Grant allows researcher to study ‘scissor-like’ protein in cancers

OKLAHOMA CITY — Much like a mechanic fixing a car, a cell biologist must understand how the parts of a healthy cell function in order to make repairs when the cell stops working correctly and contributes to disease.

Marie Hanigan, Ph.D., a researcher in the Department of Cell Biology in the OU College of Medicine, recently received a three-year, $960,000 grant from the National Institutes of Health to further her research on a protein called GGT – gamma-glutamyl transpeptidase. When it is functioning normally, GGT serves a positive role in the body. But when the amounts are too high or it is present in the wrong location in the body, GGT can be destructive.

“As is often the case, too much of a good thing can be harmful,” Hanigan said of GGT. “We were able to solve the structure of GGT at the molecular level, which helps us to understand how it contributes to specific diseases and provides insight into how to block its activity.”

Hanigan, who holds a doctorate in oncology, is especially interested in GGT’s role in cancers of the liver, prostate, breast and ovary. GGT, which sits on the outer surface of several types of cells in the body, is actually like a pair of scissors whose role is to cut a gamma-glutamyl bond into two pieces. A low level of cutting is useful and contributes to good health. But the role of GGT changes when it is present in high amounts and cuts too much.

“GGT is overexpressed in several types of cancers, so we want to be able to block this overexpression and calm everything down in the body,” Hanigan said. “There are currently no compounds that can be used in humans to safely inhibit GGT.”

Hanigan’s ultimate goal is to create a new drug that can block, or inhibit, the cutting activity of GGT. Her team has had some initial success creating molecules that inhibit GGT, and she holds two patents for those discoveries. Her new grant will allow her team to develop more refined inhibitors and to test them for toxicity.

In the process of testing inhibitors, Hanigan made an additional – and surprising – discovery. When GGT is inhibited, it completely eliminates the kidney toxicity associated with a widely used type of chemotherapy. That discovery identifies another important use for a GGT inhibitor – chemotherapy is often less effective than desired because toxic side effects limit the dose that can be used to treat patients, she said.

Hanigan’s research is an example of the importance of collaboration on the path to drug discovery. To solve the structure of GGT at the molecular level, the protein was first formed into crystals. However, to see its structure, high-energy radiation was required. For that step, the crystals were sent to national synchrotron laboratories in New York and California. Hanigan also collaborates with a colleague at the University of Florida who specializes in molecular modeling, as well as with colleagues at the OU College of Pharmacy who are synthesizing new drugs. In addition, Hanigan’s laboratory received funding from Oklahoma’s Presbyterian Health Foundation that enabled her to make the discoveries that attracted federal funding.

“Science is really a huge team effort because you need the expertise and equipment from a large number of sources,” she said.

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Research reported in this press release was supported by the National Institute of General Medical Sciences of the National Institutes of Health under the award number 1R01GM125952-01.