August 21, 2001
Drug hits new molecular target in mice, shrinks hard-to-treat "Estrogen Receptor-Negative" Breast Cancers
About 30 percent of the 180,000 breast cancers diagnosed each year are not fueled by the estrogen in a woman's body, so estrogen-blocking treatments like the drug tamoxifen do not affect them. Dana-Farber Cancer Institute researchers report that in a mouse study, such "estrogen receptor-negative" breast tumors were halted and shrunk by an experimental drug aimed at a new target in the cancer cells.
The drug, injected directly into tumors implanted under the rodents' skin, appeared to have no serious side effects, says Debajit K. Biswas, PhD, a senior associate in the laboratory of Arthur B. Pardee, PhD, in the Division of Cancer Biology.
"This drug is inhibiting the growth of tumors and causing fully-grown tumors to regress and go away, and the mice show no signs of toxicity," says Biswas, though the animals were only treated for 32 days. Biswas is lead author of a report being published on line of a report being published on line by the Proceedings of the National Academy of Science (PNAS). It will appear in the August 28 issue of PNAS.
The scientists note that this was a small study involving 20 mice, and there are no current plans for trying it in people with cancer. "It's still a big jump to the human," cautions Pardee.
The drug, known as Go6976, hits a crucial control point in cancer cells that allows them to grow when they shouldn't and keeps them from dying when they're supposed to. This control point - one relay station in a cascade of signals that leads to cancer - is a protein called NF-kappaB. The protein is a regulatory molecule that's normally inactive in most cells, but which gets improperly activated in breast tumors that lack estrogen receptors, goading them into aggressive overgrowth.
What is important in the work, says Biswas, is not so much the particular drug that was used, but rather showing that blocking the activation of NF-kappaB shuts down its tumor-promoting ability.
"This clinches the point that NF-kappaB is the target" that can be switched off in estrogen receptor-negative cancer cells, halting the tumors' growth, says Biswas. At least in mice, that is. The Go6976 drug has its effect on NF-kappaB by blocking an enzyme that otherwise would activate NF-kappaB. The enzyme is known as a kinase, and Go6976 is a kinase inhibitor - a type of drug that researchers are finding useful to attack cancer's growth control points without poisoning normal cells and tissues as standard chemotherapy does. The recently approved cancer drug Gleevec, which has had stunning results in treating a type of leukemia and a rare stomach cancer, is a kinase inhibitor and the first example of the new "smart" cancer drugs.
When doctors diagnose and plan treatment for breast cancers they look for various indicators of how aggressive they are and what treatments will work best. Two-thirds of breast tumors are made up of cells that have receptor molecules for estrogen on their cell surface. The growth of these estrogen-receptor-positive (ER+) tumors depends in part on estrogen in the woman's body. Treatment for these cancers, along with surgery, usually involves a hormone blocker such as tamoxifen, which cuts off the growth-stimulating hormone.
But there's no such method to treat ER- tumors, which are independent of estrogen, and investigators like Biswas have been searching for other ways of stemming their uncontrolled growth. Some ER- tumors respond to the drug Herceptin, a monoclonal antibody that blocks another signal relay station in the chain that leads to cells growing out of control and forming tumors. Biswas and his colleagues have been studying the cell growth signaling mechanism, and last year [2000] reported in PNAS that activation of NF-kappaB was a crucial step in the pathway causing cells to lose their growth control.
As a followup experiment, Biswas tested the effects of the NF-kappaB inhibitor, Go6976, in mice as reported today. The results, however, don't apply to all ER- breast tumors in mice. He only tried it in mice with breast tumors that are ER- and which also are marked by having high activity of another signalling molecule, epidermal growth factor receptor, or EGFR. The scientists are continuing their experiments by testing Go6976 in ER- tumors that don't exhibit high EGFR activity, says Biswas.
Funding for the research was provided by the Massachusetts Breast Cancer Program in the state Department of Public Health.
