title: 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.
authors: Division of Immunology, Department of Dermatology, Allergy and Infectious Diseases, Medical University of Vienna, Vienna, Austria.
authors: Hans
authors: H
authors: Skvara
authors: Frank
authors: F
authors: Kalthoff
authors: Josef G
authors: JG
authors: Meingassner
authors: Barbara
authors: B
authors: Wolff-Winiski
authors: Heinrich
authors: H
authors: Aschauer
authors: Joseph F
authors: JF
authors: Kelleher
authors: Xu
authors: X
authors: Wu
authors: Shifeng
authors: S
authors: Pan
authors: Lesanka
authors: L
authors: Mickel
authors: Christopher
authors: C
authors: Schuster
authors: Georg
authors: G
authors: Stary
authors: Ahmad
authors: A
authors: Jalili
authors: Olivier J
authors: OJ
authors: David
authors: Corinne
authors: C
authors: Emotte
authors: Ana Monica Costa
authors: AM
authors: Antunes
authors: Kristine
authors: K
authors: Rose
authors: Jeremy
authors: J
authors: Decker
authors: Ilene
authors: I
authors: Carlson
authors: Humphrey
authors: H
authors: Gardner
authors: Anton
authors: A
authors: Stuetz
authors: Arthur P
authors: AP
authors: Bertolino
authors: Georg
authors: G
authors: Stingl
authors: Menno A
authors: MA
authors: De Rie
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001713:Biphenyl Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D002280:Basal Cell Carcinoma / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006197:Hair / Q000187:drug effects / Q000254:growth & development; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011247:Pregnancy; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000072086:Smoothened Receptor
chemical_list: D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D053823:Hedgehog Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011725:Pyridines; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C509239:SHH protein, human; C491023:SMO protein, human; C465570:Shh protein, mouse; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; C561435:sonidegib