Abstract 4912: Effect of the combined treatment with mifepristone and chemotherapy on breast cancer brain metastases

Abstract

Abstract The treatment of brain metastasis is limited due to the drug’s inability to cross the blood brain barrier, because of the presence of endothelial cells’ multidrug resistance efflux transporters, such as the P-glycoprotein (P-gp). The antiprogestin Mifepristone (MFP) is known to inhibit the P-gp activity. We hypothesize that a combination of MFP and Pegylated doxorubicin liposomes (doxo) improves the drug efficacy on breast tumors that do not express progesterone receptors. Using the metastatic triple negative MDA-231-BrM2 breast cancer cell line, transfected with GFP and luciferase, we explored different protocols to generate tumors growing in the brain of NSG mice. Spontaneous metastases were obtained by subcutaneous injection (sc) of 2 x 106 cells, and experimental metastases by intracardiac injection (ic) of 1 x 106 cells or by intracranial injection of 2 x 105 cells. In the ic and sc models small and scattered brain metastases as well as liver, lung and kidney metastases were observed. The intracranial model enabled us to obtain measurable brain tumors in a short time. Thus we selected this method to evaluate the effect of MFP (6 mg pellets, sc) and /or doxo (4,5 mg/kg, iv) on tumors growing in the brain. Treatment was initiated 10 days after cell inoculation. The amount of tumor cells after brain excision was measured by flow cytometry (GFP) and by luminometry (luciferase activity). A decreased luminescence signal was observed in brains from mice treated with both agents as compared with the control mice (p<0.05), whereas no effects were observed between the single treatment groups and the controls. Moreover, the flow cytometry analysis showed that the combined treatment, MFP+doxo, reduced the number of tumor cells further than the single chemotherapeutic agent (p<0.05). Our data suggest that MFP may be a promising agent to treat brain metastasis of breast cancers, which do not necessarily express progesterone receptors, to increase the effectiveness of chemotherapeutic agents. The participation of the P-gp mediating this effect needs to be confirmed. Citation Format: Ayelen Rubin, Veronica de la Fuente, Edgardo Salvatierra, Silvia Vanzulli, Osvaldo Podhajcer, Claudia Lanari, Paola Rojas. Effect of the combined treatment with mifepristone and chemotherapy on breast cancer brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4912. doi:10.1158/1538-7445.AM2017-4912