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

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Cancer in EB

John Marshall

Cancer in EB John Marshall

Cancer in RDEB- Is our research getting us closer to a treatment?

John F Marshall Barts Cancer Institute, London

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……..

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 Lymphatic vessels Blood vessels Collagen-rich fibrotic matrix Cancer Associated Fibroblasts (CAFs) Inflammatory and immune cells

How do you make a cancer cell from a normal cell?

• Survive and grow better
• Attract blood vessels
• Hide from the immune system
• Trick nearby cells to help them
• Become immortal

By multiple mutations occurring in important genes in our chromosomes These mutations help the cells to:

Are SCC cancer cells genetically different in people with RDEB as compared with those without RDEB ?

RDEB SCC Non- EB SCC

versus

=

Significant differences in

• nly 18 genes

Compared which genes are used in

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 Lymphatic vessels Blood vessels Collagen-rich fibrotic matrix Cancer Associated Fibroblasts (CAFs) Inflammatory and immune cells

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

• ther SCC.

They used over 650 different genes when compared with the

• ther 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 TGFβ working- called DECORIN Suggests that the more TGFβ the more severe the disease

Collagen 7 seems directly responsible for regulating TGFβ activity

Inactive-TGFβ

Active-TGFβ

Normal fibroblast Cancer Associated Fibroblast

Too much TGFβ can cause fibrosis, cancer growth and spread

Activation Signal

Quick Summary

• High levels of TGFβ is strongly associated with

severity of RDEB and with SCC in RDEB

• Natural (DECORIN) blockade of TGFβ can

reduce the severity of RDEB

• Can we identify drugs that can stop the

effects of TGFβ?

Treated mice with RDEB with LOSARTAN, a drug that stops active TGFβ.

• Stopped fibrosis in paws
• Stopped fusion of the digits
• Reduced the levels of molecules

that promote inflammation

• Reduced inflammation

Inactive-TGFβ

Active-TGFβ

Normal fibroblast Cancer Associated Fibroblast

Too much TGFβ can cause fibrosis, cancer growth and spread

Activation Signal

X

LOSARTAN

Inactive-TGFβ

Active-TGFβ

Normal fibroblast Cancer Associated Fibroblast

Too much TGFβ can cause fibrosis, cancer growth and spread

Activation Signal

αvβ6 is on 86% of RDEB SCC tested

αvβ6 is upregulated significantly on RDEB healing wounds Wound edge Blister

Oral Skin Breast Lung

Normal Carcinoma

Levels of αvβ6 in many cancers is high. It is associated with poor survival It helps cancer cells to grow directly and activates TGFβ

How ‘targeted’ therapy works

Targeting αvβ6 in breast cancer in vivo Grow breast tumours in mice then treat with

• Inactive antibody
• Herceptin- stops HER2
• 264RAD- Stops αvβ6
• 264RAD+Herceptin

Inactive-TGFβ

Active-TGFβ

Normal fibroblast Cancer Associated Fibroblast

Too much TGFβ can cause fibrosis, cancer growth and spread

Activation Signal

X

264RAD

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, can we restore normal

cell behaviour?

• Is the chronic inflammation and fibrosis helping to promote the

SCC?

• Are the SCC in RDEB patients different to SCC in non-EB

patients?

YES! YES! YES! Yes! but it’s the cells surrounding the cancer cells that show the most differences YES!

The future?

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

Premium sponsors:

DEBRA Members’ Weekend 2017

Cancer in EB

John Marshall