• Traitements

  • Traitements systémiques : découverte et développement

  • Colon-rectum

ML264 - a novel small-molecule compound that potently inhibits growth of colorectal cancer

Menée in vitro et in vivo sur des modèles de cancer colorectal, cette étude met en évidence des mécanismes par lesquels, en inhibant l'expression de KLF5 et EGR1, un composé appelé ML264 exerce une activité antitumorale

Colorectal cancer (CRC) is one of the leading causes of cancer mortality in Western civilization. Studies have shown that CRC arises as a consequence of the modification of genes that regulate important cellular functions. Deregulation of the WNT and RAS/MAPK/PI3K signaling pathways has been shown to be important in the early stages of CRC development and progression. Krüppel-like factor 5 (KLF5) is a transcription factor that is highly expressed in the proliferating intestinal crypt epithelial cells. Previously, we showed that KLF5 is a mediator of RAS/MAPK and WNT signaling pathways under homeostatic conditions and that it promotes their tumorigenic functions during the development and progression of intestinal adenomas. Recently, using an ultrahigh-throughput screening (uHTS) approach we identified a number of novel small molecules that have the potential to provide therapeutic benefits for colorectal cancer by targeting KLF5 expression. In the current study, we show that an improved analog of one of these screening hits, ML264, potently inhibits proliferation of CRC cells in vitro through modifications of the cell cycle profile. Moreover, in an established xenograft mouse model of colon cancer, we demonstrate that ML264 efficiently inhibits growth of the tumor within five days of treatment. We show that this effect is caused by a significant reduction in proliferation and that ML264 potently inhibits the expression of KLF5 and EGR1, a transcriptional activator of KLF5. These findings demonstrate that ML264, or an analog may hold a promise as a novel therapeutic agent to curb the development and progression of colorectal cancer.

http://mct.aacrjournals.org/content/early/2015/11/26/1535-7163.MCT-15-0600.abstract

Voir le bulletin