RDEB skin cancer

A high proportion of patients with RDEB develop a skin cancer called cutaneous squamous cell carcinoma, which is often fatal. This research aims to increase understanding of the behaviour of a particular molecule and identify new opportunities for future drug development to treat skin cancer.

Prof Gareth Inman works at the University of Glasgow, UK, on skin cancer in RDEB. A substance called transforming growth factor beta (TGF-β) is found at higher levels in the skin of RDEB patients with skin cancer. Deactivating TGF-β can stop cancer cell growth in some samples but increase it in others. Before therapies that inactivate TGF-β can be developed, this project will help to understand more clearly how it is involved in the growth and movement of cancer cells.

About our funding:

Research leader	Prof Gareth Inman
Institution	Cancer Research UK Beatson Institute, University of Glasgow, Scotland, UK
Type of EB	RDEB
Patient involvement	None
Funding amount	£157,138
Project length	2 years (extended due to Covid)
Start date	January 2019
DEBRA internal ID	Inman1

Latest progress summary:

The researchers have cells from eleven RDEB cancers growing in their laboratory and have tested how they respond to different treatments. They have identified six genes that encourage RDEB cancer cells to multiply that may be good targets for therapies.

The researchers published their latest findings in 2021.

About our researchers:

Lead researcher: 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. By understanding TGFβ’s role as both a cancer promoter and a cancer inhibitor Professor Inman hopes to develop strategies for future cancer therapeutics.

Collaborators: Dr Peter Bailey, Dr Karen Blyth (Glasgow, Scotland, UK) and Dr Andrew South (Thomas Jefferson University, Philadelphia, US).

Why this research is important:

RDEB patients will ultimately benefit from this research, not only in the context of cancer but also the proposal will potentially inform on how TGFβ signalling contributes to the gradual deterioration of overall dermal architecture. TGFβ therapies are in clinical trial and this proposal will determine when they will have clinical utility for RDEB patients. SCC arising in other forms of EB may also benefit from these studies.

Prof Gareth Inman

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Researcher’s abstract:

Grant Title: Mechanisms of TGF-beta mediated tumour promotion in RDEB cSCC.

Recessive Dystrophic epidermolysis bullosa (RDEB) is an inherited disorder associated with chronic blistering, wounding and excessive scarring of the skin. A high proportion of RDEB patients develop a skin cancer called cutaneous squamous cell carcinoma (cSCC), which is often fatal. Cells within the body rely on specific signals for survival and growth. In cancer these signals are either lost or can be elevated to assist tumour growth and spread.

This research group and others have recently shown that a specific signalling system, involving a molecule called Transforming Growth Factor- beta (TGF-β), is elevated in the skin of people with RDEB related cSCC. Importantly this group has found that blocking active TGF-β signalling can inhibit (stop) cancer cell growth in 50% of RDEB samples tested. Interestingly, blocking the signalling pathway can also promote cancer cell growth in selected RDEB cSCC samples.

These observations indicate that it is critical to understand when and how TGF-β functions to promote or suppress cancer growth in RDEB to enable identification of patients that will benefit from inhibiting this signaling pathway. In this project the group plan to investigate how TGF-β promotes cancer growth and to achieve this, the group aims to develop biomarkers of TGFβ signalling using in vitro and in vivo state of the art biological assays, (procedures used to analyse the behaviour and activity of molecules).

Objective 1. To understand the molecular characteristics (biomarkers) of how TGFβ behaves in RDEB skin cancer that will inform the use of an anti - TGFβ signalling therapy.

Objective 2. Understand the mechanism of how TGFβ signalling can lead to cancer migration, invasion and tumour growth and identify targets for therapeutics (e.g. a protein or molecule that can be modified using a drug or treatment to target cancer cells).

This research will provide the basis for further understanding of TGFβ signalling in RDEB and could identify new targets for future drug development to treat squamous cancers. These therapies are in clinical trials in other cancers or are in pre-clinical development already. The study will also inform on avenues of novel therapeutic development.

Previous DEBRA-funded research into TGF-β signalling in RDEB cSCC by Professor Gareth Inman contributed to this new research.

Researcher’s progress update:

Transforming growth factor-beta (TGFβ) is a molecule that drives a signalling system that controls a range of processes important for normal functioning of cells. TGFβ signalling is involved in cancer initiation, development and progression but can also suppress tumour growth and development in a context dependant manner. RDEB patients that suffer from a severe skin blistering condition develop skin tumours that progress fast and are difficult to treat which results in the death of nearly 90% patients by the age of 55.

We and others have found that RDEB cancer patients have increased levels of TGFβ in their skin and tumours. It is not clear if TGFβ is causing tumours to grow or not in cancers arising in RDEB patients.

Using cells extracted from RDEB cancer patients, we have shown that drugs that suppress TGFβ signalling could benefit a subset of RDEB skin cancer patients where TGFβ is causing tumour cell growth. In a small number of RDEB patients TGFβ is potentially acting to stop tumour cell growth, therefore, using drugs to block TGFβ signalling in these patients may be detrimental.

We are now investigating ways to identify which patients would benefit from therapies that target TGFβ signalling and are investigating how TGFβ signalling promotes cancer growth to enable us to identify new therapeutic strategies. (From 2020 progress report.)