| Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. | |
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MedLine Citation:
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PMID: 22670904 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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.). |
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Authors:
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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:
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Type: Journal Article; Randomized Controlled Trial; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: The New England journal of medicine Volume: 366 ISSN: 1533-4406 ISO Abbreviation: N. Engl. J. Med. Publication Date: 2012 Jun |
Date Detail:
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Created Date: 2012-06-07 Completed Date: 2012-06-22 Revised Date: 2012-10-09 |
Medline Journal Info:
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Nlm Unique ID: 0255562 Medline TA: N Engl J Med Country: United States |
Other Details:
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Languages: eng Pagination: 2180-8 Citation Subset: AIM; IM |
Affiliation:
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Children's Hospital Oakland Research Institute, Oakland, California 94609, USA. |
| Data Bank Information | |
Bank Name/Acc. No.:
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ClinicalTrials.gov/NCT00957229 |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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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:
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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; R01CA109584/CA/NCI NIH HHS; UL1RR02413/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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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:
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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 ] |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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