Translational advances in CYLD cutaneous syndrome (CCS)
Novel clinical trial and associated experimental study demonstrate feasibility in the topical treatment of CCS.
Patients with the inherited condition (CYLD cutaneous syndrome – CCS) develop multiple, painful, hair follicle tumours on the head and body over the course of their entire life. Transmitted genetically from generation to generation, the prognosis is poor, with up to 1 in 4 CCS patients requiring complete surgical removal of the scalp, associated with significant disfigurement and profound psychological impact. Skin tumours can become cancerous, with malignant cylindrocarcinoma invading the skull, tumours metastasising to the lung, as well as to bone and liver resulting in death. There are no effective medical therapies to treat this rare condition, whose genetic basis was originally discovered in Newcastle families.
To improve patients’ outcome, we studied Newcastle CCS patient tumours using genetic technologies, that led to the discovery of an attractive molecular target in these skin tumour cells, named tropomyosin receptor kinase (TRK). The research agenda behind this work was set in partnership with CCS patients. It aimed to develop a pre-emptive treatment that patients can apply at home at the first signs of tumour development, allowing them to regain control over a progressive disease that has affected generations of their families. We successfully partnered with a biotechnology company (Creabilis SA) that had produced an ointment containing a TRK inhibitor, designed for topical delivery.
Together, we obtained funding from the Health Innovation Challenge Funding (Wellcome/DOH) and developed a novel clinical trial and associated experimental medicine study (“TRAC” study) in partnership with CCS patients and trial investigators. By leveraging the multiplicity of tumours, we developed a novel trial design in CCS that was statistically powered, which is exceptional in rare disease trials.
The trial demonstrated safety and feasibility of topical TRK inhibition in CCS, and established a road-map for future dose escalation studies. Importantly, it demonstrated that pain was reduced in a subset of painful tumours, and confirmed drug penetration into CCS skin tumours. Our group is currently involved in further partnerships with companies and medicinal chemists that are developing candidate molecules that could be trialled in CCS patients to determine efficacy, based on the methodology employed in the TRAC study. In parallel, ongoing basic science studies continue to refine mechanistic understanding of CCS tumour formation, with insights gained having relevance to both CCS and common skin cancers.
Rajan N, Elliott R, Clewes O, et al. Dysregulated TRK signalling is a therapeutic target in CYLD defective tumours. Oncogene. 2011;30(41):4243-4260. doi:10.1038/onc.2011.133
Danilenko M, Stamp E, Stocken DD, et al. Targeting Tropomyosin Receptor Kinase in Cutaneous CYLD Defective Tumors With Pegcantratinib: The TRAC Randomized Clinical Trial. JAMA Dermatol. 2018;154(8):913-921. doi:10.1001/jamadermatol.2018.1610
Davies HR, Hodgson K, Schwalbe E, et al. Epigenetic modifiers DNMT3A and BCOR are recurrently mutated in CYLD cutaneous syndrome. Nat Commun. 2019;10(1):4717. doi:10.1038/s41467-019-12746-w