Community Research and Development Information Service - CORDIS

Final Activity Report Summary - MET-CANCER THERAPY (Animal models and drug design for therapy of cancers induced by the oncogene, met)

Merging knowledge from cancer biology and chemistry has been crucial to develop chemical compounds that block action of key oncogenes in specific cancers. A fraction of these chemical compounds are currently in clinical trials or already used for therapies in human patients as they cause reduced side effects compared to radio and chemo-therapies. The HGF Receptor tyrosine kinase (RTK) Met triggers the molecular and biological processes underlining tumour growth and metastasis when it is aberrantly activated in cells. For example, Met over-expressing cells acquire invasive phenotype during progression of breast cancer, and autocrine activation by HGF is responsible for spontaneous metastasis to the lung. Mutations or amplifications of Met have been found in different types of human cancer cells and Met is a prognostic marker for different carcinomas.

Recent studies on anti-cancer drug therapy have demonstrated that lung cancer cells develop resistance to EGFR inhibitors by recruiting Met to activate HER3 and the PI3K-Akt cell survival pathway. Altogether, these results make evident the clinical impact of new molecular therapies for cancers where oncogenic Met is the primary cause or where it confers drug resistance.

As part of the ToK framework, we have established collaboration with the lab of Prof. J. L. Kraus to search for anti-Met activity drugs. We have identified a new chemical compound that selectively blocks Met activity and biological responses with the biological EC50 of 40 nM. Research achievements of the Transfer of knowledge (TOK) programme have also let us to uncover unique chemical and physical properties of effective synthetic Met inhibitors and developed a second generation of compounds aiming at further increasing Met inhibitory properties and bioavailability. Their therapeutic potential will be evaluated by performing pre-clinical trials using our engineered mouse model for Met-triggered cancer.

These transgenic mice are one major milestone of our TOK programme and represent a valuable in vivo system for anticancer drug development. One of their major features is that over-expression of Met can be controlled in a temporal and spatial regulated manner. Met-overexpressing cells will also express the Luciferase reporter gene to allow non-invasive monitoring of primary tumours and metastasis in vivo. These mice will be used to perform preclinical trials of new Met inhibitors in cancer and establish appropriated therapeutic protocols.

The TOK programme has also been instrumental to establish strong cohesions and interactions among scientists with complementary expertises, performed training of students and researchers involved in the programme and build a large European network to follow up at best the outcome of such research.

This programme offered at the TOK-financed researcher and at the coordinator the challenge to:
1) perform an ambitious research using a truly interdisciplinary approaches;
2) develop competences on drug screening and identification;
3) perform a more medical oriented research that will possibly contributes to the social objectives of improving life quality and human health.

Reported by

Parc Scientifique et Technologique de Luminy
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