Making the RARE voice heard
In Summer 2017 we published 'Let's Work Together' an article by Dr. Neil Rajan highlighting the need for research in CYLD cutaneous syndrome (CCS) and his success in being granted a clinical trial. In this follow up we hear from Dr Rajan what the results mean for the CSS community.
History of CSS Research
Around 1985, people affected by a rare skin disease in Newcastle, joined forces with Prof Sir John Burn to push for research on inherited cylindromas, now called CYLD cutaneous syndrome (CCS).
Half of people with CCS have at least one painful skin tumour and up to a quarter undergo complete scalp removal.
These patients wanted research to improve this outcome, and wanted alternative treatments to surgery. The first steps to this was establishing what was different in the DNA of these patients and their tumours and in 1995 in a partnership led by Professor Burn with collaborators at the Sanger Institute, a difference was found. This gene locus was called CYLD. In 2000 CYLD was cloned, and in 2003 Prof Alan Ashworth published one of three papers in the journal Nature highlighting CYLD’s function.
It has been a great privilege to work alongside Professor Ashworth and Professor Chris Lord, and in 2011 we highlighted a dependency on an enzyme called TRK in cylindroma cells. This enzyme, when blocked in cylindroma cells in the lab, would kill them off. But would it work in patients? The next seven years involved delivering a clinical trial to Newcastle patients that used a drug that would block this very enzyme.
This month we reported on this, the first ever targeted, randomized, placebo-controlled clinical trial for CCS called “TRAC”. In this study, we tested an ointment that blocked TRK in cylindroma skin tumours. Partnering with a company who had already made this ointment and found it was safe to use in patients with other skin conditions like psoriasis, we used the highest strength with human safety data available in the TRAC study. Although we showed this was safe for the study period, this ointment doesn’t appear to be strong enough. We now we need to see if stronger strengths of the ointment can have an effect, in dose escalation studies.
For more information on this report read here
We are not there yet, but have learnt a lot about CCS. The TRAC trial has allowed us to study the natural history of this poorly understood rare disease, teaching us about the rate of growth cylindroma tumours. We have learnt about the impact of this disease on patient quality of life, and have developed clinical trial tools to measure symptoms such as pain, which interestingly, improved in some tumours in the TRAC study.
Importantly we have developed a roadmap for future trials, and this is relevant at a time when newer drugs that block TRK are being developed.
Lessons learned: Perseverance, patience, and patient partnership are crucial to take steps forward for rare disease and to keep going.
Figure 1. By studying multiple tumours in each patient with CCS, we were able to design a placebo-controlled statistically powered clinical trial – an uncommon feat in rare disease. Also, at the end of the study, we biopsied selected skin tumours, allowing us to study the effect of the drug and its penetration into tumour tissue. (Image by Marina Danilenko)
Rare Revolution Editor