Ph.D. Boston University
Certain pathogenic bacteria such as Salmonella typhimurium have the innate ability to target and selectively replicate within solid tumors in a number of different animal species, including humans. Pathogenic bacteria can be genetically modified in order to eliminate debilitating aspects of their pathogenesis while retaining their ability to traverse the body and target tumors. My laboratory is exploring a variety of mutations in Salmonella that decrease pathogenesis and/or increase their ability to colonize solid tumors in order to identify strains that have the potential to serve as anticancer agents in humans. In these studies, and in attempts to understand the fundamental nature of the bacterial physiology relating to tumor-targeting, we have identified spontaneous and genetically engineered mutations that have compensatory functions relating to their ability to exist under mammalian physiological conditions and may have the ability to enhance their antitumor effects.
My laboratory uses a number of biochemical, cell and molecular biological techniques to generate novel mutations and to determine their physiological effects and their ability to kill cancer cells. Our investigations also include combination chemotherapeutic approaches using cytotoxic and biologic agents. Students have the opportunity to participate in the genetic selection of novel suppressor mutations for sensitivities associated with the non-pyrogenic lipid of highly attenuated msbB strains, identify the suppressor mutation and determine the physiological effects associated with that mutation. In the process of these studies, students have the opportunity to learn basic DNA manipulation, transposon library generation, chromosomal insertions and deletions, genomic libraries, gene cloning and expression, bioinformatics and mammalian tissue culture.
Because of the ability of these bacteria to safely colonize humans and other animals, we are also exploring the ability of these bacteria to deliver heterologous antigens, such as the influenza hemagglutinin, for use as live attenuated vaccines.
Additional Academic History
1996-2006 Adjunct Assistant Professor of Clinical Medicine, Yale University School of Medicine, New Haven, CT
1993-1995 Associate Research Scientist, Yale University School of Medicine, New Haven, CT
1991-1993 Postdoctoral Associate, Yale University, School of Medicine, New Haven, CT
Karsten, V, SR Murray, J Pike, K Troy, M Ittensohn, M Kondradzhyan, KB Low and D Bermudes 2009. msbB deletion confers acute sensitivity to CO2 in Salmonella entericaserovar Typhimurium that can be suppressed by a loss-of-function mutation in zwf. BMC Microbiol. Aug 18;9:170.
King, I, M Ittensohn and D Bermudes 2009. Tumor-targeted Salmonella typhimuriumover-expressing cytosine deaminase: A novel, tumor-selective therapy. Methods Mol Biol. 542: 649-659.
Friedlos, F, P Lehouritis, L Ogilvie, D Hedley, L Davies, D Bermudes, I King, J Martin, R Marais, and CJ Springer 2008. Attenuated Salmonella targets prodrug activating enzyme CPG2 to mouse melanoma, human breast and colon carcinomas for effective suicide gene therapy. Clinical Cancer Research 14: 4259-4266.
Murray, SR, RK Ernst, D Bermudes, SI Miller and KB Low 2007.PmrA(Con) ConferspmrHFIJKL-Dependent EGTA and Polymyxin Resistance on msbB Salmonella by Decorating Lipid A with Phosphoethanolamine. J. Bacteriol. 189: 5161-5169.
Soghomonyan, SA, M Doubrovin, J Pike, X Luo, M Ittensohn, JD Runyan, J Balatoni, R Finn, J Gelovani-Tjuvajev, R Blasberg and D Bermudes 2005. Positron Emission Tomography (PET) Imaging of Tumor-Localized Salmonella Expressing HSV1-TK. Cancer Gene Therapy 12: 101-108.
Murray, SR, K Suwwan de Felipe, PL Obuchowski, J Pike, D Bermudes and KB Low 2004. Hot spot for a large deletion in the 18-19 Cs region confers a multiple phenotype in Salmonella enterica serovar Typhimurium strain ATCC 14028. J. Bacteriol. 186:8516-23.
Low, KB, M Ittensohn, X Luo, L-M Zheng, I King, J Pawelek and D Bermudes 2004. Construction of VNP20009, a novel, genetically stable antibiotic sensitive strain of tumor-targeting Salmonella for parentral administration in humans. Methods Mol. Med. 90: 47-60.
