The INCA project will concentrate on the four themes that are key to all the other cancer inducing infectious agents (EBV, KSHV, HPV, HTLV-I, HCV, and H. pylori) on which the research work will be carried out: persistence, predisposing factors, intracellular mechanisms and prevention and therapy. The research work will be structured in 5 sub-projects (SP). The research carried out in these five sub-projects will be supported by a common technology platform that will make advanced bioinformatics technologies available to all research groups involved in INCA. Persistence How oncogenic infectious agents manage to persist in an infected host: This is a complex theme which involves issues related to the replication of viral genomes, their switch between latency and reactivation, and how oncogenic infectious agents escape the immune system. INCA will investigate issues that will become amenable to experimental therapies in the near future. For two of these INCA will attempt to develop new substances with therapeutic potential or to evaluate existing chemical compounds in an animal model. Basic research on this theme will be managed in sub-project SP1 and translational aspects in SP5 as shown in the figure below. Predisposing Factors How variability in the viral or bacterial genome, or genetic polymorphism in the infected host, affect infection with an oncogenic microorganism or the progression to infection-associated cancer: this theme is of practical importance because it has the potential to lead to the identification of bacterial or viral genes of relevance for the development of cancer or to highlight the importance of particular intracellular pathways (e.g. inflammatory signalling pathways) and of mutagenic effects for the long term persistence of the infectious agent or progression to cancer. This theme will primarily generate new knowledge and will be handled in SP2. Results that would have an impact on aspects of prevention (e.g. an association of particular strains with particular cancers) will be transferred and managed in SP5 (see figure below). Intracellular Mechanisms How oncogenic infectious agents perturb the intracellular signalling networks and may thereby initiate the progression to infection-associated cancer: The understanding of how viral or bacterial gene products affect the complex network of intracellular signalling will help in the selection or design of small molecule inhibitors to neutralise their effect. Since many of the signalling pathways engaged by oncogenic viruses or bacteria also play a key role in other cancers and in inflammation, the inhibitors developed for these fields may prove useful in counteracting the effects of oncogenic viruses and bacteria. Because of the complexity of this theme it has been divided into two sub-projects (SP3 and SP4): SP3 will focus on the alterations in cellular gene expression patterns induced by viral and bacterial agents with the aim of identifying (i) key intracellular signalling pathways that could be targeted pharmacologically and (ii) cellular genes expressed during the development of infection-associated cancer that could be used as novel diagnostic tools. SP4 will focus on the biochemical events through which oncogenic infectious agents achieve their effect on cellular homeostasis. At the translational level these sub-projects are linked to SP5, which includes a project to investigate the potential of kinase inhibitors in the therapy of H. pylori-associated gastric cancer in an animal model, as well as a project to exploit alterations in proteomic patterns for diagnostic purposes. Prevention & Therapy New approaches to prevention and therapy: This theme, managed in SP5, groups together the INCA translational studies. These studies will involve the development of new diagnostic tests and their evaluation in patient cohorts, as well as animal models for the evaluation of experimental therapies. SMEs and academic groups experienced in the development or screening of small molecule inhibitors will identify chemical compounds or small peptides with biological activity in vitro assays, which will provide the basis for potential future therapeutic exploitation. INCA will use animal models to take such inhibitors to preclinical testing. Technology Service Platform The partners will combine their most advanced methodological tools to create a technology service platform provided as central facility for the INCA project. This will have several benefits: (i) availability of a much more powerful technology platform than the individual partners have at their disposal (ii) homogenisation of experimental data formats (iii) centralisation of data storage and analysis and central evaluation of the potential as well as refinement of this methodology. The Technology Service Platform will be composed of a micro-array gene expression facility, an RNA interference high-throughput facility, data-warehouse, existing micro-array data from infection experiments, proteomic technology and novel analysis software tools.

INCA Project