Document Detail


Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome.
MedLine Citation:
PMID:  22670904     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Dysregulated hedgehog signaling is the pivotal molecular abnormality underlying basal-cell carcinomas. Vismodegib is a new orally administered hedgehog-pathway inhibitor that produces objective responses in locally advanced and metastatic basal-cell carcinomas.
METHODS: We tested the anti-basal-cell carcinoma efficacy of vismodegib in a randomized, double-blind, placebo-controlled trial in patients with the basal-cell nevus syndrome at three clinical centers from September 2009 through January 2011. The primary end point was reduction in the incidence of new basal-cell carcinomas that were eligible for surgical resection (surgically eligible) with vismodegib versus placebo after 3 months; secondary end points included reduction in the size of existing basal-cell carcinomas.
RESULTS: In 41 patients followed for a mean of 8 months (range, 1 to 15) after enrollment, the per-patient rate of new surgically eligible basal-cell carcinomas was lower with vismodegib than with placebo (2 vs. 29 cases per group per year, P<0.001), as was the size (percent change from baseline in the sum of the longest diameter) of existing clinically significant basal-cell carcinomas (-65% vs. -11%, P=0.003). In some patients, all basal-cell carcinomas clinically regressed. No tumors progressed during treatment with vismodegib. Patients receiving vismodegib routinely had grade 1 or 2 adverse events of loss of taste, muscle cramps, hair loss, and weight loss. Overall, 54% of patients (14 of 26) receiving vismodegib discontinued drug treatment owing to adverse events. At 1 month, vismodegib use had reduced the hedgehog target-gene expression by basal-cell carcinoma by 90% (P<0.001) and diminished tumor-cell proliferation, but apoptosis was not affected. No residual basal-cell carcinoma was detectable in 83% of biopsy samples taken from sites of clinically regressed basal-cell carcinomas.
CONCLUSIONS: Vismodegib reduces the basal-cell carcinoma tumor burden and blocks growth of new basal-cell carcinomas in patients with the basal-cell nevus syndrome. The adverse events associated with treatment led to discontinuation in over half of treated patients. (Funded by Genentech and others; ClinicalTrials.gov number, NCT00957229.).
Authors:
Jean Y Tang; Julian M Mackay-Wiggan; Michelle Aszterbaum; Robert L Yauch; Joselyn Lindgren; Kris Chang; Carol Coppola; Anita M Chanana; Jackleen Marji; David R Bickers; Ervin H Epstein
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Publication Detail:
Type:  Journal Article; Randomized Controlled Trial; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The New England journal of medicine     Volume:  366     ISSN:  1533-4406     ISO Abbreviation:  N. Engl. J. Med.     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-06-07     Completed Date:  2012-06-22     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  0255562     Medline TA:  N Engl J Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2180-8     Citation Subset:  AIM; IM    
Affiliation:
Children's Hospital Oakland Research Institute, Oakland, California 94609, USA.
Data Bank Information
Bank Name/Acc. No.:
ClinicalTrials.gov/NCT00957229
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MeSH Terms
Descriptor/Qualifier:
Adult
Anilides / adverse effects,  therapeutic use*
Antineoplastic Agents / adverse effects,  therapeutic use*
Basal Cell Nevus Syndrome / drug therapy*,  pathology
Double-Blind Method
Female
Hedgehog Proteins / antagonists & inhibitors*
Humans
Kaplan-Meier Estimate
Male
Middle Aged
Pyridines / adverse effects,  therapeutic use*
RNA, Messenger / metabolism
Signal Transduction / drug effects
Skin Neoplasms / drug therapy*,  pathology
Transcription Factors / genetics,  metabolism
Treatment Outcome
Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:
1K23AR056736/AR/NIAMS NIH HHS; 5P30AR044535-11/AR/NIAMS NIH HHS; K23 AR056736/AR/NIAMS NIH HHS; P30 AR044535/AR/NIAMS NIH HHS; R01 CA109584/CA/NCI NIH HHS; R01 DK079953/DK/NIDDK NIH HHS; R01CA109584/CA/NCI NIH HHS; UL1RR02413/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Anilides; 0/Antineoplastic Agents; 0/GLI1 protein, human; 0/Hedgehog Proteins; 0/HhAntag691; 0/Pyridines; 0/RNA, Messenger; 0/Transcription Factors
Comments/Corrections
Comment In:
N Engl J Med. 2012 Jun 7;366(23):2225-6   [PMID:  22670909 ]
N Engl J Med. 2012 Sep 6;367(10):970; author reply 970-1   [PMID:  22931271 ]

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