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Novel anticancer therapeutics based on modulation of apoptosis through dependence receptors


Since 1998, a new concept has emerged, based on the notion that a receptor unoccupied by its ligand is not necessarily inactive. Rather, such a receptor can mediate two different signalling pathways, depending on whether or not it is bound by its ligand. In the absence of ligand, signalling leads to an active process that results in cell death through apoptosis. The survival of a cell expressing such a receptor can therefore be seen as dependent on the presence of the ligand, hence the concept of 'dependence receptors' (DR).
The fact that the different DRs trigger apoptosis in the absence of ligand suggests that they may all act as regulators of tumorigenesis. In addition, expression of DRs is lost or decreased in many tumours, suggesting that they act as tumour suppressors and that their loss represents a selective advantage for tumoral cells. HERMIONE proposes that unravelling the link between different DRs (DCC, UNC5H, KAI1 and RET), downstream molecules and apoptosis will lead to the identification of new potential targets for anti-cancer drugs. HERMIONE will provide a better understanding of the signalling pathways acting downstream of DRs, observe the association of mutations with the onset and progression of tumours (grade, prognosis) and generate murine models in which the apoptotic signalling of the DR is turned off to study the implication of DRs in tumorigenesis in vivo. Through this, HERMIONE will generate knowledge on DR signalling pathways involved in the apoptosis of tumoral cells (colorectal, breast, thyroid and prostate cancers) and use the general concept of DRs to select and perform pre-clinical testing of novel anti-cancer drugs. The HERMIONE consortium gathers leading academics in the fields of DR, death signalling and cancer genetics, a biotechnology SME specialised in the production of reagents, a major pharmaceutical company and a consulting firm specialised in communication and dissemination activities/ project management.'

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