New Therapy for Triple-negative Breast Cancer Shows Promise in Laboratory Studies

Recent laboratory findings provide novel insight into potential new therapeutic approaches for triple-negative breast cancer, a particularly difficult-to-treat and aggressive form of the disease. In a recent study published in Clinical Cancer Research (2015; doi:10.1158/1078-0432.CCR-15-0187), scientists demonstrated in preclinical experiments that the drug cabozantinib inhibits growth of several triple-negative breast cancer subtypes.

"Triple-negative breast cancer accounts for 15% to 20% of all breast cancer cases, yet is responsible for a disproportionate number of cancer-related deaths," said corresponding author Carrie Graveel, PhD, research assistant professor at the Van Andel Research Institute (VARI) in Grand Rapids, Michigan.

"This higher mortality rate is due to a lack of targeted therapies, the disease's aggressive nature, and the diverse cell population that comprises the tumor. It is crucial we develop better diagnostic tests and an array of targeted therapies to better classify cancer subtypes and effectively treat the disease on a patient-by-patient basis."

Triple-negative breast cancer is resistant to many current therapies because it lacks the three major receptors, or proteins that receive and transmit messages to and from the cell, that are present in other forms of the disease. These proteins—estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (HER2)—are targets for many common breast cancer treatments. Their absence in triple-negative disease eliminates many of the treatment options available to patients with other types of breast cancer, underscoring the importance of developing new, more targeted therapies.

"In this study, we used two complementary preclinical models to analyze drug responses of the tumor in the context of interactions with its microenvironment, which is known to contribute to malignancy," said co-senior author Bonnie Sloane, PhD, of Wayne State University in Detroit, Michigan. "These types of analyses may identify novel pathways for therapeutic intervention."

One target of cabozantinib is the MET protein, which drives many of the processes that make cancer aggressive and challenging to treat, including invasion of other tissues, proliferation, and survival of cancer cells. MET is overexpressed in 20% to 30% of all breast cancer cases, and is typically associated with a poor outcome. In a 2009 paper, Graveel and VARI's George Vande Woude, PhD, demonstrated that MET is expressed in triple-negative breast cancer and is a potential therapeutic target.

In addition, cabozantinib, discovered and developed by Exelixis Inc, is the subject of ongoing clinical trials in advanced kidney and liver cancers, and is approved to treat metastatic medullary thyroid cancer.

Preclinical experiments demonstrated that cabozantinib impedes triple-negative breast cancer progression and spread by inhibiting the MET protein. Graveel's and Sloane's laboratories used unique cancer models that included both breast cancer cells and the connective tissue cells that often support cancer growth. Their findings not only provide evidence for cabozantinib's therapeutic potential for triple-negative breast cancer, but also imply that MET plays a crucial role in growth and invasion by triple-negative cancer cells.

Graveel and Sloane plan to continue exploring the potential of MET inhibitors as therapies for triple-negative breast cancer in addition to conducting further analysis on their models to define characteristics that may be used as diagnostic tools.

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