Abstract:
The Wnt/Frizzled signaling pathway regulates many critical steps during development of various metazoans from sponges to humans. It is also involved in the regulation of a number of adult physiologic activities, such as synaptogenesis and stem cell proliferation. Aberrant functioning of this pathway underlies a number of diseases, most notably cancers in the colon and the breast. As an example, the Wnt-dependent triple-negative breast cancer (TNBC) currently lacks any targeted therapies and continues to take quarter of million lives annually.
Despite decades of research on the molecular organization of the Wnt/Frizzled pathway, new players continue to be discovered. Our studies have provided crucial insights into the G protein-coupled receptor (GPCR) activities of Frizzled receptor proteins, identifying heterotrimeric Gi/o proteins and their Gα-subunits as critical transducers of the Wnt pathway. Numerous partners of Gαo in the pathway have been further identified, including proteins controlling multiple steps of vesicular trafficking. These findings not only expand the knowledge about the functioning of this important signaling cascade, but also identify novel potential targets to develop future drugs.
Using the basic knowledge we accumulated, we have launched several drug discovery programs aiming at targeting the Wnt pathway in TNBC. These programs include high-throughput screening of libraries of synthetic small molecules, rational drug design and in silico screening, repositioning of existing approved drugs, and search for natural compounds from plants and marine organisms across the globe to identify and develop drug candidates targeting Wnt signaling and TNBC cell proliferation. With two molecules currently demonstrating promise in mouse xenographt models, we hope that our pipeline will eventually lead to appearance of first-in-class therapies for TNBC and other Wnt-dependent diseases.
