BACTERIA AND LYMPHOCYTE SUPPRESSION IN PERIODONTITIS

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DESCRIPTION (provided by applicant): The University of Pennsylvania contributes substantially to the Southeastern Pennsylvania and New Jersey economy. The University employs 22,000 scientists and research support personnel. Moreover, in 2008 Penn scientists were the recipient of over $800 million in total research awards; it is estimated that these awards had an economic impact on the Philadelphia region equivalent to $3.15 billion. The School of Dental Medicine is an important component of this economic impact; thus far in 2009, SDM scientists have been the recipient of >$48 million in total research awards. Moreover, the School contributes >$40 million to the region in salary, employee benefits and purchases. Additionally, the SDM employs over 260 faculty, 60 in full time positions, and the equivalent of 434 full time equivalent support staff. The current proposal will create or retain two skilled jobs at the level of research technician and/or postdoctoral research fellow. Cancer cells escape normal growth control as a consequence of activating mutations or increased expressionofcellularprotooncogenesand/orinactivatingmutationsordecreasedexpressionoftumorsuppressor genes. It is evident that the phosphoinositide 3-kinase (PI-3K)/PI-3,4,5-P3/PTEN/Akt) signaling pathway is often altered in cancer making it a potent target for pharmacologic intervention. Regardless of whether the defect in this pathway involves synthesis or degradation, PI3,4,5-P3 elevations lead to activation of pAkt and downstream signals that favor growth, proliferation and survival. During the current funding period of the parent grant, we demonstrated the active subunit of the cytolethal distending toxin, CdtB, functions as a PI-3,4,5-P3 phosphatase. We propose to extend our observations in a new direction and begin to harness the pharmacologic potential of this microbial toxin. In this competitive supplement, we plan to generate novel chimeric fusion toxins which target PI-3,4,5-P3 to block cell proliferation and survival of malignant cells derived from cutaneous T-cell lymphoma (CTCL) patients or patients with head, neck and oral squamous cell carcinoma (SCC). We propose to generate chimeric fusion toxins that target either CTCL or to SCC and test the hypothesis that the toxins retain PI-3,4,5-P3 phosphatase activity and specifically bind to and intoxicate CTCL cells that over-express CCR4 or SCC cells that over-express EGFR. CdtB will be chemically linked to anti-receptor antibodies which are commercially available or genetically linked to cytokines, TARC or EGF, to also target the chimeric toxin to CCR4 and EGFR, respectively. The chimeric toxins will be evaluated for PI-3,4,5P3-phosphatase activity, capacity to bind to tumor cells and deliver CdtB intracellularly and for toxicity. Significance: The studies described in this proposal extend our current investigation on the role of Cdt as a putative virulence factor to a consideration of its utility as a potential therapeutic agent for treating certain types of cancer with defects in the PI-3K/PIP3/Akt signaling pathway. These studies are significant in that they will provide the underpinnings for a novel therapeutic approach to treat cancers such as CTCL and SCC. PUBLIC HEALTH RELEVANCE: The active subunit of the bacterial cytolethal distending toxin, CdtB, exhibits a novel enzymatic activity that targets a mediator of a critical signaling pathway that controls cell growth and survival. We propose to take advantage of this unique activity and develop fusion proteins that will potentially target tumor cells resulting in growth arrest and ultimately cell death. These studies are significant in that they will provide the underpinnings on which to base future novel therapeutic approaches to treat certain forms of cancer.