Biomedical Sciences ETDs

Author

Shelby Kenney

Publication Date

7-1-2015

Abstract

Ovarian cancer is the 5th leading cause of cancer death for women in the United States and is frequently diagnosed at an advanced stage with multiple metastases. Rho family GTPases contribute to metastasis through regulation of the actin cytoskeleton, cell motility, cell-cell and cell-extracellular matrix adhesion and these GTPases are altered in a number of human cancers. High throughput screening and in silico modeling identified the R-enantiomer, but not S-enantiomer, of the non-steroidal anti-inflammatory drug ketorolac as a novel inhibitor of Rac1 and Cdc42. Ketorolac is administered as a racemic mix of both enantiomers and is used clinically for surgical pain relief. The analgesic effect of ketorolac occurs through cyclooxygenase inhibition by S-ketorolac. R- ketorolac is a poor inhibitor of cyclooxygenase, but little is known about its pharmacologic activities or targets. This project identified the expression of the Rho family GTPases Cdc42 and Rac1 in ovarian cancer and inhibition of these GTPases by R-ketorolac. The effects of R-/S-ketorolac, R-ketorolac, and S-ketorolac on Cdc42 and Rac1 regulated cellular events were investigated using SKOV3ip ovarian cancer cells. An intra-peritoneal xenograft mouse model of tumor implantation was used to determine the effects of ketorolac in vivo. A phase 0 clinical study examined ketorolac distribution to the peritoneal cavity of ovarian cancer patients following surgery. Additionally, primary ovarian cancer cells from these patients were examined ex vivo to determine GTPase activity and a retrospective analysis determined that patients who received ketorolac had improved clinical outcomes. Together, this work identified Cdc42 and Rac1 as valid therapeutic targets in ovarian cancer. R-ketorolac is shown to inhibit Cdc42 and Rac1 regulated adhesion and migration related events. These results provide evidence to support the idea that the use of ketorolac in the clinic at the time of surgery will improve ovarian cancer patient outcome.

Keywords

Cdc42, Rac1, ovarian cancer, ketorolac, migration, adhesion, Rho GTPases

Sponsors

IDeA Network of Biomedical Research Excellence Department of Defense National Institutes of Health University of New Mexico Cancer Center

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Advisor

Hudson, Laurie G

First Committee Member (Chair)

Hathaway, Helen

Second Committee Member

Prossnitz, Eric

Third Committee Member

Wandinger-Ness, Angela

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