$2 million NCI grant supports research into pancreatic cancer’s cholesterol survival strategy

Oklahoma researchers have received a five-year, $2 million grant from the National Cancer Institute to investigate how pancreatic cancer alters its use of cholesterol to survive chemotherapy. The project, led by Surendra Shukla, Ph.D., assistant professor of oncology science at the University of Oklahoma College of Medicine and a research member of OU Health Stephenson Cancer Center, could reveal why some pancreatic tumors remain resistant to treatment and identify strategies for making existing therapies more effective.

Pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer, is among the deadliest cancers because it is often diagnosed after it has spread and frequently develops resistance to chemotherapy. Although cholesterol is commonly associated with cardiovascular disease, it is an essential component of every cell. The molecule helps maintain cell membranes, supports signaling pathways and serves as a raw material for the production of steroid hormones and other biologically important compounds. Cancer cells, which divide rapidly and constantly remodel their membranes, have particularly high demands for cholesterol.

Shukla’s research focuses on a protein called ZC3H15, which preliminary studies suggest may help pancreatic tumors adapt to the metabolic stress imposed by chemotherapy. The investigators found that pancreatic cancers with elevated levels of ZC3H15 were more likely to withstand treatment and were associated with poorer survival among patients. These observations suggest that ZC3H15 may be more than a marker of aggressive disease: it could be an active component of the molecular machinery that enables tumor cells to persist.

ZC3H15 belongs to a class of RNA-binding proteins that regulate the fate of messenger RNA, the temporary genetic instructions cells use to manufacture proteins. By binding to RNA molecules, these proteins can influence how long a message survives, how efficiently it is translated or whether it is destroyed. The Oklahoma team’s preliminary work indicates that ZC3H15 protects the RNA instructions encoding KDM3A, a protein involved in gene regulation and cellular adaptation. Increased KDM3A production may then reshape the way pancreatic cancer cells acquire, synthesize and use cholesterol.

This relationship could provide a mechanistic explanation for how pancreatic tumors respond to chemotherapy. Rather than treating cholesterol as a passive nutrient, cancer cells may actively reprogram cholesterol metabolism to preserve membrane integrity, sustain growth signals and tolerate cellular damage caused by drugs. Such metabolic flexibility can give malignant cells an advantage when chemotherapy disrupts DNA replication or triggers cell death. By maintaining access to cholesterol and related metabolic pathways, tumor cells may be able to repair damage and continue dividing even under treatment pressure.

The researchers have also linked the ZC3H15-KDM3A pathway to epithelial-to-mesenchymal transition, or EMT. During EMT, cells lose some of the characteristics that keep them attached to neighboring cells and acquire a more mobile, adaptable state. In cancer, this transition can increase the ability of tumor cells to invade surrounding tissues and enter the bloodstream. EMT is also associated with resistance to several forms of therapy, making the process important not only for metastasis but also for the survival of residual disease after treatment.

Over the next five years, the team will examine how ZC3H15 changes cholesterol biology in pancreatic cancer and determine whether interrupting that pathway can weaken tumors. The experiments will use patient-derived laboratory models, genetically engineered mice and other systems designed to reproduce key features of human pancreatic cancer. These models will allow researchers to track cholesterol movement and metabolism, measure changes in gene regulation and test whether reducing ZC3H15 or KDM3A makes cancer cells more vulnerable to chemotherapy.

A central part of the project will test whether the cholesterol-lowering drug rosuvastatin can be combined with FOLFIRINOX, a standard chemotherapy regimen for pancreatic cancer. Rosuvastatin is widely prescribed to reduce blood cholesterol by inhibiting a major enzyme in the body’s cholesterol-production pathway. In the new studies, the drug will be evaluated for a different potential role: disrupting the metabolic adaptations that pancreatic tumors use to resist chemotherapy. The researchers will determine whether this combination reduces tumor growth, limits EMT and improves the response of cancer models to treatment.

If the findings are confirmed, ZC3H15 could become a therapeutic target and a possible indicator of tumors that depend heavily on cholesterol-related survival mechanisms. The work may also clarify whether an approved medication can be repurposed to support pancreatic cancer treatment, although laboratory success would still need to be followed by carefully designed clinical trials. “Our goal is to understand how pancreatic cancer adapts to survive treatment,” Shukla said. “If we can interrupt the biological processes that help these tumors thrive, we may be able to make existing therapies more effective.” The research is supported by the National Cancer Institute under award R01CA316828-01, along with funding from Oklahoma’s Tobacco Settlement Endowment Trust and Oklahoma Shared Clinical and Translational Resources.

Web References: University of Oklahoma Health Campus — https://www.ouhsc.edu

References: National Cancer Institute award R01CA316828-01; Oklahoma Tobacco Settlement Endowment Trust; Oklahoma Shared Clinical and Translational Resources, NIH grant U54GM104938.