A devastating side-effect of ovarian cancer is ascites, a buildup of fluid in the abdominal cavity. The most common treatment for the condition is puncturing the abdomen to drain the fluid; it is a painful procedure that must be repeated every few weeks. Now, UCLA researchers have reported on the discovery of a drug that inhibits a receptor called the Colony-Stimulating-Factor-1 Receptor (CSF1R); it reduces ascites with minimal side effects. This inhibition therapy does not targets cancer cells, rather, it acts on macrophages, a special type of immune cell, and prevents them from assisting the seeding of cancer cells in the abdominal cavity. The findings were published on November 16 in the journal Cancer Research.
The study authors explain that the drug alters the environment of the abdominal cavity into one that is less conducive to cancer growth. Thus, it may prove to be an effective treatment that can be used in combination with conventional cancer treatments such as chemotherapy. The findings may lead to a clinical trial of the drug in patients with epithelial ovarian cancer, explained senior author Lily Wu, MD, PhD, a professor of pharmacology, pediatrics and urology at UCLA and a member of UCLA’s Jonsson Comprehensive Cancer Center. She said that 50-70% of the approximately 22,000 women diagnosed with epithelial ovarian cancer in the US year will also develop ascites. She explained, “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.”
Ascites is not exclusive to epithelial ovarian cancer, noted first author Diana Moughon, the study’s first author and a graduate student in pharmacology at UCLA. She explained, “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.” She added, “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 by a problem with the abdominal blood and lymphatic vessels that causes the blood vessels to “leak” and the lymphatic vessels, which would otherwise drain the excess fluid, to become occluded with cancer cells. Previous research has focused on inhibiting a protein called VEGF, which promotes the growth of blood vessels. However, Dr. Wu said that the treatment is risky and has been reported to cause catastrophic intestinal perforation in up to 10% of patients in clinical trials. In contrast, people treated with CSF1R inhibitors experienced no major side effects.
“Specifically targeting the cells with CSF1R inhibitors lessens the number of pro-tumor macrophages and allows the vessels in the abdomen to become normal again, easing ascites accumulation,” explained Dr. Wu. She added, “All of this is accomplished without dangerous side effects or pain.” One of the ways tumors recruit and change macrophages is through a long-distance signaling mechanism. Tumors pump out a protein called CSF-1, which floats around until it finds the receptor it is looking for, in this case CSF1R. When the signal meets the receptor, the cell in contact with the receptor receives the message from the tumor.
Macrophages express CSF1R and respond to the signaling by traveling toward the tumor and becoming pro-tumor. When CSF1R was inhibited, the number of macrophages in the ascites surrounding the tumor was vastly reduced, which, in turn made the ascites environment much less favorable to the tumor. After just two weeks of treatment, the laboratory animals’ blood vessels carried blood normally instead of leaking it. Dr. Wu said this caused the ascites to at least stop accumulating, and in many cases to regress. The researchers 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.