In the last decade, an encouraging decline of the death rate from cancer has been observed, as a result of recent advances in prevention, early diagnosis and therapy. Efforts are made towards the generation of "smart" anti-cancer drugs that will target specific molecules depending on the molecular phenotyping of the patient's tumour. TNF-related apoptosis-inducing ligand (TRAIL) is currently a promising anti-tumour agent with proven activity on several cell and animal cancer models. A unique feature of TRAIL is its specificity towards malignant cells while sparing normal cells. At present, pre-clinical studies with recombinant TRAIL are in progress as well as with an anti-TRAIL-R2 monoclonal antibody with no hepatotoxicity.
The aim of the present proposal is to identify components in colon tumours which confer sensitivity or resistance to cell death induced by TRAIL. This project is based on recent findings that oncogenes like RAS or MYC sensitise cells to TRAIL induced apoptosis. For this purpose, human cancer cells a) bearing oncogenic mutations, b) overexpressing oncogenes and c) silencing mutated forms of oncoproteins by RNAi or homologous recombination will be utilised.
In order to identify specific cell death determinants induced by KRAS, BRAF and PIK3CA oncogenes, examination of specific pathways like B-RAF, MEK, PI3K, Rho, BCL-2 will be performed. Studies will be further extended to animal models of tissue specific K-ras induced carcinogenesis. Combined action of TRAIL with other therapeutic molecules will be utilised, in order to succeed optimum effects with minimum concentrations and toxicity. The potential findings of our study will be determined by the present research network and will provide mechanistic basis for a pharmacogenomic approach which could be further therapeutically exploited.
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