Advances in bacterial cancer therapies using synthetic biology

Abstract

Synthetic biology aims to apply engineering principles to biology by modulating the behavior of living organisms. An emerging application of this field is the engineering of bacteria as a cancer therapy by the programming of therapeutic, safety, and specificity features through genetic modification. Here, we review progress in this engineering including the targeting of bacteria to tumors, specific sensing and response to tumor microenvironments, remote induction methods, and controllable release of therapeutics. We discuss the most prominent bacteria strains used and their specific properties and the types of therapeutics tested thus far. Finally, we note current challenges, such as genetic stability, that researchers must address for successful clinical implementation of this novel therapy in humans.

Figure 1. Overview of engineered bacterial cancer therapeutics

Synthetic biology is capitalizing on bacteria's natural ability to colonize immunoprivileged, hypoxic core regions of tumors through escaping from leaky vasculature. A variety of strategies such as targeting, inducing gene expression, quorum-sensing, expressing and releasing cytotoxics, and intracellular gene delivery have been engineered to control the behavior of these bacteria and produce anti-tumor effects.

Figure 2. Engineered circuits for bacterial cancer therapy

(A) Targeting to tumor cells can be achieved by expression of tumor-specific peptides on the bacterial outer membrane. (B) Tumor microenvironments can be sensed specifically by AND logic gates, which expresses an output such as a therapeutic only if all required inputs or markers of the tumor microenvironment are present. (C) In many cases lysis of bacteria must be induced to release therapeutics into the tumor; one relevant circuit is the synchronized lysis circuit which uses quorum sensing. (D) Therapeutics or other actions can be driven by inducing promoters through chemical inducers or radiation.