You also want an ePaper? Increase the reach of your titles
YUMPU automatically turns print PDFs into web optimized ePapers that Google loves.
using pathway-specifi c reporter cell lines. Therefore, genes<br />
are screened at high throughput and are annotated immediately<br />
by their functional contribution to individual cancer<br />
pathways. Second, the development of RNAi screens and<br />
bar-code screens will allow us to conduct for the fi rst time<br />
systematic loss-of-function screens in mammalian cells.<br />
Using these technology platforms, the work carried out in<br />
this consortium addresses all three key aims of this specifi c<br />
topic: it will help to identify novel potential oncogenes and<br />
tumour suppressor genes and will provide insights into the<br />
role of telomere shortening and genomic stability (p53) in<br />
tumour biology. Most importantly, however, it fi lls a key<br />
technological gap in the identifi cation of novel targets for<br />
tumour therapy. The identifi cation of strong dominant<br />
oncogenes like bcr-abl has subsequently led to spectacular<br />
successes in the development of drugs that specifi cally<br />
target the mutated gene product. Thus, as highlighted by<br />
the paradigm drug Gleevec, insights into the molecular<br />
pathways that control cancer development can lead to the<br />
development of highly cancer-specifi c drugs. In recent<br />
years, it has become clear that disruption of a limited<br />
number of tumour suppressor pathways, such as the TGF-β,<br />
pRB, the p53 or the APC pathways, is causal for the development<br />
of most human tumours. However, fi ndings drugs<br />
that specifi cally target cancer cells with disruption of any<br />
of these pathways has been much more diffi cult to achieve.<br />
Clearly, current technologies are unable to identify drug<br />
target genes on a genome-wide scale. The technology<br />
developed in this consortium addresses this need and will<br />
allow the systematic identifi cation of two classes of genes:<br />
First, we will identify genes that show synthetic lethality<br />
with disruptions in known tumour suppressor pathways.<br />
Synthetic lethal genes are genes whose disruption by<br />
themselves cause little or no phenotype, but become<br />
lethal in the presence of a second mutation. The existence<br />
of this class of genes as well as the feasibility of using<br />
them as targets for anti-tumour strategies is clearly documented:<br />
for example cells transformed by Myc, in contrast<br />
to normal cells, critically depend on the presence of antiapoptotic<br />
genes for survival. Inhibition of anti-apoptotic<br />
genes therefore selectively kills Myc-transformed cells.<br />
However, a systematic way for the identifi cation of synthetic<br />
lethal genes for tumour suppressor pathways is at<br />
present not available. The development of resources<br />
required to identify synthetic lethal genes for human<br />
tumour suppressor pathways on a genome-wide scale is<br />
the fi rst key aim of this consortium. Using this technology,<br />
the consortium will specifi cally identify and subsequently<br />
validate those genes that will cause lethality in the presence<br />
of a disrupted p53, APC or TGF-β pathway. These<br />
genes defi ne the key entry points for rational drug development<br />
of most solid tumours.<br />
BIOLOGY<br />
Secondly, RNAi technology, in combination with reporter<br />
screens, will identify novel genes that control downstream<br />
eff ector functions of tumour suppressor pathways. Such<br />
genes (for example novel regulators of the p15Ink4b gene)<br />
will identify novel entry points for targeting cancer pathways.<br />
Specifi cally, the aim of the analysis is to identify<br />
candidate genes that allow the restoration of tumour suppressor<br />
function in the presence of inactivating mutations.<br />
The inclusion of RNAi libraries and bar code screens will<br />
ensure that the analysis identifi es negative regulators of<br />
tumour suppressor pathways. Such genes will provide<br />
immediate candidates for drug screening approaches.<br />
Potential applications<br />
This consortium will develop novel high-throughput technologies<br />
for the functional annotation of the human<br />
genome and will apply these technologies to develop<br />
novel therapies to treat human cancer. We believe that<br />
these technologies allow us to address a key problem of<br />
translating current cancer research into therapy and thus<br />
our work in collaboration with SMEs will pave the way for<br />
more effi cient development of knowledge-based cancer<br />
therapeutic intervention.<br />
43
Change language