Duke/Novalon researchers identify potential mechanism behind tamoxifen resistance in breast cancers

July 30, 1999

DURHAM, N.C. -- Scientists have identified a likely reason why the breast cancer drug tamoxifen stops working in women who use it for more than five years. They say their discovery could lead to new drugs that either work better than tamoxifen or prevent a woman's resistance to the drug.

The researchers, from Duke University Medical Center and Novalon Pharmaceutical Corp., reported in the July 30 issue of Science that tamoxifen initiates a cascade of changes inside the breast cell that are far different from the effects of estrogen or other compounds that rouse the estrogen receptor into action.

Tamoxifen's desired action is to block the effects of estrogen, a hormone involved in the growth of half of all breast cancers. It works by binding to the estrogen receptor and blocking estrogen from docking to it. Hence, tamoxifen has been called an "anti-estrogen." Later, however, tamoxifen begins to lose its effectiveness, and researchers have long wondered why.

Now, they have learned that instead of acting like either an estrogen or an anti-estrogen, tamoxifen has its own distinct properties that drive the cell's estrogen receptor into a different shape than estrogen or other estrogen "mimics" would. The shape the receptor takes determines how the cell will behave and what activity it will generate.

In the case of tamoxifen, the researchers found that it causes the estrogen receptor in breast cells to form an additional and unique "pocket" or surface -- a place where other proteins inside the cell can bind to or dock themselves. While these proteins have yet to be identified, the researchers say their action of binding to this new pocket on the receptor is what changes the cell's response to tamoxifen. For reasons unknown, the cells then begin to see tamoxifen as an estrogen instead of an anti-estrogen, and hence the cancer once again proliferates.

"The implications of our discovering this new pocket formed by tamoxifen are quite exciting," said Donald McDonnell, a Duke pharmacologist and lead author of the study report. "What this means is we can develop new drugs that target the estrogen receptor but don't form this new pocket when they attach to it. On the other hand, we can also develop a drug that will bind to this pocket and block it, thereby preventing undesirable proteins from binding to it while the woman is on tamoxifen."

Although the pocket forms from the time tamoxifen is administered to the cell, the researchers believe that tamoxifen resistance begins when the elusive protein binds to this new site. What happens next to cause resistance is unclear, but researchers have shown they can block resistance by plugging up the pocket with other proteins, two of which have been identified by researchers at Novalon.

But the main thrust of drug development lies in targeting the estrogen receptor with new drugs that avoid the resistance problem altogether, McDonnell said.

Already, he said he is testing a new drug that shares some of the properties of estrogen and tamoxifen but poses fewer risks and side effects. Even if that new drug comes to the forefront, McDonnell said tamoxifen will remain a front-line defense against breast cancer because it is a "tried and true" treatment that doctors nationwide are accustomed to using.

"We can attack the tamoxifen resistance problem from two fronts: a completely new drug that has all the benefits of tamoxifen but does not induce resistance, and a drug derived from a protein that blocks the estrogenic properties of tamoxifen," said McDonnell. "Both are plausible next steps in the fight against estrogen-sensitive breast cancers."

The field of hormone replacement therapy is a hot one, McDonnell said, because estrogen plays such an important role in the health and well-being of all women. The presence of estrogen exposure has been linked to breast and uterine cancer, and estrogen deficiency has been linked to osteoporosis, heart disease and cognitive decline.

McDonnell said finding a drug that offers the best of both worlds is the goal of his research. Such drugs are known as selective estrogen receptor modulators (SERMs) because they act like estrogen in some tissues but not in others.

Tamoxifen is called a SERM because it acts like estrogen in the bones but as an anti-estrogen in breast tissues -- at least, at first. But over time, breast cells begin to see tamoxifen as an estrogen, the very hormone that is essential to the growth of many breast cancers. Once this switch-over is made -- after about five years of use -- the cancer is no longer suppressed and it begins to proliferate once again.

Scientists have long wondered why breast cells change their response to tamoxifen over time. McDonnell said the new findings provide the first real evidence as to how this occurs and how to circumvent it.

"This research program with Duke scientists has exploited the strengths of Duke's cutting edge basic science and Novalon's drug discovery program," said Dana M. Fowlkes, chairman and chief scientific officer of Novalon. "We were delighted to find that our technical approach to genomic-based drug discovery could be used to understand why drugs like tamoxifen fail, as well as to provide a path to new drugs that may offer hope to these cancer patients." Based in Research Triangle Park, researchers at Novalon tested billions of different peptides -- small proteins that bind to receptors -- to determine how each one interacted with the estrogen receptor while in the presence of different drugs. McDonnell suspected that different peptides would interact differently with the estrogen receptor when it was bound with either estrogen or tamoxifen, so the researchers analyzed what effect each peptide had on the receptor.

"What we found were peptides that were common to both estrogen and tamoxifen, and peptides that were unique to each," said McDonnell. "This told us that tamoxifen has the ability to do something totally unique from what estrogen does, and that tumors which are resistant to tamoxifen may not be resistant to other SERMs."

Moreover, said McDonnell, it implies that SERMs and estrogen all have certain properties in common, but they each have their own distinct properties as well.

"It opens up the field of drug development into limitless possibilities, now that we have a better understanding that each SERM does something unique to the estrogen receptor," McDonnell said. "The ideal outcome would be to develop a drug to treat breast cancer and one that high-risk women could take to prevent breast cancer."

McDonnell said his next step is to further test his new SERM to determine its safety and efficacy in animals and humans.
-end-


Duke University Medical Center

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