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

项目摘要 T细胞淋巴瘤（TCL）是一种高度侵袭性和异质性的非霍奇金淋巴瘤， 来自胸腺后成熟的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，没有被认为是治愈性的。其中，组蛋白去乙酰化酶 抑制剂（HDACi）已成为一类表观遗传药物，在患有 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，即使在最初确实有反应的患者中，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。该建议的中心假设是在T细胞中观察到的HDACi的治疗作用， 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 这些途径可以绕过或补偿HDACi介导的抑制以驱动对HDACi治疗的抗性。到 为了验证这一假设，我将利用一个明确的皮肤T细胞淋巴瘤（CTCL）原发性 用HDACi处理的患者样品以及建立的CTCL细胞系模型。这一系列的主要 患者样本将使个体肿瘤的纵向分析沿着HDACi的分组分析 敏感和耐药肿瘤。使用这些模型，我建议解决的中心假设， 以下两个具体目的：目的1，鉴定T细胞中对HDACi的应答和抗性机制 淋巴瘤细胞系和原代患者样本通过批量和单细胞测序技术，以及 作为全基因组CRISPR敲除筛选;以及目标2，开发基于HDACi的协同疗法 使用克服HDACi抗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的小组密切合作， 哥伦比亚大学系统生物学系，以确保严格的分析和利用专业知识 在与所提出的实验相关的广泛领域。这个项目的目标是揭示基因 在T细胞淋巴瘤中驱动HDACi耐药性的机制，并利用这些知识来确定潜在的 可以逆转HDACi耐药性的治疗剂。这些结果不仅将进一步加深我们对 T细胞淋巴瘤的治疗，但也有强大的临床应用，以解决预后不良， T细胞淋巴瘤诊断携带。

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.