Tamoxifen is a widely used breast cancer drug but some women with advanced, postmenopausal estrogen receptor-positive (ER+) breast cancer
don't respond to it.
A study in Clinical Cancer Research found that the inexpensive anti-malarial drug hydroxychloroquine (HCQ) reverses resistance to tamoxifen in mice, meaning that adding HCQ to tamoxifen could provide a new treatment option for women with the ER+ subtype, which accounts for an estimated 70 percent of all breast cancers. While many of these women are treated with tamoxifen, which blocks estrogen from fueling the tumor, 50 percent of these cancers will either not respond or will become resistant to tamoxifen over time.
"Tamoxifen resistance when treating breast cancer is a big issue in the clinic, and we believe our findings provide a very promising fix to the problem," says the study's senior investigator, Robert Clarke, PhD, DSc, dean for research at Georgetown University Medical center.
HCQ was developed to treat malaria, but has since been repurposed as therapy for rheumatoid arthritis and lupus. The study is the first to test HCQ's ability to restore breast cancer cell sensitivity to tamoxifen or to a different anti-estrogen drug known as faslodex.
Both drugs are inexpensive, on the market and have a well-defined safety profile.
The research team set out to test HCQ in mice with either tamoxifen or faslodex-resistant human breast cancer cells. Previous research found that tamoxifen resistance occurs because a pro-survival pathway is switched on in breast cancer cells. HCQ functions by turning off that very same molecular pathway, Cook says.
The researchers found that the combination of tamoxifen and HCQ is more effective than faslodex and HCQ due to activities within the tumor's microenvironment.
"Faslodex and tamoxifen, while both effective as antiestrogen therapies, have different effects on the immune system thus making the combination of faslodex and HCQ less effective," says first author Katherine Cook, PhD, a postdoctoral research fellow in the tumor biology department at Georgetown Lombardi. "Many people have been trying combinations of drugs to restore the ability of tamoxifen to fight breast cancer. We believe this pairing is very worthy of additional research, as well as clinical study."