Abstract 2616: Inhibition of TGFß to prevent brain metastases of breast cancer
Authors: Chris E. Adkins, Afroz S. Mohammad, Emma Dolan, Jessica Griffith, Tori Terrell-Hall, Paul R. Lockman
Journal: Cancer Research (2016)

Abstract Introduction: Because systemic chemotherapy fails to effectively treat brain metastases, the need for novel strategies designed to prevent brain metastasis is urgent. Recently, transforming growth factor beta (TGFß) has been shown to influence the development of brain metastases of breast cancer and may offer a therapeutic target to prevent metastatic disease in brain. This study seeks to evaluate the efficacy of TGFß inhibition, using losartan, at preventing metastases in an experimental model of brain metastases of breast cancer. Methods: Human breast cancer cells (MDA-MB-231Br-Luc) were inoculated into female NuNu mice after TGFß knockdown or treatment with inhibitor; after 1-week mice were sacrificed, their brains removed and sliced, and metastatic cells counted and localized to determine seeding. Survival studies were then initiated with daily low (10mg/kg) or high (25mg/kg) doses of losartan, or SB431542 (5mg/kg) prior to the injection of one of two human breast cancer cell lines (MDA-MB-231Br-Luc or JIMT-1-Br3-Luc) transfected with luciferase. Treatments resumed daily until neurological symptoms developed. Animals were sacrificed, brains removed, and sliced to evaluate the number of metastases and their respective sizes. Results: The number of metastatic cells seeding brain was reduced after knockdown of TGFß (from 3,331 ± 263 cells to 1,079 ± 495 cells; p&amp;lt;0.01) and after treatment with galunisertib (808 ± 82 cells; p&amp;lt;0.01). There was a 33% reduction (p&amp;lt;0.05) in extravasated metastatic cells after TGFß knockdown and a 23% reduction (p&amp;lt;0.05) after galunisertib treatment. Mice inoculated with MDA-MB-231Br-Luc had a median survival of 32 days while losartan treatments groups exhibited extended median survival (38 days low, 43 days high) and inhibitor survival extended to 46 days. The MDA-MB-231Br-Luc TGFß knockdown median survival increased to 65 days. Median survival of mice inoculated with JIMT-1-Br3-Luc was 28 days and no difference (p&amp;gt;0.05) in median survival was observed for the JIMT-1-Br3-Luc losartan (30 days, low; 26 days, high) or inhibitor (29 days) treatment groups. Conclusions: Inhibition of TGFß reduced the total number of metastatic MDA-MB-231Br cells seeding brain and simultaneously reduced the percentage of cells that had extravasated the vessel. While losartan did not increase survival for animals inoculated with JIMT-1-Br3-Luc cells, the MDA-MB-231Br model exhibited enhanced survival with losartan (15% survival rate; high dose), inhibitor (20% survival rate) treatment, and after TGFß knockdown (38% survival rate). The data indicate that TGFß offers a potential therapeutic target to reduce the risk of brain metastases of breast cancer. Citation Format: Chris E. Adkins, Afroz S. Mohammad, Emma Dolan, Jessica Griffith, Tori Terrell-Hall, Paul R. Lockman. Inhibition of TGFß to prevent brain metastases of breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2616.