Novel Inhibitors of Wnt Signaling

The involvement of Wnt signaling in so many different diseases makes this pathway a desirable therapeutic target, but the involvement of Wnt signaling in so many aspects of development and the maintenance of stem cells also makes this pathway an undesirable therapeutic target.  For example, would inhibiting Wnt signaling in colorectal cancer stem cells also lead to osteoporosis or increased hair loss?  Numerous high throughput Wnt inhibitor screens have been conducted, mainly using a cell based reporter system, but surprisingly none of these compounds have made it to late stage clinical trials.  Perhaps the cell-based screens cannot capture the complexity of the Wnt signaling pathway.  We believe that the zebrafish embryo can capture more of these complexities and would be a useful paradigm for novel drug discovery.  We are currently conducting a medium-low throughput phenotypic screen for novel Wnt inhibitors.  We first activate the Wnt pathway in the early zebrafish embryo by treating them with LiCl, which by itself would result in an eyeless zebrafish at 1 day of development. The screen is to simultaneously treat the fish with LiCl and a small molecule from a library and look for rescue of the eyeless phenotype along with other toxicities. The transparency of the zebrafish allows for quick evaluation of the brain, kidney, heart, vasculature, gut and several other tissues.  The high evolutionary conservation of the Wnt pathway suggests that any hits would have a similar effect in mammalian cells, which we subsequently test. We continue to develop other disease models and collaborate with others to develop their models for novel discovery. Some of these models can be very elaborate, but others, like our eyeless screen, are very simple.