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Identification of novel targets for cancer therapy

Final Report Summary - INTACT (Identification of Novel Targets for Cancer Therapy)

Despite intensive worldwide research efforts, cancer remains a devastating, often poorly treatable disease. The project proposed to develop and apply new functional genomic technologies that will provide unique approaches to the design of new pathway-specific cancer therapies. To reach their objectives, they 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 small and medium-sized enterprises (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 ensured optimal conditions for the development of novel cancer-specific treatments. This proposal provided 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 (FP6).

The availability of the complete human genome sequence has provided unparalleled opportunities to examine changes in both deoxyribonucleic acid (DNA) sequence and gene expression in normal and cancer cells. Several major projects are under way to identify cancer-specific mutations by large-scale sequencing or cancer specific 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 identified through these methodologies play a real role in malignant development would be a massive task.

The team therefore proposed 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 identification 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, the project team were 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.

Genomic information had been used mainly to develop expression array technologies. Such technologies had been commercialised and were applied in many laboratories; indeed, members of this consortium have published key profiling papers on several human tumours. The central weakness of this approach was that expression profiling 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 defining prognostic profiles 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 genome wide scale. Two key technological developments formed the basis of this consortium.

First, scientists developed retroviral screening technologies to allow phenotypic screens that have specific cellular or organismal phenotypes as readout. Genes are therefore annotated by their contribution to specific cellular phenotypes.

Within this consortium, these screens were adopted to specific cancer pathways using pathway-specific reporter cell lines. Therefore, genes were screened at high throughput and were annotated immediately by their functional contribution to individual cancer pathways.

Second, the development of RNAi screens and bar-code screens allowed them to conduct, for the first time, systematic loss-of-function screens in mammalian cells.

Using these technology platforms, the work carried out addressed all three key aims of this specific topic: to identify novel potential oncogenes and tumour suppressor genes and provide insights into the role of telomere shortening and genomic stability (p53) in tumour biology. Most importantly, however, it filled a key technological gap in the identification of novel targets for tumour therapy.

The identification of strong dominant oncogenes like bcr-abl subsequently led to spectacular successes in the development of drugs that specifically target the mutated gene product. Thus, as highlighted by the paradigm drug Gleevec, insights into the molecular pathways that control cancer development can lead to the development of highly cancer-specific drugs. At the time of the project, it had become clear that disruption of a limited number of tumour suppressor pathways, such as the TGF-beta, pRB, the p53 or the APC pathways, is causal for the development of most human tumours.

However, findings drugs that specifically target cancer cells with disruption of any of these pathways was much more difficult to achieve. Clearly, technologies at the time were unable to identify drug target genes on a genome-wide scale. The technology developed in this consortium addressed this need and hoped to allow the systematic identification of two classes of genes.

The team believed that these technologies allowed a key problem to be addressed: that of translating current cancer research into therapy; project work in collaboration with small and medium-sized enterprises (SMEs) will pave the way for more efficient development of knowledge-based cancer therapeutic intervention.