About 50% of estrogen receptor-positive or ER+ breast cancers treated with receptor-? or ER?-targeted therapies, including tamoxifen (Nolvadex?;AstraZeneca/Soltamox?/DARA BioSciences) and fulvestrant (Faslodex?; AstraZeneca) develop resistance to these interventions. Research shows that autophagy, the basic catabolic mechanism that involves cell degradation of unnecessary or dysfunctional cellular components through the actions of lysosomes, has been implicated as a major driver ofanti estrogen resistance.[1]
Now researchers from Georgetown Lombardi Comprehensive Cancer Centersuggest that a very inexpensive anti-malarial drug, hydroxychloroquine (Plaquenil?; Sanofi) whichinhibits autophagy, reverses resistance to tamoxifen in mice. The findings of their research, which was supported by a Department of Defense Breast Cancer Research Program Postdoctoral Fellowship and awards from the US Department of Health and Human Services, are published in the June 15, 2014 issue of Clinical Cancer Research.[2]
Many people have been trying combinations of drugs to restore the ability of tamoxifen to fight breast cancer. We believe that pairinghydroxychloroquine to tamoxifenis very worthy of additional research, as well as additional clinical study…
Resistance to tamoxifen
According to the investigators, adding hydroxychloroquine to tamoxifen could provide a new treatment option for some women with advanced, postmenopausal estrogen receptor-positive (ER+) breast cancer. The ER+ subtype accounts for an estimated 70% of all breast cancers. While many of these women are treated with tamoxifen, which blocks estrogen from fueling the tumor, 50% of these cancers will either not respond or will become resistant to tamoxifen over time.
A big issue
“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, and co-director of the breast cancer program at Georgetown Lombardi.
Clarke adds that both drugs are inexpensive, on the market and have a well-defined safety profile.
Restoring cancer cell sensitivity
Hydroxychloroquine, which belongs to the quinolone family, was initially developed to treat malaria, but has since been repurposed as therapy for rheumatoid arthritis (RA) and systemic lupus erythematosus or SLE, an autoimmune disease, which canleads long-term or chronic inflammation. The study is the first to test the ability of hydroxychloroquineto restore breast cancer cell sensitivity to tamoxifen or to a different anti-estrogen drug known as faslodex.
The research team, led by first author Katherine Cook, PhD, a postdoctoral research fellow in the tumor biology department at Georgetown Lombardi, purposely set out to test hydroxychloroquinein mice with either tamoxifen or faslodex-resistant human breast cancer cells. Previous research led by Clarke and Cook found that tamoxifen resistance occurs because a pro-survival pathway is switched on in breast cancer cells. Hydroxychloroquinefunctions by turning off that very same molecular pathway, Cook explained.
Different effects
The researchers found that the combination of tamoxifen and hydroxychloroquineis more effective than faslodex and hydroxychloroquinedue to activities within the tumor’s own microenvironment. “Faslodex and tamoxifen, while both effective as antiestrogen therapies, have different effects on the immune system thus making the combination of faslodex and hydroxychloroquineless effective,” Cook noted.
“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,” she concluded.
The authors further conclude that the beneficial combination of tamoxifen and hydroxychloroquinesuggests that it may be reasonable to expect a positive outcome for ongoing neoadjuvant clinical trials using this combination for the treatment of estrogen receptor-positiveductal carcinoma in situ lesions.
For more information:
[1] Mizushima N. Autophagy: process and function. Genes Dev. 2007 Nov 15;21(22):2861-73.[Article][PubMed]
[2] Cook KL, W?rri A, Soto-Pantoja DR, Clarke PA, Cruz MI, Zwart A, Clarke R. Hydroxychloroquine Inhibits Autophagy to Potentiate Antiestrogen Responsiveness in ER+ Breast Cancer. Clin Cancer Res. 2014 Jun 15;20(12):3222-32. doi: 10.1158/1078-0432.CCR-13-3227. [Article][PubMed]
Photo: Katherine Cook, PhD, a post doctoral fellow at Georgetown Lombardi Comprehensive Cancer Center.Photo Courtesy:Georgetown University Medical Center(GUMC).
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