MIT researchers demonstrated that blocking caspase-1, an enzyme involved in lung inflammation, significantly reduces the risk of lung tumor formation in mice. The findings, published in Science Advances, indicate that repurposing existing small-molecule inhibitors of the enzyme could offer a preventative treatment for people at high risk of developing lung cancer.
Cathy Wang led the study alongside senior author Sangeeta Bhatia, a professor at MIT and member of the Koch Institute for Integrative Cancer Research. To track inflammation, the team adapted diagnostic nanosensors that detect active proteases in tissue. Proteases cleave other proteins, including the inflammatory cytokine IL-1 beta, and play key roles in tumor migration and immune signaling.
Testing in a mouse model engineered with cancer-causing p53 and Kras mutations revealed that untreated mice developed tumors showing elevated caspase-1 activity. Mice treated with a caspase-1 inhibitor developed fewer and smaller tumors. When researchers administered both the caspase-1 inhibitor and an IL-1 beta antibody, nearly 20 percent of the mice never developed tumors.
Examinations of human lung fluid samples, conducted with Harvard Medical School physician Lecia Sequist, showed higher caspase-1 activity in lung cancer patients than in healthy donors with similar smoking histories.
Because caspase-1 inhibitors are oral drugs already tested in human clinical trials for conditions such as rheumatoid arthritis, the researchers plan to evaluate the compounds in preventative clinical trials. Funding for the research came from Johnson & Johnson, Upstage Lung Cancer, the Virginia and D.K. Ludwig Fund for Cancer Research, the National Cancer Institute, and the National Institute of Environmental Health Sciences.
