Osteoporosis Drug Stops Growth of Breast Cancer Cells, Even in Resistant Tumors

Presented on June 15, 2013, at the annual Endocrine Society meeting in San Francisco (CA, USA), the findings demonstrate that the drug bazedoxifene triggers a formidable one-two punch that not only blocks estrogen from promoting breast cancer-cell growth, but also targets 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, chair of Duke Cancer Institute’s (Durham, NC, USA) department of pharmacology and cancer biology.

In animal and cell culture studies, the drug suppressed 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, 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 an agent that, similar to tamoxifen, belongs to a class of drugs known as specific estrogen receptor modulators (SERMs). These drugs act like estrogen in some tissues, while substantially blocking estrogen action in other tissues. However, unlike tamoxifen, bazedoxifene has some of the characteristics of a newer group of drugs called 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 lab. Many researchers had presumed that once breast cancer cells developed resistance to tamoxifen; however, “We discovered that the estrogen receptor is still a good target, even after it resistance to tamoxifen has developed,” he said.

The investigators evaluated a range 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 strongly inhibited cell growth.

Ironically, in bone tissue, bazedoxifene mirrors the action of estrogen, helping protect it from destruction. Because bazedoxifene has already undergone safety and effectiveness studies as a treatment for osteoporosis, it may be a feasible near-term alternative for patients with advanced breast cancer whose tumors have become resistant to other treatment approaches, Dr. Wardell reported. In clinical trials, the most frequently reported side effect was hot flashes in the bazedoxifene treatment groups.

The study was funded by a research grant from Pfizer Pharmaceuticals (New York, NY, USA), maker of bazedoxifene.

Related Links:
Duke Cancer Institute