PHD, 2001, Columbia University BS, 1997, Cornell University
Crosby, J. A., and S. C. Kachlany. 2007. TdeA, a TolC-like protein required for toxin and drug export in Aggregatibacter (Actinobacillus) actinomycetemcomitans. Gene. 388: 83-92.
Balashova, N. V., R. Diaz, S. V. Balashov, J. A. Crosby, and S. C. Kachlany. 2006. Regulation of Aggregatibacter (Actinobacillus) actinomycetemcomitans leukotoxin secretion by iron. Journal of Bacteriology. 188: 8658-8661.
Fine, D. H., J. B. Kaplan, S. C. Kachlany, and H. C. Schreiner. 2006. How we got attached to Actinobacillus actinomycetemcomitans: a model for infectious diseases. Periodontology 2000. 42:114-157.
Balashova, N. V., J. A. Crosby, L. Al Ghofaily, and S. C. Kachlany. 2006. Leukotoxin confers beta-hemolytic activity to Actinobacillus actinomycetemcomitans. Infection and Immunity. 74:2015-21.
Diaz, R., L. Al Ghofaily, J. Patel, N. V. Balashova, A. C. Freitas, I. Labib, and S. C. Kachlany. 2006. Characterization of leukotoxin from a clinical strain of Actinobacillus actinomycetemcomitans. Microbial Pathogenesis. 40:48-55.
Bacteria as anticancer agents. For many years, bacteria and their toxins have been investigated for their anticancer activities. In the 1970s, bacteria (such as non-pathogenic Clostridium) were used for the treatment of malignant brain tumors. While the therapy was successful in the short term, the tumors recurred in these brain tumor patients. Subsequent to this initial work, more than 100 microorganisms have been studied for their potential anticancer activities. Interestingly, many bacteria have a growth specificity for tumors that is 1000 times greater than for other tissue.
While data suggests that many bacteria make attractive therapeutic agents, there are inherent risks to administering live bacteria to humans. A safer and more effective strategy has been to use biological toxins, specifically from bacteria, as therapeutic agents. Bacterial toxins are not only toxic, but are also highly specific for certain cell types, or can be engineered to be specific by fusing the toxin to other molecules. Many bacterial toxins are able to enter mammalian cells where they exert their toxic effects. Because of extensive evolutionary adaptation between bacteria and their hosts, bacteria have become very good at ?developing? highly effective toxins.
Each year, more than 60,500 people die of hematologic malignancies (leukemia, lymphoma, myeloma) with more than 110,000 new annual diagnoses in the US alone. Current treatment for these cancers includes the use of synthetic compounds that target the cell division process of nearly all cells of the body, not just the cancerous ones. As a result, devastating side effects are all too common. Furthermore, a significant percentage of patients eventually show resistance to many of the drugs, thus rendering treatment largely ineffective. Indeed, there is an effort to identify agents that induce cancer cell death by methods other than damage to DNA or cell division.
A. actinomycetemcomitans is a Gram negative bacterium that is the etiological agent of localized aggressive periodontitis (LAP). A. actinomycetemcomitans produces an RTX (repeats in toxin) leukotoxin (LtxA). A. actinomycetemcomitans LtxA is a ~115 kDa protein that kills specifically leukocytes of humans and Old World Primates by forming pores in the membrane and 2 integrin on the surfacecausing apoptosis or necrosis. LtxA binds to LFA-1, a of white blood cells (26). LFA-1 is expressed only on cells of hematopoietic origin, which helps explain the specificity of the toxin. Because of the toxicity and specificity of A. actinomycetemcomitans LtxA, we propose to investigate the therapeutic potential of the toxin for the treatment of hematologic malignancies.