refers to the process where cells degrade and recycle their components. This finding suggests that targeting autophagy could be a potential strategy for treating brain metastases of breast cancer. The study also found that a specific protein, called ATG7, plays a critical role in the upregulation of autophagy in brain metastases. This protein could be a potential therapeutic target for developing new treatments for this aggressive form of breast cancer. The researchers are hopeful that these findings will lead to more effective and targeted treatments for patients with brain metastases from breast cancer.
Autophagy is a process that cancer cells can use to survive stressful conditions caused by anti-cancer drugs. Senior author Jennifer Carew, PhD, stated that the prognosis for individuals with brain metastases from breast cancer is very poor, and managing breast cancer metastases in the brain is a significant challenge. The researchers were able to prevent breast cancer cells from forming brain metastases by disrupting the autophagy pathway. In the study published in Clinical and Translational Medicine, the researchers demonstrated that targeting the key autophagy pathway could inhibit the formation of brain metastases.The ability of breast cancer cells to form brain metastases in mouse models was significantly reduced by regulating the gene ATG7. The research team aimed to develop a strategy to bring this discovery to patients and investigated whether the FDA-approved drug hydroxychloroquine could be used to treat breast cancer brain metastases. Hydroxychloroquine inhibits autophagy at a later point in the pathway and can readily cross the blood-brain barrier, which is important because most drugs do not efficiently cross this barrier, making brain metastases difficult to treat.”Great,” exclaimed Carew, a professor of medicine at the UArizona College of Medicine — Tucson and a member of the UArizona Cancer Center Clinical and Translational Oncology Program. The research team partnered hydroxychloroquine with lapatinib, an FDA-approved treatment for breast cancer. Their findings revealed that this drug combination effectively reduced the size and quantity of breast cancer brain metastases in mouse models. Hydroxychloroquine has been tested with various anticancer agents in initial phase clinical trials, but this study marks the first time researchers have analyzed its effectiveness.
This study found that the combination of everolimus and lapatinib can be effective in treating breast cancer. The researchers were surprised by the significant reduction in the ability of breast cancer cells to spread to the brain when targeting a single pathway. According to Carew, cancer cells have developed multiple ways to evade treatment, so it was unexpected to see the impact of targeting just one mechanism. The activation of autophagy has been shown to make it more difficult for cancer therapies to kill cancer cells and leads to drug resistance.
“Because hydroxychloroquine and lapatinib are already FDA approved, we can quickly move this drug combination into a clinical trial for patients with breast cancer brain metastases,” said Steffan Nawrocki, PhD, the co-director of the Cancer Center Clinical and Translational Oncology Program and a professor in the UArizona College of Medicine — Tucson. Brain metastases, which are the most common adult central nervous system tumors, are found in 20% to 30% of cases in breast cancer patients, especially those with triple negative and HER2 amplified disease. It is difficult to manage breast cancer metastases in the brain.Breast cancer brain metastases have a poor prognosis, with only 20% of patients surviving beyond five years. Co-authors of the study include Wei Wang, PhD, a professor in the R. Ken Coit College of Pharmacy; former doctoral student Trace M. Jones, PhD; Claudia M. Espitia, an assistant staff scientist in the College of Medicine — Tucson; postdoctoral fellow Maria Janina Carrera Espinoza, PhD; and doctoral students Madison E. Gamble, Sruthi Sureshkumar, and Mengyang Chang. The research was supported by the National Cancer Institute, a division of the National Institutes of Health, under Award Nos. T32CA009213, R21CA184649, R01CA190789, and R01CA268383.P30CA023074.
