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) ? ?
