Cancer is among the most devastating human diseases and a major aim of the biomedical research is to develop anti-neoplastic molecularly targeted therapies. Receptor tyrosine kinases (RTKs) are pivotal targets for anti-cancer therapies because deregulated RTK signals underlie most events of tumour growth, angiogenesis and metastasis. Strategies to block aberrant RTK signalling involve the development of small chemical compounds that selectively interfere with receptor activation. The RTK Met is a prognostic marker for different carcinomas. Its hyperactivity is thought to be a key event into the development of the invasive/metastatic phenotype of neoplastic cells. The aim of this proposal is to develop Met-specific anticancer drugs. First, a collection of pot ential Met chemical inhibitors will be synthesized and tested for their ability of blocking Met-mediated cell scattering in vitro and activation of its downstream signal transducers. In addition, the first genetically defined animal model of Met-mediated t umour and metastasis will be generated by over-expressing Met only in specific cell types (CRE-mediated recombination). These cells will also express the Luciferase gene allowing non-invasive monitoring of primary tumours and metastasis in vivo. Finally, t his novel mouse strain will be used to optimise the in vivo responses of Met-induced cancers to candidate Met inhibitors. One of the main driving forces of this project is the multi-disciplinary approach undertaken to tackle problems of human health like c ancer. Given the complexity of the cancer biology many researchers with different intellectual and technical skills, ranging from chemical to biology, molecular to in vivo, genetics to pathology will converge. This novel research team will lead this propos al to achieve scientific goals that are at the cutting edge of cancer research, and will potentially set new trends to establish European research as having a world-leading role in this field.
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