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.

伯基特淋巴瘤（BL）是发展中国家最常见的小儿淋巴增生性疾病，与爱泼斯坦Barr病毒高度相关（EBV）。这些有毒的肿瘤可以用化学疗法治愈，但复发或抗性疾病通常很常见，通常致命。我们假设以BL的流行形式存在EBV既可以用来监测对治疗的反应和治疗靶标。在我们的第一个目标中，我们建议研究接受治疗方案的BL患者的EBV病毒负荷。我们将确定EBV病毒负荷是否与对治疗的反应相关，还是与复发或抗性疾病相反。我们还将研究化学疗法对病毒重新激活的影响。 我们进一步假设，抗病毒剂氮化噻噻替氨酸（AZT）通过独特的，有针对性的机制诱导EBV+ BL的凋亡：NF-kappab的抑制和病毒潜伏期的破坏。这会导致病毒激酶和凋亡对AZT的磷酸化。 因此，AZT本质上是一种廉价的基因治疗形式，可利用EBV的存在。 没有有效的复发性BLS疗法。在AIM 2中，我们将为这些患者进行化学/抗病毒（AZT，HYDERA）治疗的试验。已知常见的化学治疗剂可诱导EBV裂解周期，包括病毒胸苷激酶，从而增强AZT的磷酸化。我们的小组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，提供了这项翻译研究所需的多学科专业知识。我们的合作者位于一个独特的地点，那里通常被诊断出病毒淋巴增生性疾病，具有出色的基础设施来参与这项研究。通过该项目获得的数据应广泛适用于免疫损害个体中发生的高级淋巴瘤。这些研究应导致新的非癌性，缩写疗法，该治疗适用于这种常见肿瘤的发展中国家。