Abstract 392: Synergistic anti-tumor effects of dabigatran etexilate and cyclophosphamide co-treatment are associated with decreased circulating tissue factor positive microparticles

Abstract

Introduction: Coagulation proteases and the generation of thrombin are increased in tumors. The incidence of cancer-associated thromboses is also increased by treatment with chemotherapeutic agents commonly used to treat malignant cancers. Thrombin can drive cancer progression directly through the activation of protease-activated receptors and platelets or indirectly by generating fibrin matrices. Aim: To investigate the extent to which treatment with the oral thrombin inhibitor, dabigatran etexilate (Pradaxa®) may increase the anti-tumor efficacy of a chemotherapeutic agent that promotes a pro-thrombotic state. Materials and Methods: The effect of combined treatment with the standard chemotherapeutic agent, cyclophosphamide (CP), and dabigatran etexilate was evaluated following orthotopic injection of 4T1 mammary adenocarcinoma cells in the mammary fat pad of Balb/c mice. Treatment was initiated when 4T1 primary tumors were 25-50 mm3 in size, at 2 weeks following 4T1 tumor cell injection. Mice were treated once a week with cyclophosphamide (15-25 mg/kg, i.p.) with or without dabigatran etexilate (oral gavage, 80 mg/kg, bid or ad lib chow supplemented with dabigatran, 10 mg/g chow). Results: Mice receiving co-treatment with both low dose CP and dabigatran etexilate had significantly smaller mammary tumors and fewer lung metastases than mice treated with CP or dabigratran etexilate alone. 4T1 tumors express procoagulant tissue factor (TF) and spontaneously release TF+ microparticles which are potent procoagulant factors that promote thrombin generation. Treatment with chemotherapeutic agents increased the number of shed TF+ microparticles from tumor cells in vitro as well as circulating TF+ microparticles in vivo. Treatment with dabigatran etexilate with or without CP attenuated the increased platelet activation seen in 4T1 tumor bearing mice by 40% and prevented tumor-induced increases in circulating TF+ microparticles. Co-treatment with dabigatran etexilate and CP also inhibited the accumulation of splenic arginase/Gr-1/CD11b positive myeloid derived suppressor cells more than either treatment alone. Conclusion: Co-treatment with dabigatran etexilate and low dose CP synergistically inhibits the growth and metastasis of mammary tumors, and is accompanied by inhibition of platelet activation and decreased generation of circulating TF+ microparticles. These results suggest that the oral administration of the thrombin inhibitor dabigatran etexilate 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: Eric T. Alexander, Allyson R. Minton, Candace S. Hayes, Ashley Goss, Joanne Van Ryn, Susan K. Gilmour. Synergistic anti-tumor effects of dabigatran etexilate and cyclophosphamide co-treatment are associated with decreased circulating tissue factor positive microparticles. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 392. doi:10.1158/1538-7445.AM2015-392