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The real jigsaw puzzle of the Brooke-Spiegler Syndrome: Translating the molecular biology to therapy

DII small banner By Warren R. Heymann, MD
Oct. 22, 2018

Residents jump for joy when they see the characteristic “jigsaw puzzle” appearance of cylindromas under the microscope. Histopathology, however, takes us only so far. The future lies in elucidating the molecular pathways of these tumors that lead to therapy. Who could have imagined that the smoothened inhibitor vismodegib could shrink basal cell carcinomas, or that inhibition of the mTOR pathway by sirolumus could diminish the burden of angiofibromas in tuberous sclerosis patients? The potential for medical therapy to obviate surgical approaches for cutaneous tumors is no longer science fiction.

The Brooke-Spiegler syndrome [BSS, also known as the CYLD cutaneous syndrome, CCS], an autosomal dominant disorder, is characterized by the presence of cylindromas, trichoepitheliomas, and occasionally spiradenomas, predominantly on the head and neck, beginning of the second decade of life. The coalescence of scalp cylindromas has been labeled as “turban” tumors. Mutations for BSS reside in the CYLD gene located on chromosome 16. Benign, sporadic dermal cylindromas express MYB-NFIB gene fusion. (1)

CYLD, a gene that encodes a ubiquitin-specific protease, functions as a tumor suppressor gene, having crucial functions in the negative regulation of the NFkB signaling pathway. Interestingly, although there has been a long-standing debate about the origin of cylindromas (are they eccrine, apocrine, or hair-derived?), the multipotency of stem cells in the hair follicle is their likely origin. Cylindromas express hair keratins and the hair stem cell marker CD200 that are not expressed in eccrine glands. (2)

Tropomysin receptor kinase (TRK) was discovered as a candidate target following a search for targetable kinases in inherited CYLD defective tumors. An overexpression of TRK was selectively observed in tumor cells. Although the mechanism by which loss of functional CYLD results in perturbation of TRK homeostasis is not completely understood, it appears to increase tumor cells’ resistance to apoptosis. TRK has been recognized as an oncogenic kinase overexpressed in several malignancies, including breast cancer and leukemia. (3) TRK inhibitors were initially developed for inflammatory disorders such as psoriasis and atopic dermatitis. Pegcantratinib is the first topically applied TRK inhibitor. Unlike oral TRK inhibitors, a mini-PEGylated K252a derivative allows for pharmacologic optimization for topical application. (4)

Danilenko et al questioned if targeting TRK with pegcantratinib, 0.5% will reduce cutaneous cylindroma tumor volume more than placebo in patients with CCS. They performed a phase 2 clinical trial that included 150 tumors from 15 patients with CCS. Pegcantratinib-treated tumors did not achieve the primary outcome of response (tumor volume reduction of 30%) – 2 tumors treated with pegcantratinib achieved the primary outcome measure of response compared with 6 tumors treated with placebo. Molecular analyses of biopsy material demonstrated drug penetration; however, drug concentrations achieved were inadequate to abrogate tropomyosin receptor kinase signaling in CYLD cutaneous syndrome tumors. Despite this, they found that pain reduction was observed in some tumors (presumably spiradenomas) in 3 patients, suggesting that TRK inhibition may target nocioceptive pain fibers in these lesions. (5) Perhaps it will find utility in other painful dermal tumors such as leiomyomas, angiolipomas, neuromas, glomus tumors, etc.

CCS is a devastating disorder for those with significant disease. Although pegcantratinib, 0.5% is not the answer, the process by which this agent was developed is awe-inspiring. Further insights of the molecular biology of these tumors will lead to development of novel topical agents that will solve this jigsaw puzzle.

Point to remember: Molecular analysis is shedding new light into our understanding of adnexal tumors that will lead to novel nonsurgical therapies for these lesions.

1. Jordão C, et al. Cylindroma: An update. Int J Dermatol 2015; 54: 275-8.
2. Rajan N, Ashworth A. Inherited cylindromas: Lessons from a rare tumor. Lancet Oncol 2015; 16: e460-9.
3. Cranston A, et al. Tropomysin receptor antagonism in cylindromatosis (TRAC), and early phase trial of a topical tropomysin kinase inhibitor as a treatment for inherited CYLD defective skin tumors: Study protocol for a randomised controlled trial. Trials 2017; 18:111.
4. Zangarini M, et al. Development and validation of LC-MS/MS with in-source collision-induced dissociation for the quantification of pegcantratinib in human skin tumors. Bioanalysis 2017; 9: 279-88.
5. Danilenko M, et al. Targeting tropomysin receptor kinase in cutaneous CYLD defective tumors with pegcantratinib. JAMA Dermatol 2018; 154: 913-21.

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