Targeting of EBV Latency in Burkitt's Lymphoma

伯基特淋巴瘤中 EBV 潜伏期的靶向治疗

• 批准号: 7492826
• 负责人: Juan Carlos Ramos
• 金额: $ 23.65万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-22 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7492826
• 关键词: Adult; Antiviral Agents; Apoptosis; Biological Assay; Biological Markers; Burkitt Lymphoma; Cells; Childhood; Clinical Trials; Common Neoplasm; Data; Developed Countries; Developing Countries; Diagnosis; Disease Resistance; Disease remission; Disruption; Doctor of Medicine; Enrollment; Epstein-Barr Virus latency; Hematologist; Human Herpesvirus 4; Immune; Individual; Lead; Link; Lymphoma; Lymphoproliferative Disorders; Lytic Phase; Mediating; Monitor; NF-kappa B; Nursing Research; Oxeron; Pathologist; Pathway interactions; Patients; Phase; Phosphorylation; Phosphotransferases; Primary Neoplasm; Property; Protocols documentation; Recurrent disease; Relapse; Research Infrastructure; Site; Therapeutic; Thymidine Kinase; Viral; Viral Load result; Virulent; Virus Latency; Zidovudine; chemotherapeutic agent; chemotherapy; gene therapy; hydroxyurea; lytic gene expression; multidisciplinary; outcome forecast; p65; response; therapeutic target; translational study; tumor

Burkitt lymphoma (BL), the most common pediatric lymphoproliferative disease in developing nations, is highly associated with Epstein Barr virus (EBV). These virulent tumors can be cured with chemotherapy but relapsed or resistant disease is quite common and generally fatal. We hypothesize that the presence of EBV in the endemic form of BL can be used both to monitor response to therapy and as a therapeutic target. In our first aim we propose to study EBV viral load in BL patients enrolled on a therapeutic protocol. We will determine whether EBV viral load correlates with response to therapy or conversely with relapsing or resistant disease. We will also investigate the effect of chemotherapy on viral reactivation. We further hypothesize that the antiviral agent azidothymidine (AZT) induces apoptosis in EBV+ BL through a unique, targeted mechanism: suppression of NF-kappaB and disruption of viral latency. This results in phosphorylation of AZT by viral kinases and apoptosis. Therefore, AZT is essentially an inexpensive form of gene therapy that exploits the presence of EBV. There is no effective therapy for relapsed endemic type BLs. In aim 2 we will conduct a trial of chemo/antiviral (AZT, hydrea) therapy for these patients. Commonly available chemotherapeutic agents are known to induce the EBV lytic cycle including viral thymidine kinase and thereby potentiate phosphorylation of AZT. Our group, comprised of pediatric and adult hematologists, virologists, research nurses and pathologists offers multidisciplinary expertise required for this translational study. Our collaborators, located at a unique site where viral lymphoproliferative diseases are commonly diagnosed, have excellent infrastructure in place to participate in this study. Data acquired through this project should be broadly applicable to high grade lymphomas that occur in Immune compromised individuals. These studies should lead to new, non-carcinogenic, abbreviated therapy that is applicable in developing nations for this common tumor.

Burkitt淋巴瘤是发展中国家最常见的儿童淋巴增生性疾病，与EB病毒密切相关。这些致命的肿瘤可以通过化疗治愈，但复发或耐药的疾病相当常见，通常是致命的。我们假设EB病毒的存在既可以用来监测治疗反应，也可以作为治疗的靶点。在我们的第一个目标中，我们建议研究接受治疗方案的BL患者中的EBV病毒载量。我们将确定EBV病毒载量是与治疗反应相关，还是与复发或耐药疾病相关。我们还将研究化疗对病毒重新激活的影响。 我们进一步假设，抗病毒药物齐多夫定(AZT)通过一种独特的靶向机制诱导EBV+BL细胞凋亡：抑制NF-kappaB和破坏病毒潜伏期。这导致病毒激酶对AZT的磷酸化和细胞凋亡。因此，AZT本质上是一种利用EBV存在的廉价基因治疗形式。目前对复发的地方性BLS尚无有效的治疗方法。在目标2中，我们将对这些患者进行化疗/抗病毒(AZT，Hydrea)治疗的试验。众所周知，常用的化疗药物可以诱导EBV裂解循环，包括病毒胸苷激酶，从而增强AZT的磷酸化。我们的团队由儿科和成人血液学家、病毒学家、研究护士和病理学家组成，提供这项转化性研究所需的多学科专业知识。我们的合作者位于病毒淋巴增生性疾病常见诊断的独特地点，拥有参与这项研究的出色基础设施。通过这个项目获得的数据应该广泛适用于发生在免疫受损个体的高级别淋巴瘤。这些研究应该会导致新的、非致癌的、简短的治疗方法，这种疗法适用于发展中国家的这种常见肿瘤。