Until recently, little research has taken place to understand the nature of SCCs in EB, i.e. why people with the condition have a so much higher risk of developing these cancers and why fatality is so much more common than in the population at large. Given the rarity of EB, there is little or no interest from commercially or publicly funded research programmes into cancers associated with the condition or in understanding their causes. DebRA, therefore, has concentrated its funding on projects that lead to a specific increase in the understanding of cancers in EB so that, as the state of knowledge about cancers in general increases, we will be able to more easily identify those elements that have a relevance to EB.


Research into cancer in EB is jointly funded by DEBRA Ireland and DebRA UK.

Current focus of work

The currently funded DebRA projects focus on three main objectives. These are:

1    The development of a mouse model that can be used as a platform in which different treatments can be used to induce cancers.

2    Understanding the physiology of squamous cell carcinomas (SCCs) in RDEB and, in particular, the high risk of metastasis

3    The collection of SCC tissue from RDEB patients as a resource for researchers.

CURRENT RESEARCH FUNDED

Programme grant:

Skin carcinogenesis and RDEB

Patients with recessive dystrophic EB (RDEB) experience disproportionate numbers of squamous cell carcinomas (SCC), which are the significant cause of death in this patient group. 53% of patients will have had at least one SCC by the age of 35 and American statistics indicate that death usually occurs within five years of the first SCC being diagnosed. Until recently, virtually no research had taken place to investigate this but DebRA has now funded a number of preliminary studies.

A programme grant led by Prof. Irene Leigh of the Centre for Cutaneous Research at Barts and Royal London Hospitals, in conjunction with colleagues at Guy’s and St. Thomas’ Hospitals and the Sanger Centre in Cambridge, started in April 2005.

The objectives of this programme are to:

·    Examine the differences between SCCs in patients with RDEB and SCCs experienced by the non-EB population (since the mortality in EB patients is much higher).
·    Examine the genetics of SCCs in REDEB
·    Develop a means of gene therapy for SCCs
·    Establish a research network of international researchers into skin cancers in EB, with annual workshops and an international conference.

The benefits of this programme are that it will establish whether gene therapy will have an effect on wound healing and tumour development. The coordinating centre also houses the Cancer Research UK Skin Tumour Laboratory so there are significant opportunities for collaboration with other specialist research groups.

The cost of this programme is approximately £950,000.

Project grants

Dr John Marshall & Prof. Ian Hart, Barts & The London Queen Mary’s School of Medicine & Dentistry

“Development of peptide antagonists to avß6 for the treatment of squamous cell carcinoma in recessive dystrophic epidermolysis bullosa. “
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“Inhibiting the invasive potential of Squamous cell carcinoma in recessive dystrophic EB by inhibiting the invasion-promoting activity of the integrin v6.”

“Generation and assessment of peptide and scFv antagonists to the integrin avb6 for the therapy of squamous cell carcinoma of the skin. “

“Creation of a murine model of squamous cell carcinoma in epidermolysis bullosa”

The most life-threatening aspect of Recessive Dystrophic Epidermolysis Bullosa (RDEB) is that patients develop skin cancer. Usually these types of skin cancer, called squamous carcinoma (SCC), are not life-threatening as they do not spread to other parts of the body. Sadly, the SCCs that develop in people with RDEB do spread to other areas. When a tumour invades beyond its initial site of growth and actually develops in distant tissues (a process called metastasis) this usually results in poorer chances of long-term survival for the patient. Thus preventing this initial invasion is a goal in anti-cancer medicine.

Thus to help RDEB patients we must either find a means to stop the cancers developing or stop the ones that do develop from spreading. These projects investigate the second option. Several years ago Dr Marshall’s laboratory discovered that SCC cancer cells invade the local tissues by means of a protein that appears on the surface of all the cancer cells. This protein, called alphav-beta6, does not appear on normal skin. They found in the laboratory that, if you stopped the alphav-beta6 on cancer cells from binding to the proteins in the local environment, this stopped their ability to invade.

