This partnership with Cancer Research UK Scotland Institute will drive the creation of new models of RDEB cancer that can be used to understand how cancer occurs and progresses and to test future therapies. 

 

 

Prof Gareth Inman works at CRUK Scotland Institute, UK, on this partnership to create new models of RDEB cancer. New treatments cannot be trialled on people until good evidence exists that they will be safe and effective. The pre-clinical models this partnership proposes to create are vital for this step in the process of moving towards new therapies for RDEB cancer.

 

 

 

Contents:

• Project summary (top of page)
• About our funding
• Latest progress summary
• About our researchers
• Why this research is important
• Researcher’s abstract
• Researcher’s progress update

 

About our funding:

 

Research leader	Prof Gareth Inman
Institution	Cancer Research UK (CRUK) Scotland Institute (formerly CRUK Beatson)
Type of EB	RDEB
Patient involvement	No
Funding amount	Joint funded by DEBRA UK and CRUK Scotland Institute
Project length	5 years
Start date	April 2024
DEBRA internal ID	GR000051

 

Latest progress summary:

Due 2025.

 

About our researchers:

Lead researcher: Prof Gareth Inman is Director of Research Strategy at the Cancer Research UK (CRUK) Scotland Institute. His studies are focused on squamous cell carcinomas of the skin, including in patients living with Recessive Dystrophic Epidermolysis Bullosa.

Co-researcher: Prof Karen Blyth, CRUK Scotland Institute; 

Collaborators:

Prof Owen Sansom, CRUK Scotland Institute. 

Prof Crispin Miller, CRUK Scotland Institute.

Dr Andrew South, Thomas Jefferson University, Philadelphia.

Prof Irene Leigh, Queen Mary’s University, London, UK.

Dr Alexander Nyström, University of Freiberg, Germany.

 

Why this research is important:

Importantly we will develop pre-clinical models which are vital for the rigorous pre-clinical testing of therapeutic agents prior to their trialling in a desperate patient population... we will make these models available to the wider research community to enable much needed progress in RDEB research.

Prof Inman

 
Researcher’s abstract:

Grant title: Pre-clinical models 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.

There is an inadequate understanding of the mutational genetic events that drive tumour formation and how tumour cells interact with the C7 depleted skin. Consequently, there are no approved targeted therapies for treatment of this devastating disease. This unacceptable reality is due in part to the paucity of RDEB cSCC experimental models that faithfully recapitulate the tumour genetics and the tumour microenvironment interactions. Here we will bridge this gap by endeavouring to develop and molecularly characterise state of the art genetically engineered and novel syngeneic reproducible and transplantable models of RDEB cSCC that accurately reflect the tumour and host genetics. We will define the role of C7 loss in tumorigenesis and we will interrogate the molecular landscape of tumours and gain a deeper insight into the pathogenesis of RDEB cSCC. These models will provide invaluable platforms for understanding RDEB cSCC disease progression and critical robust systems in which to test drugs that target the driving processes prior to future patient clinical trials.

RDEB patients frequently develop early onset multiple aggressive skin tumours (cSCC). A detailed understanding of RDEB cSCC remains elusive and there are no effective treatments or approved targeted therapies. Furthermore, there are a limited number of pre-clinical models available to understand the biological events that lead to RDEB cSCC development and progression, all of which currently suffer from caveats of cSCC disease relevance, practicality of use and amenability to pre-clinical drug testing for urgently needed therapeutics for this devastating and ultimately lethal complication of RDEB. Here we will develop complimentary autochthonous genetically engineered and easily tractable syngeneic models of RDEB cSCC based on the underpinning genetic events of this cancer. We will shed new light on the pathogenesis of disease potentially identifying new targets for therapeutic intervention. We will determine the relative importance of loss of C7 expression from tumour cells and the epidermal keratinocyte and dermal fibroblast compartments in the skin critical for the appropriate targeting of future C7 therapeutic replacement strategies. Importantly we will develop pre-clinical models which are vital for the rigorous pre-clinical testing of therapeutic agents prior to their trialling in a desperate patient population.

The models we will develop here will be amenable for not only testing of emerging biological hypotheses but also for precision prevention drug intervention studies, drug treatment studies and for design of drug treatment scheduling and toxicity studies, maximising the likelihood of safe and effective clinical trials and the implementation of urgently needed new therapeutic strategies.

 

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Researcher’s progress update:

Due 2025.