Disarming Pancreatic Cancer With Enzyme Inhibitors

Researchers at West Virginia University are advancing pancreatic cancer treatment by targeting a specific enzyme, myeloperoxidase, which typically aids in fighting infections but exacerbates cancer when overactive.

The study, inspired by poor outcomes in existing therapies and a survival rate of only 13% for pancreatic cancer patients, explores how inhibiting this enzyme could enhance the body’s immune response and improve the efficacy of immunotherapies.

Innovative Research in Pancreatic Cancer

West Virginia University scientists are building on their research to alter the immune system by inhibiting a certain enzyme responsible for the progression of pancreatic cancer, one of the most challenging cancers to manage.

The five-year survival rate for patients with pancreatic cancer is about 13%. Since there are no identifiable early symptoms, it’s usually diagnosed in later stages.

“It’s at a stage where we have to do some type of treatment,” said Tracy Liu, assistant professor in the WVU School of Medicine Department of Microbiology, Immunology and Cell Biology and a member of the WVU Cancer Institute. “It’s a very deadly disease that needs new treatment options.”

Enhancing Treatment Effectiveness

Liu and colleagues from the School of Medicine, Cancer Institute, and School of Pharmacy have embarked on a study to better understand how pancreatic cancer and myeloid cells interact and to find a way to inhibit myeloperoxidase — a naturally occurring enzyme in humans which typically activates to fight off infections and aid in wound healing. However, in pancreatic cancer, its presence is elevated and works against the body.

The three-year project is supported by a $330,000 Career Development Award for Pancreatic Cancer Research in honor of late U.S. Supreme Court Justice Ruth Bader Ginsburg from the Lustgarten Foundation and American Association for Cancer Research.

Immune System Manipulation Against Cancer

Currently, chemotherapy is the most common treatment but, because of the way pancreatic cancer interacts with innate immune cells called myeloid cells, the response rate is low.

“We found that in pancreatic cancer, myeloid cells can alter the environment that cancer grows in and can dictate how other therapies can fight cancer,” Liu said. “We’re looking at one key enzyme, called myeloperoxidase, that is primarily expressed in myeloid cells. We think by inhibiting or limiting this enzyme, we can also increase a body’s own immune system to respond to cancer.”

The cancer basically reprograms this enzyme to work to support cancer growth.

“It also limits the function of anti-cancer immune cells like T cells and natural killer cells,” Liu explained. “What happens is twofold — the increased activity of this enzyme is supporting cancer growth, but then it’s also limiting anti-cancer immunity so your body can’t even fight off the cancer.”

Advancements in Immunotherapy and Study Techniques

The team’s work is a follow-up to an earlier study in which researchers showed that by limiting the enzyme they could enhance immune checkpoint therapy response in mice.

“Immunotherapy has become a standard of care in certain cancers, but it hasn’t demonstrated much benefit in pancreatic cancer,” Liu said. “In our mouse models, we’re showing that when we combine inhibition of myeloperoxidase with these immune checkpoint inhibitors we can get them to work better.”

Immunotherapy is a treatment that harnesses the body’s own immune system to boost or change how it works so it can find and attack cancer cells. Checkpoint inhibitors, a type of immunotherapy, blocks the proteins that keep the immune system from attacking cancer cells.

To conduct the study, Dr. Brian Boone, cancer surgeon and member at the WVU Cancer Institute and associate professor in the School of Medicine, has provided two models. In an orthotopic model, researchers will inject mice pancreas with cancer cells that mimic what happens in humans with the disease. The second, called a spontaneous transgenic model, will allow the cancer to develop naturally over time. The team will use intravital imaging to study, in real time, tumor immune interactions throughout disease progression and treatment response.

“We’re basically implanting a window on the mouse and then we put the mouse on the microscope,” Liu explained. “What that allows us to do is capture, over time, both spatial and temporal information, which is often lost if you’re just doing classic biology or immunology techniques because those things are often like snapshots in time.”

Angisha Basnet, a doctoral candidate in the biomedical sciences program from Kathmandu, Nepal, is assisting Liu in the project.

While other researchers have used myeloperoxidase inhibitors in clinical trials for patients with neurodegenerative disorders such as Parkinson’s disease, ALS, and cardiomyopathy, Liu said she hopes findings from her study will provide enough data to support a clinical trial for pancreatic cancer patients.

Liu and her team are also working on another grant based on data that suggests targeting the enzyme can enhance chemotherapy response.

“That’s just another direction where our research is going and it uses all the same models and same resources,” she said. “Beyond that, I’d like to also get into pancreatic cancer metastases in the future. That’s also another really big problem that does have a lack of treatment options. I could see our project expanding.”

Editor’s note: The use of animals in this project was evaluated by the WVU Institutional Animal Care and Use Ethics Committee. WVU is voluntarily accredited by AAALAC, a national peer organization that establishes a global benchmark for animal well-being in science.

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