In these studies we aim to

·    Make two types of alphav-beta6 blocking-drugs. Some progress has already been made in designing new drugs based on their knowledge of the proteins to which alphav-beta6 usually binds. These new drugs are based on small fragments of these proteins and are called peptides. The second type of drug is based on antibodies. Antibodies are large proteins in the blood that bind to, and therefore block the ability to function, of foreign bodies such as viruses and bacteria. The part of the antibody that recognises the “antigen” on the foreign body is only a tiny fragment at the tip of the antibody. Scientists have found methods to produce only this tip of the antibody and still retain the ability to recognise antigens. These mini-antibodies are called single-chain Fv (scFv). There are so-called “libraries” of scFv that contain hundreds of millions of different scFv, each one recognising a different antigen. Using laboratory tricks those scFv that can recognise and inhibit the function of alphav-beta6 will be identified. The scFv will then be turned back into whole antibodies for injection into RDEB patients in the hope that this will help stop the skin cancers spreading.

·    Develop a reliable animal model for testing anti-invasive therapies against SCC, using a technique where the resulting gene is genetically “cut out” in a specific area of the skin, and to characterise the specific biological characteristics of the cancers arising in this site of skin blistering. The researchers have developed such a model using human SCC cells derived from RDEB patients using 1) antibodies and peptides designed to block the ability of v6 to bind to the ECM (thereby inhibiting traction and thus movement) and 2) drugs which disturb the biochemical pathways required for v6 to promote invasion. By these techniques it is hoped to develop new strategies to limit the invasive potential of SCC in RDEB.

Dr Edel O’Toole, Barts & The London Queen Mary’s School of Medicine & Dentistry

Why does absent type VII collagen expression lead to aggressive squamous cell carcinoma in RDEB patients?

Inhibition of receptor tyrosine kinase signalling in RDEB squamous cell carcinoma.

In the first project SCC cells from RDEB patients are compared with SCC cells from non-RDEB patients and how they invade the collagen layers in skin is examined. Their levels of metalloproteinases (enzymes that break down collagen and are necessary for invasion) are compared.

In the second project, a specific receptor cell, called Axl, is investigated to see how it may promote or inhibit the movement of tumour cells.

The results of this work should increase our understanding of why people with RDEB develop SCC and, in the future, lead to the development of new therapeutic targets for the prevention of RDEB SSCs in patients.

Dr V-M Kähäri, University of Turku, Turku, Finland

Matrix metalloproteinases as prognostic markers and therapeutic targets in cutaneous squamous cell carcinoma in dystrophic EB.

SCC arises in keratinocytes, i.e. cells in the upper part of the skin. When keratinocytes become cancerous they invade through the lower layers of the skin to capillaries and lymph nodes. The group has noted that SCC cells specifically produce a substance called collagenase-13 (MMP-13), which is not found in normal keratinocytes. Dr Kähäri’s group has also shown that MMP-13 is responsible for the ability of SCC cells to invade through the lower layers of the skin and affect other body parts. They have found that by inhibiting the expression of MMP-13 by SCC cells in a mouse model, they can potentially inhibit SCC cell invasion and the growth of SCCs. Additionally, they have found that another substance produced in keratinocytes, matrix metalloproteinase-19 (MMP-19) is shut down when keratinocytes turn into cancer cells. It is believed that these two substances, MMP-13 and MMP-19, can be used both as diagnostic markers and as targets for treatment of SCCs in RDEB.

This project extends these observations in the following ways. Firstly, samples of SCCs from patients with RDEB will be tested to evaluate the diagnostic and prognostic value of MMP-13 and MMP-19 in comparison with other similar substances found in SCCs. Secondly, the role and activity of these MMPs in SCC will be examined in cell samples and in an animal model, using specially generated adenoviruses and, in particular, whether a newly developed substance can inhibit the invasive properties of the SCC. Lastly, the precise means whereby the SCC cells grow will be studied, using adenoviruses. These adenoviruses will first be tested in cells and in experimental animals and, hopefully, ultimately in humans.

Prof. Leena Bruckner-Tuderman, University of Freiburg, Germany

Skin Cancer and EB: Registry and Material Bank. 

DEBRA is funding a number of research projects to help understand the process whereby people with RDEB are so prone to SCCs. A supply of tissue removed from patients is needed by many of the groups undertaking this research, which can be difficult to obtain.

This project will establish a central database of where suitable tissue is stored and to set up a number of decentralised tissue storage facilities in several European countries. The first two years will be a pilot project to establish the protocols in a centre in Germany before rolling out to other countries.