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Identification of novel targets for cancer therapy

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A global approach to pathway-targeted cancer therapy

The complete human genome sequence and associated protein expression has provided an opportunity to study DNA changes and their effects in the cancer cell. The next step is to use this information to design pathway specific therapies.

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The 'Identification of novel targets for cancer therapy' (Intact) project aimed to apply advanced genomic and proteomic technology to identify, with high-throughput screening, new signalling molecules and targets that are critical for survival of tumour cells. Validation in vivo in the mouse and human xenograft models to closely mimic the disease condition would then lead to new therapeutic strategies. The EU-funded consortium comprised a team of top, multidisciplinary scientists combined with small to medium-sized enterprises (SMEs). The Intact consortium successfully merged academic excellence with commercial experience in gene screening and identification of molecular targets for cancer therapy. Intact researchers developed retroviral screening technologies with readouts that have a specific cell or model organism phenotype. Genes can therefore be connected with a contribution to a certain phenotype. Moreover, information was collected on the functional contribution of the genes to specific cancer pathways. One major breakthrough led to development of systematic loss-of-function screens in mammalian cells. The team developed new RNA interference (RNAi) and bar-code screening techniques. RNAi screening is a powerful technology that systematically shuts down genes of interest in a cell, the effects of which can then be linked to a specific phenotype or loss of a pathway. Using these technology platforms, Intact scientists identified potentially new oncogenes and tumour-suppressor genes. Another research avenue with great promise explored was the area of telomere shortening and stability of the genome. The team also focused in the main on the genes and cascades known to be associated with tumour formation, including transforming growth factor-beta (TGF-beta), retinoblastoma protein (pRB), p53 and anaphase-promoting complex (APC) pathways. The Intact project approach addressed the need to identify drug targets on a genome-wide scale. Results have provided a firm platform on which to develop a more efficient knowledge-based cancer therapeutic programme through intervention.

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