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Agnès Desroches-Castan

Inhibition of tumor angiogenesis: Screening of a chemical library and characterization of a new compound that targets the Ras-ERK signaling pathway

Published on 3 October 2014


Thesis presented October 03, 2014

Abstract :
Several anti-tumoral therapies targeting angiogenesis have been developed over the recent years and have demonstrated benefits for several metastatic cancers. However, in many cases, resistances to these treatments appear over time, allowing tumor escape. The development of new anti-angiogenic compounds is thus dramatically urged in order to propose second-line anti-angiogenic treatments. In this work, our aim was to identify new anti-angiogenic compounds through high throughput screening of the academic library from the University of Grenoble. We adapted the endothelial cell scratch assay to 96-well plates. We identified a family of molecules that specifically inhibited endothelial cell migration. The anti-angiogenic activity of the leader molecule (COB223) was confirmed in vitro in 3D cellular models of angiogenesis and in vivo using a mouse model of subcutaneous sponge implantation. We tested the anti-tumoral activity of COB223 on a mouse xenograft model. We observed that tumor growth was significantly reduced in treated mice correlated with decreased micro vessel​ density. In search for its mechanism of action, we observed that COB223 inhibits cell proliferation and reduces VEGF-A-induced phosphorylation of MEK and ERK1/2 in endothelial cells. We also showed that COB223 did not affect VEGFR2 and PLCγ phosphorylation but reduces Raf phosphorylation responsible for its activity. These results allow us to propose that the molecular site of action of COB223 is located in the VEGF/ PLCγ /PKC/ERK pathway, between PKC and MEK.


Keywords:
Angiogenesis, high throughput screening, VEGF receptor, ERK pathway, anti-angiogenic therapy, endothelial cell

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