Engineered Commensal Microbes to Target Colorectal Cancer

Commensal microbes are known to regulate a healthy intestinal microbiota, translating to improved metabolism and immunity. Genetically engineered commensals have been studied for the treatment of inflammatory bowel disorders such as Crohn’s disease, ulcerative colitis, as well as for diseases linked to hyperactivity of the host immune system. Using the commensal microbes as a chassis, it is possible to add health benefiting properties that can enhance the gut conditions of the host. Herein, we present our recent work using engineered commensal microbes to target colorectal tumor leading to tumor regression. A combination of two strategies is employed in order to allow effective targeted drug delivery to colorectal tumors by the engineered commensal microbes. First, the commensal microbes are designed to express cancer biomarker-binding proteins on the surface of the probiotic membrane for specific binding to colorectal tumors. Second, these microbes are engineered to secrete an enzyme that converts compounds derived from daily food consumption into anti-cancer compounds. The class of enzyme was screened to have stronger binding affinity to the substrate as well as improved pH and temperature tolerance for better performance in the gastro-intestinal tract. As the microbes attaches on the tumor surface, the enzyme is then delivered to the cancer cells a secretion tag. These engineered probiotics caused cell-line specific cancer cell death of up to 95% in vitro and led to latent tumor formation and reduced tumor size upon treatment in in vivo murine models. Our work demonstrates that our engineered microbes can potentially be deployed for enhanced for cancer treatment, leading to reduced colorectal cancer incidences and improved patient recovery.