The discovery that a gene known for causing cancer in mice also plays a role in human cancer is leading scientists to reconsider how they target their research.
Researchers at Duke and the University of North Carolina at Chapel Hill have uncovered a previously undetected cancer-causing pathway of the Ras gene, a major cancer-causing agent in pancreatic cancer. Although research on the gene, which had been studied only in mice, could hold a bright future for the development of anti-cancer drugs, researchers say a more immediate concern highlights the limitations of relying on mouse models in the laboratory.
The Ras study began two years ago when Christopher Counter--assistant professor of pharmacology and cancer Biology as well as radiation and oncology--realized that Ras caused different types of cancer in mice and in humans.
"If you look at the cancers associated with Ras, the result [in humans] was different with the kinds of cancers you modeled with Ras [in mice]," said Counter, who headed the research project. In humans, Ras is partly responsible for thyroid, lung and colon cancer and causes 90 percent of pancreatic cancer. By contrast, the gene does not cause pancreatic cancer, but rather breast and skin cancer in mice.
The research team, which paired the Duke Comprehensive Cancer Center with UNC's Lineberger Comprehensive Cancer Center, discovered that Ras communicates with a previously unknown protein, RALGEF, which then causes normal cells to proliferate permanently.
Counter emphasized that although the newly found pathway exists in mice, it was overlooked because of the minor role the pathway plays in that organism.
Research collaborator Bob Abraham, director of the Burham Cancer Research Center in La Jolla, Calif., cautioned about mouse models because of this oversight.
"Mouse models have limits that haven't been recognized previously," Abraham said.
Counter believed that his team's recently completed research was "on line" with research in other labs to reinvestigate pathways previously thought to be understood.
Abraham added that research situations such as theirs "point out limitations on relying extensively on rodent models" and that time would soon tell whether other such "rediscoveries" could occur.
Although both Counter and Abraham were somewhat critical of the mouse model, neither entertained the viewpoint that a human model could be a viable option. Abraham proposed taking existing human cell lines to see the pathways and downstream targets encountered directly in a human line. This method of research, however, inhibits the ability of scientists to see the effects of cancer development across an organism, he said.
Researchers said the next step was to determine if what was found in the lab occurred in human patients afflicted with cancer caused by Ras.
"What we have to do is take this research from the lab to the clinic," said Counter, warning that this next step could take some time. He stressed that before the final stage of drug development can take place, scientists must understand how the gene actually operates. "It is particularly important because you want to know how a gene works to know how it does not work," he said.
Abraham noted that the average time frame between clinical trials and drug marketing to the public varies between 11 and 14 years. He stressed instead the broader significance of this research project. "I think the importance [of this research] may be telling us we're not necessarily looking for targets the right way," he said.
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