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Epithelial ovarian cancer is the major cause of gynecologic malignancy deaths. Because of their roles in cell adhesion and migration, Rho family GTPases have been suggested as potential therapeutic targets in human cancers. We identify the Rac1 and Cdc42 GTPases as relevant targets in papillary serous and endometriod tumors. Cdc42 is overexpressed in primary human ovarian tumors and cancer cell lines, and a novel splice variant Rac1b is upregulated in tumors of advanced stage and grade. GTPase activities in primary ascites are 3 to 6-fold higher than in cultured cells. R-Naproxen was identified by high throughput screening of a Prestwick compound library as a select non-steroidal anti-inflammatory drug (NSAID) from 23 tested that selectively targets Rac1 and Cdc42 in a bead-based assay using purified proteins. The drug is demonstrated to have positive benefit against cell behaviors required for ovarian cancer dissemination and metastasis using both cell lines and primary human tumor cell isolates. Human ovarian cells show slowed cell proliferation, as well as impaired migration, adhesion and invadopodia formation. Other NSAIDs with structural similarity (S-naproxen and 6-methoxy naphthalene acetic acid) lack these properties, while a specific Rac inhibitor NSC 23766 mimics the effects. Molecular docking shows R-Naproxen can bind the GDP-bound, but not GTP-bound Rac1, suggesting it may act by stabilizing Rac and Cdc42 in the inactive state. R-Naproxen has potential for rapid translation and efficacy in the treatment of metastatic ovarian cancer on account of FDA approval and novel activities against Rho-family GTPases. Funding for this study was generously provided by NIH grants U54MH074425, U54MH084690, R03MH081231, P30CA118100 and UNM Cancer Center FIG.0990MD. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-214. doi:10.1158/1538-7445.AM2011-LB-214