Upstream regulation of Wnt Signaling: Biology and Therapy

Key speaker Professor David M. Virshup, MD, Director of the Programme in Cancer & Stem Cell Biology, Duke-National University of Singapore

Abstract

Wnt are secreted lipoproteins that travel short distances to regulate development and stem cell proliferation in adults. Dysregulated Wnt signaling caused by specific genetic mutations underlies a subset of diseases including pancreatic and colorectal cancer. These mutations increase the sensitivity of cells to secreted Wnt ligands. We study the mechanism of Wnt secretion and how to block it. Secretion of all Wnt ligands begins with their palmitoylation in the endoplasmic reticulum by the membrane-bound O-acyl transferase PORCN. Wnts are subsequently transported to the plasma membrane by the carrier protein Wntless/WLS. The secretion of all Wnts can be inhibited by drugs that target PORCN. In Singapore, we have developed a potent PORCN inhibitor ETC-159 with activity in multiple genetically defined preclinical models, that has recently completed a Phase 1A study in humans. PORCN inhibitors are powerful tools to understand the role of Wnt signaling in health and disease.

Biosketch of David Virshup

David M. Virshup, MD, is the inaugural Director of the Program in Cancer and Stem Cell Biology at the Duke-NUS Graduate Medical School in Singapore, and a tenured Professor of Pediatrics at Duke University in North Carolina, USA. His research focuses on signal transduction via protein phosphorylation, with a special interest in Wnt signaling and circadian rhythms. Virshup received his B.A. magna cum laude in Chemistry from Beloit College in 1977 and his medical degree from Johns Hopkins University School of Medicine in 1981. He completed his clinical training in Pediatrics and Pediatric Hematology/Oncology and research training all at Johns Hopkins. From 1990 until 2007, he was at the University of Utah. In 2007, he joined the newly-established Duke-NUS Graduate Medical School in Singapore. Virshup is a member of the American Society of Pharmacology and Experimental Therapeutics, the American Society of Clinical Investigation, the Association of American Physicians, and a Fellow of the American Association for the Advancement of Science, He has been on the Editorial Board for Journal of Biological Chemistry and the Journal of Clinical Investigation.