Creating Bacterial Anticancer Therapies with Synthetic Biology

Neil Forbes

Engineered bacteria have the potential to overcome the limitations that cause common cancer therapies to fail. Synthetic biology is playing a critical role in the creation of these therapies.  We have shown that bacteria, specifically Salmonella, have three main qualities that enable them to overcome the limitations of chemotherapy. Bacteria 1) preferentially target tumors, 2) penetrate tissue, and 3) can kill non-mitotic cells. By manipulating the ribose/galactose chemoreceptors we can direct Salmonella to resistant tumor regions and by transiently inducing inflammation can promote accumulation in mice. To make Salmonella suitable for clinical use, we have solved two additional problems. Currently, bacteria do not sufficiently kill cancer cells and have residual toxicity. By screening 169 molecules, we identified α-hemolysin from Staphylococcus aureus, which we found kills 99% of culture cells in 5 minutes and significantly reduces tumor volume in mice. To enhance expression we have engineered an inducible cell-communication system that increases sensitivity to molecular triggers more than 10,000 fold. To control toxicity, we have engineered a density-dependent gene circuit that induces protein expression only after bacteria have colonized tumor tissue. These results have established Salmonella as a tunable platform for cancer therapy. Integrating these gene components will produce a wide array of therapeutic bacteria, able to eradicate previously untreatable tumors and reduce cancer mortality.