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Twenty-five years ago, the first component was discovered of what was later found to be part of one of the most important signaling pathways for development and disease, the Wnt signaling pathway. Now, researchers are using the insights they have gained into this cell communication to interfere with this pathway to develop new therapies against cancer. From a group of 68,000 compounds, the biochemist Professor Dr. Trevor Dale from Cardiff University, Wales, UK, identified four which stop Wnt signaling and thus block tumor cell growth in the cell culture and in experiments with zebrafish embryos, tiny organisms that are being used for studying developmental processes. He now plans to stop cancer in mice, as he reported at the international conference on "Wnt Signaling in Development and Disease" at the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch, Germany.
In trying to interfere with the Wnt signaling pathway, the researchers face two major problems. First, due to its central role in living organisms, interference with the Wnt pathway can cause severe side-effects. "Therefore we need to find out where we can intervene without interfering with vital functions", Professor Walter Birchmeier from the MDC and one of the organizers of this conference pointed out.
The second issue is that the core components of the Wnt pathway are "hard" drug targets, according to Dr. Dale. "Drugs that inhibit easy targets, such as enzymes, can be developed through standard screening approaches using purified enzymes. The drugs usually fit into small pockets on the enzyme like a broken key fitting into a lock and preventing the normal key from getting access."
"Drugs that inhibit hard targets, such as protein-protein interactions, are more difficult to develop since they usually don't have small pockets. Most "core" targets of the Wnt pathway fall into this class", Dr. Dale explains.
Two of the core targets of the Wnt pathway are the proteins beta-catenin and TCF. In normal cells, the level of beta-catenin in the cytoplasm is regulated by a complex of three proteins to which it is bound and which label it for destruction in the waste basket of the cell, the proteasome. One of the three proteins is the tumor suppressor APC (adenomatous polyposis coli).
In the presence of Wnt signaling, beta-catenin is set free from this complex of three proteins and moves into the cell nucleus. There, beta-catenin activates genes by binding to the TCF/Lef factor.
This activation of genes in the cell's nucleus leads to the onset of diseases such as cancer, brain and heart disorders, and others. Thus researchers try to prevent beta-catenin from being translocated from the cytoplasm to the cell's nucleus. Questions remain as to when, and where to intervene.
According to Dr. Dale, much of the pathway outside the core pathway has not been well studied. However, this allowed Dr. Dale and his team to apply a broader approach for drug screening. They decided to use the response of live cells to screen 68,000 compounds for activity against the Wnt pathway. "Once the active compounds were identified, we were then faced with the problem of identifying the targets of the pathway."
They were able to show that two of the compounds block the pathway near beta-catenin in the core pathway and two block the pathway near the TCF protein. The compounds blocked tumor cell growth in the cell culture and in zebrafish embyros. "However, we don't know as of yet exactly what the compounds bind", Dr. Dale says.
Furthermore, some of the zebrafish embryos showed developmental abnormalities that were similar to those previously described in mutated Wnt proteins. "This suggests that the compounds were having the same effect as blocking Wnt production." For example, one side effect was a loss of part of the zebrafish brain. In addition, side effects varied with the compounds. In some cases, there were no side effects whereas for others , there were many additional developmental changes which may - or may not - be related to blocking the Wnt pathway. This is still being studied.
In future studies, Dr. Dale and his co-workers want to use variants of their four compounds to block colon cancer in mice with de-regulated Wnt signaling. Researchers believe that APC triggers this disease, as it is mutated in 90 percent of all cases of colon cancer in humans.
It remains to be seen if, based on the results in mice, the researchers will be able to move on to human trials in the near future.
Barbara Bachtler
Press and Public Affairs
Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch
Robert-Rössle-Straße 10; 13125 Berlin; Germany
Phone: +49 (0) 30 94 06 - 38 96
Fax: +49 (0) 30 94 06 - 38 33
e-mail: presse@mdc-berlin.de
http://www.mdc-berlin.de/englisch/about_the_mdc/public_relations/e_index.htm
http://www.cardiff.ac.uk/biosi/research/molecular/staff/dale.html
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