Targeting Factor XII Functions to Limit Ovarian Cancer Progression and Associated Thrombosis

About This Grant

Background. High grade serous epithelial ovarian cancer (EOC) is the deadliest gynecologic cancer and has one of the highest rates of venous thromboembolic (VTE) complications. As the number of female Veterans is rapidly growing, the incidence of EOC has also significantly risen. An estimated 5–25% of ovarian cancer patients will have a VTE within the first two years of cancer diagnosis and these women will have lower survival rates than their counterparts without VTEs. The prothrombotic potential of EOC has been directly linked to overexpression of specific coagulation factors, among them Factor XII (FXII), and proinflammatory chemokines that contribute to exuberant thrombin activity in the circulation and the tumor niche. Our preliminary studies in human ovarian tumor samples show that FXII is expressed by cancer cells themselves and tumor-associated myeloid cells. In a very aggressive mouse model of EOC, FXII deficiency conferred protection from deep vein thrombosis in a model of inferior vena cava ligation. FXII deficiency also dramatically halted tumor peritoneal dissemination and metastatic burden. We identified that neutrophils endow EOC cancer cells with proinvasive properties, which are reversed by genetic deletion of FXII. These findings support the central hypothesis that targeting FXII functions has the potential to improve prothrombotic risk and perturb tumor-host interactions to suppress tumorigenesis and metastasis. To test our hypothesis, we propose to: 1) characterize the selective contribution of canonical and non-canonical FXII functions on systemic hypercoagulability in ovarian cancer; 2) determine the mechanisms linking FXII-uPAR to tumor growth and progression; 3) examine if targeted inhibition of FXII functions will limit EOC progression and suppress EOC-associated thrombophilia. Innovation. Our proposed research to characterize the bi-directional relationship between thromboinflammatory pathways and tumor biology represents a new strategy to solve the problem of EOC progression and cancer- associated thrombosis, the two leading causes of death among ovarian cancer patients. Since FXII is one of the few proteins that affects thrombosis without impacting hemostasis, the proposed work will further define a target whose inhibition is not accompanied by an increased bleeding risk. In this project, we use a state-of-the-art luminescent mouse mode for in vivo analysis of intraperitoneal tumor burden, patient-derived xenograft (PDX) models, novel modified peptides and cutting-edge nanomedicine to interfere with FXII functions in vivo. Significance and Impact to Veterans Healthcare. Women Veterans are the fastest growing segment of new VA users. As a result, BLR&D announced “Women Veterans’ Health” in its list of priority research areas. A recently conducted VA study found an increased incidence of ovarian cancer in active-duty Veteran females less than 45 years of age compared to the general US population. The potential immediate impact of our research is the establishment of novel scientific insight regarding the crosstalk of thrombo-inflammatory processes in ovarian cancer pathology. Most importantly, the envisioned long-term impact of our research will be realized via the clinical translation of our novel findings, given the current statistics indicating that 2,600 members of the military have spent over 14,000 days in hospitals for treatment of ovarian cancer in the last five years. Path to translation/implementation. We have secured non-provisional patents for all major components of this project i.e., composition of matter and use in disease for: i) peptide sequences to target the FXII-uPAR interaction; ii) neutrophil elastase-binding peptides, iii) neutrophil-targeted nanoparticles. A considerable advantage of this application is that all peptide sequences are human-derived and soluble in aqueous solution, the nanoparticle formulations utilize the same liposomal composition as other licensed drugs (e.g., liposomal doxorubicin, amphotericin B). We envision that completion of studies proposed in this application will support a pharmacology package required for pre-IND discussions with the FDA, as well as for customer discovery and acquisition source feedback from potential licensors.