Screening drugs to target RDEB cancer

• Primary Researcher: Prof Gareth Inman
• Institution: Cancer Research UK Beatson Institute, University of Glasgow, Scotland, UK
• Type of EB: RDEB
• Funding amount: £96,892 co-funded with DEBRA UK
• Project length: 18 months

Due in 2024

Prof Gareth Inman is the Director of Research Strategy at The CRUK Beatson Institute for Cancer Research and Professor of Cell Signalling in the Institute of Cancer Sciences, University of Glasgow, Scotland. His primary interests are to understand the role that members of the Transforming Growth Factor Beta (TGFβ) family play in cancer development and progression. His studies are focused on squamous cell carcinomas of the skin, head and neck and pancreas and now involve these cancers arising in patients living with Recessive Dystrophic Epidermolysis Bullosa.

Co-researcher

Prof Karen Blyth, senior staff scientist at CRUK Beatson Institute.

Collaborators

Prof Owen Sansom, Prof Crispin Miller, Dr Leo Carlin, Dr Lynn McGarry (all at CRUK Beatson Institute); Dr Andrew South (Thomas Jefferson University, Philadelphia) and Prof Irene Leigh (Queen Mary’s University, London, UK).

Grant Title: Drug repurposing for the treatment of RDEB squamous cell carcinoma

Recessive Dystrophic Epidermis Bullosa (RDEB) is caused by inherited mutations in the COL7A1 gene that encodes type VII collagen (C7), the principal component of anchoring fibrils that are required for the structural integrity of the epidermal-junction in the skin. RDEB patients suffer from severe skin fragility, persistent skin blistering and wounding and have an exceptionally high risk of developing early-onset, aggressive and ultimately lethal cutaneous squamous cell carcinoma (cSCC). RDEB cSCC develops in a permissive environment of chronic inflammation, wound healing and fibrosis facilitated in part by cancer associated fibroblasts (CAFs). There is currently an incomplete understanding of the pathogenesis of RDEB cSCC and no currently clinically approved targeted treatment therapies.

Here we will undertake a drug re-purposing screen of over 3,000 drugs already approved for use in patients with other disease conditions. We will develop and refine a stringent step-wise pre-clinical pipeline designed to assess the efficacy of drugs for inhibiting RDEB cSCC tumour cell survival both in-vitro and in-vivo; important indicators of therapeutic use. We will reveal the importance of CAFs in tumourigenesis and drug response and we will identify 2 drugs which show efficacy all the way through our pipeline.

This process will circumvent the prohibitively time consuming and costly process of drug development and safety testing and will provide compelling evidence for the rapid and safe deployment of these 2 drugs in patients in clinical trials for RDEB cSCC therapy.

Due in 2024