Epigenetic Targeting of Afro-Caribbean Variant of HTLV-1 Related Adult T-cell Leukemia-lymphoma

HTLV-1 相关成人 T 细胞白血病-淋巴瘤的非洲-加勒比变体的表观遗传靶向

基本信息

批准号：
10079478
负责人：
Juan Carlos Ramos
金额：
$ 34.53万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10079478
关键词：
Acetylation Adult T-Cell Leukemia/Lymphoma Affect African African Caribbean Antineoplastic Agents Apoptosis Area Autoimmune Binding Biological Breast Feeding CREB1 gene Cell Death Cells ChIP-seq Chromatin Clinical Clinical Trials Clonal Expansion Clone Cells Consolidation Therapy Cytotoxic T-Lymphocytes Data Dermatologic Development Disease Disease remission Dose EP300 gene Epigenetic Process Florida Generations Genetic Haiti Histone Deacetylase Histone Deacetylase Inhibitor Human Human T-Cell Leukemia Viruses Human T-lymphotropic virus 1 Immigrant Immune response Individual Infection Inflammatory Interferon-alpha Interferons Jamaica Long Terminal Repeats Lymphoma cell Maintenance Therapy Malignant Neoplasms Molecular New York City Paresis Pathogenicity Patients Play Population Population Group Pre-Clinical Model Prognosis Proteins Proviruses Public Health RNA Regimen Regulation Residual state Retroviridae Reverse Transcriptase Inhibitors Role Sexual Transmission T cell clonality T cell response T-Cell Lymphoma T-Lymphocyte Taxes Transcriptional Regulation United States Valproic Acid Variant Vertebral column Viral Viral Proteins Virus West Indies Zidovudine bZIP Domain base cancer type cell killing chemotherapy drug maintenance genome-wide human subject immunogenic in vivo neglect nervous system disorder novel novel drug class novel therapeutic intervention pilot trial promoter recruit response tax Gene Products therapeutic target

项目摘要

PROJECT SUMMARY Adult T-cell leukemia-lymphoma (ATL) is an aggressive and fatal malignancy caused by the human T- lymphotropic virus, type 1 (HTLV-1). The retrovirus is primarily transmitted sexually or via breastfeeding. At least 10 million people worldwide may be infected with HTLV-1. ATL occurs disparately in the U.S. affecting mainly African descendants from the Caribbean islands, such as Haiti and Jamaica, where HTLV-1 is endemic. HTLV- 1 and related diseases represent a public health concern in South Florida and New York City, which are the U.S. areas most populated by immigrants from the Caribbean islands, and their descendants. Between 2-5% of HTLV- 1 infected individuals develop ATL during their lifetime. The aggressive and most common ATL variants have a median survival of 6-10 months, and cannot be cured by conventional chemotherapy. HTLV-1 infection is challenging to treat because it establishes latency in host T-cells, which undergo clonal expansion and genetic instability over a lifetime. The HTLV-1 provirus promoter is under transcriptional control of histone deacetylases (HDACs) at the 5' LTR, and by HTLV-1 basic leucine zipper factor (HBZ), which is constitutively transcribed from the negative strand at the 3' end of the provirus. The HTLV-1 promoter is transactivated by its own viral protein, Tax, which binds CREB and recruits p300/CBP to the 5' LTR. Given these mechanisms of regulation, HDAC inhibitors, which are widely used anti-neoplastic agents, promote the activation of HTLV-1 from latency. We recently conducted a pilot trial using the old generation HDAC inhibitor valproic acid (VPA) combined sequentially with AZT/interferon-α (IFNα) during maintenance therapy in patients with ATL. We hypothesized that VPA would reactivate HTLV-1 thus provoking an immune response against minimal residual circulating ATL cells, which normally persist during AZT/IFNα therapy alone. Supporting this notion, adding VPA resulted in reduction of HTLV-1 proviral load in treated subjects, and induced molecular remission in one subject. We recently observed that HDAC inhibitors (VPA, and belinostat) completely abrogate HBZ and activate Tax followed by apoptosis. Combining AZT with belinostat augmented ATL cell death. Based on these concepts, we proposed a pilot trial using belinostat as consolidation therapy with AZT-based regimen. The objectives of this study are to determine whether adding belinostat to AZT-based therapy eradicates ATL in human subjects, to investigate whether belinostat disrupts HTLV-1 latency thus provoking a cytotoxic T-cell response in vivo, and to elucidate the molecular basis of belinostat and HDAC inhibitors in ATL using our pre-clinical models. We are poised to carry out this high-impact proposal that promises to help advance the treatment of ATL.

项目概要成人 T 细胞白血病淋巴瘤 (ATL) 是一种由人类 T 细胞引起的侵袭性致命恶性肿瘤。嗜淋巴细胞病毒，1 型 (HTLV-1) 逆转录病毒主要通过性行为或至少通过母乳喂养传播。全世界可能有 1000 万人感染 HTLV-1，ATL 的发生情况各不相同，主要影响的是美国。来自加勒比岛屿（例如海地和牙买加）的非洲人后裔，HTLV-1 是这些岛屿的地方病。 1 及相关疾病是美国南佛罗里达州和纽约市的一个公共卫生问题。来自加勒比岛屿的移民及其后裔人口最多的地区 HTLV- 的 2-5% 之间。 1 感染者在其一生中会出现 ATL，其中最具攻击性且最常见的 ATL 变种具有以下特征：中位生存期为6-10个月，并且不能通过常规化疗治愈HTLV-1感染。治疗具有挑战性，因为它会在宿主 T 细胞中建立潜伏期，而宿主 T 细胞会经历克隆扩增和遗传 HTLV-1 原病毒启动子受组蛋白脱乙酰酶的转录控制。 (HDAC) 在 5' LTR 处，并由 HTLV-1 碱性亮氨酸拉链因子 (HBZ) 组成，该因子是从原病毒 3' 端的负链 HTLV-1 启动子由其自身的病毒蛋白反式激活， Tax，结合 CREB 并将 p300/CBP 招募到 5' LTR 考虑到这些调节机制，HDAC。抑制剂是广泛使用的抗肿瘤药物，可促进 HTLV-1 从潜伏期开始激活。最近进行了一项试点试验，使用老一代 HDAC 抑制剂丙戊酸（VPA）顺序组合在 ATL 患者维持治疗期间使用 AZT/干扰素-α (IFNα) 我们突击检查了 VPA 的效果。重新激活 HTLV-1，从而激发针对最小残留循环 ATL 细胞的免疫反应，通常在单独使用 AZT/IFNα 治疗期间持续存在，支持这一观点，添加 VPA 导致了减少。我们最近观察到，接受治疗的受试者中存在 HTLV-1 前病毒载量，并在一名受试者中诱导了分子缓解。 HDAC 抑制剂（VPA 和 belinostat）完全消除 HBZ 并激活 Tax，随后导致细胞凋亡。基于这些概念，我们提出了一项试点试验。使用belinostat作为基于AZT的方案的巩固治疗本研究的目的是确定。在基于 AZT 的治疗中添加 belinostat 是否可以根除人类受试者的 ATL，以研究是否 belinostat 破坏 HTLV-1 潜伏期，从而在体内激发细胞毒性 T 细胞反应，并阐明我们准备使用我们的临床前模型来研究 ATL 中贝利司他和 HDAC 抑制剂的分子基础。提出这项高影响力的提案，有望帮助推进 ATL 的治疗。