Common cholesterol drug may help disrupt ovarian cancer cell protection

A fluid that women with advanced ovarian cancer know all too well - ascites, the buildup of liquid in the belly - may be doing more than causing discomfort.

A federally funded Duke University School of Medicine study finds this fluid helps cancer cells survive and spread – and that a decades-old cholesterol drug may be able to disrupt that protection.

The findings, based on lab experiments and analysis of patient samples, do not show the drug treats ovarian cancer. But, they suggest that changing the environment cancer depends on could make it more vulnerable to existing cancer treatment.

Doctors have mostly viewed ascites as a symptom rather than an active driver of disease. We've learned it gives cancer a survival advantage, which fills a major gap in understanding how ovarian cancer spreads."

Jen-Tsan Chi, PhD, senior study author, professor in the Department of Molecular Genetics and Microbiology and co-leader of the Cancer Biology Program, Duke Cancer Institute

Doctors will drain ascites to ease pain, improve mobility, and make breathing easier, which offers patients relief even if it doesn't stop the disease. The fluid occurs in 90% of those with advanced ovarian cancer.

According to the new study, it also acts as a shield, helping cancer cells evade a specific form of cell death called ferroptosis.

Ferroptosis is a kind of cellular rusting. It happens when iron inside a cell reacts with certain fats causing the cell membrane to break apart. Many metastatic cancer cells - those that float freely through the abdomen looking for new places to grow - are naturally vulnerable to this kind of damage.

The new study in Nature Communications shows how they survive anyway.

Scientists bathed cancer cell lines and patient-derived tumor cells in real ascites collected from patients and watched how they responded to ferroptosis triggers.

The fluid protected cancer cells by changing how they store fats and control iron levels, effectively blocking cell death. The protection required only trace amounts: as little as 2% immersion shielded cancer cells from destruction, even though in patients these cells are entirely enveloped by the fluid.

"What surprised us was how selective this effect was," said the study's first author Yasaman Setayeshpour, a graduate student in molecular genetics and microbiology at Duke School of Medicine. "Ascites didn't protect the cancer cells from other well-known types of cell death, like apoptosis or necrosis - it only blocked ferroptosis.

"To figure out why, we broke ascites down into major parts, like lipids, proteins, and small molecules, and tested what happened when each was removed. When we took the lipids out, the protective effect disappeared. That told us lipids are the key reason ascites helps these cancer cells survive," she said.

But researchers found an unexpected helper: bezafibrate, an older cholesterol drug used to lower triglycerides by altering how the body processes fats.

"The idea behind testing lipid-lowering drugs was to mimic what happens when lipids are removed from ascites," Setayeshpour explained.

The cholesterol drug restored sensitivity to ferroptosis but only when ascites was present. On its own, the drug did not trigger cell death, nor did it slow tumor growth in mice.

The drug's impact hinged on the cancer's surroundings, in this case, the fat-rich fluid bathing the tumor. Researchers found that targeting this environment, using repurposed drugs like bezafibrate, could leave cancer cells more exposed to existing cancer treatments.

Chi said the finding could have implications beyond ovarian cancer. Other cancers, including colorectal and pancreatic cancers, can also spread within the abdominal cavity.

"This work shows how much the environment around a tumor matters," Chi said. "Biological fluids like ascites don't just give cancer cells a place to move. They actively help drive how cancer spreads.

Additional authors include Ssu-Yu Chen, Divya L Dayanidhi, Yunji Lee, Shao-Chin Wu, Juan J. Aristizabal-Henao, Jianli Wu, Chao-Chieh Lin, Nazanin Setayeshpour, Chiara Federico, Alexander A. Mestre, Michael A. Kiebish, David S. Hsu, and Susan Murphy, MD; Andrew Berchuck, MD; Zhiqing Huang, of the Duke Department of Obstetrics and Gynecology.

The study was supported by the Ovarian Cancer Research Alliance, the Department of Defense and the R.O.C. National Science and Technology Council.