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Bacteria cancer therapy
: When bacteria meet with cancer
Jung-Joon Min, MD, PhD
Institute for Molecular Imaging & Theranostics, Department of Nuclear
Medicine, Chonnam National University Medical School
Current cancer therapies, including chemotherapy and radiotherapy, cannot
completely destroy all cancer cells and are toxic to normal tissue. Three major
causes of these problems are (1) incomplete tumor targeting, (2) inadequate
tissue penetration and (3) limited toxicity to all cancer cells. These drawbacks
prevent effectual treatment and are associated with increased morbidity and
mortality. For example, chaotic vasculature and large intercapillary distances in
tumors impede the delivery of therapeutic molecules. Low levels of oxygen and
glucose create quiescent cells that are unresponsive to chemotherapeutics that
are designed to target rapidly growing cells. Besides, the concentration of
chemotherapeutic molecules drops as a function of distance from vasculature.
Therefore, proper intratumoral targeting enables direct drug delivery to these
distal, unresponsive cells that are far from the tumor vasculature.
Some strains of bacteria have unique capabilities: (1) the ability to
specifically target tumors, (2) preferential growth in tumor-specific
microenvironment, (3) intra-tumoral penetration, (4) native bacterial cytotoxicity.
Motility is the key feature of bacterial therapies that enables intratumoral targeting.
Bacteria can actively swim away from the vasculature and penetrate deep into
tumor tissue. Within tumor, bacteria actively proliferate, resulting in 1000-fold or
even higher increases in bacterial numbers in tumor tissue relative to normal
organs. Because their genetics can be easily manipulated, bacteria can be
engineered to synthesize drugs at sufficient concentrations to induce therapeutic
effects. Although this strategy led to significantly greater therapeutic effects, they
still have significant limitations; for example, multiple injections of bacteria are
required, the tumors tend to recur quickly, and efficacy is unclear in the treatment
of metastatic disease.
Our group developed an attenuated strain of S. typhimurium, which was
defective in guanosine 5’-diphosphate-3’-diphosphate synthesis (ΔppGpp S.
typhimurium) and genetically engineered this strain to express diverse cargo
molecules that can provoke anticancer immunogenicity or direct cell killing. In this
lecture, I will introduce several strategies of genetic engineering of bacteria for
cancer treatment and describe unique mechanisms related to bacteria cancer
therapy.