Novel drug combination can target triple-negative breast cancer for treatment

While triple-negative breast cancer is relatively rare, it is more aggressive and puts patients at increased risk for metastases. Furthermore, unlike other breast cancers, the triple-negative variety holds the distinction of not expressing receptors for either estrogen, progesterone or human epidermal growth factor 2, which has impeded developing treatments tailored to the disease. And so, finding suitable biological targets for triple-negative breast cancer has been an active area of research. Many lines of evidence from preclinical triple-negative breast cancer work have pointed to an aberrance in nitric oxide signaling. Although a tiny gaseous molecule, nitric oxide is multifaceted, playing a pivotal role in vasorelaxation, transmission and inflammation. Thus, nitric oxide is an important signaling molecule in tumor microenvironments that contain a variety of cell types, including immune and endothelial cells, alongside cancer cells. Nitric oxide is synthesized by nitric oxide synthase enzymes, among which the inducible nitric oxide synthase and its mediated pathways have been implicated in triple-negative breast cancer metastases. Furthermore, Chang's previous in vitro work using triple-negative breast cancer xenografts in mice have demonstrated that suppressing inducible nitric oxide synthase with the inhibitor, NG-monomethyl-l-arginine (L-NMMA), decreased tumor growth and metastases. Motivated by these results, Chang and her team conducted a Phase I/II clinical trial to test the efficacy and toxicity of different doses of the combination of taxane and L-NMMA in treating patients with metastatic and locally advanced triple-negative breast cancers. For their study, they recruited 35 patients of which 15 were for Phase I and 24 for Phase II trial. The researchers found that the drug was well-tolerated by the patients with only 21% of patients experiencing adverse effects that were largely attributed to taxane. Further, when they analyzed the patients' serum samples for the principal metabolites of nitric oxide, nitrates and nitrites, they found a sharp reduction, pointing to a successful on-target effect of the treatment. Patients with locally advanced breast cancer, who before the clinical trials were unresponsive to chemotherapy, were the most responsive to the treatment, having a response rate of 81% with 27% showing no residual disease at surgery. On the other hand, patients with metastatic breast cancer had a response rate of 15.4%.