Engineering Salmonella typhimurium to be a targeted anti-cancer therapeutic Bacteria engineered to specifically target therapeutically resistant regions of tumors and controllably kill cancer cells will be able to overcome therapeutic resistance and increase the efficacy of cancer treatment. Therapeutic resistance is caused by limited drug penetration and poor cell susceptibility. 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 therapeutic resistance. To date, the mechanisms of bacterial motility in tumors are poorly understood. Our approach will elucidate these mechanisms and will manipulate them to target tumor quiescence. The project is unique because it introduces the concept of intratumoral therapeutic delivery and the cylindroid tumor model, which was specifically designed to quantify bacterial chemotaxis in tumors. The proposed research program has three Specific Aims that combine expertise in tumor biology, molecular biology, and mathematical modeling. They are interrelated and will be performed concurrently:
Aim 1 is to determine the mechanisms that control S. typhimurium accumulation in tumors;
Aim 2 is to design S. typhimurium mutants with enhanced targeting;
and Aim 3 is to create S. typhimurium mutants with increased tumor cytotoxicity. The three hypotheses of the research plan are: 1) S. typhimurium are attracted to and induce cellular apoptosis in tumors, 2) ribose-receptor-knockout S. typhimurium preferentially accumulate in quiescent regions of tumors, and 3) S. typhimurium expressing a radiation-inducible, cytotoxic polypeptide payload will more effectively reduce tumor mass. These hypotheses will be tested by measuring the localization of S. typhimurium in mouse tumors, deleting the ribose receptor from the S. typhimurium genome, and transforming S. typhimurium to express the mTRAIL polypeptide under control of the RecA promoter. The efficiency of the transformed bacteria to reduce tumor mass will be measured in culture and in mice. The experimental plan is part of a research program to develop a therapeutic strategy to overcome therapeutic 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 stage-four breast cancer patients. Using bacteria to overcome therapeutic resistance and increase treatment efficiency will significantly reduce systemic toxicity, limit the deleterious effects of metastatic disease, and increase life expectancy. The experimental plan descries a therapeutic strategy to overcome therapeutic resistance using quiescence- targeted, controllably cytotoxic S. typhimurium. Combined administration of engineered bacteria and adjuvant chemotherapy will increase therapeutic efficiency by more effectively killing all cancer cells in tumors. This increased efficacy will reduce systemic toxicity, prevent local recurrence, limit the deleterious effects of metastatic disease, and increase life expectancy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA120825-03
Application #
7745439
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Arya, Suresh
Project Start
2008-01-14
Project End
2011-12-31
Budget Start
2010-02-17
Budget End
2010-12-31
Support Year
3
Fiscal Year
2010
Total Cost
$286,954
Indirect Cost
Name
University of Massachusetts Amherst
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
153926712
City
Amherst
State
MA
Country
United States
Zip Code
01003
Panteli, Jan T; Forbes, Neil S (2016) Engineered bacteria detect spatial profiles in glucose concentration within solid tumor cell masses. Biotechnol Bioeng 113:2474-84
Brackett, Emily L; Swofford, Charles A; Forbes, Neil S (2016) Microfluidic Device to Quantify the Behavior of Therapeutic Bacteria in Three-Dimensional Tumor Tissue. Methods Mol Biol 1409:35-48
Swofford, Charles A; Van Dessel, Nele; Forbes, Neil S (2015) Quorum-sensing Salmonella selectively trigger protein expression within tumors. Proc Natl Acad Sci U S A 112:3457-62
Van Dessel, Nele; Swofford, Charles A; Forbes, Neil S (2015) Potent and tumor specific: arming bacteria with therapeutic proteins. Ther Deliv 6:385-99
Panteli, Jan T; Forkus, Brittany A; Van Dessel, Nele et al. (2015) Genetically modified bacteria as a tool to detect microscopic solid tumor masses with triggered release of a recombinant biomarker. Integr Biol (Camb) 7:423-34
Thornlow, Dana N; Brackett, Emily L; Gigas, Jonathan M et al. (2015) Persistent enhancement of bacterial motility increases tumor penetration. Biotechnol Bioeng 112:2397-405
Zhang, Miaomin; Forbes, Neil S (2015) Trg-deficient Salmonella colonize quiescent tumor regions by exclusively penetrating or proliferating. J Control Release 199:180-9
Swofford, Charles A; St Jean, Adam T; Panteli, Jan T et al. (2014) Identification of Staphylococcus aureus α-hemolysin as a protein drug that is secreted by anticancer bacteria and rapidly kills cancer cells. Biotechnol Bioeng 111:1233-45
Kasinskas, Rachel W; Venkatasubramanian, Raja; Forbes, Neil S (2014) Rapid uptake of glucose and lactate, and not hypoxia, induces apoptosis in three-dimensional tumor tissue culture. Integr Biol (Camb) 6:399-410
Zhang, Miaomin; Swofford, Charles A; Forbes, Neil S (2014) Lipid A controls the robustness of intratumoral accumulation of attenuated Salmonella in mice. Int J Cancer 135:647-57

Showing the most recent 10 out of 24 publications