Abstract 1998: Selinexor effectively inhibits tumor growth in a triple negative breast cancer brain metastasis mouse model

Abstract

Abstract Introduction: Breast cancer brain metastasis (BCBM) is a devastating disease and remains largely incurable. Patients with triple negative breast cancer (TNBC) develop brain metastasis at a significantly higher incidence (46%) than patients with other breast cancer subtypes. Median survival after brain metastases in TNBC can be as short as 5 months. Selinexor is a first-in-class oral SINE (Selective Inhibitor of Nuclear Export) drug that inhibits XPO1 (exportin-1/ CRM1) activity and exhibits remarkable anti-cancer activity in advanced clinical trials. Moreover, selinexor can penetrate the blood-brain barrier and shows promising anti-tumor activity in animal models of glioblastoma and central nervous system lymphoma. Previous studies have shown that most TNBC cell lines tested in vitro and in vivo are sensitive to selinexor-induced growth inhibition and cell death. To explore the possibility of using selinexor as an effective treatment for TNBC brain metastasis, a mouse model was established and tested. Methods: TNBC cell line HCC1806 (ATCC# CRL-2335) was transformed with RediFect Red-Fluc-Puromycin and selected using puromycin to generate HCC1806-Fluc cells that expressed both puromycin resistance gene and a luciferase gene. Twenty-four nu/nu mice were inoculated intracranially with 1 x 104 HCC1806-Fluc cells. Four days post implant, mice were allocated to three groups of eight mice and treated with either vehicle, selinexor 10 mg/kg, or selinexor 15 mg/kg through oral gavage, three times per week (Mon, Wed, Fri). Body weight and condition of animals were recorded daily, and tumors were imaged twice per week (Tue and Thu). Brain tissues were collected at the end of study and analyzed by immunohistochemistry (IHC). Results: HCC1806-Fluc cells injected intracranially successfully implanted in the brains of host mice. All mice survived the duration of the study (day 16 after treatment initiation) and no significant difference in body weight was observed between different treatment groups. Mice treated with selinexor had a significant reduction in tumor area relative to vehicle controls. Tumor growth inhibition (TGI) was 103% for selinexor at 10 mg/kg and 97% for selinexor at 15 mg/kg compared to vehicle controls. IHC showed reduced tumor cell proliferation, decreased expression of Myc and Survivin, and increased nuclear expression of p21 and p27 in tumor samples from the brain of mice treated with selinexor as compared to that of controls. Decreased expression of HDAC1 and HDAC5 was also observed in brain tumor samples from selinexor-treated mice. Conclusions: Oral intake of selinexor effectively inhibited TNBC cell growth in a mouse model of brain metastasis. The anti-cancer effect is likely achieved through multiple signaling pathways, including cell cycle regulation, down-regulation of oncogenes and HDACs. Citation Format: Hua Chang, Marsha Crochiere, Sophie Debler, Trinayan Kashyap, Thaddeus J. Unger, Erkan Baloglu, William Senapedis, Sharon Shacham, Yosef Landesman. Selinexor effectively inhibits tumor growth in a triple negative breast cancer brain metastasis mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1998.