title: Vismodegib: an inhibitor of the Hedgehog signaling pathway in the treatment of basal cell carcinoma.
abstract: OBJECTIVE
  To review vismodegib, the first Food and Drug Administration (FDA)-approved Hedgehog (Hh) signaling pathway inhibitor, in the treatment of advanced basal cell carcinoma (BCC).
  
  
  METHODS
  MEDLINE and PubMed were searched using the terms vismodegib, GDC-0449, RG3616, and basal cell carcinoma for relevant clinical trials through September 2013. The FDA Web site, the National Clinical Trials registry, and abstracts from the American Society of Clinical Oncology (ASCO) were also evaluated to identify unpublished data and future clinical trials.
  
  
  METHODS
  All identified clinical and preclinical studies published in the English language were assessed, including selected references from the bibliographies of articles.
  
  
  RESULTS
  Activation of the Hh signaling pathway is well documented in BCC. Vismodegib is a small-molecule inhibitor of Hh signaling that acts by antagonizing the protein Smoothened (SMO), thereby preventing downstream transcriptional activation of genes involved in cell proliferation and survival. Vismodegib was approved by the FDA in January 2012 for the treatment of recurrent, locally advanced BCC (laBCC), or metastatic BCC (mBCC) for which surgery or radiation cannot be utilized. A pivotal phase 2 trial evaluating 104 patients demonstrated that treatment with vismodegib, 150 mg orally once daily, resulted in a 30% and 43% objective response rate in patients with mBCC and laBCC, respectively. The most common adverse effects from vismodegib were mild to moderate and included muscle spasms, dysgeusia, decreased weight, fatigue, alopecia, and diarrhea. However, clinical studies noted a high incidence of discontinuation of therapy by patients for reasons other than disease progression.
  
  
  CONCLUSIONS
  The approval of vismodegib represents the only targeted, prospectively studied treatment option for patients with advanced BCC. Further research assessing the utility of vismodegib in the treatment of other malignancies and the development of resistance patterns will more clearly define the role of Hedgehog inhibition in the broader scheme of oncological disorders.
authors.affiliation: University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA.
authors.forename: Amber E
authors.initials: AE
authors.lastname: Proctor
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Thompson
authors.forename: Cindy L
authors.initials: CL
authors.lastname: O'Bryant
mesh_terms: D000813:Anilides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D002280:Basal Cell Carcinoma / Q000188:drug therapy*; D004347:Drug Interactions; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000188:drug therapy*
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; C538724:HhAntag691; D011725:Pyridines
keywords: Hedgehog inhibitor; basal cell carcinoma; vismodegib