Ovarian Cancer Ascites May Be Reduced With New Targeted Agent

UCLA researchers have discovered a new drug that helps reduce ascites in patients with ovarian cancer through inhibiting certain receptors.

The findings of the preclinical study, published in theCancer Researchjournal,¹state that the drug inhibits a receptor known as the colony-stimulating-factor-1 receptor, or CSF1R, and creates an adverse space for cancer growth in the abdominal cavity.

According to the study abstract, researchers targeted macrophage functions to reverse the vascular pathology of malignant ascites using fluid from human patients, as well as an immunocompetent murine model (ID8) of epithelial ovarian cancer. This model mimics human disease by developing progressive vascular disorganization and leakiness culminating in massive ascites. To further the macrophages' role in the pathogenesis of malignant ascites, the researchers blocked macrophage function in ID8 mice using the CSF1R inhibitor.

Administration of GW2580 in the late stages of disease resulted in reduced infiltration of protumorigenic (M2) macrophages and dramatically decreased ascites volume.

Ascites are a buildup of fluids in the abdomen in patients with ovarian cancer. The most common treatment for ascites is to puncture the abdomen and manually drain the fluid. The procedure is not only painful and risky, but must be done several times over the span of a few weeks. These ascites occur when a problem in the abdominal cavity forces the abdominal blood to leak, in turn causing lymphatic vessels to fill with cancer cells instead of flushing out the excess fluid.

The new drug is believed to be most effective when coupled with conventional cancer treatments like chemotherapy. Clinical trials for the newly founded drug would hypothetically focus on its effects on patients who have epithelial ovarian cancer.

Lead study author Lily Wu, MD, PhD, professor of pharmacology, pediatrics and urology, UCLA, said that of the 22,000 women diagnosed with epithelial ovarian cancer in the United States, nearly 50% to 70% of them will eventually 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, in a statement.

Previous studies have focused on hindering the VEGF protein as a means of encouraging growth in blood vessels. Wu warned the protein-focused treatment comes with serious side effects such as “cause catastrophic intestinal perforation in up to 10 percent of patients in clinical trials,” according to previous reports.

This new research revealed to Wu and her research team that patients treated with the CSF1R inhibitor experienced little to no major side effects. Targeting the cells with this inhibitor helped to ease ascites accumulation by decreasing the number of pro-tumor macrophages and letting the vessels of the abdomen reach normal levels again.

The research team intends to take this drug to clinical trial and explore if the CSF1R inhibitor can work in correlation with other standard ovarian cancer treatments. Wu and her team said they hope to see if the drug could fight both the ascites and the cancer simultaneously in the context of the trial.

Diana Moughon, pharmacology graduate at UCLA and first study author, added that ascites can develop in other cancers of the abdomen, including the liver and pancreas, as well as metastatic cancers elsewhere in the body like breast cancer.

“Macrophages have also been shown to assist in these aggressive malignancies and to be a mechanism of their ascites accumulation,” said Moughon in a statement. “We are hopeful that our therapeutic strategy can eventually be broadened to include ascites induced by other cancers.”

References

1. Irwin K. Researchers find experimental drug can help fight debilitating side effect of ovarian cancer. UCLA Newsroom. 2015. http://newsroom.ucla.edu/releases/researchers-find-experimental-drug-can-help-fight-debilitating-side-effect-of-ovarian-cancer. Accessed November 19, 2015.