To identify and test potential drug targets for the treatment of triple-negative breast cancer.

Impact

Triple-negative breast cancer (TNBC) is a particularly aggressive form of breast cancer and while new immunotherapy drugs have shown some effectiveness in these patients, the response rate remains low. Dr. Chang and her team are testing the hypothesis that modification of the tumor microenvironment (TME, the environment surrounding a tumor) can dramatically improve the response to immune-based novel therapies. Their work may reveal new targeted therapeutic strategies for TNBC patients, who have poor outcomes due to high rates of recurrence, metastatic spread, and lack of approved targeted therapies.   

Progress Thus Far

Dr. Chang and her colleagues discovered that the drug, L-NMMA, targets a molecule known to promote tumor growth and metastasis. Laboratory studies revealed that L-NMMA plus chemotherapy was better at reducing tumor growth and lung metastasis than chemotherapy alone. In the last year, Dr. Chang reported the promising results of a phase 1/2 trial that tested L-NMMA in combination with taxane chemotherapy in patients with advanced or metastatic TNBC. Overall, 45.8 percent of patients that had some response to L-NMMA in combination with a taxane. In patients with locally advanced breast cancer, the response rate was an impressive 81.8 percent with 36.4 percent showing a complete response; and while patients with metastatic TNBC had a 15.4 percent response rate, 53.8 percent received some clinical benefit. Building on her continued interest in the role of immune cells in the TME, Dr. Chang examined the effect of the combination treatment on the levels of immune cells. They found that the levels of neutrophils were increased in patients that responded to the combination, while macrophages (another immune cell type) were increased in non-responders.  

What’s next

Further studies are planned to unravel the mechanism behind the neutrophil and macrophage shifts in responders and non-responders, and what these shifts might mean for patient response. Based on the positive results of the phase 1/2 trial, Dr. Chang concluded that L-NMMA and chemotherapy warrants further testing in larger phase 3 trials—if successful, this will move this strategy for treating TNBC and other aggressive breast cancers closer to FDA approval and give hope to these patients with limited treatment options.