Inhibiting The Survival And Proliferation Of EBV-Associated Tumor Cells

抑制 EBV 相关肿瘤细胞的存活和增殖

基本信息

批准号：
8254295
负责人：
Shannon Celeste Kenney
金额：
$ 35.87万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8254295
关键词：
17-(Allylamino)-17-demethoxygeldanamycin AIDS-Related Lymphoma Acquired Immunodeficiency Syndrome Adult Affect Africa B-Cell Neoplasm B-Lymphocytes Burkitt Lymphoma Cells Childhood Burkitt&apos s Lymphoma China EBV-associated malignancy Epithelial Cells Epstein-Barr Virus Infections Epstein-Barr Virus latency Epstein-Barr Virus-Related Lymphoma Gene Expression Gene Expression Regulation Genes Genetic Transcription Genome Growth Heat-Shock Proteins 90 Histone Deacetylase Inhibitor Hodgkin Disease Human Immunocompromised Host In Vitro Infection Knowledge Lead Lesion Lymphoma Lymphoproliferative Disorders Lytic Lytic Phase Malignant Neoplasms Molecular Biology Molecular Genetics Nasopharynx Carcinoma Niacinamide Oncogenic Viruses Pathogenesis Patients Pharmaceutical Preparations Phenotype Proteins Regulation Research Personnel Role SCID Mice Sirtuins Therapeutic Therapeutic Effect Viral Viral Genes Viral Genome Viral Oncogene Proteins Viral Pathogenesis Viral Proteins Virus Virus Latency Work base inhibitor/antagonist killings large cell Diffuse non-Hodgkin&apos s lymphoma lytic replication mouse model mutant neoplastic cell novel strategies novel therapeutic intervention particle prevent protein expression tumor

项目摘要

EBV is associated with a number of B cell and epithelial cell malignancies, including B-cell lymphoproliferative disease in immunosuppressed patients, Burkitt lymphomas, and nasopharyngeal carcinomas. We hypothesize that new approaches that specifically target EBV-infected cells for destruction will be useful for the treatment of EBV-positive malignancies. In this project, we propose to develop three different EBV-based approaches for the treatment of EBV-induced tumors, capitalizing upon our extensive knowledge of EBV gene regulation and viral pathogenesis. In aim 1, we will inhibit the latent viral protein, EBNA1, to identify viral contributions that sustain EBV-associated lymphomas and thereby identify targets for specific anti-viral, anti-tumor therapies. In aim 2, we will examine the role of sirtuins (type III HDACs) in regulating viral latency, and determine if strategies for lytic-induction (whereby the virus is switched from the latent to lytic form of infection in tumor cells) can be enhanced using agents which regulate sirtuin activity, or agents that block the function of a negative regulator of lytic gene transcription (ZEB-1). In aim 3, based upon our exciting finding that HSP-90 is required for expression of an essential viral transforming protein, we will examine the importance of HSP-90 in viral pathogenesis and determine if newly developed HSP-90 inhibitors can be used specifically to kill EBV-transformed B cells in vitro and inhibit the growth of lymphoproliferative lesions in SCID mouse models. We will also determine if HSP-90 inhibitors can be used to block the lytic form of viral replication. Our proposed studies will lead to the identification of new targets for developing anti-EBV therapies and may lead to the identification of known drugs rationally chosen by EBV-based strategies for treating EBV-associated malignancies.

EBV与许多B细胞和上皮细胞恶性肿瘤有关，包括免疫抑制患者的B细胞淋巴增生性疾病，Burkitt淋巴瘤和鼻咽癌。我们假设专门针对EBV感染细胞破坏的新方法将有助于治疗EBV阳性恶性肿瘤。在这个项目中，我们建议开发三种基于EBV的方法来治疗EBV诱导的肿瘤，利用我们对EBV基因调节和病毒发病机理的广泛了解。在AIM 1中，我们将抑制潜在的病毒蛋白EBNA1，以确定维持与EBV相关的淋巴瘤的病毒贡献，从而确定针对特定抗病毒，抗肿瘤疗法的靶标。 In aim 2, we will examine the role of sirtuins (type III HDACs) in regulating viral latency, and determine if strategies for lytic-induction (whereby the virus is switched from the latent to lytic form of infection in tumor cells) can be enhanced using agents which regulate sirtuin activity, or agents that block the function of a negative regulator of lytic gene transcription (ZEB-1).在AIM 3中，基于我们令人兴奋的发现，HSP-90是表达必需病毒转化蛋白所必需的，我们将检查HSP-90在病毒发病机理中的重要性，并确定新开发的HSP-90抑制剂是否可以专门用于杀死EBV转化的B细胞体外并抑制Scid鼠标模型中淋巴细胞生长的生长。我们还将确定HSP-90抑制剂是否可以用于阻断病毒复制的裂解形式。我们提出的研究将导致确定开发抗EBV疗法的新靶标，并可能导致通过基于EBV的策略理性地鉴定已知药物以治疗与EBV相关的恶性肿瘤。