This submission is in response to NOT-OD-09-058, entitled """"""""NIH Announces title Availability of Recovery Act Funds for Competitive Revision Applications."""""""" Enzymatic targeting of a radiopharmaceutical for the treatment of EBV-associated tumors is a novel strategy recently tested preclinically at Johns Hopkins. This work is based on our observation that EBV+ tumors may be induced to express viral thymidine kinase (EBV-TK). This kinase but not cellular TK's will phosphorylate a variety of nucleoside analogues, such as FIAU, resulting in their trapping in cells expressing the viral enzyme. When EBV-TK expressing tumor cells are exposed to 131-l-FIAU, tumor regression results. However, EBV-TK is not expressed in most EBV-i- cancers, but rather only in the lytic phase of infection. This raises the possibility that pharmacologic induction of EBVTK expression followed by administration of 131-l-FIAU will result in targeted radiation. In murine xenograft models of EBV-i- lymphomas and solid tumors, we found that pharmacologic activation of EBV-TK followed by 131-l-FIAU indeed led to tumor regression. The approach is based on the following premises: a) Tumors harboring EBV genomes carry viral enzymes with specificities that differ from those of host cells;b) Although these virus-encoded enzymes may not be expressed at baseline, pharmacologic interventions modify viral gene expression;c) Expression of viral enzymes in even a minority of tumor cells will result in targeted radiation. If similar activation of EBV-TK can be achieved in tumor cells in patients, it should be possible to target 131-l-FIAU to tumor for therapeutic purposes. However, to begin to integrate such radiopharmaceuticals into therapeutic clinical trials for lymphoma, inducers of the EBV-TK must be identified. A multitude of chemotherapeutic agents have been reported to induce viral lytic gene expression. Among these are chemotherapy agents commonly used in the treatment of lymphoma. The present project seeks to evaluate chemotherapy regimens used commonly for relapsed lymphomas with respect to their ability to activate EBV-TK, as evidenced by the ability to image tumor by FIAU-PET, and evaluate the utility of plasma EBV DNA markers in this setting.
The approach considered herein represents a new paradigm for approaching the imaging as well as targeted therapy of lymphoma. The information gathered from this project will provide important insights that will help to shape future therapeutic trials of EBV-associated lymphomas, offering the possibility of reduced failure rates through the targeting of tumor cells.
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