It’s the spread of the original cancer tumor that kills most people. That’s why cancer researchers vigorously search for drugs that can prevent metastases, the spread of cancer. But most drugs take a decade—and frequently, more—to go from concept to Food and Drug Administration approval. One way to reduce this time investment is to look for already-approved drugs that could lessen or stop metastases. That’s just what a team of scientists from the University of New Mexico is doing. Led by Angela Wandinger-Ness, PhD, and Laurie Hudson, PhD, the team is testing Ketorolac against ovarian cancer. They are using support from the NCI Provocative Questions Initiative, DOD Teal funding, and gap funding from STC.UNM, the University of New Mexico’s technology-transfer office. With no overt symptoms and no screening tests to find it, ovarian cancer is among the most deadly of cancers.
Ketorolac is an NSAID, or non-steroidal anti-inflammatory drug. The FDA approved its use for pain relief in humans in 1991. “Inflammation is an important process in cancer,” says Dr. Hudson, a UNM Professor of Pharmaceutical Sciences. Dr. Wandinger-Ness, UNM Professor of Pathology, adds, “So the provocative question is: why? Why are some NSAIDs protective in cancer, while others are not? What are the protective mechanisms, anti-inflammatory or other? We know that NSAIDs work, but lack a complete understanding of the basis of anti-cancer efficacy.” The team’s work centers on demonstrating how anti-inflammatory drugs can protect against cancer.
Dr. Wandinger-Ness and Dr. Hudson started by looking for drugs that could control GTPases in a cell. GTPases are chemical switches that control almost everything from cell growth to how cells adhere to each other. Dr. Wandinger-Ness and Dr. Hudson wanted to modify cell behaviors by turning GTPases on and off. To do that, they sought the help of Larry Sklar, PhD, who created and oversees the UNM Center for Molecular Discovery. Dr. Sklar helped the team to identify drugs that act on the GTPases using a technology called flow cytometry. The whole process was like finding the needle in a haystack. “Technologies like flow cytometry and advanced computer modeling allow this kind of discovery to be made,” says Dr. Hudson.
The team then drew on the expertise of Tudor Oprea, MD PhD, a UNM Professor of Medicine , and Oleg Ursu, PhD. Dr. Ursu created three-dimensional models of the GTPases. His models enabled the team to envision how a drug might hinder their function the way throwing a circuit breaker might inactivate a switch. The first drug the team found, R-naproxen, was not available for human use. The team then looked through the database that Dr. Oprea and Dr. Ursu manage to find other approved drugs that matched their requirements. Using computer models, Dr. Oprea then suggested ketorolac, an FDA approved drug.
Once R-ketorolac proved to be active, the team began working with Jennifer Golden, PhD, Assistant Director at the Kansas University Specialized Chemistry Center. Dr. Golden is refining R-ketorolac to precisely control the GTPases that affect tumor growth and spread. So far, cell and animal studies using R-ketorolac against ovarian cancer look very promising in keeping tumor growth in check.
Ketorolac is marketed as Toradol® for post-operative pain. Dr. Oprea suggested it because it contains both R-ketorolac and S-ketorolac in the mixture, so people receive both forms of the drug in a single dose. Although both forms have exactly the same chemical formula, they are not the same molecule in three dimensions just as your left hand and your right hand are not the same. Thus, the team believes the two forms behave differently inside a cell. S-ketorolac is well known as a potent NSAID. It shuts down a specific class of proteins called cyclooxygenases that drive inflammation. The team’s work shows that R-ketorolac is not a mere bystander but acts instead on different proteins, namely the GTPases. Just as “the right hand only fits a right hand glove, but doesn’t fit into the left hand glove,” as Dr. Hudson explains, the two forms of ketorolac have distinct benefits.
“Because R-ketorolac interacts with the GTPases,” says Dr. Wandinger-Ness, “it impacts cell growth and cell adherence,” two important traits of ovarian cancer cells. “We have good of evidence that R-naproxen interacts with this GTPase pathway,” Dr. Hudson says. So now they’re working to show that R-ketorolac can slow or stop the specific GTPases that enable ovarian cancer cells to grow and spread.
Dr. Wandinger-Ness and Dr. Hudson, along with Carolyn Muller, MD, are expanding the studies to benefit people now. The team has a Phase 0 trial in progress supported by a DOD Teal award and STC.UNM has filed a patent application for the technology. This trial is testing tumor responses and the bioavailability of R-ketorolac in the peritoneum. Phase I clinical trials of R-ketorolac for ovarian cancer is the next step. “Building something like this requires time,” says Dr. Wandinger-Ness. But they’ll still be able to bring this research to the clinic far faster than any new drug to the marketplace.
