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, according to an Aug. 6 announcement. The research aims to uncover how tumors use this essential nutrient to grow and evade treatment, potentially identifying new approaches for treating one of the deadliest forms of cancer.
Cholesterol is widely recognized for its role in heart disease, but it is also necessary for every cell in the body to build membranes and perform essential functions. Cancer cells similarly rely on cholesterol. Researchers believe that pancreatic tumors can reprogram their cholesterol production and usage, allowing them 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 at OU Health Stephenson Cancer Center, and principal investigator for the grant.
The project will focus on a protein called ZC3H15, identified by the research team as a potential driver of pancreatic ductal adenocarcinoma—the most common form of pancreatic cancer. Preliminary studies have found that tumors with high levels of ZC3H15 are more likely to survive chemotherapy and are associated with poorer patient outcomes. The researchers also discovered that ZC3H15 acts as an RNA-binding protein which helps control cellular genetic instructions; by protecting RNA instructions for making KDM3A protein, ZC3H15 appears to alter how pancreatic cancer cells use cholesterol.
Over five years, researchers will examine exactly how ZC3H15 affects cholesterol metabolism in pancreatic cancer cells using laboratory models derived from patients' tumors as well as specially bred mice designed to mimic human disease progression. They will also test whether combining rosuvastatin—a widely prescribed cholesterol-lowering drug—with standard FOLFIRINOX chemotherapy can make tumors more responsive by disrupting changes that enable resistance.
"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.
