Project Summary/Abstract Venous thromboembolism (VTE) develops in about one-fourth of patients with ovarian cancer and is associated with significant morbidity and mortality. Chemotherapy increases VTE risk, but administration of prophylactic anticoagulation to all patients on chemotherapy is associated with a substantial risk of bleeding. Therefore, it is crucial to identify patients with a higher risk of VTE. In the University of Texas MD Anderson Cancer Center (MDACC) Ovarian Cancer Moon Shot program, we have assembled a cohort of 354 patients who have received neoadjuvant chemotherapy. The availability of tumor specimens, blood samples, and an extensive clinical database from these patients provides us a unique opportunity to investigate the novel predictive biomarkers for VTE in ovarian cancer. Most previous studies on cancer thrombosis analyzed clinical, demographic, or hemostatic factors already known to be risk factors for VTE in cancer patients instead of identifying tumor-specific prothrombotic factors. We will explore cancer cell products that increase VTE risk and particularly investigate the impact of cancer cell-derived podoplanin and mitochondria on VTE. We found mitochondria in plasma samples of cancer patients and showed that ovarian cancer cells release mitochondria (both free and microvesicle-embedded). Injection of mitochondria caused venous thrombi in mice, rich in neutrophils and neutrophil extracellular trap (NETs). We speculate that mitochondria-targeted antioxidants and antibiotics blocking the synthesis of chemotactic formylmethionine(fMet)-tagged peptides reduce cancer VTE. We found that podoplanin is expressed on ovarian cancer cells and tumor-derived extracellular vesicles (EVs), and its expression is increased by chemotherapy. Podoplanin-expressing EVs activate platelets, and their injection into mice causes platelet-rich venous thrombi. We propose that a small molecule blocking podoplanin interaction with platelets reduces cancer thrombosis. We will examine whether the number of mitochondria and concentration of podoplanin in plasma predict VTE risk in ovarian cancer patients receiving chemotherapy. We will investigate the effect of a mitochondria-targeted antioxidant, an antibiotic blocking synthesis of fMet peptides, and a podoplanin inhibitor on venous thrombosis in a murine model of IVC ligation. Finally, we will compare the mutation profile and mutation burden of mitochondria and nuclear genes in tumors of ovarian cancer patients with and without VTE to identify the genetic changes in cancer cells associated with an increased VTE risk.

NARRATIVE Many patients with ovarian cancer suffer and even die from blood clots. Our goal is to determine the risk factors for blood clots in ovarian cancer. We will use tumor specimens, blood samples from patients, and extensive clinical and laboratory data available in our institution to achieve our goals.