Dr Kenneth Ewan
Cell-based screening for inhibitors of the WNT signalling pathway
Oncogenic deregulation of the Wnt signalling pathway is a causal factor in the initiation of cancer in a diverse range of tissues including the colon, breast and liver. To identify small-molecule inhibitors of Wnt signaling as potential therapeutics, a diverse chemical library at the Cancer Research UK Centre for Cancer Therapeutics was screened using a transcription factor reporter cell line in which the activity of the pathway was induced at the level of Disheveled protein. A series of deconvolution studies was used to focus on three compound series that selectively killed cancer cell lines with constitutive Wnt signaling ( Cancer Res  70, 5963–73 ). Activities of the compounds included the ability to induce degradation of β-catenin that had been stabilized by a glycogen synthase kinase-3 (GSK-3) inhibitor. This initial screen illustrated a practical approach to identify small-molecule inhibitors of Wnt signaling which now is being used for a full scale drug discovery project in collaboration with Merck-Serono, the Institute of Cancer Research and Cancer Research Technology. My present work includes mouse PD biomarker and efficacy assays, cultured intestinal organoid growth and biomarker assays.
I obtained my BSc. from the University of Sydney, Sydney Australia in Genetics, Biochemistry and Microbiology in 1987 and my Ph.D from the Department of Physiology, University of Western Australia in 1995 on the topic of somitic cell migration. Following short research positions at the University of Sydney and at the Max Planck Institute of Biophysical Chemistry in Germany, I commenced a postdoc with Dr. Barcellos-Hoff at the Lawrence Berkeley National Laboratory, California, USA in 1999. Here, I worked on the role of TGF-β1 in the mammary gland finding that a) ovarian hormones estrogen and progesterone induce activation of TGF-β1 in the ER/PR positive cells of the mammary gland resulting in inhibition of their proliferation and b) TGF-β1beta1 mediates the cellular response to ionising radiation induced DNA damage via the activation of p53.
I joined Cardiff University in the laboratory of Prof. Trevor Dale in 2004.