Project: Development of drug for the chemoprevention and/or treatment of HDGC
Lyvianne Decourtye-Espiard PhD
We have proposed that the loss of E-cadherin due to pathogenic CDH1 mutations creates vulnerabilities in early-stage T1a gastric cancer cells that can be targeted with drugs. In this project, we have investigated these cells' vulnerability to histone deacetylases (HDACs) inhibitors, a class of enzymes with multiple roles in cancer development. HDAC inhibitors are the subject of strong research interest internationally, with over 97 clinical trials in numerous cancers currently recruiting worldwide.
Our earlier studies had identified HDAC inhibitors as potential chemoprevention compounds for hereditary diffuse gastric cancer (HDGC) . In this latest research funded by No Stomach For Cancer, we have extended that early work to a wider range of drugs in this class and validated their effect in an advanced pre-clinical model known as ‘organoids.’ Gastric organoids are 3D cell cultures derived from normal stomach tissue or stomach tumors and better recapitulate in vivo conditions than standard lab models (cell lines). We have used genetic engineering techniques to modify mouse stomach organoids to include a CDH1 mutation, thus generating a novel model of early-stage HDGC. We have now tested several HDAC inhibitors in this and other related models and identified two promising HDAC inhibitors for further development as HDGC chemoprevention drugs.
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