Abstract
In addition to their central role in blood hemostasis, it is increasingly clear that platelets contribute to multiple steps in the metastatic cascade. Platelets are one of the most abundant cells with which tumor cells interact once they enter the circulation, and the interaction of platelets with tumor cells can improve tumor cell survival, arrest and adhesion at secondary sites, and extravasation. Therefore, targeting the interaction between platelets and circulating tumor cells could be an effective approach for reducing metastasis. Here, we repurpose the thromboxane A2-prostanoid receptor (TPr) inhibitor, ifetroban, to block platelet-tumor cell interactions and reduce metastasis in models of triple negative breast cancer (TNBC). We utilize in vitro co-culture models of platelets and tumor cell lines to assess the impact of ifetroban treatment on the adhesion of platelets to tumor cells. In each case, platelet-tumor cell adhesion was significantly increased when the TPr agonist U46619 was introduced, while pre-treatment with ifetroban (TPr antagonist), significantly reduced platelet-tumor cell adhesion. Further, we used a zebrafish model system to rapidly assess metastasis and platelet interactions in vivo, showing that ifetroban reduces metastasis of MDA-MB-231 xenografts without reducing platelet number in CD41 transgenic zebrafish embryos. Finally, we confirm that ifetroban significantly reduces both lung and liver metastasis in multiple murine models of TNBC (4T1 and MDA-MB-231). In these models, we observed that ifetroban reduces metastasis in the absence of a primary tumor and when TPr is deleted from tumor cells, further supporting the notion that ifetroban attenuates the supportive role of platelet TPr in the metastatic cascade. Based on the results of this study, ifetroban could be pursued as a clinical agent to reduce metastasis in TNBC patients.