Gene Therapy for Breast Cancer Shows Potential
Injecting the recently discovered breast cancer gene into breast tumors eliminates the malignant cells--at least in mice carrying human cancer cells, scientists reported Thursday.
Reflecting how quickly research in this field has accelerated in the past year, human testing of this anti-cancer therapy could begin later this year, researchers said.
“We now have something that we can really home in on to develop new forms of therapy,” said Roy Jensen, a professor of pathology and cell biology at Vanderbilt University and one of the authors of two related articles that appear in today’s issue of Nature Genetics.
Dr. Daniel F. Hayes, medical director of the breast evaluation center at Boston’s Dana Farber Cancer Institute, described his reaction to the news as a “cautious gee-whiz.”
“These are very exciting first papers, but we have to accept all these things with temperance,” Hayes said. “These are some of our first steps on our way to running.”
The researchers, from the University of Washington and Vanderbilt University in Tennessee, also say they have picked out the protein that the gene, called BRCA1, produces to perform its curative magic. That result conflicts with findings in November from scientists at the University of Texas at San Antonio. The molecule the Texas team claims to be the BRCA1 protein is slightly heavier and acts completely different from what is described today.
Nonetheless, both sets of findings hint that understanding its role in the cell could lead to new treatments of these cancers.
In one of the experiments, the Vanderbilt and Washington researchers injected human breast cancer cells into the abdomens of 10 mice. Within a couple of weeks, the tumors grew large enough to be felt under the animal’s skins. Through gene therapy, researchers then introduced the BRCA1 gene into the cancer cells, with half of the mice getting a normal working gene, and half getting a defective version.
All of the mice that received the mutant BRCA1 gene died within two weeks. Those that received the pristine gene lived at least two weeks and up to 41 days.
Autopsies of the second group showed that the BRCA1 injection sharply diminished the size of the tumors, and in two cases, eliminated all traces. It was not clear why the mice died despite fighting off the cancer, but researchers said the cancer had probably already weakened the mice’s systems beyond recovery.
University of Washington geneticist Mary-Claire King, another of the articles’ authors and whose pursuit of a breast cancer cure dates back two decades, predicted that researchers will be able to devise an effective treatment against the disease within 20 years.
“I’m getting more optimistic as time goes on,” King said.
Pending approval by the National Institutes of Health and the federal Food and Drug Administration, the gene therapy technique could be tested in 10 to 20 women with ovarian cancer in six months to one year, Jensen said. Ovarian cancer is generally easier to treat because it spreads through the body much more slowly than breast cancer, Jensen said.
What is particularly promising is that the gene acts quite specifically against breast and ovarian cancers. “You could make a scoop-shovel full of it and it doesn’t have any effect on [other types of cancer] at all,” Jensen said.
Because of this specificity, Jensen and the other researchers envision it as a potential replacement for chemotherapy without the side effects, such as destruction of healthy cells and weakening the immune system.
Another possibility is to create a drug to mimic the effects of the BRCA1 protein. Synthetic drugs are often easier to produce and are more stable than the naturally occurring protein.
Scientists knew from BRCA’s genetic data that it produced a large protein, three or four times the typical size. The Washington and Vanderbilt researchers built antibodies that hooked into the protein. Those antibodies, which included fluorescent molecules, lit up like bicycle reflectors when light was shined on them and enabled the scientists to pinpoint the proteins’ location.
What the researchers found was that in a normal working breast cell, the BRCA1 protein is secreted out of the cell. They hypothesize that it then attaches to the outside of the cell and tells it to stop growing.
“That’s a surprise,” said Nancy Davidson, director of the breast cancer program at the Johns Hopkins Oncology Center in Baltimore.
All tumor-suppressing proteins known up to now operate within the central nucleus of cells, not outside. “What is not a surprise is BRCA1 does retard growth and inhibit tumors,” Davidson said. “That confirms what we suspected.”
The Texas group had painted a more conventional picture of the protein--residing exclusively in the cell nucleus, except in late-stage cancers. On Thursday, Wen-Hwa Lee, head of the Texas research group, said, “We stand by our data.”
It is likely that one of the groups has sunk its antibody hooks into wrong protein, though it is possible that the protein acts differently in different situations. The difference in weight could be accounted for by an enzyme shearing off a small chunk.
“It won’t surprise me if we don’t have some bouncing around of hypotheses and ideas and data without clear-cut confirmation of what this protein does for a while,” said Hayes of the Dana Farber Institute.
According to the American Cancer Society, breast cancer each year strikes an estimated 182,000 women in the United States, and 46,000 die. About 26,000 U.S. women develop ovarian cancer annually, and 14,500 die annually.
Genetic errors in BRCA1 are thought to cause half of the inherited cases of breast and ovarian cancer, or about 2.5% of all cases. But because the new therapy appears to work against the non-inherited type of breast cancer as well, the researchers suspect that the gene may figure in a much greater percentage of cases.
