Bone Marrow Transplantation in Human Disease

描述(由申请人提供)：本意见书是对NOT-OD-09-058号文件的回应，标题为“NIH宣布恢复法资金可用于竞争性修订申请”。酶标靶向治疗EBV相关肿瘤的放射性药物是最近在约翰霍普金斯大学进行的临床前测试的一种新策略。这项工作是基于我们观察到EBV+肿瘤可能被诱导表达病毒胸苷激酶(EBV-TK)。这种激酶而不是细胞内的TK会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EB病毒-TK的肿瘤细胞暴露于131-L-FIAU时，肿瘤消退。然而，EBV-TK在大多数EBV-I-癌中不表达，而只在感染的裂解期表达。这增加了药物诱导EBVTK表达，然后给药131-L-FIAU将导致靶向辐射的可能性。在小鼠EBV-I淋巴瘤和实体瘤的异种移植模型中，我们发现药物激活EBV-TK和131-L-FIAU确实导致了肿瘤的消退。该方法基于以下前提：a)携带EBV基因组的肿瘤携带的病毒酶具有不同于宿主细胞的特异性；b)尽管这些病毒编码的酶可能不在基线水平上表达，但药物干预会改变病毒基因的表达；c)即使在少数肿瘤细胞中表达病毒酶也会导致靶向辐射。如果在患者的肿瘤细胞中也能实现类似的EB病毒-TK的激活，那么将131-L-FIAU靶向肿瘤用于治疗目的应该是可能的。然而，要开始将这种放射性药物整合到淋巴瘤的临床治疗试验中，必须确定EBV-TK的诱导剂。据报道，多种化疗药物可诱导病毒裂解基因的表达。其中包括淋巴瘤治疗中常用的化疗药物。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那样，并评估血浆EBV DNA标记物在这种情况下的应用。

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.