Objectif
The efficacy of current treatments for some types of solid tumours is disappointingly poor. Thus, new therapies using novel tumour-selective anti-cancer agents are necessary. A major aim of anti-tumour therapies is to inhibit proliferation and induce death of tumour cells without affecting normal cells. In this regard, members of TNF ligand/receptor family are of interest since they regulate both apoptosis and cell proliferation.
One TNF family member, TRAIL, is of particular interest since it selectively induces death of tumour cells without affecting normal cells. Currently, TRAIL and TRAIL-specific antibodies are being investigated as anti-cancer agents. However, one drawback to their efficacy is that they bind to multiple receptors, not all of which transduce an apoptotic signal. Previously, we developed receptor-selective TRAIL variants which are potent inducers of apoptosis in various tumour cells, are more efficacious than native TRAIL, and display synergistic effect in combination with other chemotherapy treatments or radiotherapy.
This proposal will further investigate and characterise TRAIL variants pre-clinically in solid-tumour models and define new treatment protocols in combination with already proven treatments. Furthermore, we will elucidate the role of other TNF receptor family members in signalling in tumour cell survival/death. Biochemical and structural characterisation will identify new targets for molecular cancer therapy and computational design and molecular evolution techniques will be used to develop novel receptor-selective apoptosis-inducing agonists and cell-proliferation antagonists. We will also develop intracellular acting agents which will block the unwanted proliferative signals activated by some TNF members. These will be tested using conventional, viral and cell based delivery strategies which will utilise peptide sequences to specifically target them to tumour cells.
Champ scientifique
Thème(s)
Appel à propositions
FP6-2005-LIFESCIHEALTH-6
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