Partenaires et organisations internationales
(Anglais)
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Centro de Biologia Molecular 'Severo Ochoa' , Madrid (E), (CBMSO) Imperial Cancer Research Fund (ICRF) (UK), Centre the Biochimie-CNRS Laboratoire D'Etude Du Controle de Ia Division Cellulaire & Des Mecanismes, Nice (F)
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Résumé des résultats (Abstract)
(Anglais)
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The original project was stimulated by the observation that the immunosuppressant rapamycin is known to selectively block hematopoetic cytokine Interleukin-2 (IL-2)-stimulated T cell proliferation. As the target of rapamycin, mTOR, was known to have several downstream effectors, the prediction was that one might be able to identify a more specific target by unraveling the signaling pathway which couples phosphatidyl inositol 3-kinase (PI3K), mTOR, p70S6K (S6K) and the cell cycle. The main goals to be achieved were three-fold: 1) To elucidate connections between three intracellular signaling molecules in regulating cell cycle proliferation in T cells 2) to determine whether the inhibitory effects on cell growth of the immunosuppressant rapamycin are exerted through p70S6K (S6K) and 3) to develop in vitro assays to be used for both chemical screens and to validate the biological application of specific drugs. To accomplish these goals we united the effort of four laboratories: J. Moscat, CBM, Madrid; D. Cantrell, ICRF, London; J. Pouyssegur, CNRS, Nice and G. Thomas, FMI, Basel.. The EEC provided the resources for us to come together and to act on this timely question in Biological Medicine. The goals, as outlined, were largely accomplished, including :(1) the establishment of previously unknown connections in this signaling pathway, i.e. the link between atypical PKCs, mTOR and S6K, (2) a direct connection between S6K, and therefore mTOR, and progression in the cell cycle and (3) probably most importantly, that the effects of rapamycin could be extended to other human diseases such as cancer and restenosis. This provided preliminary data to be used to progress into Phase 1/2 clinical trails in Oncology (T cell lymphomas) and for the completion in transplantation, in kidney and more recently for ( cells. Finally, triggered by the latter results, we approached Novartis about employing a rapamycin analogue, RAD001, which has almost completed phase 3 clinical trials in the USA for transplantation therapy, as an anti-cancer agent. In brief, Novartis Oncology set-up a team of basic scientists and clinical oncologists to explore this possibility. They have been analyzing a number of tumor cell lines in vitro as well as in the animal. The preliminary results have been very encouraging. During the last month and until December, we have been transferring the technology for S6K and 4EBP1 (another downstream target of this pathway) assays into their hands, such that they will be conducting these assays in their own laboratories. If all goes well, this compound has the potential to move into Phase 1/2 clinical trials (as toxicology is complete) by next Spring.
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