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Dr Kenneth Ewan

Dr Kenneth Ewan

Research Associate

School of Biosciences

+44 (0)29 20879073
Sir Martin Evans Building, Museum Avenue, Cardiff, CF10 3AX

I am a cell biologist with interests in the Wnt pathway, drug discovery and 3D tissue organoids. The projects I am currently working on are: 1) Small molecule inhibitors of the WNT signalling pathway; 2)  3D tissue organoids 

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 Professor Trevor Dale in 2004.













2018-19: Journal Club for Masters Students  (BI4003): – Assessing the ability of Masters level students to understand and interpret research papers.

2007-2014: Lecturing - Animal Development Module (BI2350): One lecture on head mesenchyme and pharyngeal cleft development and one lecture on the development of the urogenital system.

Student Supervision

2018: Supervised a student from the Johannes Gutenberg University of Mainz for a project investigating the effect of Wnt pathway inhibitors on Axin1 and Axin1/Axin2 deficient liver-derived organoids.

2018: Co-supervised a Masters level Erasmus research student from the University of the Basque Region on the effect of porcupine inhibitors on the growth of liver-derived organoids. The student subsequently enrolled in a Ph.D program.

2011-2012: Direct supervision of a Masters level Erasmus research student for 3 months: Project was “Wnt inhibitors and intestinal crypt organoids”. The student subsequently enrolled in a Ph.D program.

2009: Direct supervision of undergraduate student for 3-month final year research project: Research title was “Interaction of Fus with b-catenin”. The student subsequently undertook a graduate-entry medicine degree.

2005: Direct supervision of two undergraduate students for 3-month final year research projects: Research titles were 1) “Wnt pathway inducers”, 2) “Intersection of Wnt and inositol signalling pathways”. One student subsequently completed a Ph.D degree.

Small Molecule 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 signalling. 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. A lead compound series from the cell-based screen was used in a full drug discovery project with Merck Serono and the Institute of Cancer Research as partners. Optimised variants of the compound were highly potent inhibitors against its molecular targets (CDK8/CDK19). Unfortunately, inhibiting CDK8/CDK19 had toxic effects that precluded moving to clinical studies. My role included determining the drug efficacy in reversing intestinal hyperplasia and inhibiting tumour xenograft growth in in vivo models, assaying drug efficacy in inhibiting growth of hyperplasic intestinal and tumour 3D organoids in culture, determining the drug effect on intestinal stem cells in vivo and assisting the development of a protein target identification strategy. Subsequently, I have been testing small molecule tankyraseinhibitors in collaboration with Merck in both tumour xenograft models and the Axin1 deficient mouse system liver.

Patient-derived breast cancer organoids to transform drug discovery screening assays

There is unmet need for 3D cell culture models that accurately predict the efficacy of novel breast cancer therapies. Evidence suggests that 3D tumour organoids are better at predicting efficacy than cell lines, since they replicate key aspects of tumours: genetic diversity, differentiation, multicellularity, drug penetration and signalling pathway interactions. For example, organoids derived from metastatic biopsies predict responses to tamoxifen that are subsequently observed in patients from whom the organoids were derived. Through a collaborative partnership with Cellesce, which currently markets colorectal tumour organoids, we are developing bioreactor culture of mammary tumour organoids on an industrial scale for drug screening. Tissue for 3D-culture were sourced both from 9 primary patient biopsies and 3 PDX models. Organoids were derived from tissue that was partially digested and triturated, then seeded in Matrigel for culture in defined medium, with an additional mouse cell depletion step for PDX tissue. For three organoid lines, bioreactor-expanded organoids were compared to equivalent manually-grown organoids. Whole exome sequencing showed that the driver gene mutation profile was unaltered. Expression of biomarkers at both the protein level and RNA level were largely similar as was the histology. Moreover, RNA-seq showed that global expression was similar at the RNA level. Additionally, bioreactor-derived organoids show similar responses to a panel of standard of care drugs to manually-grown organoids but with lower sample-to-sample variance. These data suggest that bulk-cultured organoids can transform in vitropre-clinical drug-screening and lead to improved, specifically-targeted treatments.

2018: Member of Organising Committee for Engineering and Biosciences Forum. This forum brought together researchers in the School of Biosciences and the School of Engineering for talks on collaborative projects and included a "speed-dating" networking session.

2016-18: Chair of Biosciences Research Staff Group Committee.The committee articulates issues that are raised by and associated with research staff. I also attended the Research Committee as the Research Staff representative.  In 2017 and 2018, I organised, with other members of the Research Staff Committee, a Research Day that had technique and Technology Hub related networking opportunities and career-related talks.

2015-18: Seed Corn grant assessor and assessment committee chair. This School of Biosciences funding initiative is for small project proposals by Research Staff. I was an assessor in 2015-16 and chaired the assessment committee in 2017-18.

2016: Participation in the European Cancer Stem Cell Research Institute Open Day: communication of research to the lay public.

2008-16: Member of Biosciences Research Staff Group Committee.

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