Bone Marrow Transplantation in Human Disease

描述（由申请人提供）：本次提交是对NOT-OD-09-058的回应，标题为“NIH宣布为竞争性修订申请提供恢复法案资金”。“酶靶向放射性药物治疗EBV相关肿瘤是一种新的策略，最近在约翰霍普金斯临床前测试。这项工作是基于我们的观察，EBV+肿瘤可以诱导表达病毒胸苷激酶（EBV-TK）。这种激酶而不是细胞TK将磷酸化各种核苷类似物，如FIAU，导致它们被捕获在表达病毒酶的细胞中。当表达EBV-TK的肿瘤细胞暴露于131- 1-FIAU时，产生肿瘤消退。然而，EBV-TK在大多数EBV-i-癌症中不表达，而是仅在感染的裂解期表达。这提高了药物诱导EBVTK表达，然后施用131-l-FIAU将导致靶向辐射的可能性。在EBV-I-淋巴瘤和实体瘤的鼠异种移植物模型中，我们发现EBV-TK的药理学活化随后是131-I-FIAU确实导致肿瘤消退。该方法基于以下前提：a）携带EBV基因组的肿瘤携带特异性不同于宿主细胞的病毒酶; B）尽管这些病毒编码的酶可能在基线时不表达，但药理学干预改变病毒基因表达; c）即使在少数肿瘤细胞中表达病毒酶也会导致靶向辐射。如果可以在患者的肿瘤细胞中实现EBV-TK的类似活化，则应该可以将131- 1-FIAU靶向肿瘤用于治疗目的。然而，为了开始将这些放射性药物整合到淋巴瘤的治疗性临床试验中，必须鉴定EBV-TK的诱导剂。已经报道了许多化疗剂诱导病毒裂解基因表达。其中包括常用于治疗淋巴瘤的化疗药物。本项目旨在评估复发性淋巴瘤常用的化疗方案激活EBV-TK的能力，如FIAU-PET成像肿瘤的能力所证明的，并评估血浆EBV DNA标记物在这种情况下的效用。

DESCRIPTION (provided by applicant): 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.