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

• 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
• 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

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.

项目摘要 成人T细胞白血病-淋巴瘤（ATL）是由人类T细胞白血病引起的侵袭性和致命性恶性肿瘤。 嗜淋巴细胞病毒1型（HTLV-1）。逆转录病毒主要通过性行为或母乳喂养传播。至少 全世界可能有1000万人感染了HTLV-1。ATL在美国频繁发生，主要影响 来自加勒比群岛的非洲后裔，如海地和牙买加，HTLV-1是地方病。HTLV- 1和相关疾病代表了美国南佛罗里达和纽约市的公共卫生问题。 加勒比群岛移民及其后裔居住的地区。2-5%的HTLV- 1感染者在其一生中发展ATL。攻击性和最常见的ATL变体具有 中位生存期6-10个月，常规化疗不能治愈。HTLV-1感染 治疗具有挑战性，因为它在宿主T细胞中建立了潜伏期，这些T细胞经历克隆扩增和遗传 不稳定的一生。HTLV-1前病毒启动子受组蛋白脱乙酰酶的转录控制 HTLV-1碱性亮氨酸拉链因子（HBZ），其由HTLV-1碱性亮氨酸拉链因子（HBZ）组成型转录， 前病毒3'端的负链。HTLV-1启动子被其自身的病毒蛋白反式激活， Tax，它结合CREB并将p300/CBP募集到5' LTR。考虑到这些调节机制，HDAC 广泛使用的抗肿瘤剂抑制剂促进HTLV-1从潜伏期活化。我们 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）。我们假设VPA 重新激活HTLV-1，从而激发针对最小残留循环ATL细胞的免疫应答， 通常在AZT/IFNα单独治疗期间持续存在。支持这一观点的是，添加VPA导致 HTLV-1前病毒载量，并在一名受试者中诱导分子缓解。我们最近观察到 HDAC抑制剂（VPA和贝利司他）完全消除HBZ并激活Tax，随后细胞凋亡。 联合AZT和贝利司他增加ATL细胞死亡。基于这些概念，我们提出了一个试点试验 使用贝利司他作为以AZT为基础的方案的巩固治疗。本研究的目的是确定 在基于AZT的治疗中加入贝利司他是否根除了人类受试者中的ATL，以调查是否 贝利司他破坏HTLV-1潜伏期，从而在体内引起细胞毒性T细胞应答，并阐明 使用我们的临床前模型，研究贝利司他和HDAC抑制剂在ATL中的分子基础。我们已经准备好 提出了这一高影响力的提案，该提案有望帮助推进ATL的治疗。