Topical Treatment of Basal Cell Carcinomas in Nevoid Basal Cell Carcinoma Syndrome with a Smoothened Inhibitor

Abstract

Basal cell carcinoma (BCC) is a distinctive manifestation in nevoid basal cell carcinoma syndrome (NBCCS) patients. Both inherited and acquired mutations of patched 1 (PTCH1), a tumor-suppressor gene controlling the activity of Smoothened (SMO), are the primary cause of the constitutive activation of the Hedgehog (HH) pathway, leading to the emergence of BCCs in NBCCS. LDE225, a distinct, selective antagonist of SMO, showed potent inhibition of basaloid tumor nest formation and mediated regression of preformed basaloid tumors in organ cultures of skin derived from Ptch1 heterozygous knockout mice. In a double-blind, randomized, vehicle-controlled, intraindividual study, a total of 8 NBCCS patients presenting 27 BCCs were treated twice daily with 0.75% LDE225 cream or vehicle for 4 weeks. Application of 0.75% LDE225 cream was well tolerated and showed no skin irritation. Of 13 LDE225-treated BCCs, 3 showed a complete, 9 a partial, and only 1 no clinical response. Except for one partial response, the vehicle produced no clinical response in any of the 14 treated BCCs. Treatment with 0.75% LDE225 cream in NBCCS patients was very well tolerated and caused BCC regression, thus potentially offering an attractive therapeutic alternative to currently available therapies for this indication.JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article, please go to http://www.nature.com/jid/journalclub.

Non-melanoma Skin Cancer in Canada Chapter 4: Management of Basal Cell Carcinoma

“…21 Basal cell nevus syndrome (BCNS) is an autosomal dominant condition characterized by a germline mutation of the human patched gene (PTCH), a key player in the Hedgehog signalling pathway. 22 The condition affects multiple systems, including skin, where patients classically develop multiple BCCs. At times, management of BCNS may require aggressive treatment and multidisciplinary input.…”

The Utility of Hedgehog Signaling Pathway Inhibition for Cancer

“…trast to only one partial response out of 14 BCC tumors treated with the vehicle [79]. Clinical activity of LDE-225 was seen in medulloblastoma (partial response in one patient) and advanced BCC (complete response in one patient and partial responses in four patients).…”

Efficacy of Hedgehog Pathway Inhibitors in Basal Cell Carcinoma

“…A topical formulation of CUR61414 showed good antitumoral activity on BCCs from K14-CreERT2; Ptch1 þ/À ; Trp53 fl/fl mice; however, it failed to induce tumor shrinkage in humans potentially due to species effects on potency or poor bioavailability in human skin (66). A topical formulation of LDE225 was also studied in 8 patients with BCNS presenting 27 BCCs, who received 0.75% sonidegib cream or vehicle (67). Among the 13 sonidegib-treated BCCs, 3 CR and 9 PR were observed, whereas only one PR was observed in the 14 vehicle -treated BCCs.…”