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(Bacterial) Cancer Therapy on Therapy Development Because It Enables Precise Tuning and Limitless Functional Combinations

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(Bacterial) Cancer Therapy on Therapy Development Because It Enables Precise Tuning and Limitless Functional Combinations Nature Reviews Cancer | AOP, published online 14 October 2010; doi:10.1038/nrc2934 PERSPECTIVES using light5,31,32, magnetic resonance imaging INNOVATION (MRI)33 and positron emission tomography (PET)34–36. Finally, and most importantly, the Engineering the perfect ease of genetically manipulating bacteria is the feature that will have the greatest effect (bacterial) cancer therapy on therapy development because it enables precise tuning and limitless functional combinations. Neil S. Forbes Once fully implemented and tested, the Abstract | Bacterial therapies possess many unique mechanisms for treating cancer unique capabilities of bacterial therapies will change the way cancer is treated. The that are unachievable with standard methods. Bacteria can specifically target manufacture of drugs in tumours would tumours, actively penetrate tissue, are easily detected and can controllably induce beneficially shift temporal drug concentra- cytotoxicity. Over the past decade, Salmonella, Clostridium and other genera have tion profiles compared with intravenous been shown to control tumour growth and promote survival in animal models. In administration (FIG. 2). Because bacteria can this Innovation article I propose that synthetic biology techniques can be used to migrate and accumulate far from the vas- culature, more of the therapeutic would be solve many of the key challenges that are associated with bacterial therapies, such present in distal regions for longer periods as toxicity, stability and efficiency, and can be used to tune their beneficial features, of time compared with small molecules allowing the engineering of ‘perfect’ cancer therapies. that diffuse only passively. Intratumoural production would be more toxic to can- Bacteria have unique capabilities that make about where and when drugs are admin- cer tissue and less toxic to normal tissue. them well-suited to be ‘perfect’ anticancer istered. Finally, the ability to be externally This inversion of drug localization would agents. Because their genetics can be easily detected would provide crucial information eliminate tumours from the inside out, manipulated, bacteria can be engineered about the state of the tumour, the success of and would have the simultaneous effects of to overcome the limitations that hamper localization and the efficacy of treatment. increasing efficacy and decreasing damage current cancer therapies. Many treatments, Bacteria can be viewed as these perfect to normal tissue. including chemotherapy and radiation, are robot therapies because they have bio- To date, many different bacterial strate- toxic to normal tissue and cannot completely logical mechanisms to carry out all of the gies have been implemented in animal destroy all cancer cells1. Three major causes ideal functions mentioned above (FIG. 1b). models (TABLES 1,2) and some human trials of these problems are incomplete tumour Over the past century, many genera of have been carried out (TABLE 3). Using these targeting, inadequate tissue penetration and bacteria have been shown to preferen- strategies, many researchers have observed limited toxicity to all cancer cells1–3. These tially accumulate in tumours, including experimental success, with reduced tumour drawbacks prevent effectual treatment and Salmonella4, Escherichia5, Clostridium6,7 and volume and increased survival and treat- are associated with increased morbidity Bifidobacterium8. Caulobacter 9, Listeria10,11, ment of metastatic disease (TABLE 1). Success and mortality. Proteus12 and Streptococcus13 have also has also been shown in treating multiple Using a top-down engineering approach, been investigated as anticancer agents. tumour sites (TABLE 1); the most notable is the ideal cancer therapy can be envisioned: For propulsion and sensing, bacteria have pancreatic cancer13,37, for which new targeted it would be tiny programmable ‘robot facto- flagella that enable tissue penetration14 and treatments could dramatically improve the ries’ (FIG. 1a) that specifically target tumours, chemotactic receptors that direct chemotaxis poor current prognosis of less than 25% are selectively cytotoxic to cancer cells, are towards molecular signals in the tumour 5-year survival. Since the mid-1990s, the self-propelled, are responsive to external microenvironment15,16. For example, the number of published bacterial therapy signals, can sense the local environment and TAR receptor detects aspartate secreted papers has increased, with a doubling time are externally detectable. Specific targeting by viable cancer cells, and the TRG recep- of 2.5 years (FIG. 1c). This rapid rise has been