New Compound May Help Treat Both Breast Cancer And Osteoporosis

August 14, 1997

DURHAM, N.C. - Scientists have found a new compound they say appears to act as a natural estrogen where it is needed in the body, but as an anti-estrogen in tissues where the hormone can be harmful.

The researchers, from Duke University Medical Center and Glaxo Wellcome Research Institute, reported that the chemical compound, GW5638, seems to strengthen bones and improve cardiovascular health like natural estrogen does, while stopping the ability of estrogen to speed the growth of cancer in uterine cells.

Although the research has only been conducted in laboratory animals, the scientists say GW5638's potential may be important for women. The researchers said it could possibly replace tamoxifen, afirst line therapy against breast cancer, as well as out-perform synthetic estrogen mimics now being tested to prevent osteoporosis.

"This appears to be a dynamite compound that not only may answer our clinical needs, it also has helped us to understand how estrogen functions in different parts of the body," said Duke pharmacologist Donald McDonnell, who led the investigation. "It represents a wonderful convergence between the science of estrogen replacement therapy and anti-cancer drugs. We're about ready to test GW5638 in humans and if it works as predicted, a drug may be ready in a few years."

The work on GW5638 is published in the September issue of Endocrinology. The report details findings on bone function, blood cholesterol and uterine tissues in rats. Further research on animals and in the lab indicates that GW5638 works as an anti-estrogen in breast cells, the researchers said.

"We all thought that estrogen works the same way in every cell and that it would be difficult to develop an estrogen replacement that works in bones but not other tissues," McDonnell said in an interview. "Now we find the action of estrogen in bones and the cardiovascular system is very different than in the breast and uterus, and this compound appears to offer us estrogen's benefits."

Identification of the chemical was the result of a $10-million, five-year grant from the National Cancer Institute awarded to Duke to create a Specialized Program of Research Excellence (SPORE) in breast cancer. Working with SPORE investigators, McDonnell contacted researchers at Glaxo Wellcome, which developed the chemical, in Research Triangle Park. As an expert on the estrogen hormone, McDonnell's goal was to find a new compound that functions as an anti-estrogen in the breast and uterus.

Most breast cancer is "estrogen receptor positive," suggesting estrogen helps stimulate the growth of cancer, McDonnell said. Although the process is not well understood, estrogen apparently targets a cellular gene in breast tissue that causes proliferative growth. Tamoxifen works by blocking the action of estrogen, and so the growth of cancer. It is called a chemotherapy because it helps halt the spread of cancer, but it differs from other chemotherapy that kills tumors through toxic chemicals.

Because the body can begin to "see" tamoxifen as estrogen, the National Cancer Institute has recommended that some women not take tamoxifen after five years of use. Other women never respond to tamoxifen at all. But there is no other toxic-free drug that can be used instead, according to oncologist Dr. Dirk Iglehart, who directs the Duke SPORE grant. Furthermore, tamoxifen itself may not be the best primary treatment possible - it can over-stimulate the growth of uterine cells, thus posing a small increased risk of uterine cancer, he said. "Having a toxic-free alternative to tamoxifen would be of great help in clinical practice," Iglehart said.

McDonnell wanted to find a substitute for estrogen that would halt cancer growth in breast tissue but not pose a threat of uterine cancer. "The idea we had was to find a chemical with a different shape than tamoxifen so that a patient who became resistant to tamoxifen could continue her cancer protection on a new therapy," McDonnell said.

He said he also hoped the compound would offer the benefits of natural estrogen to organs and tissues that need it, such as bone cells and the cardiovascular system, without the risks of estrogen. Natural estrogen also poses an increased risk of uterine cancer, and possibly of breast cancer, in post-menopausal women who want to use hormone supplements to protect bone strength. While experimental estrogen mimics, such as raloxifene, protect bones and do not increase the risk of cancer, they are not as potent as natural estrogen, McDonnell said.

He collaborated with Tim Willson, a chemist and senior research investigator at Glaxo Wellcome. Willson had previously identified a group of chemicals that appeared to be related to tamoxifen but functioned in a slightly different manner. But the unique properties of these compounds were unknown until McDonnell tested them with a set of cellular assays he had developed. He and Willson found a chemical, GW5638, that was then tested extensively in animals.

To study the compound's effects on bones, the team used rats that had their ovaries, and thus their natural supply of estrogen, removed. Those animals given either natural estrogen or GW5638 did not develop osteoporosis while rats given a placebo did. The researchers also found that rats given GW5638 did not show signs of cell division that leads to uterine cancer while those given natural estrogens did. Details of the study are included in the Endocrinology report.

They then conducted further studies with mice implanted with human breast tissue tumors to study the compound's anti-cancerous effects. "Milligram per milligram, GW5638 was as effective as tamoxifen in stopping cancer growth," McDonnell said. Those findings have not been published.

"This compound immediately showed a unique profile of activity that we hope can be translated into some clinical benefit," Willson said.

The compound has led to a new understanding of estrogen's effects, McDonnell says. "It shows that bones and the cardiovascular system can't distinguish natural estrogen from estrogen mimics, but other tissues can tell the difference, with varying sensitivity," McDonnell said.

"The genetic machinery that recognizes estrogen is tissue distinct," he said. "It's not a matter of estrogen turning a cell switch "on" or "off," but is more an issue of how each particular estrogen-like compound drives cellular receptors to different shapes, producing different responses in each tissue."

Once a hormone finds an estrogen-sensitive tissue, it binds to small sites called receptors in the cell. This works to stimulate the receptor, which starts changing shape, McDonnell said. That activation is more than just a switch; the shape produced by the binding of the estrogen, or estrogen mimic, with the receptor determines whether or not the genes inside will be turned on, and what response will be generated. For example, if the receptor takes on a triangular shape, it might fit like a puzzle piece into the genetic coding material inside bone cells but not to the genetic coding material inside breast cells.

"Because the effects of estrogen are unique in different tissues, it offers us a great opportunity to select the best compound to function how we want estrogen to," McDonnell said.

Working with McDonnell and Willson on the study were, from Duke, John Norris, Brandee Wagner, and Ian Aspin, all of department of pharmacology and cancer biology. Collaborators from Glaxo Wellcome were Phil Baer, Roger Brown, Stacey Jones, Brad Henke, Howard Sauls, Steve Wolfe and David Morris.

Duke University Medical Center

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