The target consists of telomeres, which are stretches of the genetic molecule DNA, with some associated proteins, that normally shrink each time a cell divides. When a telomere gets short enough, the cell can die. In cancer cells, however, an enzyme called telomerase works to keep the telomere from shrinking, a major element in the devastatingly endless reproduction of those cells.
That process can be stopped by producing a mutated version of telomerase, the researchers report in the July 3 issue of the Proceedings of the National Academy of Sciences.In jujitsu, lead researcher Elizabeth Blackburn says, the idea is "to turn the force of the opponent against the opponent." So her group's method is to keep the gene that produces telomerase working at full force -- but with a mutated gene that "makes the enzyme work in a warped way," so that the telomere stops growing and the cancer cell dies.
It's a way to aim therapy primarily at cancer cells, adds Blackburn, a professor of biochemistry and biophysics at the University of California, San Francisco. That's because "it only works if the telomerase gene is activated. In many normal cells, gene activity is downrated or turned off," she says.
The idea is to mutate the gene just enough to cause a disabling defect in RNA, the molecule that carries the genetic signal, Blackburn says. "We were surprised at how sensitive cancer cells are to this mutation," she says. "Targeting a very low fraction of the RNA is enough to kill cells."
So far, the method has worked in laboratory studies, the journal report says. After tests in cell lines grown in laboratory dishes, the next step was to put human breast cancer cells into mice. The mutated telomerase gene decreased the growth of the implanted cancers. "We could see that those cells were committing suicide," Blackburn says.
"Obviously, we would like to see if the results are reproducible in real cancers," she says. "We are talking to surgeons here about obtaining samples of breast cancer tissue from human patients."
If that work gives further proof that the attack on telomeres works, the next step might be to try something other than a mutated gene, Blackburn says.
"Ideally, we would like to make some small molecule work with telomerase and have the same effect," she adds. "We would like to get together with chemists and think about how to make those small molecules."
The San Francisco work is a new variation on a theme that other researchers have explored, says Dr. Richard Hodes, author of an accompanying editorial in the journal.
Previous efforts have either aimed at limiting telomerase activity or stimulating the immune system to attack cells that express telomerase, says Hodes, the director of the National Institute on Aging, who also does research at the National Cancer Institute.
"This approach would appear to have an advantage because it would have a relatively immediate effect on inhibiting cell growth," he says. "The other approaches require multiple cell divisions and gradual shortening of the telomeres. The creation of poisons has a more immediate effect on eliminating cancer cells."
But as with any new idea, Hodes says, "translating an intervention that is effective in tissue culture into an effective treatment without intolerable toxicities in an animal model or human patients is a very demanding transition."
"The challenge is to deliver the treatment to cells growing in a living patient without causing undue damage to normal cells. A number of normal human cells express telomerase, so there is uncertainty about side effects," he adds.
What To Do
This kind of basic research will not have an immediate impact on treatment of cancer, but it is an example of the many avenues being explored for new cancer therapies.