New path discovered for colon cancer drug discovery

Saturday, November 20, 2010

LONDON - Scientists have found an old pinworm medicine to be a new lead in the search for compounds that block a signalling pathway implicated in colon cancer.

The findings have suggested a fresh approach for developing therapeutics that target the pathway.

More than 90 percent of sporadic (non-inherited) colon cancers 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, senior investigator of the current study.

To explore Wnt signalling 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 signalling pathway.

Using this system, they established a screening strategy to search for chemicals that modify Wnt signalling - 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. hey found that pyrvinium, an FDA-approved anti-parasite drug, blocked Wnt signaling in the frog extracts.

They tested pyrvinium in cultured cells and in multiple animal models of early development (frogs, nematode worms, fruit flies) and demonstrated that in each case, pyrvinium blocked Wnt signaling.

They also found that in cultured colon cancer cells, pyrvinium inhibited both Wnt signaling and cell proliferation.

To identify the target of pyrvinium, Lee and his colleagues combined four isolated proteins, all with known roles in the Wnt pathway. They found that pyrvinium increased the activity of one of the proteins, an enzyme called casein kinase 1alpha (CK1alpha).

“The targeted cancer therapies that are being intensively studied right now are mostly kinase inhibitors. It’s intriguing to think that maybe there are certain kinases - like CK1alpha - that we can activate as targets for treating cancer,” said Lee.

The frog embryo extract and screening strategy may also be applied to identifying compounds that modify other developmentally important signaling pathways, added Lee.

The findings were reported in the journal Nature Chemical Biology. (ANI)

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