Advanced stage ovarian cancer accounts for the majority (>75%) of the approximately 24,000 new cases of epithelial ovarian cancer in year 2008 in the United States. Over 16,000 deaths per year occur, making this cancer the most lethal gynecologic malignancy. However, there are only a few biomarkers that can be used to predict overall ovarian cancer patient survival. In addition, many prognostic biomarkers can ultimately serve as important therapeutic targets if their molecular action is well understood. Using transcriptional profiling technology combined with Cox regression analysis, we have previously identified a putative gene signature, which can predict survival in patients with advanced stage high-grade serous ovarian cancers. The gene with highest Cox score in the signature is called microfibril-associated glycoprotein (MAGP-2), which has been shown to be associated with fibrillin-containing microfibrils and to interact specifically with 1V23 integrin in fibroblasts. However, its role in cancer pathogenesis has not been explored. Our preliminary studies demonstrated that MAGP-2 expression in ovarian tumor tissues samples significantly correlated with patient survival. In addition, MAGP-2 was shown to induce cell growth and motility in both human umbilical vein endothelial cells (HUVECs) and ovarian cancer cells, which expressed high levels of 1V23 integrin. Furthermore, exogenous MAGP-2 was shown to significantly induce Ca2+ oscillation and FAK phosphorylation in HUVECs and an ovarian cancer cell line OVCA429. We therefore hypothesize that ovarian cancer cells expressing high levels of MAGP-2 modulate ovarian cancer growth and through its interaction with 1V23 integrin, which subsequently leads to poorer overall ovarian cancer patient survival. In this application, we proposed to further validate the prognostic value of MAGP-2 using a large collection of multi-center clinical trial specimens, and delineate the functional role of MAGP-2 in ovarian pathogenesis. First, we will correlate MAGP-2 expression with outcomes using specimens obtained from patients entered into the Gynecologic Oncology Group (GOG) protocol 218. Second, we will delineate the functional role of MAGP-2 in modulating ovarian tumor growth and progression, in vitro and in vivo. Finally, we will delineate the signaling network for MAGP-2-induced cell proliferation, migration and invasion in both ovarian cancer cells and endothelial cells. This proposed study if successful will provide us with a new prognostic biomarker for ovarian cancer. It will lead us to the identification of new therapeutic targets and the development of new therapeutic regimens for ovarian cancer treatment.
This grant proposes to validate MAGP-2 as a prognostic biomarker for advanced stage ovarian cancer using prospectively collected specimens from a randomized phase III trial. Mechanistic studies will be performed to understand the mechanisms of action of MAGP2 in ovarian cancer growth.
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