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Research Grants Awarded
Design of Targeted Bacteria to Overcome Multidrug Resistance
Bacteria engineered to specifically target therapeutically resistant regions of tumors and controllably kill cancer cells will be able to overcome multidrug resistance and increase therapeutic efficacy. Multidrug resistance is caused by limited drug penetration and poor cell susceptibility to chemotherapeutics. Only motile bacteria, which can penetrate into tumor tissue and overcome diffusion limitations, are able to effectively kill therapeutically resistant cells distant from tumor vasculature. Controlling bacterial motility is therefore the key to developing effective therapies able to overcome multidrug resistance. To date, the mechanisms of bacterial motility in tumors are poorly understood. We hypothesize that the chemotaxis machinery of Salmonella typhimurium controls its accumulation in solid tumors and can be tuned to increase its tumor cytotoxicity . We propose to 1) determine the predominant chemoreceptor that controls S. typhimurium accumulation in tumors and 2) design bacterial mutants that are specifically targeted to tumor quiescence using directed evolution. The proposed research program combines our expertise in tumor biology, directed evolution, and mathematical modeling. We will use cylindroids, an in vitro model that mimics the microenvironments of tumors, and fluorescence imaging to quantify the behavior bacteria in tumors. Directed evolution, a genetic selection method, will be used to create Salmonella mutants with increased targeting abilities. The project is unique because of its focus on intratumoral therapeutic delivery , a new approach to enhancing therapeutic efficiency. The experimental plan is part of a research program to develop a therapeutic strategy to overcome multidrug resistance. Combined administration of tumor-quiescence-targeted S. typhimurium and adjuvant chemotherapy will increase therapeutic efficiency by more effectively killing cancer cells distant from tumor vasculature. Future human trials will investigate the ability of combined administration of bacteria and chemotherapy to reduce local recurrence and metastatic disease in late-stage breast cancer patients. Using bacteria to overcome multidrug resistance and increase therapeutic efficiency will significantly reduce systemic toxicity, limit the deleterious effects of metastatic disease, and increase live expectancy.
The inability of chemotherapeutic drugs to penetrate into all regions of tumors is a problem that limits our ability to treat metastatic disease and stop tumor recurrence. In this proposal we describe a series of experiments designed to demonstrate how engineered bacteria can be selected to target these therapeutically resistant regions of tumors. We call this concept intratumoral therapeutic delivery . Only bacteria, which can swim and penetrate into tumor tissue are be able to overcome the limitations the impeded standard chemotherapeutics. Recently, a non-toxic strain of Salmonella was developed. We found that these bacteria are selectively attracted to tumors. Being able to control how bacterial are attracted to tumors is the key to effective intratumoral therapy. However, to date, little is known about how bacteria are attracted to tumors. We believe that the chemotaxis machinery of Salmonella typhimurium controls its accumulation in solid tumors and can be tuned to increase its tumor cytotoxicity . To test whether this is true, 1) we will identify the genes and cellular components that control Salmonella accumulation in tumors and 2) we will design bacteria that are specifically targeted to the hard-to-treat regions of tumors using cutting-edge genetic techniques. The proposed research program combines expertise in tumor biology, molecular biology, and mathematical modeling. We will use techniques designed in our lab to mimic breast tumors and Salmonella with parts of their chemical-detection machinery deleted to determine how Salmonella sense tumors and migrate towards them. The experimental plan is part of a larger research program to develop general therapeutic strategies to overcome drug resistance. We expect that non-toxic, targeted bacteria will increase the effectiveness of current therapies and will extend life expectancy. We also believe that engineered bacteria will be inexpensive therapy to manufacture. We anticipate that success research will lead to human trials within five years. These trials will investigate the ability of combined administration of tumor-targeted Salmonella and adjuvant chemotherapy to reduce local recurrence and metastatic disease in late-stage breast cancer patients. Using bacteria to overcome drug resistance will significantly reduce the toxicity of chemotherapeutics, limit the deleterious effects of metastatic disease, and increase live expectancy.