to allow phenotypic screens that
have specifi c cellular or organismal phenotypes as readout.
Genes are therefore annotated by their contribution
to specifi c cellular phenotypes. Within this consortium,
these screens will be adopted to specifi c cancer pathways
CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME