An old pinworm medicine is a new lead in the search for compounds that block a signaling pathway implicated in colon cancer. The findings, reported by Vanderbilt University Medical Center researchers in the November issue of Nature Chemical Biology, suggest a fresh approach for developing therapeutics that target the pathway.
More than 90 percent of sporadic (non-inherited) colon cancers the second deadliest type of cancer in the developed world are caused by mutations that result in inappropriate activation of the Wnt (pronounced "wint") signaling pathway. Blocking this pathway has been a desirable therapeutic target, but its complexity has made it difficult to determine which molecular participants to inhibit.
"There's no obvious target in the pathway where we could say, 'OK, if we inhibit the activity of this protein, that will inhibit Wnt signaling,'" said Ethan Lee, M.D., Ph.D., associate professor of Cell and Developmental Biology, Vanderbilt-Ingram Cancer Center researcher, and senior investigator of the current study.
Lee and his colleagues were interested in understanding the details of the Wnt pathway, which also plays an important role in early development. In frogs, loss of early Wnt signaling results in headless embryos; too much early Wnt signaling causes two heads to form.
"To me, that's really quite remarkable and says this pathway is biologically important," Lee said.
To explore Wnt signaling at a biochemical level, Lee and his team developed frog embryo extracts and showed that this cell-free system retained many events of the Wnt signaling pathway. Using this system, they established a screening strategy to search for chemicals that modify Wnt signaling with the goal of learning more about the biology of the pathway.
The investigators screened several thousand chemical compounds, from a "library" of FDA-approved drugs and other bioactive compounds. They found that pyrvinium, an FDA-approved anti-paras
|Contact: Leigh MacMillan|
Vanderbilt University Medical Center