The role of tumor endothelium-specific prion-gene PRND in epithelial ovarian cancer

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Project Summary Among all of the gynecological cancers, ovarian cancer shows high clinical challenge because it is difficult to be detected in the early stage and it has the highest mortality rate. Despite advances and the development of diagnostic tools such as biomarkers and detection techniques, ovarian cancer remains a fatal cancer with high progression. There are different types of ovarian cancer based on histological classification; Epithelial Ovarian Cancer (EOC) is the most common. EOC is identified in over 80% of women at late-stage with complications include the spread of tumor implants throughout the peritoneal cavity. Thus, it is necessary to find new biomarkers with high specificity and sensitivity to detect ovarian cancer in the early stages of disease. Recently, we identified a highly conserved membrane-associated prion-like protein Doppel that express only in tumors and regulate the functions of VEGF in tumors. Furthermore, we demonstrated that Doppel interacts and collaborates with VEGFR2 to stimulate tumor angiogenesis. Previous studies thus confirmed our conjecture that Doppel is a TEC-specific marker and an optimal target for anti-tumor therapy. We hypothesize that Doppel drives ovarian cancer progression. The ultimate goals of this proposal are to evaluate whether Doppel expression could be utilized as an EOC-specific serum biomarker and to develop a novel therapeutic strategy by targeting Doppel against both platinum-sensitive and platinum-resistant EOCs. The two specific aims of this study are: (1) To assess Doppel as a serum biomarker and the degree of Doppel expression in ovarian cancers and (2) To study the role of Doppel in malignant ascites formation in a microfluidic-based organoid and orthotopic model of EOC. We will shed lights into the processes that regulate and intensify the Doppel-regulated ascites formation in ovarian tumors. The proposed research will elucidate the relationship between Doppel expression, malignant ascites formation, and neoangiogenesis in ovarian cancers. The homologous similarity between human and murine Doppel protein also suggest that a candidate mouse anti-Doppel mAb can be translated into clinical use by humanizing it.