Jenny C. Chang, MD

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 is investigating new therapeutic strategies that may expand the arsenal of tools for treating this aggressive subtype of breast cancer. She has designed two experimental approaches to move towards this end. The first approach investigates a novel and promising regimen against metaplastic breast cancer (MpBC), a rare but highly chemotherapy-resistant breast cancer that is often triple-negative and associated with a higher rate of recurrence and poorer overall survival. The second approach is to target nitric oxide synthase (NOS) in combination with chemotherapy for treating TNBC. Her team has established state-of-the-art laboratory models to test both approaches. 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 a nitric oxide synthase inhibitor, targets a molecule known to promote tumor growth and metastasis. Using their previously developed laboratory models, they found that L-NMMA plus chemotherapy was better at reducing tumor growth and lung metastasis than chemotherapy alone. Results from an early phase clinical trial also demonstrated benefit of L-NMMA in combination with taxane chemotherapy in patients with advanced or metastatic TNBC. The benefit was greatest in patients with locally advanced breast cancer, with a complete response – no evidence of tumor – in about one-third of patients. Studies are underway to determine the mechanism of action of this combined treatment. In the last year, Dr. Chang’s team focused on the iNOS pathway’s role in the poor outcomes observed in obese patients with TNBC. Using sophisticated models they developed, the team found obesity exacerbates TNBC outcomes, possibly through chronic inflammation and modulation of iNOS pathways. Furthermore, iNOS inhibition could reverse some obesity-associated effects. A second set of studies tested iNOS inhibition in combination with an antibody-drug conjugate (ADC) to treat another aggressive disease, inflammatory breast cancer (IBC). They showed that iNOS inhibition enhances ADC therapy and reduces the metastatic potential of IBC.

What’s next

Based on the positive phase I/II clinical results, Dr. Chang believes that L-NMMA and chemotherapy warrant further clinical 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. The team will also follow up on the studies examining chronic inflammation and modulation of iNOS pathways in the models of obesity-associated TNBC as well as take a deeper dive into the results with ADC therapy and IBC. Together, results of these novel studies may expand the arsenal of treatment strategies in the most aggressive breast cancers, TNBC and IBC.