Basal cell carcinomas (BCCs) are one of the most common cancers in the U.S. While surgical excision can be effective in treating BCCs, additional non-surgical therapies are needed. Advances in our understanding of the role that induction of sonic hedgehog (Shh) target genes plays in BCC pathogenesis have expanded the possibilities for tumor-specific therapies. The goal is to combine the rapidly expanding knowledge of Shh signaling with novel delivery systems to create molecular therapeutics for BCCs. Toward this end they propose to: 1) Determine the fate of treated BCC cells in the human BCC model. An initial step in assessing the efficacy of antagonists of Shh target gene induction for treating BCCs is knowing the fate of cells that have turned off Shh target genes in an otherwise malignant tumor. They will use a previously described human BCC model and establish that Ptc inhibits Shh target gene induction in skin and then determine the fates of Ptc infected cells marked with lacZ using lentiviral vectors. 2) Assess the efficacy of antagonists of Shh target gene induction using novel protein transduction sequences (PTS). Recent evidence suggests that the cutaneous barrier can be overcome by attaching PTS to otherwise non-absorbable antagonists. They will test the validity of this approach using the Smo antagonist cyclopamine. They will test the efficacy of topical cycloparnine in blocking Shh signaling in human BCC model and then compare the efficacy of an oligoarginine linked cycloparnine in inhibiting tumor growth. 3) Determine the role of the Shh target gene BEG4 in neoplasia. To broaden the armamentarium. of potential therapeutics for BCCs, additional information is needed on how Shh target genes mediate BCC growth. BEG4 is a conserved, novel Shh target gene expressed in all BCC epithelial cells. Forced expression of BEG4 in regenerated human epidermis results in adhesion defects seen in invaginating Shh-dependent hair follicle epithelium and BCC tumors. This suggests BEG4 contributes to BCC formation by regulating cellular adhesion. To determine its role in BCC formation, they will determine how BEG4 regulates epidermal basement membrane zone components, determine which portion of BEG4 is required to regulate adhesion, and determine the role of BEG4 dependent alterations in adhesion in BCC formation. These experiments will determine the efficacy of using novel antagonists of Shh target gene induction for BCCs while deepening our understanding of how Shh target genes mediate BCC formation through signaling molecules like BEG4.
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