Seed Grant Recipient Identifies Potential New Targets for Treating Peritoneal Spread
In an estimated 40% of gastric cancer patients, the disease travels to the abdominal lining, a condition known as “malignant ascites” that renders patients resistant to immunotherapy and lowers their odds of survival. In the fall of 2023, the Gastric Cancer Foundation awarded a $100,000 grant to Dr. Alexandra-Chloé Villani, a faculty member at Massachusetts General Hospital (MGH), who has dedicated her research to finding potential new treatments for malignant ascites.
Dr. Villani reports that with the one-year grant, her lab was able to generate crucial data and insights into malignant ascites that she’s hopeful will ultimately lead to new therapeutic targets.
The first goal of Dr. Villani’s project was to identify components of the peritoneal fluid in the abdomen that suppress the immune response to cancer. She co-led this study with Dr. Samuel Klempner and Dr. Steven Blum, using advanced single-cell analysis techniques to examine ascites and blood specimens taken from gastric cancer patients treated at MGH and Cedars-Sinai Medical Center. They also optimized a cellular model of ascites derived from gastric cancer patients, which captures not only malignant cells, but also the entire microenvironment of ascites, including immune cells.
In their analysis, Dr. Villani and her colleagues found small proteins known as cytokines, as well as subsets of immune cells that seem to be enriched in gastric and esophageal cancer ascites. They believe targeting these molecules could reverse immunosuppression. “We could not have identified these new biological drivers of disease without having done all the work that was supported by the Gastric Cancer Foundation,” she said.
“Two years ago, we knew so little about what was happening in the peritoneal cavity. The biology of peritoneal fluid is way more complex than we had appreciated before,” Dr. Villani added. “Thanks to the Foundation’s support, we now have a map of the key cellular and biological components that make-up the ascites microenvironment. This map will help us identify the drivers of malignant ascites and potential targets for therapeutic intervention.”
Dr. Villani’s second goal was to test potential therapeutic agents against the targets her team identified in models of malignant ascites. Using a cellular model they optimized, they generated promising preliminary data that they hope to build upon in future studies. The leads Villani’s team identified from the study are so promising that she’s confident in their potential to attract larger research grants to continue the research, and possibly down the road, a partnership with a biopharmaceutical company that could fund clinical trials of novel drugs targeting the immunosuppressive biological drivers within the ascites environment.
An important mission of the Gastric Cancer Foundation is to bridge a significant funding gap faced by early and mid-career researchers who are pursuing novel approaches. The opportunity to apply for the grant was invaluable, Dr. Villani said. “With this pilot funding, we were able to take a high-risk, high-reward approach,” she said. “We generated a wealth of data that led us to formulate several new hypotheses we’re now actively exploring, which is incredibly exciting.”
