Improving bacterial cancer therapeutics

PROJECT SUMMARY (ABSTRACT) Bacterial cancer therapy has existed since Dr. William Coley employed deliberate bacterial infection of tumors over a century ago in the first known example of cancer immunotherapy. Bacteria are genetically tractable self-replicating therapeutics which can be tuned to deliver various payloads, modify specificity, and decrease side effects. Additionally, intravenously administered bacteria (particularly Escherichia and Salmonella) are intrinsically capable of selectively colonizing tumor tissue in mouse models, showing reduced colonization with rapid clearance from other organs. These properties make bacteria attractive potential vehicles for delivering cancer therapy. However, early clinical trials have been stymied by low colonization rates in human patients. Though much work has been done to develop therapeutic payloads for bacterial delivery, comparatively little is known about the mechanisms by which bacteria colonize tumors and thereby deliver these payloads. At present, there is little pre- existing literature using comprehensive and unbiased screens to identify pathways for tumor- specific bacteria colonization. These screens are urgently needed to not only identify essential pathways for tumor colonization by bacteria, but also to identify pathways which may be manipulated to increase tumor-specific colonization by bacteria. This information can be leveraged both to identify pathways essential for tumor colonization and to develop strains with increased tumor specificity. By identifying these genes, this project aims to understand the mechanisms by which E. coli specifically migrate to and grow within tumors and identify targets which can be manipulated to tune colonization efficiency and specificity. Ultimately, this work will advance the production of living medicines as cancer therapy. The strong community of immunologists, synthetic biologists, and bioinformaticians supervising the trainee's work will support this fellowship. Throughout the award, the trainee will benefit from the outstanding training environment at Columbia in both research and clinical components, as well as the integration of the two distinct disciplines in training physician scientists, to develop fundamental skills for becoming an independent physician investigator.