Analysis of current data on the use of topical mTOR inhibitors in the treatment of facial angiofibromas in tuberous sclerosis complex—An update

Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous syndrome causing hamartomatous growths in multiple organs. Facial angiofibromas occur in up to 80% of patients and can be highly disfiguring. Treatment for these lesions is challenging. Recently, topical rapamycin has been proposed as an effective option to treat angiofibromas but a commercially available compound has not yet been developed in Europe. We conducted a retrospective review with the aim to update the current data on the use of topical rapamycin in the treatment of angiofibromas in TSC, focusing on the optimal concentration and trying to establish which vehicle should be preferred. Thirty‐nine reports describing the use of topical rapamycin in the treatment of angiofibromas in TSC were considered, involving a total of 483 patients. An improvement of the lesions has been shown in over 90% of subjects, particularly if the treatment was started at early stages. Several different formulations (ointment, gel, solution and cream) with a wide range of concentrations (0.003%–1%) were proposed, of which a pharmacological analysis has also been performed. Topical rapamycin can be considered an effective and safe option for the treatment and the prevention of facial angiofibromas in younger patients, but the best formulation has yet to be established. Our review demonstrates that ointment and gel should be preferred, but it is not clear which concentration is optimal. However, according to this study, the 0.1% concentration represents the first choice. Long‐term and comparative studies between topical rapamycin formulations are required in order to establish which treatment has a better outcome and lower recurrence rate.

mTORC1 activity negatively regulates human hair follicle growth and pigmentation

“…In vitro , mTORC1 functions as an important regulator of MITF activity (Ohguchi et al , 2005; Ho et al , 2011; Yun et al , 2016; Slade & Pulinilkunnil, 2017; Napolitano et al , 2022). In vitro , rapamycin treatment of primary epidermal melanocytes silenced for TSC1/2, which is increasingly used in clinical TS management (Balestri et al , 2022), can restimulate melanin production, mainly by restoring MITF function and MITF target gene expression (Cao et al , 2017). While mTOR inhibition by rapamycin in cultured murine and human melanocytes or melanoma cells was shown to increase and/or restore MITF expression levels, promote the expression of MITF target genes such as TYR , TYRP1 , and PMEL , and increase tyrosinase activity in vitro (Buscà et al , 1996; Ohguchi et al , 2005; Ho et al , 2011; Yun et al , 2016), active mTORC1 blocks the nuclear translocation of MITF (Roczniak‐Ferguson et al , 2012; Martina & Puertollano, 2013).…”

“…Translationally, our data strongly encourage one to next probe in a clinical trial whether topical rapamycin can significantly retard the graying process or even repigment graying/white hair, namely in younger individuals with recent onset of hair graying, and whether this indeed prolongs anagen duration in vivo . That topical rapamycin is already frequently used in daily dermatological practice (Mercurio et al , 2021; Balestri et al , 2022; Effendi et al , 2022) facilitates its repurposing for canities and poliosis management, provided that a sufficient level of rapamycin reaches the HFPU of graying/white human anagen HFs.…”

Progress in Dermatology and Venereology in 2023 as reflected in the Journal of the European Academy of Dermatology and Venereology

“…3 A topical mTOR inhibitor (rapamycin) has shown marked effects in the treatment of facial angiofibromas with 90% improvement in 39 reports about a total of 483 patients. 4…”