CSF1R Inhibition May Ease Debilitating Adverse Event of Ovarian Cancer

Women who have ovarian cancer often develop ascites, a buildup of fluids in the abdomen. The most common treatment is to puncture the abdomen and manually drain the fluid, a painful and risky procedure that must be repeated every few weeks.

However, researchers have found that ascites can be reduced with minimal side effects through the use of a drug that inhibits the colony-stimulating-factor-1 receptor (CSF1R). This inhibition therapy targets not cancer cells but macrophages, a special type of immune cell, to prevent them from helping the cancer take root in the abdomen.

In effect, the drug changes the abdominal cavity, where ovarian cancers often spread, into an environment less conducive to cancer growth. It may prove to be an effective treatment in combination with conventional cancer treatments such as chemotherapy, based on this preclinical research in mice.

The findings, published in Cancer Research (doi:10.1158/0008-5472.CAN-14-3373), may lead to a clinical trial of the drug in patients with epithelial ovarian cancer, said senior author Lily Wu, PhD, a professor of pharmacology, pediatrics, and urology at University of California at Los Angeles.

Wu said 50% to 70% of the approximately 22,000 women with epithelial ovarian cancer diagnosis in the United States each year will also develop ascites.

"Trying to fight a battle on two fronts can seem hopeless, and patients fighting ascites while trying to survive a particularly deadly cancer is unacceptable," said Wu, who is also a member of UCLA Jonsson Comprehensive Cancer Center.

Ascites is not exclusive to epithelial ovarian cancer, said first author Diana Moughon, a graduate student in pharmacology at UCLA.

"Some other cancers of the abdomen, such as liver and pancreatic cancers, and some highly invasive and metastatic cancers from elsewhere, such as breast cancer, can also cause ascites," Moughon said. "Macrophages have also been shown to assist in these aggressive malignancies and be a mechanism of their ascites accumulation. We are hopeful that our therapeutic strategy can eventually be broadened to include ascites induced by other cancers."

Ascites is caused when the abdominal blood vessels leak and the lymphatic vessels, which would otherwise drain the excess fluid, become plugged with cancer cells. Previous research has focused on inhibiting the VEGF protein, which promotes the growth of blood vessels.

However, that treatment is risky and has been reported to cause catastrophic intestinal perforation in up to 10% of patients in clinical trials. By contrast, people treated with CSF1R inhibitors experienced no major side effects.

"Specifically targeting the cells with CSF1R inhibitors lessens the number of protumor macrophages and allows the vessels in the abdomen to become normal again, easing ascites accumulation," Wu said. "All of this is accomplished without dangerous side effects or pain."

Going forward, Wu and her team want to try the therapy in a clinical trial. They also will explore whether the CSF1R inhibition therapy can be combined with standard ovarian cancer treatments to fight both the ascites and the cancer.

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