Metastatic disease accounts for nearly 90% of all cancer-related deaths, highlighting the urgent need for pharmacologic strategies to block tumor metastasis. Although a cornucopia of cytotoxic and targeted-molecular therapies is available to breast cancer patients, almost no approved drugs are designed to prevent metastasis directly. Thus, new approaches that neutralize the metastatic spread of tumor cells would be transformative. Platelets play a critical, supportive role within the metastatic cascade, helping circulating tumor cells (CTCs) aggregate to promote CTC survival, to avoid immune surveillance, and to increase CTC adhesion to the vascular endothelium, thus promoting extravasation and distant site seeding. Thromboxane A2/Prostaglandin endoperoxide Receptor (TPR) is known to stimulate platelet aggregation. Its ligand, thromboxane A2, has been implicated in metastatic disease and in key steps of the metastatic process (e.g, angiogenesis). Moreover, an unbiased Phenome-Wide Association Study (PheWAS) conducted within Vanderbilt?s BioVU database, an archive of > 40,000 de-identified patient genotypes linked to corresponding scrubbed electronic medical records (EMRs), discovered single nucleotide polymorphisms (SNPs) in TBXA2R (TPR gene) correlating significantly with metastasis of many solid cancers, including breast. These SNPs are known to confer increased activity and/or expression of TPR, suggesting that increased TPR signaling enhances metastatic dissemination of cancers. Our goal here is to test the hypothesis that TPR contributes to metastasis by activating platelet aggregation with circulating tumor cells. To test this hypothesis, we will define the mechanism of TPR-dependent platelet-tumor cell and tumor cell-endothelial cell interactions (Aim 1), establish the effect of common TBXA2R gain-of-function SNPs on the metastatic cascade (Aim 2), determine the impact of ifetroban, a potent and selective TPR antagonist, on platelet- assisted metastasis in breast cancers, alone and in combination with standard-of-care cytotoxic therapies (Aim 3). This study will be the first to assess the role of TPR in the metastatic spread of breast cancer, and has the potential to both define a mechanism for TPR within the metastatic cascade and eradicate breast cancer mortality safely, efficaciously, and cost-effectively.
Phenome-Wide Association Study (PheWAS) has identified that gain-of-function mutations of the Thromboxane A2/Prostaglandin endoperoxide Receptor (TPR), which helps govern platelet activation, associate with metastasis in human patients. We will assess the role of TPR in platelet- assisted metastasis of breast cancers and determine if ifetroban, a potent and selective antagonist of TPR, can be used to block metastasis and increase progression-free survival of breast cancer patients. The current study will be the first to assess the role of TPR in breast cancer metastasis, and has potential to rapidly transform the way metastatic breast cancer is treated.
