Abstract 5681: Modulation of Wnt/β-catenin signaling by niclosamide and related derivatives.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC The Wnt signal transduction pathway is dysregulated in many cancers, including colorectal cancer (CRC) where activating mutations in this pathway occur in over 80% of sporadic colorectal cancers. As a result, drugs that inhibit the pathway are highly sought-after as the basis of a new generation of innovative therapeutic agents. Unfortunately, a gap exists in the ability to target the pathway with small, drug-like molecules, a gap that is the barrier to discovering drugs targeting defects in this pathway. Recently, we reported the FDA-approved anthelmintic drug niclosamide inhibits Wnt/β-catenin signaling via a novel mechanism that internalizes Frizzled receptors and leads to decreases in Dishevelled and β-Catenin proteins, even in cells harboring mutations in APC and β-catenin. The biological target driving inhibition of Wnt signaling by niclosamide is unknown. To support efforts to translate these findings in clinical trials and assist target identification efforts, we interrogated the mechanism and structure-activity relationships. We will present our findings indicating inhibition of Wnt signaling by niclosamide appears unique among the structurally-related anthelmintic agents tested and that Wnt/β-catenin activity was dependent on small changes in the chemical structure of niclosamide - including the ability to convert inhibition to activation. Overall, the findings support efforts to identify the target of niclosamide inhibition of Wnt/β-catenin signaling and the discovery of novel inhibitors of Wnt/β-catenin signaling to treat cancer, and thus accelerate the translational application of niclosamide and its derivatives to improve patient survival from cancer. Citation Format: Robert A. Mook, Minyong Chen, Jiuyi Lu, Larry S. Barak, H. Kim Lyerly, Wei Chen. Modulation of Wnt/β-catenin signaling by niclosamide and related derivatives. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5681. doi:10.1158/1538-7445.AM2013-5681