Posted October 30, 2014
Katherine Cook, Ph.D., Georgetown University
About 70% of breast cancer cases are estrogen receptor positive (ER+) and the standard of care for these patients is endocrine therapy, which includes tamoxifen or fulvestrant. Up to 50% of breast cancer patients will develop resistance to these endocrine treatments due to either de novo or acquired resistance. Endocrine resistance is not well understood but needs to be addressed in the hopes of developing new therapeutic options for patients.
Dr. Katherine Cook, under the mentorship of Dr. Robert Clarke and with funding from an FY11 BCRP Postdoctoral Award, is studying why ER+ breast cancer becomes resistant to ER-targeted therapies like tamoxifen or fulvestrant. She is investigating the possibility that autophagy - a biological mechanism that allows the cell to degrade unnecessary or damaged cellular components - may help the cancer cells survive the treatments. This process has been found to be increased in endocrine-resistant BC cell lines. Studies in ER+ breast cancer cells have also shown that both tamoxifen and fulvestrant treatments can induce autophagy.
Dr. Cook tested the use of an autophagy inhibitor, hydroxychloroquine (HCQ), to convert endocrine-resistant cells to endocrine-sensitive cells. Hydroxychloroquine has been used for many years to treat malaria as well as other conditions. Dr. Cook found that treating tamoxifen-resistant breast cancer cell lines with HCQ resensitized the cells to tamoxifen. She also tested the use of HCQ with tamoxifen or fulvestrant against established endocrine-resistant tumors in an orthotopic mouse model. Interestingly, the combination of ICI 182, 780 (fulvestrant) and HCQ was less effective than HCQ alone at inhibiting tumor growth. However, the combination of tamoxifen and HCQ was able to restore anti-estrogen sensitivity and reduce tumor growth. Dr. Cook's research suggests the potential for clinical benefit for patients with ER+ breast cancer by combining HCQ with anti-estrogen therapy. An ongoing BCRP-funded clinical trial (www.clinicaltrials.gov; NCT01023477) examining the effect of tamoxifen and HCQ in ER+ breast cancer may provide further clinical evidence to support this new treatment modality.
Cook KL, Wärri A, Soto-Pantoja DR, et al. 2014. Hydroxychloroquine inhibits autophagy to potentiate antiestrogen responsiveness in ER+ breast cancer. Clin Cancer Res 20(12):3222-3232.