Abstract 708: A novel hedgehog signaling inhibitor blocks hedgehog-mediated carcinogenesis

The link of hedgehog (Hh) signaling activation to human cancer and synthesis of a variety of Hh signaling inhibitors raise great expectation that inhibiting Hh signaling may be effective in human cancer treatment. We have developed a novel hedgehog signaling inhibitor Cyc-T, which has better solubility and higher efficacy in inhibiting hedgehog signaling. In analyses of motor neuron differentiation and osteoblast differentiation, we found that Cyc-T is very effective in preventing hedgehog-mediated functions. Using a mouse model based on keratin 14 promoter-driven expression of an activated form of SMO, SmoM2, we found that a cyclopamine derivative cyc-T are effective in shrinkage of Smo-mediated tumors. K14cre/R26SMO m2yfp mice develop skin dysplasia on postnatal day 3 and BCC-like tumors by day 15. We performed topical application of cyclopamine or its derivatives CPA006, Cyc-T on the skin of K14cre/R26SMO m2yfp mice daily for seven days with the solvent ethanol as the control. The effects of these reagents on the tumors were examined by histological examination of skin biopsies and expression of Hh target genes. In comparison with the control group, we found that 6 out of 9 mice treated with cyclopamine reduced tumor mass and decreased expression of Hh target genes. The mice with no effects by cyclopamine and its derivatives had no changes in Hh target gene expression. In an orthotopic mouse model of pancreatic cancer, we measured the tumor progression following drug treatment and obtained promising results. Taken together, we discovered that Cyc-T are an effective inhibitor for Hh signaling-mediated carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 708.