A national study led by researchers at Houston Methodist has identified potential inhibitor drugs that could help treat metaplastic breast cancer (MpBC), a rare and highly aggressive form of the disease. The study, published in Nature Communications, indicates that a combination therapy of a phosphoinositide 3 kinase inhibitor (P13K) with a nitric oxide inhibitor (NOS) that is commonly used to treat septic shock, cardiovascular disease and other conditions interrupted two distinct signaling pathways of MpBC.
“This is a significant finding because it offers a promising therapeutic option for one of the most aggressive and difficult-to-treat subtypes of breast cancer,” said Jenny Chang, MD, executive vice president, president, and CEO at the Houston Methodist Academic Institute. “We have the potential to improve outcomes for patients who currently face limited treatment options and poor prognoses, marking an important step forward in cancer research and therapy.”
Metaplastic breast cancer, which often occurs as triple-negative breast cancer (TNBC), grows faster than other forms of breast cancer and is more likely to metastasize to other parts of the body. Due to its aggressive nature, it is more difficult to treat successfully and frequently recurs after initial treatment. MpBC patients often receive similar treatments as those with TNBC, but standard therapies have been show to have limited efficacy.
In this study, the Houston Methodist team, working with researchers across the country, examined human MpBC tumor samples and discovered that higher levels of NOS2 expression correlated with worse metastasis-free survival (MFS) in patients. This finding led them to propose that dual targeting of the NOS and PI3K pathways could offer a more effective treatment for MpBC, which is often resistant to conventional therapies.
The preclinical results were further supported by a phase Ib/II clinical trial evaluating the combination of L-NMMA (a NOS inhibitor) and taxane in treating patients with chemorefractory, locally advanced breast cancer (LABC), or metastatic TNBC. Tumor biopsies from responding patients revealed an increase in tumor differentiation and a decrease in cancer stem cell markers, which suggests that the combination therapy was successful in targeting the cancer’s most resilient cells.
Their findings reveal that MpBC tumors exhibit heightened co-activation of two specific signaling pathways, namely phosphoinositide 3 kinase (PI3K) and nitric oxide synthase (NOS), both of which contribute to its aggressive nature.
The researchers tested a combination of two inhibitor drugs to disrupt these pathways. The first drug, a PI3K inhibitor (alpelisib), is typically used to treat advanced cancers. The second, a nitric oxide synthase (NOS) inhibitor, is generally used to treat conditions such as septic shock and cardiovascular disease. By combining these two drugs, the researchers effectively blocked the signaling pathways that fuel MpBC tumor growth.
“Our findings highlight a promising therapeutic combination that could hopefully change the landscape of metaplastic breast cancer treatment,” said first author of the study Tejaswini Reddy, MD, PhD, a resident physician at Baylor College of Medicine. “Translating this research into a National Cancer Institute-funded clinical trial is crucial to improving outcomes for patients facing this rare and aggressive disease.”
The investigators noted that while their study is a promising step, the sample size of human tumor biopsies was small, and further research is needed to validate these results. They also pointed out the challenges of studying MpBC, given its rarity and the complexity of its molecular features. The team is now working to launch a NCI-funded clinical trial to refine the treatment strategy for MpBC which could also influence treatment regimens for other cancers where the NOS and PI3K signaling pathways are activated.
