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.

项目概要 T 细胞淋巴瘤 (TCL) 是一组高度侵袭性和异质性的非霍奇金淋巴瘤来源 来自胸腺后成熟 T 细胞和 NK 细胞。对 TCL 的遗传学和发病机制了解有限 导致相对较少的靶向治疗，而且没有一个被认为是治愈的。其中，组蛋白脱乙酰酶 抑制剂（HDACi）已成为一类表观遗传药物，对患有以下疾病的患者具有单药活性： 皮肤和外周 T 细胞淋巴瘤，复发 TCL 的总体缓解率 (ORR) 约为 27-33%。 然而，即使在最初有反应的患者中，反应的持续时间也是短暂的，并且患者 最终复发。在这里，我将正式探讨 HDACi 耐药性的遗传机制。 TCL。该提案的中心假设是 HDACi 在 T 细胞中观察到的治疗效果 淋巴瘤的发生是由于与生长和进展有关的关键致癌途径的改变 T 细胞淋巴瘤。此外，我认为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，从而驱动对 HDACi 治疗的耐药性。到 为了检验这个假设，我将利用皮肤 T 细胞淋巴瘤 (CTCL) 原发性的明确临床系列 使用 HDACi 处理的患者样本以及已建立的 CTCL 细胞系模型。本系列初级 患者样本将能够对单个肿瘤进行纵向分析以及 HDACi 的分组分析 敏感和耐药肿瘤。使用这些模型，我建议解决以下问题中的中心假设： 以下两个具体目标： 目标 1，确定 T 细胞中对 HDACi 的反应和耐药机制 淋巴瘤细胞系和原发性患者样本也通过批量和单细胞测序技术进行 作为全基因组 CRISPR 敲除筛选；目标 2，开发基于 HDACi 的协同疗法 使用克服 HDACi 耐药性的体内和体外模型。与这两个目标相关的实验将 与赫伯特·欧文综合癌症中心内的小组密切合作进行 哥伦比亚大学系统生物学系确保严格分析并利用专业知识 在与所提出的实验相关的广泛领域。该项目的目标是揭示基因 T 细胞淋巴瘤中驱动 HDACi 耐药的机制，并利用这些知识来识别潜在的 可能逆转 HDACi 耐药性的治疗方法。这些结果不仅将加深我们对背后的理解 T细胞淋巴瘤的治疗，而且还具有强大的临床应用来解决预后不良的问题 T细胞淋巴瘤诊断进行。