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Sensitisation of solid tumour cells to death receptor related therapies (ONCODEATH)


Scientific and technological objectives
The presence of specific activated oncogenes or the expression pattern of certain proteins can provide an explanation of the sensitivity or resistance of tumour cells to TRAIL induced apoptosis in several systems.

Therefore, it is essential that careful therapeutic strategy selection should be made, as the combination of molecules inhibiting e.g. oncogene pathway components that can potentially play also the role of TRAIL agonists may not give the desired synergistic effect. In the recent years, 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 and many of these potential or current drugs influence signalling pathways.

Examination of the Impact on health and solving of societal problems

Cancer is one of the major causes of mortality in Europe and a disease with major socioeconomic impact. The ONCODEATH Project is concerned with a unique approach to cancer treatment: the analysis of defective apoptotic pathways in colon tumour cells in a oncogene dependent manner in order to exploit them for novel treatment protocols based on TRAIL as a ''monotherapy'' or in combination with novel pathway specific inhibitors, like PI3K, Rho and aurora kinase pathways. In combination therapies the two drugs can be used in low concentrations, thus minimising side-effects. Moreover, drugs targeting signalling pathways allow or amplify the activity of TRAIL by targeting resistance mechanisms and pathways in particular tumours. This treatment has been already been successful in both in vitro and in vivo applications. Regarding public health, it is obvious that the optimal use of therapeutic protocols should be taking into account the specific oncogenic mutations of the particular tumour and the apoptotic components involved. The ultimate goal is to shift the therapeutic emphasis to tumour specific drugs, with a consequence for low hospitalisation time, costs and high efficiency.

The benefits on the society of a project focusing on novel cancer therapeutics are evident, since cancer is a major cause of death in Europe. This project contains groups of scientists from different disciplines like Molecular Biology, Genomics, Cell Biology, Tumour Biology and Biochemistry. The synergy between the labs is evident at structuring the experimental tasks. Already bilateral interactions exist and this project will enhance already successful co-operation by adding a value
at the European level. Dissemination of the technologies developed at the individual national level will provide patients in all over Europe access to new developments concerning cancer treatment, thus enhancing the benefit for the ''European Citizen''.

Contribution to policy objectives of the ''Life Sciences, Genomics and Biotechnology for Health'' Programme
A new era in human biology has been opened by the sequencing of the human genome offering opportunities to improve human health and to stimulate industrial activity. Our project represents a basic research programme aimed to exploit the potential of functional genomic approaches to decipher mechanisms underlying oncogenic vs. apoptotic signal transduction mechanisms in oncogenesis. The goals of this proposed project are in accordance with the relevant objectives of the Life Science Health priority laid down in the 6th EU framework programme because our research is focused on major fundamental biological processes concerning cell proliferation and cell death which can be exploited for novel anti-cancer therapies.
Furthermore, results obtained in this project will contribute to our understanding of defects in cell death pathways during tumour formation in general and help to strengthen the link between cancer and apoptosis. New knowledge about tumour formation will eventually be translated to an application stage, to the design of new drugs to treat cancer and thus improve competitiveness of Europe in the new specific drug development, which finally will improve medicine in Europe and life quality.

Enhancement of Transnational cooperation
The multidisciplinary nature of the project as well as the complexity and the quantity of the work demands the collaboration of many laboratories possessing diverse but complementary expertise, therefore enhancing integration of individual activities and resources, which can be combined and expanded to a more comprehensive collaboration.

Reinforcing European competitiveness
''ONCODEATH'' has aspects in very important and competitive areas on preclinical models of cancer, cancer genetics and genomics as well in imaging technologies. While a number of leading scientists within the field are active in Europe today, judging from the published literature it is evident that European research output lags behind that of the United States in production of efficient new cancer therapeutics. The domination of US laboratories of the field has as a consequence the continuous drain of talented young European researchers towards the US. The proposed Project has the potential to establish world leadership in the field, mainly due to the competitive edge provided by EU support for intensive collaboration of a critical mass of researchers from different disciplines. The integrated approach will neutralize the problem of fragmentation of relevant expertise in Europe, thus translating the potential success of the consortium into tangible benefits for European science. This eventually will lead to better and more specific drug development by the pharmaceutical industry at a European level.

Dissemination/Exploitation/Raising public participation and awareness
The project partners will make all possible efforts to advertise their scope and findings in scientific as well as in other relevant social meetings, in order to inform European Citizens about novel approaches of drug discovery and about novel emerging treatments at a local, national and European level.

Dissemination activities will include publications in international scientific journals, presentations in scientific conferences, workshops for training of oncologists.Seminars with local oncologists' societies and meetings with local journalists will be organized, in order that the development of novel therapeutic agents as well as the achievements of ONCODEATH consortium will be presented.

The project will also participate in joint efforts at a European level with other EU funded projects of similar aims, in order to maximise efficiency.

Unique training opportunities
The participating laboratories will have continuously open calls in the project's own web site and other publications of positions for young European researchers. Given the cutting-edge scientific level of research to be performed and the opportunity to carry-out research projects in collaboration with laboratories of a different discipline, the project would provide a competitive alternative to US laboratories for training young researchers interested in the field of tumour genetics and cancer therapeutics. Via short-term visits, the young fellows may have an opportunity to work in more than one laboratories. The opportunity to meet and collaborate with several project members and to be exposed to the continuous information exchange of the whole project will set up a precedent of a novel, highly productive training method.










National Hellenic Research Foundation (NHRF), 48 Vassileos Constantinou Ave., 11635 Athens, Greece, Tel. +302107273700, Fax. +302107246618