Abstract 2271: Dabigatran etexilate blocks breast cancer progression in vitro and in a 4T1 breast cancer tumor model in mice

Abstract

Abstract Introduction: Coagulation proteases and the generation of thrombin are increased in tumors. Thrombin can modify tumor cell behavior directly through the activation of protease-activated receptors (PAR) or indirectly by generating fibrin matrices. Aim: To test the hypothesis that dabigatran etexilate (Pradaxa®), an oral direct thrombin inhibitor, can prevent the progression of tumor cells in experimental models. Materials and Methods: The effect of dabigatran on invasiveness of MDA-MB-231 breast carcinoma cells was evaluated in vitro by invasion across Matrigel-coated membranes and in vivo using a tracheal xenotransplant invasion assay in athymic nude mice. To evaluate the effect of dabigatran on the development of metastatic foci, 4T1 tumor cells were injected orthotopically in the mammary fat pads of syngeneic Balb/c mice. Tumor growth and metastasis was monitored weekly. Dabigatran etexilate was administered twice daily at a dose of 45 mg/kg over 4 weeks in all in vivo models. Results: Whereas dabigatran had no effect on the proliferation index of cultured tumor cells, it inhibited invasiveness of MDA-MB-231 cells across Matrigel-coated membranes. In vivo evaluation of invasiveness of MDA-MB-231 cells in tracheal xenotransplants in mice administered dabigatran for 3 and 4 weeks demonstrated significantly less penetration of tumor cells through the tracheal wall. Dabigatran treatment had a modest inhibitory effect on growth of the primary 4T1 mammary carcinoma (∼50% reduction in tumor volume at 4 weeks) in syngeneic Balb/c mice, and it reduced both 4T1 tumor cells in the blood and liver micrometastases by 50-60%. Dabigatran treatment resulted in no weight loss in mice. Conclusion: Oral administration of the direct thrombin inhibitor, dabigatran etexilate, inhibits both invasion and metastasis of malignant breast tumors, suggesting that dabigatran may be beneficial in not only preventing thrombotic events in cancer patients, but also as adjunct therapy to treat malignant tumors. (Supported by funds from Boehringer Ingelheim Pharma) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2271.