Researchers from the University of Arizona Cancer Center at UArizona Health Sciences have identified a biological mechanism that could lead to more effective treatments for breast cancer metastasis to the brain. The study focused on the metabolic differences between primary breast cancer cells and those that spread to the brain, revealing that autophagy, a cellular recycling process, was significantly upregulated in brain metastases. This discovery sheds light on how cancer cells can survive under stressful conditions triggered by anticancer drugs.
Senior author Jennifer Carew, PhD, emphasized the unfavorable prognosis for individuals with brain metastases from breast cancer and the challenges in managing these metastases. By impairing the autophagy pathway in breast cancer cells, the researchers were able to disrupt the formation of brain metastases. Targeting the key autophagy regulating gene ATG7 significantly reduced the ability of breast cancer cells to spread to the brain in mouse models, providing a potential treatment strategy for patients.
The research team investigated the use of hydroxychloroquine, an FDA-approved drug that inhibits autophagy, in combination with lapatinib, an FDA-approved drug for breast cancer treatment. The combination of these drugs successfully reduced the number and size of breast cancer brain metastases in mouse models. Hydroxychloroquine’s ability to cross the blood-brain barrier makes it a promising candidate for treating brain metastases, which are often difficult to treat due to limited drug penetration into the brain.
While hydroxychloroquine has been combined with other anticancer agents in early-phase clinical trials, this study is the first to evaluate its effectiveness when combined with lapatinib for breast cancer therapy. Carew highlighted the significant impact of targeting a single pathway in diminishing the ability of breast cancer cells to form brain metastases. The research findings suggest that by inhibiting autophagy, cancer cells become more susceptible to treatment, potentially overcoming drug resistance.
The study’s first author, Steffan Nawrocki, PhD, explained how the activation of autophagy in cancer cells can hinder the effectiveness of various cancer therapies, leading to drug resistance. By leveraging the FDA-approved status of hydroxychloroquine and lapatinib, the research team aims to quickly advance this drug combination into clinical trials for patients with breast cancer brain metastases. Brain metastases are a common complication in breast cancer patients, particularly those with triple-negative and HER2-amplified disease, and have a poor prognosis with only 20% of patients surviving beyond five years.
The study was a collaborative effort involving researchers from different disciplines, including pharmacology and oncology. The research was supported by the National Cancer Institute, a division of the National Institutes of Health, highlighting the importance of continued funding for innovative research in cancer treatment. This promising study provides new insights into the biological mechanisms of breast cancer brain metastasis and offers a potential targeted therapy that could improve outcomes for patients facing this challenging condition.
