7th Annual Symposium
Physics of Cancer
October 4-6, 2016
|PoC - Physics of Cancer - Annual Symposium|
Bacteria-Associated Cancer Theranostics : When Bacteria Meet Cancer
Institute for Molecular Imaging & Theranostics, Department of Nuclear Medicine, Chonnam National University Medical School, Republic of Korea
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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-mediated cancer therapy.