Biomedical Sciences ETDs

Yuna Guo

Publication Date

12-1-2015

Abstract

Cdc42 (cell division control protein 42) and Rac1 (Ras-related C3 botulinum) are attractive therapeutic targets in ovarian cancer based on their established importance in tumor cell migration, adhesion and invasion. Despite a predicted benefit, targeting GTPases has not yet been translated to clinical practice. Based on lead identification through high-throughput screening and computational shape homology approaches, R-ketorolac is identified as a Cdc42 and Rac1 regulator, an activity that is distinct from the anti-inflammatory, cyclooxygenase inhibitory activity of S-ketorolac. In this dissertation, R-ketorolac is established as an allosteric inhibitor of Cdc42 and Rac1. Studies on immortalized human ovarian adenocarcinoma cells (SKOV3ip), and primary, patient-derived ovarian cancer cells show R-ketorolac is a robust inhibitor of growth factor or serum dependent Cdc42 and Rac1 and their downstream effector p21-activated kinases activation. Multiple assays of cell behavior show that R-ketorolac significantly inhibits cell adhesion, migration and invasion. A clinical trial on ovarian cancer patients shows that ketorolac is enriched in the R-enantiomer in peritoneal fluids and GTPase activity is inhibited in ascites-derived tumor cells. A retrospective study suggests that a single dose of ketorolac in the perioperative period benefits patient outcomes. In sum, R-ketorolac inhibits Cdc42 and Rac1 activities and subsequent physiological consequences which are critical to tumor metastasis and likely contributes to the observed survival benefit in ovarian patients.

Keywords

Rho GTPases, ketorolac, ovarian cancer, NSAIDs, Cdc42, Rac1

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Hudson, Laurie

Second Committee Member

Sklar, Larry

Third Committee Member

Buranda, Tione

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