Clinical trials are underway after scientists using the advanced photon source discovered that 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 very effective, but healthcare professionals are constantly looking for more effective ways to slow the growth and spread of breast cancer tumors.
A team of scientists from the University of Chicago have found that lasofoxifene, a drug used to treat osteoporosis, may be one of these most effective treatments. In a study published in Breast Cancer Research, the team found that lasofoxifene outperformed fulvestrant, the current benchmark drug, in reducing or preventing primary tumor growth of breast cancer in mice.
The drug was also more effective at preventing metastasis to the lungs, liver, bones and brain – the four most common areas where breast cancer spreads. Additionally, while fulvestrant and similar drugs often cause unwanted side effects similar to menopause, lasofoxifen did not produce some of these symptoms in mice.
“People should be very excited about this,” said Geoffrey Greene, chair of the Ben May cancer research department at the University of Chicago and lead author of the article. “Besides being more effective, this medicine is better able to treat the whole person, including bone density and certain other symptoms, such as vaginal atrophy.”
The research team used the Advanced Photon Source (APS), a U.S. Department of Energy (DOE) science facility at DOE’s Argonne National Laboratory, to confirm that lasofoxifen 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 nourish the tumor and make it grow.
APS uses ultra-bright x-rays to illuminate structures of proteins like estrogen receptors, often looking to see if drug compounds attach to these proteins. The structures were determined at the Center for Structural Biology (SBC) and the beamlines of the Southeast Regional Collaborative Access Team.
“We have provided facilities to help determine the structures of the drug with estrogen receptors,” said Andrzej Joachimiak, director of SBC Argonne and the University of Chicago. “It is rare to find such a promising drug compound to become a treatment. This is potentially a very important finding.
Although effective, drugs like fulvestrant can cause side effects similar to menopause, including loss of bone density, hot flashes, and vaginal atrophy.
“You get these unwanted side effects that really make people miserable,” Greene said.
Previous observational studies of lasofoxifene had shown that in addition to preventing bone loss, it was also effective in preventing breast cancer, reducing the incidence of ER-positive breast cancer by approximately 80%, compared to other drugs.
“It has a good safety profile, maintains bone density, prevents vaginal dryness, and does not increase the risk of uterine cancer,” Greene said.
But while it was clear that lasofoxifen could help prevent breast cancer, it was not yet clear whether it had anti-tumor properties as well.
Researchers at the University of Chicago worked with mice with ER-positive breast cancer tumors with activating ER mutations. They treated some of the mice with lasofoxifene and others with fulvestrant. They also tested the two 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 in preventing tumor growth and reducing metastasis when used alone. The addition of palbociclib improved the effectiveness of both drugs, but again the lasofoxifene / palbociclib combination was more effective.
“This study demonstrated that lasofoxifene appears to be superior, both alone and in combination, compared to fulvestrant,” Greene said.
Besides having fewer side effects, lasofoxifene offers several other notable benefits. Unlike fulvestrant, which is injected, lasofoxifene can be taken orally. It also has a long half-life, which means that it persists 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, there is a drug to block it,” Greene explained. “One of the advantages of lasofoxifene is that it is more likely to be there to do its job.”
A phase 2 clinical trial is now underway at the University of Chicago Medicine to study lasofoxifene as a second-line treatment in postmenopausal women with ER-positive metastatic breast cancers who have ER mutations. A separate clinical trial, which is currently recruiting 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, research associate in the Ben May department and lead author of the study. “Lasofoxifene definitely seems to have more promise for these women.”
A version of this version was originally released by Chicago Medical University.
The study was supported by Sermonix Pharmaceuticals and the US Department of Energy, Bureau 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 in Chicago; and Barry Comm from Komm-Sandin Pharma Consulting.