We have developed an effective bacterial cancer therapy strategy by targeting viable tumor tissue by using Salmonella typhimurium auxotrophs that we have generated which grow in viable as well as necrotic areas of tumors. However, the auxotrophy severely restricts growth of these bacteria in normal tissue enabling them to be used for cancer treatment. The S. typhimurium A1-R mutant, which is auxotrophic for leu-arg and has high antitumor virulence was developed in our laboratory. In vitro, A1-R infects tumor cells and causes nuclear destruction. A1-R was initially used to treat metastatic human prostate and breast tumors that had been orthotopically implanted in nude mice. Forty percent of treated mice were cured completely and survived as long as non-tumor-bearing mice. A1-R administered i.v. to the nude mice with primary osteosarcoma and lung metastasis was highly effective, especially against metastasis. A1-R was also targeted to both axillary lymph and popliteal lymph node metastasis of human pancreatic cancer and fibrosarcoma, respectively, as well as lung metastasis of the fibrosarcoma in nude mice. The bacteria were delivered via a lymphatic channel to target the lymph-node metastases and systemically via the tail vein to target the lung metastasis. The metastases were cured without the need of chemotherapy or any other treatment. A1-R was administered intratumorally to nude mice with an orthotopically-transplanted human pancreatic tumor. The primary pancreatic cancer regressed without additional chemotherapy or any other treatment. A1-R also was effective against pancreatic cancer liver metastasis when administered intrasplenically to nude mice. A1-R has also shown to be effective for spinal glioma in orthotopic mouse models. The approach described here, where bacterial monotherapy effectively treats primary and metastatic tumors, is a significant improvement over previous bacterial tumor-therapy strategies that require combination with toxic chemotherapy. The present application will develop bacterial therapy of cancer with S. typhimurium A1-R in immunocompetent mice as a bridge to the clinic.
The specific aims of the present application are (1) Determine the maximum tolerated dose (MTD) of S. typhimurium A1-R in tumor-bearing C57 immunocompetent mice. (2) Determine the optimal dose, route and schedule of S. typhimurium A1-R in tumor-bearing immunocompetent mice. Exploitation of the tumor-killing capability of Salmonella has great potential for a new paradigm of cancer therapy.

Public Health Relevance

We have developed a bacterial cancer therapy strategy using Salmonella typhimurium variants. These bacteria kill cancer cells but do not grow in normal tissue. Our S. typhimurium A1-R mutant has antitumor virulence against a number of cancer cell lines in nude mouse models. In vitro, A1-R infects tumor cells and can cause rapid nuclear fragmentation and apoptosis. A1-R was found to be effective against metastatic human prostate, breast, and pancreatic cancer cell lines as well as osteosarcoma, fibrosarcoma and glioma cell lines in clinically-relevant mouse models. Treated mice were often cured completely and survived as long as non- tumor-bearing mice. The approach described here, where bacterial monotherapy effectively treats primary and metastatic tumors, is a significant improvement over previous bacterial tumor-therapy strategies that require combination with toxic chemotherapy. The present application will develop bacterial therapy of cancer in immunocompetent mouse models as a bridge to clinical trials. Exploitation of the tumor-killing capability of Salmonella has great potential for a new paradigm of cancer therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
2R44CA126023-02
Application #
7909549
Study Section
Special Emphasis Panel (ZRG1-OTC-Y (13))
Program Officer
Rahbar, Amir M
Project Start
2007-09-21
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
2
Fiscal Year
2010
Total Cost
$374,950
Indirect Cost
Name
Anticancer, Inc.
Department
Type
DUNS #
173844010
City
San Diego
State
CA
Country
United States
Zip Code
92111
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Miwa, Shinji; Yano, Shuya; Tome, Yasunori et al. (2013) Dynamic color-coded fluorescence imaging of the cell-cycle phase, mitosis, and apoptosis demonstrates how caffeine modulates cisplatinum efficacy. J Cell Biochem 114:2454-60
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