Osteoporosis drug stops growth of breast cancer cells, including resistant cells

A drug approved in Europe to treat osteoporosis has been shown to stop the growth of breast cancer cells, even in tumors that developed resistance to current targeted therapies, according to a new study. The findings were presented at the annual meeting of The Endocrine Society in San Francisco, California, on June 15, 2013.

The study found that the drug bazedoxifene not only prevents estrogen from fueling breast cancer cell growth, but also flags the estrogen receptor for destruction.

"We found bazedoxifene binds to the estrogen receptor and interferes with its activity, but the surprising thing we then found was that it also degrades the receptor; it gets rid of it," said senior author Donald McDonnell, PhD, of Duke University in Durham, North Carolina.

In animal and cell culture studies, the drug inhibited growth both in estrogen-dependent breast cancer cells and in cells that had developed resistance to the antiestrogen tamoxifen and/or to the aromatase inhibitors. These are two of the most widely used types of drugs to prevent and treat estrogen-dependent breast cancer. Currently, if breast cancer cells develop resistance to these therapies, patients are usually treated with toxic chemotherapy agents that have significant side effects.

Bazedoxifene is a pill that, like tamoxifen, belongs to a class of drugs known as specific estrogen receptor modulators (SERMs). These drugs are distinguished by their ability to behave like estrogen in some tissues, while significantly blocking estrogen action in other tissues. But unlike tamoxifen, bazedoxifene has some of the properties of a newer group of drugs, known as selective estrogen receptor degraders (SERDs), which can target the estrogen receptor for destruction.

"Because the drug is removing the estrogen receptor as a target by degradation, it is less likely the cancer cell can develop a resistance mechanism because you are removing the target," said lead author Suzanne Wardell, PhD, a research scientist working in McDonnell's laboratory.

Many investigators had assumed that once breast cancer cells developed resistance to tamoxifen, they would be resistant to all drugs that target the estrogen receptor, McDonnell explained.

"We discovered that the estrogen receptor is still a good target, even after resistance to tamoxifen has developed," he said.

The investigators tested a variety of breast cancer cell types, including tamoxifen-sensitive cells that are resistant to the drug lapatinib, another targeted therapy that is used to treat patients with advanced breast cancer whose tumors contain the mutant HER2 gene. These cells had previously been shown to reactivate estrogen signaling in order to acquire drug resistance. In this cell type, bazedoxifene also potently inhibited cell growth.

Because bazedoxifene has already undergone safety and efficacy studies as a treatment for osteoporosis, it may be a viable near-term option for patients with advanced breast cancer whose tumors have become resistant to other treatment options, Wardell reported. In clinical trials, the most often reported side effect in the bazedoxifene treatment groups was hot flashes.
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