MRC DiMeN Doctoral Training Partnership: Exploring the anti-fibrotic activity and underlying molecular mechanisms of targeted compounds in patient derived models of Dupuytren’ disease and cancer

Fibrosis is characterised by an excessive accumulation of collagen within tissues, which impedes tissue function. Organ fibroses have limited treatment options, create a clinical burden and are life-limiting diseases¹. Cancer-associated fibrosis impacts cancer growth and progression², whilst creating a barrier to chemotherapeutics and immunotherapies. Cancer treatments such as radiotherapy and chemotherapy can further exacerbate fibrosis³.

The aim of this PhD project is to test the extent to which anti-fibrotics can reduce synthesis of collagen in Dupuytren’s disease and cancer. For this iCASE project, you will collaborate with a biotechnology company, RedEx Pharma, alongside research and study at the University of Liverpool.

Your university supervisors will be Dr Elizabeth Laird and Prof Daniel Palmer.

Dr Laird is an expert in collagen biology^4-6, is Lead for Research in the Institute of Life Course and Medical Sciences and Directs the Extracellular Matrix Ageing Network ‘ECMage’⁷. She has supervised 12 PhD students to completion (9 as primary supervisor).

https://www.liverpool.ac.uk/life-course-and-medical-sciences/staff/elizabeth-laird/

https://uk.linkedin.com/in/elizabeth-laird-31258518

X: @LairdLiz

Prof Palmer is a clinical academic in medical oncology. His research involves basic laboratory science, translational research and clinical trials^8-10. He has extensive PhD supervision experience of both clinical and non-clinical studentships. He directs the Cancer Research UK Liverpool Experimental Cancer Medicine Centre and has a track record in laboratory science and clinical trials.

https://www.liverpool.ac.uk/people/daniel-palmer

https://www.clatterbridgecc.nhs.uk/patients-and-visitors/consultants/daniel-palmer

The industrial supervisor will be Dr Elaine Kilgour, Head of Translational Science at Redx Pharma. Dr Kilgour has over 20 years’ experience in the pharmaceutical industry spanning all phases of drug discovery and development and was team leader at the Cancer Research UK Manchester Cancer Biomarker Centre. She has experience as co-supervisor and advisor for several PhD students and clinical fellows including industrial placement students.

https://uk.linkedin.com/in/elainekilgour

RedEx develops medicines for fibrotic disease, cancer and cancer-associated fibrosis. It has state of the art labs within a large science park, and a small-molecule pipeline including ROCK2, pan-ROCK, Porcupine, Wnt and Discoidin Domain Receptor inhibitors. The inhibitors are anti-fibrotic in preclinical models and Redx has clinic ready or near clinic ready molecules across these targets. The effects of these inhibitors on collagen synthesis and downstream signalling will be tested in human 3D culture and tissue explant. The project will also follow-up on a lead identified by our prior screening of 10 cytokine/pathway inhibitors in Dupuytren’s fibrosis.

At the University of Liverpool, you will be trained in use of our Dupuytren patient derived 3D culture system which comprises fibroblast-derived collagen in a tensioned 3D environment, and use of and legal and ethical considerations for human tissue explant models. Assays will include qPCR, Western blotting and established protein labelling approaches. Cancer organoids and fibroblast/cancer cell co-cultures will be tested in parallel and with radiation treatment to evaluate how the inhibitors affect collagen production.

During the placement at Redx you will follow an in-house drug discovery training workshop, an on-line modular programme covering cross-disciplinary aspects of drug discovery and development from target identification to early clinical trials, and work alongside Redx laboratory scientists to investigate the anti-fibrotic mechanism of action of compounds.

iCASE industrial partner web link: https://www.redxpharma.com/

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of-the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, training opportunities or internships in science policy, science communication and beyond. Further information on the programme and how to apply can be found on our website:

https://www.dimen.org.uk/