Engineering Improvements in a Bacterial Therapeutic Delivery System for Breast Cancer

摘要

Serendipitously, the bacterium Salmonella accumulates 1000-fold more in tumors than in normal tissue and we have shown that Salmonella sometimes cures cancer in animal models. We wished to improve Salmonella as a therapeutic system for cancer. In this first funding period there were three objectives and all three were achieved. First, in Aim 1, task 1, we were able to identify over 100 gene mutants of Salmonella that are better than any current vaccine strains (safe bacteria) at surviving in tumors but were less virulent than wild type bacteria. These mutants are potentially useful for an improved delivery agent. Second, we had previously identified promoters that were preferentially activated in tumors when compared to spleen. In Aim 2, task 1, we further characterized these regions, which are potentially useful to activate therapeutic genes engineered into the bacterium only when the bacterium is in the tumor. Third, in Aim 2, task 2, we screened promoters in vitro for their response to pH (tumors are more acidic than the rest of the body) and anoxia (tumors have lower O2 levels than the rest of the body). A comprehensive survey was performed of all candidate promoters. We also developed a set of bioinformatics programs to help perform, store, analyze, and interpret these experiments, as a foundation for year two of the project.