Mechanism of Transformation in T-Cell Lymphomas: Identification of Therapeutic Targets

T 细胞淋巴瘤的转化机制：治疗靶点的鉴定

• 批准号: 10372980
• 负责人: Bobby Ben Shih
• 金额: $ 4.68万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372980
• 关键词: Address; Affect; Alternative Therapies; Antineoplastic Agents; Automobile Driving; Biological Assay; Biological Markers; Bypass; CRISPR screen; Cell Line; Cell Survival; Chemicals; Clinic; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Collection; Combined Modality Therapy; Cutaneous; Cutaneous T-cell lymphoma; DNA; Development; Diagnosis; Diagnostic; Drug Combinations; Effectiveness; Ensure; Epigenetic Process; FDA approved; Genes; Genetic; Genetic Transcription; Genomics; Goals; Growth; Herbert Irving Comprehensive Cancer Center; High-Throughput Nucleotide Sequencing; Histone Deacetylase Inhibitor; Human; In Vitro; Individual; Knock-out; Knowledge; Lead; Libraries; Lymphoma; Malignant - descriptor; Malignant Neoplasms; Mature T-Lymphocyte; Measures; Mediating; Methods; Minority; Modeling; Mutation; Natural Killer Cells; Non-Hodgkin' s Lymphoma; Oncogenic; Pathogenesis; Pathway interactions; Patients; Peripheral; Pre-Clinical Model; Prognosis; Recurrence; Refractory; Relapse; Resistance; Resistance development; Role; Sampling; Series; Signal Pathway; Signal Transduction; Specimen; Systems Biology; T-Cell Lymphoma; T-Cell Receptor; Techniques; Testing; Therapeutic; Therapeutic Effect; Therapeutic Uses; Thymus Gland; Universities; base; clinical application; design; epigenetic drug; established cell line; experimental study; genome-wide; improved; in vitro Model; in vivo; in vivo evaluation; longitudinal analysis; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; resistance mechanism; response; response biomarker; single cell sequencing; specific biomarkers; targeted treatment; therapeutic target; treatment effect; treatment response; tumor

Project Summary T-cell lymphomas (TCL) are a highly aggressive and heterogeneous group of non-Hodgkin lymphomas derived from post-thymic mature T- and NK-cells. Limited understanding of the genetics and pathogenesis of TCL have led to relatively few targeted therapeutic with none considered curative. Among them, histone deacetylase inhibitors (HDACi) have emerged as a class of epigenetic drugs with single-agent activity in patients with cutaneous and peripheral T-cell lymphoma, with overall response rates (ORR) of ~27-33% in relapsed TCL. However, even among patients that do initially respond, duration of response is short lived, and the patient eventually relapses. Here, I will formally explore the genetic mechanisms underlying resistance to HDACi in TCLs. The central hypothesis of this proposal is that the therapeutic effects of HDACi observed in T-cell lymphomas occurs due to alterations in critical oncogenic pathways implicated in the growth and progression of T-cell lymphomas. Additionally, I propose that genetic aberrations affecting epigenetic and signaling pathways can bypass or compensate for HDACi-mediated inhibition to drive resistance to HDACi treatment. To test this hypothesis, I will utilize a well-defined clinical series of cutaneous T-cell lymphoma (CTCL) primary patient samples treated with HDACi as well as established cell line models of CTCL. This series of primary patient samples will enable the longitudinal analysis of individual tumors along with grouped analysis of HDACi sensitive and resistant tumors. Using these models, I propose to address the central hypothesis in the following two Specific Aims: Aim 1, to identify mechanisms of response and resistance to HDACi in T-cell lymphoma cell lines and primary patient samples through bulk and single-cell sequencing techniques as well as genome wide CRISPR knockout screens; and Aim 2, to develop synergistic HDACi-based therapeutics using in vivo and in vitro models that overcome HDACi resistance. Experiments related to these two aims will be performed in close collaboration with groups within the Herbert Irving Comprehensive Cancer Center and the Columbia University Department of Systems Biology to ensure rigorous analysis and to leverage expertise in a wide range of fields relevant to the experiments proposed. The goal of this project is to uncover genetic mechanisms driving resistance to HDACi in T-cell lymphomas and leverage this knowledge to identify potential therapeutics that may reverse HDACi resistance. These results will not only further our understanding behind the treatment of T-cell lymphomas but also have powerful clinical applications to address the poor prognosis a T-cell lymphoma diagnosis carries.

项目摘要 T细胞淋巴瘤（TCL）是衍生的非霍奇金淋巴瘤的高度侵略性和异质群 来自胸膜后成熟的T和NK细胞。对TCL的遗传学和发病机理的了解有限 导致相对较少的靶向治疗，没有被认为是治愈性的。其中，组蛋白脱乙酰基酶 抑制剂（HDACI）已成为一类表观遗传药物，具有单药活性 皮肤和周围T细胞淋巴瘤，复发性TCL的总反应率（ORR）约为27-33％。 但是，即使在最初做出反应的患者中，反应持续时间也很短，患者 最终复发。在这里，我将正式探索对HDACI的遗传机制 TCLS。该提议的中心假设是HDACI在T细胞中观察到的治疗作用 淋巴瘤发生是由于与生长和进展有关的关键致癌途径的改变而发生的。 T细胞淋巴瘤。此外，我提出影响表观遗传和信号传导的遗传畸变 途径可以绕过或补偿HDACI介导的抑制作用，以驱动对HDACI治疗的抗性。到 检验该假设，我将利用明确定义的皮肤T细胞淋巴瘤（CTCL）原发性临床系列 用HDACI处理的患者样品以及CTCL的既定细胞系模型。这一系列主要 患者样品将对单个肿瘤进行纵向分析以及HDACI的分组分析 敏感和抗性肿瘤。使用这些模型，我建议解决中心假设 以下两个具体目标：目标1，以识别T细胞中对HDACI的响应机制和抗性的机制 淋巴瘤细胞系和主要的患者样品也通过大量和单细胞测序技术 作为基因组宽CRISPR淘汰屏幕；和目标2，开发基于HDACI的协同治疗剂 使用克服HDACI抗性的体内和体外模型。与这两个目标有关的实验将 可以与赫伯特·欧文综合癌症中心的团体密切合作， 哥伦比亚大学系统生物学系，以确保严格的分析并利用专业知识 在与提出的实验相关的广泛领域中。该项目的目的是发现遗传 在T细胞淋巴瘤中推动对HDACI的抗性的机制，并利用这些知识来识别潜力 可以逆转HDACI抗性的治疗剂。这些结果不仅会进一步落后于我们的理解 T细胞淋巴瘤的治疗，但也具有强大的临床应用来解决不良预后 T细胞淋巴瘤诊断。