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

项目摘要 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的了解有限 导致相对较少的靶向治疗，没有一个被认为是治愈的。其中，组蛋白脱乙酰酶 抑制物(HDACi)已成为一类具有单一药物活性的表观遗传药物，用于治疗慢性阻塞性肺疾病 皮肤和外周T细胞淋巴瘤，在复发的TCL中总有效率(ORR)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，患者 最终会复发。在这里，我将正式探索对HDACi耐药的遗传机制 TCL。这项提议的中心假设是，在T细胞中观察到HDACi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递的基因异常 通路可以绕过或补偿HDACi介导的抑制，以驱动对HDACi治疗的耐药性。至 为了验证这一假设，我将利用一组定义明确的皮肤T细胞淋巴瘤(CTCL)原发临床系列 用HDACi处理的患者样本以及已建立的CTCL细胞系模型。这一系列的初级 患者样本将支持对单个肿瘤的纵向分析以及对HDACi的分组分析 敏感和耐药肿瘤。使用这些模型，我建议解决 以下两个具体目标：目标1，确定T细胞对HDACi的反应和耐药机制 淋巴瘤细胞系和原发患者样本也通过批量和单细胞测序技术 作为全基因组CRISPR基因敲除筛查；以及目标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，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。这个项目的目标是发现基因 驱动T细胞淋巴瘤对HDACi耐药的机制和利用这一知识识别潜在的 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细胞淋巴瘤的治疗也具有强大的临床应用价值，可解决预后不良的问题。 T细胞淋巴瘤的诊断结果是阳性的。

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.