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Tumor-targeting Salmonella expressing apoptosis-inducing cytotoxic proteins

David G Bermudes

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National Institutes of Health (NIH)
Tumor-targeting bacteria offer a number of advantages over other cancer drug delivery systems, including targeting of multiple tumors from a distant inoculation site, selective intratumoral replication, a high degree of attenuation and safety, and the ability to express anti-cancer proteins directly within the tumor. Remarkably, attenuated Salmonella localize within solid tumors at levels at least 1000 times greater than other tissues. Human clinical studies have validated the safety of intravenously administered attenuated bacterial mutants, established tolerated multiple doses, and have shown that tumor targeting occurs in some patients. However, no anti-tumor activity was observed, even in patients in which the Salmonella were verified to have colonized their tumors. We hypothesize that the lack of antitumor efficacy in the human clinical trials can be overcome by engineering apoptosis (programmed cell death) -inducing cytotoxic proteins that are able to kill tumor cells. The Specific Aims are designed to test individual proteins and protein combinations in order to develop tumor-targeted Salmonella vectors with enhanced antitumor activity. The project utilizes synthetic biology, the chemical synthesis of DNA, to construct genes encoding proteins that will kill cancer cells. The composition of these synthetic proteins is based on combinations of known cancer-killing and cancer-targeting protein components, which, when combined, result in proteins with the selective ability to kill cancer. A preliminary study of novel bifunctional fusios of the apoptosis and cytotoxic polypeptides will also be conducted in order to combine aspects of their cell targeting, subcellular transport and intracellular molecular targets as a means to confer enhanced potency together with tumor specificity, and to generate preliminary data for a new grant submission. The bacteria described here are highly safe and suitable for students to work on in the lab. Students are recruited from the microbiology courses the PI teaches and integrates his research on tumor-targeted Salmonella. Students are also recruited from the Graduate School Admission Program, and the MARC and RISE programs at CSUN. Although the PI has only been at CSUN for 1.5 years, he has already provided laboratory-based research training for 11 students, including 3 Hispanics, 2 Armenians, 2 Indians, 1 Filipino, 1 Thai, and 1 Korean. The project is expected to involve two graduate students seeking their Masters Degree over a two to three year period, with a total of up to four graduate students during the funding period, and one to two directed research undergraduates per year; up to eight during the course of the funding period, as well as one to two students per semester enrolled in the Biology research course, for a total of between 14 and 28 students during the funding period.

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