would allow the use of more toxic molecules tor promotes migration towards ribose in driven almost entirely by the increasing use without systemic effects. Self-propulsion necrotic tissue16. Selective cytotoxicity can of Salmonella as a delivery vector (FIG. 1c). would enable penetration into tumour be engineered by transfection with genes for This Innovation article describes many of regions that are inaccessible to passive therapeutic molecules, including toxins17–19, the advances that have fuelled this enthusi- therapies. Responsiveness to external sig- cytokines20,21, tumour antigens22 and apop- asm, including specific bacterial targeting of nals would enable the precise control of the tosis-inducing factors23–27. External control tumours; intratumoral penetration; native location and timing of cytotoxicity. Sensing can be achieved using gene promoter strate- bacterial cytotoxicity; expression of anti- the local environment would allow ‘smart’, gies that respond to small molecules17,28,29 or cancer agents; gene-triggering strategies; responsive therapies that can make decisions radiation23,26,27,30. Bacteria can be detected and detection of bacterial therapies. NATURE REVIEWS | CANCER ADVANCE ONLINE PUBLICATION | 1 © 2010 Macmillan Publishers Limited. All rights reserved PERSPECTIVES Bacterial targeting of tumours and protection from clearance by the could also reduce the usefulness of repeated One of the major advantages of bacterial ther- immune system42. These mechanisms enable dosing with bacteria, which is a limitation apies for cancer is the ability to specifically Salmonella to accumulate in tumours at that does not affect bacteria that are delivered target tumours. The mechanisms of bacterial ratios greater than 1000/1 compared with as spores47. accumulation in tumours differ depending organs that are rich in reticuloendothelial In in vitro tumour models, Salmonella on oxygen tolerance. Obligate anaerobes (for cells (such as the liver and spleen) and identify and penetrate tumours by detecting example, Clostridium and Bifidobacterium) Salmonella accumulate at even greater ratios and chemotaxing towards small molecule cannot survive in oxygen, and injected in other organs40,43–45. gradients of serine, aspartate and ribose15,16. bacterial spores can only germinate in the When injected systemically, Salmonella In addition, the growth rate of Salmonella is anoxic regions of tumours38,49. Completely attach to the walls of tumour vasculature greater in in vitro tumours when dying cells deoxygenated tissue is unique to tumours with a low but measurable frequency are present15, a phenomenon which is also and is not present in most other organs of the (~0.035% of bacteria in the blood)40. In addi- observed in animal tumour models40,41,46. body. Obligate anaerobes are therefore highly tion, the number of bacteria that adheres The importance of this mechanism for pro- effective at accumulating in the large hypoxic is dependent on blood velocity, suggesting moting accumulation is supported by the regions of tumours14. This absolute specificity that haemodynamics have an important increased tumour specificity of auxotrophic was demonstrated by Malmgren et al.7 who role in the initial interaction of bacteria Salmonella that require leucine and arga- injected Clostridium into tumour-bearing with tumours40. Similarly, the accumula- nine, which are nutrients derived from dying mice and showed that only the mice with tion of Salmonella is associated with an tumour tissue31,48. tumours died from this infection. influx of blood into tumours, caused by Because tumours are immune-privileged Facultative anaerobes (for example, an immunologically induced rise in the environments49, bacteria can replicate unim- Salmonella and Escherichia) use a more com- blood concentration of tumour necrosis peded by the macrophage and neutrophil plex set of mechanisms to target tumours. factor-α (TNFα)41. This mechanism would clearance mechanisms that normally serve Five interacting mechanisms are thought be reduced for attenuated msbB– strains that to eliminate them50. In this way, the immune to control the accumulation of facultative elicit much lower (~10%) TNFα levels46. system has a complicated role in bacterio- anaerobes in tumours: entrapment of bacte- The production of TNFα immediately after lytic therapy: it provides a mechanism to ria in the chaotic vasculature of tumours40; injection therefore has contradictory effects: guide bacterial accumulation, but also flooding into tumours following inflamma- it promotes accumulation in tumours but is impedes dispersion and efficacy. The inter- tion41; chemotaxis towards compounds pro- also the primary cause of bacterial toxicity action between bacteria and the immune duced by tumours15,16; preferential growth owing to septic shock46. This dependence on system also works in reverse: many bacterial in tumour-specific microenvironments15,31;
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