title: Effects of Combined Treatment With Arsenic Trioxide and Itraconazole in Patients With Refractory Metastatic Basal Cell Carcinoma.
abstract: OBJECTIVE
  Tumor resistance is an emerging problem for Smoothened (SMO) inhibitor-treated metastatic basal cell carcinoma (BCC). Arsenic trioxide and itraconazole antagonize the hedgehog (HH) pathway at sites distinct from those treated by SMO inhibitors.
  
  
  OBJECTIVE
  To determine whether administration of intravenous arsenic trioxide and oral itraconazole in patients with metastatic BCC is associated with a reduction in GLI1 messenger RNA expression in tumor and/or normal skin biopsy samples.
  
  
  METHODS
  Five men with metastatic BCC who experienced relapse after SMO inhibitor treatment underwent intravenous arsenic trioxide treatment for 5 days, every 28 days, and oral itraconazole treatment on days 6 to 28. Data were collected from April 10 to November 14, 2013. Follow-up was completed on October 3, 2015, and data were analyzed from June 5 to October 6, 2015.
  
  
  METHODS
  The primary outcome was the change in messenger RNA levels of the GLI family zinc finger 1 (GLI1) gene (HH-pathway target gene) in biopsy specimens of normal skin or BCC before and after treatment. Secondary objectives were evaluation of tumor response and tolerability.
  
  
  RESULTS
  Of the 5 patients (mean [SD] age, 52 [9] years; age range, 43-62 years), 3 completed 3 cycles of treatment and 2 discontinued treatment early owing to disease progression or adverse events. Adverse effects included grade 2 transaminitis and grade 4 leukopenia with a grade 3 infection. Overall, arsenic trioxide and itraconazole reduced GLI1 messenger RNA levels by 75% from baseline (P < .001). The best overall response after 3 treatment cycles was stable disease in 3 patients.
  
  
  CONCLUSIONS
  Targeting the HH pathway with sequential arsenic trioxide and itraconazole treatment is a feasible treatment for metastatic BCC. Although some patients experienced stable disease for 3 months, none had tumor shrinkage, which may be owing to transient GLI1 suppression with sequential dosing. Continuous dosing may be required to fully inhibit the HH pathway and achieve clinical response.
authors.affiliation: Department of Dermatology, Stanford University, Stanford, California.
authors.forename: Mina S
authors.initials: MS
authors.lastname: Ally
authors.affiliation: Department of Dermatology, Stanford University, Stanford, California2Department of Dermatology, School of Medicine, Stanford University, Stanford, California.
authors.forename: Katherine
authors.initials: K
authors.lastname: Ransohoff
authors.affiliation: Department of Dermatology, Stanford University, Stanford, California.
authors.forename: Kavita
authors.initials: K
authors.lastname: Sarin
authors.affiliation: Department of Dermatology, School of Medicine, Stanford University, Stanford, California.
authors.forename: Scott X
authors.initials: SX
authors.lastname: Atwood
authors.affiliation: Department of Dermatology, Stanford University, Stanford, California.
authors.forename: Melika
authors.initials: M
authors.lastname: Rezaee
authors.affiliation: Department of Dermatology, Stanford University, Stanford, California.
authors.forename: Irene
authors.initials: I
authors.lastname: Bailey-Healy
authors.affiliation: Department of Dermatology, School of Medicine, Stanford University, Stanford, California.
authors.forename: Jynho
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Dermatology, School of Medicine, Stanford University, Stanford, California.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Beachy
authors.affiliation: Department of Dermatology, Stanford University, Stanford, California.
authors.forename: Anne Lynn S
authors.initials: AL
authors.lastname: Chang
authors.affiliation: Department of Dermatology, Stanford University, Stanford, California2Department of Dermatology, School of Medicine, Stanford University, Stanford, California.
authors.forename: Anthony
authors.initials: A
authors.lastname: Oro
authors.affiliation: Department of Dermatology, Stanford University, Stanford, California.
authors.forename: Jean Y
authors.initials: JY
authors.lastname: Tang
authors.affiliation: Cancer Center, Stanford University, Stanford, California.
authors.forename: A Dimitrios
authors.initials: AD
authors.lastname: Colevas
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage; D002280:Basal Cell Carcinoma / Q000188:drug therapy* / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D005500:Follow-Up Studies; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D017964:Itraconazole / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010087:Oxides / Q000008:administration & dosage; D012333:RNA, Messenger / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics*; D016896:Treatment Outcome; D000071676:Zinc Finger Protein GLI1
chemical_list: D001152:Arsenicals; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D010087:Oxides; D012333:RNA, Messenger; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D017964:Itraconazole; D000077237:Arsenic Trioxide