DEBRA Members Weekend 2017 Cancer in EB John Marshall Premium - PowerPoint PPT Presentation

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Cancer in EB John Marshall

Cancer in RDEB- Is our research getting us closer to a treatment? John F Marshall Barts Cancer Institute, London

15 years ago…….. We have a problem to solve for people with RDEB 1) The occurrence of Squamous Cell Carcinoma (SCC) in RDEB is more than 75-fold higher than people without RDEB 2) The SCCs are highly invasive and metastatic (can spread to other parts) whereas the SCCs in non-EB patients are not. 3) SCC is the most serious aspect of RDEB

15 years ago……..what did we know? Collagen 7 is absent/deficient Blistering at sites of trauma, bony joints Chronic inflammation and fibrosis Squamous cell carcinomas usually developed at bony joints

15 years ago……..what didn’t know? • Does Collagen 7 do anything other than anchor the skin cells? • Can we correct the absence of collagen 7 ? • If we correct the absence of collagen 7 does this fix the cell? • Is the chronic inflammation and fibrosis helping the cancers to grow? • Are the SCC in people with RDEB different to SCC in people without EB?

Cartoon of a typical squamous cell carcinoma in an RDEB patient (or non-EB Patient) Tumour cells Blood vessels Inflammatory and Collagen-rich immune cells fibrotic matrix Cancer Associated Lymphatic vessels Fibroblasts (CAFs)

How do you make a cancer cell from a normal cell? By multiple mutations occurring in important genes in our chromosomes These mutations help the cells to: • Survive and grow better Attract blood vessels • Hide from the immune system • • Trick nearby cells to help them • Become immortal

Are SCC cancer cells genetically different in people with RDEB as compared with those without RDEB ? Compared which genes are used in Non- RDEB Significant versus = EB SCC differences in SCC only 18 genes

Are SCC cancer cells genetically different in RDEB patients and non-RDEB patients? Not very different at all

Cartoon of a typical squamous cell carcinoma in an RDEB patient Tumour cells Blood vessels Inflammatory and Collagen-rich immune cells fibrotic matrix Cancer Associated Lymphatic vessels Fibroblasts (CAFs)

Are the genes used by fibroblasts different in people with RDEB versus those without RDEB? Examined the genes used in fibroblasts from • Human skin (non-EB) NHF • Human skin (RDEB patient) RDEBF • UV light induced SCC UVSCCF • RDEB SCC RDEBSCCF

Fibroblasts from RDEB SCC are completely different to normal fibroblasts and fibroblasts from other SCC. They used over 650 different genes when compared with the other fibroblasts.

How can we show if RDEB SCC fibroblasts promote tumour development? Inject SCC cells with different fibroblasts into mice. Normal (non-EB) Human Fibroblasts RDEB SCC Fibroblasts where Collagen 7 has been restored RDEB SCC Fibroblasts that have no collagen 7

Are the genes used by fibroblasts different in RDEB patients and non- RDEB patients? Yes!! The research shows that it is the fibroblasts in the microenvironment surrounding the cancer cells that may be responsible for the aggressive behaviour of RDEB SCC.

In other studies scientists looked at the proteins released from fibroblasts from people with RDEB and those without EB. A major finding was high levels of a molecule called: TGFβ (Transforming Growth Factor Beta)

Identical twins had different clinical appearances of the RDEB. One had a severe form and the other had a mild form.

Identical twins had different clinical appearances of the RDEB. One had a severe form and the other had a mild form. The mild case had fibroblasts that produced a protein, that stops TGF β working- called DECORIN Suggests that the more TGF β the more severe the disease

Collagen 7 seems directly responsible for regulating TGF β activity

Too much TGF β can cause fibrosis, cancer growth and spread Inactive-TGF β Activation Signal Active-TGF β Normal Cancer Associated fibroblast Fibroblast

Quick Summary • High levels of TGF β is strongly associated with severity of RDEB and with SCC in RDEB • Natural (DECORIN) blockade of TGF β can reduce the severity of RDEB • Can we identify drugs that can stop the effects of TGF β ?

Treated mice with RDEB with LOSARTAN, a drug that stops active TGF β . • Stopped fibrosis in paws • Stopped fusion of the digits • Reduced the levels of molecules that promote inflammation • Reduced inflammation

Too much TGF β can cause fibrosis, cancer growth and spread Inactive-TGF β Activation LOSARTAN Signal Active-TGF β X Normal Cancer Associated fibroblast Fibroblast

Too much TGF β can cause fibrosis, cancer growth and spread Inactive-TGF β Activation Signal Active-TGF β Normal Cancer Associated fibroblast Fibroblast

α v β 6 is on 86% of RDEB SCC tested

α v β 6 is upregulated significantly on RDEB healing wounds Wound edge Blister

Normal Carcinoma Levels of α v β 6 Oral in many cancers is high. Skin It is associated with poor survival It helps cancer Breast cells to grow directly and activates TGF β Lung

Targeting αvβ6 in breast cancer in vivo How ‘targeted’ therapy works Grow breast tumours in mice then treat with • Inactive antibody • Herceptin- stops HER2 • 264RAD- Stops α v β 6 • 264RAD+Herceptin

Too much TGF β can cause fibrosis, cancer growth and spread Inactive-TGF β 264RAD X Activation Signal Active-TGF β Normal Cancer Associated fibroblast Fibroblast

15 years ago……..what didn’t know? • Does Collagen 7 do anything other than anchor the skin cells? YES! YES! • Can we correct the absence of collagen 7? • If we correct the absence of collagen 7, can we restore normal YES! cell behaviour? • Is the chronic inflammation and fibrosis helping to promote the SCC? YES! • Are the SCC in RDEB patients different to SCC in non-EB patients? Yes! but it’s the cells surrounding the cancer cells that show the most differences

The future? Clinical trials with Losartan (stops activeTGF β ) are in progress Am in conversation with AstraZeneca-Medimmune to fund a trial to test 264RAD (stops activation of TGF β and stops cancer growth signals) Once confirmed as safe 264RAD will be available for testing in EB patients Novel combination therapies for collagen replacement, TGF β suppression and cancer therapy?

Acknowledgements Andrew South (USA) Edel O’Toole (London, UK) Leena Bruckner-Tudermann (Frieburg, Germany) Simon Barry (AstraZeneca-Medimmune) Kate Moore (Barts Cancer Institute) People with RDEB ALL OF YOU FOR YOUR ATTENTION

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