Abstract 3779: Treatment of experimental brain metastasis of human breast cancer by macitentan, a dual antagonist of endothelin receptors combined with paclitaxel

Abstract

Abstract Purpose: Breast cancer is a leading cause of cancer-related mortality among women in the United States. The major cause of death is due to metastasis that is resistant to conventional therapy. The median survival of women with brain metastases is measured in months due to resistance to all standard therapies. Thus, the development of effective treatment options for these patients is mandatory. We have reported that astrocytes can protect tumor cells from chemotherapeutic drugs by a mechanism involving the phosphorylation of endothelin receptors on tumor cells (Kim et al, AACR, 2012). Moreover, we observed a heterogeneous expression of endothelin receptors A and B in clinical samples of breast cancer brain metastasis. We therefore examined whether blockade of the endothelin axis by using macitentan, a dual endothelin antagonist, combined with paclitaxel can produce therapeutic effects in an orthotopic model of human breast cancer brain metastasis. Materials and Methods: Twenty thousand MDA-MB-231 human breast cancer cells were injected into the internal carotid artery of female nude mice to produce orthotopic brain metastasis. Two weeks later, the mice were randomized into 4 groups (n=10): (1) control group - mice receiving vehicle (p.o., daily; i.p. injection once per week); (2) paclitaxel group - mice receiving paclitaxel (8 mg/kg; i.p. injection once per week) and vehicle (p.o.; daily); (3) macitentan group - mice receiving macitentan (10 mg/kg; p.o.; daily) and vehicle (i.p. injection, once per week); and (4) paclitaxel plus macitentan group. Moribund mice were euthanized, days of survival were recorded, and the brains were harvested and processed for histology and immunohistochemical analyses. The study was repeated with luciferase-labeled MDA-MB-231 cells and produced similar therapeutic results supported by IVIS imaging. Results: After 130-140 days of treatment, the survival was significantly higher in mice treated with the combination of paclitaxel and macitentan (80%) as compared with control (20%), paclitaxel (20%), and macitentan alone (40%) (p<0.0001, log-rank test). Immunohistochemical analyses revealed that the phosphorylation of endothelin receptors A and B on tumor cells and tumor-associated endothelial cells were inhibited by macitentan. Treatment with macitentan also suppressed the expression of survival proteins such as pAKT, pMAPK, BCL2L1, TWIST1, and GSTA5 in tumor cells. More importantly, only the combination therapy induced significant apoptosis of tumor cells and tumor-associated endothelial cells and reduced the number of KI67 positive tumor cells. IVIS imaging confirmed regression of brain lesions. Conclusion: Treatment with macitentan, a dual endothelin receptor antagonist, combined with paclitaxel leads to regression of experimental breast cancer brain metastasis and therefore should be considered for clinical development. Citation Format: Ho Jeong Lee, Sun Jin Kim, Seung Wook Kim, Junqin He, Qiuyu Wu, Erica J. Lawson, Francois Lehembre, Urs Regenass, Isaiah J. Fidler. Treatment of experimental brain metastasis of human breast cancer by macitentan, a dual antagonist of endothelin receptors combined with paclitaxel. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3779. doi:10.1158/1538-7445.AM2014-3779