Ovarian cancer is the most deadly gynecologic cancer and advances in treatment and prevention are desperately needed. Many novel drugs are being developed that target select interesting pathways in ovarian cancer, but brand-new drugs take many years to develop before they can be tested in humans. This process is inefficient and expensive. Drugs are available and have FDA approval for certain indications; however, doctors often use drugs for other indications based on observations or studies that show benefit to patients. Technology now allows a "virtual" way to scan thousands of drugs and predict which drugs may "fit" into a molecular target predicting a certain anticancer effect. Based on our groups' expertise in predicting new targets for existing approved drugs, we have discovered a new anticancer effect of naproxen (Naprosyn or Alleve) and ketorolac (Toradol). These drugs belong to a class of drugs called non-steroidal anti-inflammatory drugs (NSAIDs), which are known as cyclooxygenase (COX) inhibitors. Other NSAIDs have been tested in many cancers for their anti-inflammatory properties without much success. However, naproxen and ketorolac exist in two forms that are mirror images of each other -- the "image" is the (S) form and the "mirror image" is the (R) form. The COX inhibitory properties come from the (S) form, which is how naproxen is sold. The (R) form of naproxen is not commercially available but is the form that has the new anticancer properties. Similarly, the (R) form of ketorolac has these same anticancer properties. Ketorolac is prescribed as a mixture of the (R) and (S) forms so this proposal focuses on testing ketorolac (Toradol), which is a post-operative pain medication and also contains the (R) form with predicted anti-cancer benefit.

Our group has completed many experiments that show that (R)-ketorolac and (R)-naproxen block a GTPase pathway involving two proteins called Rac1 and Cdc42. We also have shown that Rac1 and Cdc42 are dysregulated in ovarian cancer. This pathway allows cells to grow fingers and adhere to each other and the surface of organs so cells can then invade and metastasize or spread. Our preliminary work shows that (R)-ketorolac and (R)-naproxen block adhesion and migration of human ovarian cancer cells. Mice that are transplanted with human ovarian cancer cells and treated with R-naproxen or (R,S)-ketorolac show a great reduction in tumor implants. This proposal will study the mechanisms of how the (R) form of ketorolac works. More importantly, we want to see if (R) ketorolac is measurable in the peritoneal cavity and if it has the same effects on ovarian cancer cells in patients with ascites. It is now common practice to put peritoneal catheters in patients at the time of debulking surgery. We plan to give patients intravenous (R,S)-ketorolac for postoperative pain management, and then access the catheter to obtain residual cancer cells and ascites fluid to see how much of the (R) ketorolac makes it to the belly cavity and if we see the same changes in the cells that we have seen in culture. The ability to do this clinical trial will help us to rapidly develop the (R) form of ketorolac for many possible indications.

We are extremely excited about this possibility. There is data that the (R)-ketorolac takes longer to be processed by the body, so we anticipate that we will see a higher ratio of the (R) form to the (S) form in both blood and the peritoneal cavity. This is the form that will block the ability of cancer cells to adhere, invade, and metastasize. The drug can be made in a pure (R) form. The (R) form does not have any significant COX-2 inhibitory properties; therefore, it should be safe to take long-term without risks of bleeding, heart problems, or other known COX-2 toxicities. It is possible that the patients who participate in this trial and future studies will achieve some cancer benefit from the ketorolac based on the drug preventing implantation and invasion of cells remaining after surgery. We see its future use as a drug to maintain remission and possibly as a drug to use as prevention in women at high risk for ovarian cancer. Because ketorolac is an approved drug, these studies will be quick and we anticipate generating the pure (R) form for subsequent efficacy studies within a few years.