Patients with the basal cell nevus syndrome (BCNS) develop dozens to hundreds of basal cell carcinomas (BCCs) yearly due to mutations in the PATCHED1 gene, whose normal function is to inhibit hedgehog signaling pathway activation. All BCCs, whether sporadic or in BCNS patients, have as their pivotal abnormality activation of the hedgehog signaling pathway, generally as a result of mutational inactivation of PTCH1. Ptcl +/- mice also develop BCCs after carcinogenic insults and hence provide a good animal model for preclinical testing of chemopreventive interventions. Of the several such interventions we have assessed during the past four years in Ptcl +/- mice, topical applications of the retinoid tazarotene (taz) have by far the greatest efficacy, causing an approximately 85% decrease in BCC tumor burden (fig), a decrease which if replicated in BCNS patients would have a major impact on their lives. We propose to build on these exceptional results by (i) investigating the mechanism of the anti-BCC efficacy of taz through a comprehensive, iterative set of in vitro and in vivo experiments utilizing cell lines and mouse strains that we have developed and (ii) conducting a clinical trial assessing the chemopreventive and therapeutic efficacy of topical taz in human BCNS patients. This joint UCSF-Columbia project will take advantage of the scientific strengths of our institutions, the knowledge and laboratory resources we have accumulated over the past years of study of this problem, and in particular the unique large cohort of BCNS patients that we have assembled over the past 17 years of interacting with these patients. ? ? REVISED: April 22, 2004 (See Revision Note) ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109584-02
Application #
6948626
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Kopelovich, Levy
Project Start
2004-09-13
Project End
2009-06-30
Budget Start
2005-09-21
Budget End
2006-06-30
Support Year
2
Fiscal Year
2005
Total Cost
$933,553
Indirect Cost
Name
University of California San Francisco
Department
Dermatology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Tang, Jean Y; Chiou, Albert S; Mackay-Wiggan, Julian M et al. (2014) Tazarotene: randomized, double-blind, vehicle-controlled, and open-label concurrent trials for basal cell carcinoma prevention and therapy in patients with basal cell nevus syndrome. Cancer Prev Res (Phila) 7:292-9
Ally, Mina S; Tang, Jean Y; Joseph, Timmy et al. (2014) The use of vismodegib to shrink keratocystic odontogenic tumors in patients with basal cell nevus syndrome. JAMA Dermatol 150:542-5
So, Po-Lin; Wang, Grace Y; Wang, Kevin et al. (2014) PI3K-AKT signaling is a downstream effector of retinoid prevention of murine basal cell carcinogenesis. Cancer Prev Res (Phila) 7:407-17
Tang, Jean Y; Mackay-Wiggan, Julian M; Aszterbaum, Michelle et al. (2012) Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med 366:2180-8
So, Po-Lin; Fujimoto, Michele A; Epstein Jr, Ervin H (2008) Pharmacologic retinoid signaling and physiologic retinoic acid receptor signaling inhibit basal cell carcinoma tumorigenesis. Mol Cancer Ther 7:1275-84
Arad, Simin; Zattra, Edoardo; Hebert, Jennifer et al. (2008) Topical thymidine dinucleotide treatment reduces development of ultraviolet-induced basal cell carcinoma in Ptch-1+/- mice. Am J Pathol 172:1248-55