OKLAHOMA CITY – A University of Oklahoma researcher has received a five-year, $2 million grant from the National Cancer Institute to investigate how pancreatic cancer uses cholesterol to survive chemotherapy. By uncovering how tumors use this essential nutrient to grow and evade treatment, the research could identify new ways to treat one of the deadliest forms of cancer.
Although cholesterol is best known for its role in heart disease, every cell in the body relies on it to build cell membranes and carry out essential functions. Cancer cells are no different. Researchers believe pancreatic tumors can reprogram the way they make and use cholesterol, giving them the resources they need to continue growing even when exposed to chemotherapy.
“Our goal is to understand how pancreatic cancer adapts to survive treatment, and it appears that cholesterol plays a role. If we can interrupt the biological processes that help these tumors thrive, we may be able to make existing therapies more effective,” said Surendra Shukla, Ph.D., assistant professor of oncology science in the OU College of Medicine, research member of OU Health Stephenson Cancer Center and principal investigator for the grant.
The project focuses on a protein called ZC3H15, which the research team has identified as a potential driver of pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer. Their preliminary studies found that tumors with high levels of ZC3H15 were more likely to survive chemotherapy and were associated with poorer patient survival.
The researchers also discovered that ZC3H15 is an RNA-binding protein, meaning it helps control how cells use genetic instructions to produce other proteins. By protecting the RNA instructions for making a protein called KDM3A, ZC3H15 appears to change how pancreatic cancer cells use cholesterol.
These cholesterol-related changes also appear to trigger a process called epithelial-to-mesenchymal transition, or EMT, in which cancer cells become more mobile and adaptable. Instead of remaining confined to the original tumor, they are better able to spread to other parts of the body.
“Rather than simply growing faster, these cancer cells appear to become more resilient,” Shukla said. “Understanding how they change the way they use cholesterol could reveal new opportunities to stop that process.”
Over the next five years, the researchers will investigate exactly how ZC3H15 changes the way pancreatic cancer cells use cholesterol and contributes to the disease’s growth and spread. To do that, they will study pancreatic cancer using laboratory models grown from patients’ tumors, specially bred mice and other research models that closely mimic the disease in humans.
The team will also test whether combining the cholesterol-lowering drug rosuvastatin with the standard chemotherapy regimen FOLFIRINOX can make pancreatic tumors more responsive to treatment. While rosuvastatin is widely prescribed to lower cholesterol, researchers will evaluate whether it can also disrupt the cholesterol-related changes that help pancreatic cancer resist chemotherapy.
“If successful, the research could identify ZC3H15 as a promising new therapeutic target and provide the foundation for future clinical studies aimed at improving treatment for one of the most difficult cancers to cure,” Shukla said.
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About the project
Research reported in this release was supported by the National Cancer Institute of the National Institutes of Health under award number R01CA316828-01. This project was also supported by Oklahoma's Tobacco Settlement Endowment Trust (TSET), a primary funder of the Stephenson Cancer Center and TSET Health Promotion Research Center at the University of Oklahoma and by the Oklahoma Shared Clinical and Translational Resources through an Institutional Development Award from the National Institute of General Medical Sciences (grant no. U54GM104938).
About the University of Oklahoma
Founded in 1890, the University of Oklahoma is a public research university with campuses in Norman, Oklahoma City and Tulsa. As the state’s flagship university, OU serves the educational, cultural, economic and healthcare needs of the state, region and nation. In Oklahoma City, the OU Health Campus is one of the nation’s few academic health centers with seven health profession colleges located on the same campus. The OU Health Campus serves approximately 4,000 students in more than 70 undergraduate and graduate degree programs spanning Oklahoma City and Tulsa and is the leading research institution in Oklahoma. For more information about the OU Health Campus, visit www.ouhsc.edu .