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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.

项目总结