Protease activated receptor-2 (PAR-2) signaling and metastatic ovarian cancer

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SUMMARY Ovarian cancer is the most lethal gynecological malignancy. One in 69 women will develop ovarian cancer, and less than half will survive for five years. Despite a number of recent advances in our understanding of ovarian cancer etiology and pathobiology, the survival rate of patients diagnosed with ovarian cancer is low when compared to that of breast or prostate cancer. Factors contributing to this poor survival rate are tumor persistence, tumor recurrence and chemoresistance. There is an urgent need to develop second line therapies to both improve the therapeutic efficacy of conventional treatments and to provide alternative therapeutic options for patients with recurrent ovarian cancer. Anti-angiogenesis therapies targeting the VEGF and the angiopoietins/Tie2 pathways have shown clinical efficacy and are currently being actively pursued as adjunct therapies for recurrent ovarian cancers. Unfortunately, outcomes of recent clinical trials have been mixed and non-responsiveness or resistance to anti-angiogenic treatment, toxicities and subsequent tumor recurrence and metastasis have limited therapeutic success. This is largely due to an incomplete of understanding of the basic mechanisms involved. The scientific premise underlying this research is that differential triggering of the G-protein coupled Protease Activated Receptor-2 (PAR-2) by different proteases modulates tumor angiogenesis important for ovarian tumor metastasis. We discovered the membrane-anchored serine protease, testisin (also known as PRSS21), to be aberrantly expressed in a broad range of ovarian cancers and to be a potent cell surface proteolytic activator of PAR-2. Strong preliminary data show that the aberrent constitutive expression of testisin in ovarian tumors promotes anti-angiogenic signaling and suppresses ovarian tumor metastasis and ascites formation in a preclinical xenograft model of ovarian cancer. This unique activity is unexpected, and reveals a major gap in our understanding of how PAR-2 angiogenic signals are modulated by different proteases, specifically those in spatial proximity to PAR-2. Such `biased agonism' may start to explain significant variations in patient responses to anti-angiogenic therapies in ovarian cancer patients. The proposed research plan will utilize primary human ovarian tumor cells and cell lines in concert with in vivo mouse models to address the following specific aims: 1) to determine mechanisms by which testisin suppresses experimental ovarian tumor metastasis, and 2) to determine molecular and cellular mechanisms associated with testisin-mediated desensitization PAR-2 and modulation of angiogenesis. Augmentation of the natural antagonism resulting from the testisin-PAR-2 pathway could find utility in combination with other anti-angiogenic therapies, to reduce therapeutic doses required, thereby minimizing side effects and provide a unique therapy for managing this devastating disease. The fact that females do not have a normal abundance of testisin makes testisin a unique and particularly attractive therapeutic target for ovarian tumors and also a potentially useful biomarker.