Murray, SR, D Bermudes, K Suwwan de Felipe and KB Low 2001. Extragenic suppressors of msbB- growth defects in Salmonella. J. Bacteriol. 183: 5554-5561.
Clairmont, C., KC Lee, J Pike, M Ittensohn, KB Low, J Pawelek, D Bermudes, SM Brecher, D Margitich, J Turnier, Z Li, X Luo, I King and L-M Zheng 2000. Biodistribution and genetic stability of the novel antitumor agent VNP20009, a genetically modified strain of Salmonella typhimurium. J. Infect. Dis. 181: 1996-2002.
Platt, P, S Sodi, M Kelley, S Rockwell, D Bermudes, KB Low and J Pawelek 2000. Antitumor Effects of Genetically Engineered Salmonella in Combination with Radiation. European J. Cancer 36: 2397-2402.
Low, KB, M Ittensohn, T Le, J Platt, S Sodi, M Amoss, O Ash, E Carmichael, A Chakraborty, J Fisher, SL Lin, X Luo, SI Miller, L Zheng, I King, JM Pawelek and D Bermudes 1999. Lipid A mutant Salmonella with suppressed virulence and TNFa induction retain tumor-targeting in vivo. Nature Biotechnol. 17: 37-41.
Pawelek, J, KB Low, and D Bermudes 1997. Tumor-targeted Salmonella as a novel anticancer agent. Cancer Research 57: 4537-4544.
Related Clinical Investigations
There have been six human clinical trials in cancer patients using two differentSalmonella strains (VNP20009 and TAPET-CD) that were generated in my laboratory. The studies were conducted at the National Cancer Institute (intravenous and continuous infusion; Bethesda, MD), The Cleveland Clinic (intratumoral administration; Cleveland, OH), Beth Israel-Deaconess Medical Center (intravenous administration; Boston, MA), and The Royal Marsden Hospital (intravenous administration; London, UK) and the Mary Crowley Medical Research Center (intratumoral administration in combination with 5FU; Dallas, TX).
Nemunaitis J, C Cunningham, N, Senzer, J Kuhn, J Cramm, C Litz, R Cavagnolo, A Cahill, C Clairmont and M Sznol 2003. Pilot trial of genetically modified, attenuated Salmonellaexpressing the E. coli cytosine deaminase gene in refractory cancer patients. Cancer Gene Ther. 10:737-44.
Heimann, DM and SA Rosenberg 2003. Continuous intravenous administration of live genetically modified Salmonella typhimurium in patients with metastatic melanoma. J. Immunotherapy 26: 179-180
Vion initiates phase I trial of Tapet with immune system modulation. [No authors listed]Expert Rev. Anticancer Ther. 2002 Oct;2(5):483
Toso, JF, VJ Gill, P Hwu, FM Marincola, NP Restifo, DJ Schwartzentruber, RM Sherry, SL Topalian, JC Yang, F Stock, LJ Freezer, KE Morton, C Seipp, L Haworth, S Mavroukakis, D White, S MacDonald, J Mao, M Sznol and SA Rosenberg 2002. Phase I study of the intravenous administration of attenuated Salmonella typhimurium to patients with metastatic melanoma. J. Clin. Oncol. 2002; 20:142-152.
Cunningham C and Nemunaitis J. 2001. A phase I trial of genetically modified Salmonella typhimurium expressing cytosine deaminase (TAPET-CD, VNP20029) administered by intratumoral injection in combination with 5-fluorocytosine for patients with advanced or metastatic cancer. Protocol no: CL-017. Hum. Gene Ther. 12:1594-1596.
Meir, J, T Olencki, M Atkins, M Sznol, S MacDonald, J Mao, B Almassian, K Lee, U Akella, P Weiss and R Bukowski 2001. Phase 1 Trial of live, attenuated Salmonella typhimurium(VNP20009) by direct intra-tumoral (IT) injection. Annual ASCO Meeting, Abstract 1043.