Screening drugs to target RDEB cancer (2025)

Of 3,135 approved drugs tested, 165 were found to slow down the growth of RDEB skin cancer cells in the laboratory. The top 50 were tested more carefully at different doses. Some of these drugs could stop cancer cells from growing and some could kill cancer cells grown in the lab. The two most promising drugs will now be further investigated in pre-clinical studies.

Research Leader:

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).

“The potential of drug re-purposing of drugs already clinically approved for safe use in patients with established dose and scheduling regimens holds exciting potential for EB patients. Here we will undertake an unbiased drug re-purposing screen of over 3,000 FDA approved drugs… At the completion of these studies we will have identified and taken 2 drugs all the way through our pipeline which will provide compelling evidence for their rapid deployment in clinical trials in RDEB patients for treatment of the ultimately lethal cancer complication of this devastating disease.”

– Prof Gareth Inman

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.

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 are undertaking a drug re-purposing screen of over 3,000 drugs already approved for use in patients with other disease conditions. We are developing and refining 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.

(From 2024 progress report).

Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a rare inherited skin disorder caused by mutations in type VII collagen—a protein that helps hold the layers of skin together. Because of this genetic defect, people with RDEB have extremely fragile skin that blisters and wounds easily. Over time, the constant injury and inflammation put these patients at high risk of developing a particularly aggressive and often fatal form of skin cancer called cutaneous squamous cell carcinoma (cSCC). Unfortunately, there are currently no approved treatments or targeted therapies for this cancer, leaving a major unmet medical need.

This project set out to tackle that problem through three main goals: identifying existing drugs that might be effective against RDEB-associated cSCC, creating accurate models to test these treatments, and validating the most promising drugs in those models.

To begin, researchers screened 3,135 FDA-approved drugs on several RDEB cancer cell lines grown from patient tumours. Each drug was tested to see if it could slow or stop cancer cell growth. From this large screen, 163 drugs were found to reduce cell growth by at least 30%. These were narrowed down to 50 top candidates, which were then tested more carefully at different concentrations. Analysis showed that many of these active drugs targeted important biological pathways involved in cancer growth and survival.

In parallel, RNA sequencing to see which genes are expressed in RDEB tumour samples revealed that many of these same pathways were unusually active in patient tumours, confirming that the drug hits were biologically relevant. Some of these drugs could stop cancer cells from growing and some could kill cancer cells grown in the lab. These results are now being followed up with additional tests, including three-dimensional tissue models and colony formation assays, to select the two best drugs for further more detailed testing.

To enable more realistic and robust preclinical testing, the researchers developed models using cancer cells taken directly from RDEB patients. They explored whether adding cancer-associated fibroblasts—support cells found in the tumour environment—would help tumours grow, but this effect was only seen in lab dishes, not in the models. Ultimately, four patient-derived cell lines were found to grow reliably in models, forming tumours that closely resembled human RDEB cSCC. These models will now serve as the foundation for testing drug effectiveness in living systems.

The next stage of the project will involve selecting the two most promising drug candidates and testing them in these newly established models. The work so far has identified key molecular pathways driving RDEB skin cancer and several FDA-approved drugs that target them. Together, these advances bring researchers significantly closer to developing real, targeted treatment options for patients suffering from this devastating disease. (From final report 2025.)