title: Targeting superficial or nodular Basal cell carcinoma with topically formulated small molecule inhibitor of smoothened.
abstract: OBJECTIVE
  Inappropriate activation of the Hedgehog (Hh) signaling pathway in skin is critical for the development of basal cell carcinomas (BCC). We have investigated the anti-BCC efficacy of topically-applied CUR61414, an inhibitor of the Hh signal transduction molecule Smoothened.
  
  
  METHODS
  In preclinical studies, we used a depilatory model to evaluate the ability of topical formulations of CUR61414 to repress Hh responsive cells found at the base of hair follicles in normal skin. We also tested the in vivo effects of topical CUR61414 on murine BCCs developed in Ptch1 (+/-) K14-CreER2 p53 fl/fl mice. In a phase I clinical study, we evaluated the safety, tolerability, and efficacy of a multidose regimen of CUR61414 (0.09%, 0.35%, 1.1%, and 3.1%) applied topically to human superficial or nodular BCCs for up to 28 days.
  
  
  RESULTS
  In mice, topical CUR61414 significantly inhibited skin Hh signaling, blocked the induction of hair follicle anagen, and shrank existing BCCs. However, we observed no clinical activity of this formulation in human superficial or nodular BCCs in a phase I clinical study.
  
  
  CONCLUSIONS
  Our data highlight some of the challenges of translating preclinical experience into successful human results for a topical anticancer agent.
authors.affiliation: Genentech, South San Francisco, California 94080, USA.
authors.forename: Tracy
authors.initials: T
authors.lastname: Tang
authors.forename: Jean Y
authors.initials: JY
authors.lastname: Tang
authors.forename: Dongwei
authors.initials: D
authors.lastname: Li
authors.forename: Mike
authors.initials: M
authors.lastname: Reich
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Callahan
authors.forename: Ling
authors.initials: L
authors.lastname: Fu
authors.forename: Robert L
authors.initials: RL
authors.lastname: Yauch
authors.forename: Frank
authors.initials: F
authors.lastname: Wang
authors.forename: Karen
authors.initials: K
authors.lastname: Kotkow
authors.forename: Kris S
authors.initials: KS
authors.lastname: Chang
authors.forename: Elana
authors.initials: E
authors.lastname: Shpall
authors.forename: Angela
authors.initials: A
authors.lastname: Wu
authors.forename: Lee L
authors.initials: LL
authors.lastname: Rubin
authors.forename: James C
authors.initials: JC
authors.lastname: Marsters
authors.forename: Ervin H
authors.initials: EH
authors.lastname: Epstein
authors.forename: Ivor
authors.initials: I
authors.lastname: Caro
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: de Sauvage
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D002280:Basal Cell Carcinoma / Q000188:drug therapy* / Q000235:genetics; D004149:Dioxoles / Q000008:administration & dosage* / Q000009:adverse effects; D004311:Double-Blind Method; D016503:Drug Delivery Systems / Q000379:methods; D004353:Drug Evaluation, Preclinical; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects; D010919:Placebos; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics; D054852:Small Molecule Libraries / Q000032:analysis; D000072086:Smoothened Receptor; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C474318:CUR 61414; D004149:Dioxoles; D010879:Piperazines; D010919:Placebos; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D054852:Small Molecule Libraries; D000072086:Smoothened Receptor