Feature Story

Osteoporosis drug may be a promising treatment for therapy-resistant breast cancer

DOE/Argonne National Laboratory

Clinical trials are underway after scientists using the Advanced Photon Source found lasofoxifene may be a safer and more effective treatment for breast cancer than the current gold standard.

In 2020, 2.3 million women worldwide were diagnosed with breast cancer, according to the World Health Organization, and the disease caused 685,000 deaths. Treatments can be highly effective, but medical professionals are constantly searching for more effective methods to slow the growth and spread of breast cancer tumors.

A team of scientists from the University of Chicago has found that lasofoxifene, a drug used to treat osteoporosis, may be one of those more effective treatments. In a study published in Breast Cancer Research, the team found that lasofoxifene outperformed fulvestrant, the current gold-standard drug, in reducing or preventing primary breast cancer tumor growth in mice.

The drug also was more effective at preventing metastasis in the lung, liver, bone and brain — the four most common areas for breast cancer to spread. Additionally, while fulvestrant and similar drugs often cause unwanted, menopausal-like side effects, lasofoxifene did not produce some of these symptoms in mice.

“People should be very excited about this,” said Geoffrey Greene, chair of the Ben May Department for Cancer Research at the University of Chicago and senior author on the paper. “In addition to being more effective, this drug is better able to treat the whole person, including bone density and some other symptoms, such as vaginal atrophy.”

The research team used the Advanced Photon Source (APS), a U.S. Department of Energy Office (DOE) of Science User Facility at the DOE’s Argonne National Laboratory, to confirm that lasofoxifene binds to estrogen receptor molecules. About 75% of breast cancers are estrogen receptor positive, or ER-positive. This means that cancer cells have receptors that respond to the hormone estrogen and use it to feed the tumor and cause it to grow.  

The APS uses ultrabright X-rays to illuminate the structures of proteins like estrogen receptors, often looking to see if drug compounds attach themselves to these proteins. Structures were determined at the Structural Biology Center (SBC) and at the South-East Regional Collaborative Access Team beamlines. 

“We provided facilities to help determine structures of the drug with estrogen receptors,” said SBC Director Andrzej Joachimiak of Argonne and the University of Chicago. “It’s rare to find a drug compound that shows such high promise of becoming a treatment. This is potentially a very important discovery.”  

While effective, drugs like fulvestrant can cause side effects similar to menopause, including bone density loss, hot flashes and vaginal atrophy.

“You get these undesirable side effects that really make people unhappy,” Greene said.

Previous observational studies on lasofoxifene had found that, in addition to preventing bone loss, it was also effective at preventing breast cancer, reducing the incidence of ER-positive breast cancer by around 80%, compared to other drugs.

“It has a good safety profile, maintains bone density, prevents vaginal dryness and doesn’t increase the risk of uterine cancer,” Greene said.

But while it was clear that lasofoxifene could help prevent breast cancer, it was not yet known whether it also had tumor-fighting properties.

University of Chicago researchers worked with mice that had ER-positive breast cancer tumors with activating ER mutations. They treated some of the mice with lasofoxifene and others with fulvestrant. They also tested both drugs in combination with palbociclib, a common chemotherapy drug that works by preventing cancer cells from multiplying.

They found that lasofoxifene was more effective than fulvestrant at preventing tumor growth and reducing metastases when used on its own. Adding palbociclib improved the effectiveness of both drugs, but once again, the lasofoxifene/palbociclib combination was more effective.

“This study demonstrated that lasofoxifene seems to be superior, both alone, as well as in combination, compared to fulvestrant,” Greene said.

In addition to having fewer side effects, lasofoxifene offers several other noteworthy benefits. Unlike fulvestrant, which is injected, lasofoxifene can be taken orally. It also has a long half-life, which means it lingers in the body for a long time.

“What you want is that every time a new estrogen receptor is synthesized, especially if it has a mutation, that there’s a drug there to block it,” Greene explained. “One of the advantages of lasofoxifene is that it’s more likely to be there to do its job.”

phase 2 clinical trial is now underway at University of Chicago Medicine to study lasofoxifene as a second-line treatment in postmenopausal women with ER positive metastatic breast cancers that have ER mutations. A separate clinical trial, now enrolling patients, will study lasofoxifene in combination with abemaciclib, a chemotherapy drug similar to palbociclib.

“Most women with ER-positive metastatic breast cancer right now are treated with fulvestrant, and based on our study, I don’t think it’s the best drug for this purpose,” said Muriel Laine, a research associate in the Ben May Department and lead author on the study. “Lasofoxifene definitely appears to be more promising for these women.”

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A version of this release was originally published by University of Chicago Medicine.

The study was supported by Sermonix Pharmaceuticals and the U.S. Department of Energy, Office of Biological and Environmental Research (DE-AC02-06CH11357). Additional authors include Ya-Fang Chang, Bradley Green, Marianne E. Greene, Justyna D. Kurleto and Linda Phung of UChicago; Sean W. Fanning of Loyola University Chicago; and Barry Comm of Komm-Sandin Pharma Consulting.


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