PhD - Pauline Gilson
Dernière mise à jour : 12 sept. 2018
Pauline Gilson defended her PhD ! Congratulations !
CHARACTERIZATION OF NEW MICROTUBULE-TARGETING AGENTS WITH A PYRROLO-PYRIMIDINE STRUCTURE FOR THE TREATMENT OF CANCERS
Despite the emergence of targeted therapies and immunotherapy, chemotherapy remains a gold-standard for the treatment of numerous malignancies. Spindle poisons that interfere with microtubule dynamics (taxanes, vinca alkaloids) are commonly used in chemotherapy drug combinations. However, their troublesome side effects and the emergence of resistance highlight the need for identifying alternative agents. Thanks to a high throughput cell-based assay, we screened agents able to restore apoptosis in apoptosis-resistant lung cancer cells. We selected 15 molecules belonging to the pyrrolopyrimidine family and investigated their anti-cancer effects in vitro and in vivo. Our aim was to identify a potential drug-candidate for the treatment of resistant cancers.
From cytotoxicity and apoptosis preliminary assays, we selected the 2 most promising molecules (PP-2, PP-13) among the 15 pyrrolopyrimidine compounds. PP-2 and PP-13 exert cytotoxic effects on a large panel of human cancer cell lines, including targeted therapy-resistant cell lines. By interfering with mitotic spindle organization and microtubule dynamics, PP-2 and PP-13 impair the congression of the chromosomes, promote spindle assembly checkpoint-dependent mitotic blockade and finally lead to asymmetric division, mitotic slippage and direct apoptotic death. PP-2 and PP-13 directly target tubulin and compete with colchicine for the binding to tubulin. Unlike conventional antimitotic agents, PP-2 and PP-13 are not sensitive to chemoresistance mechanisms involving the overexpression of efflux pumps. Moreover, at IC50, these two compounds do not affect the microtubule network during interphase suggesting a less toxic (mainly neurotoxic) effect. Among these two compounds, the PP-13 molecule appears to be the most interesting anti-cancer molecule because of its IC50 10-fold lower than PP-2 and its 2-fold higher affinity for tubulin. In vivo, PP-13 significantly reduces tumor and metastasis growth. All these results suggest that PP-13 might be a potential alternative for the treatment of many cancers including chemoresistant cancers