Notch and GATA-3 as novel therapeutic targets in T-cell lymphomas

Notch 和 GATA-3 作为 T 细胞淋巴瘤的新治疗靶点

• 批准号: 10318634
• 负责人: Ryan A Wilcox
• 金额: $ 34.97万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318634
• 关键词: Acetylation; Address; Antibodies; Binding; Biotin; Bromodomain; CDKN2A gene; Cells; Characteristics; Chemoresistance; Chimeric Proteins; Chromosome Deletion; Clinical; DNA Binding; Data; Diagnosis; Disease Progression; Disease Resistance; Disease remission; Dominant-Negative Mutation; EP300 gene; GATA3 gene; Genes; Genetic; Genetic Heterogeneity; Genetic Transcription; Genetically Engineered Mouse; Goals; Human; Impairment; Knowledge; Ligands; Ligase; Lymphoma; Lymphoma cell; Lymphomagenesis; Mediating; Minority; Molecular; Mus; Mutate; Non-Hodgkin' s Lymphoma; North America; Outcome; PTEN gene; Pathogenesis; Patient-Focused Outcomes; Patients; Pharmacology; Progressive Disease; Proteins; Published Comment; Recurrence; Recurrent disease; Refractory Disease; Resistance; Role; SMARCB1 gene; SWI/SNF Family Complex; Signal Transduction; Specimen; T-Cell Development; T-Cell Lymphoma; T-Lymphocyte; T-Lymphocyte Subsets; TP53 gene; Testing; Therapeutic; Transcriptional Regulation; Transgenes; Tumor Suppressor Genes; base; chemotherapy; chromatin remodeling; cytokine; gain of function; high risk; improved outcome; innovation; loss of function; macrophage; new therapeutic target; notch protein; novel; novel therapeutic intervention; novel therapeutics; p300/CBP-Associated Factor; patient derived xenograft model; rational design; small molecule; therapeutic development; therapeutic target; transcription factor; tumor microenvironment

Project Abstract Rapid disease progression and chemotherapy resistant disease are frequently observed among the most common T-cell lymphomas (TCL) and the majority of these patients will ultimately succumb to progressive disease within three years of diagnosis. Only a minority (≤10%) of patients will achieve a durable remission with novel agents, as the mechanisms promoting TCL progression and chemotherapy resistance are poorly understood and therapeutic strategies to overcome them are not defined. We have recently shown that the T- cell transcription factor GATA-3 identifies a molecularly, genetically, and clinically distinct subset of TCL that are highly resistant to chemotherapy. We have also demonstrated that Notch activation is prevalent in the TCL, and Notch blockade inhibits both TCL proliferation and GATA-3 expression, a Notch target gene, in preliminary studies. Genetic and pharmacologic loss-of-function (and gain-of-function) strategies were performed in genetically diverse TCL cells and subsequently demonstrated that GATA-3 directly confers resistance to chemotherapy in a cell-autonomous fashion. In addition, lymphoma-associated macrophages (LAM) within the tumor microenvironment (TME) promote chemotherapy resistance, and GATA-3 dependent cytokines regulate their functional polarization, highlighting an additional non-cell-autonomous mechanism for GATA-3-dependent chemotherapy resistance. Thus, there is a critical need to identify factors regulating GATA-3 expression and function in these aggressive TCL. In the absence of such knowledge, the development of therapeutic strategies that impair GATA-3-dependent transcriptional regulation and improve outcomes among these TCL will remain elusive. Our long-term goals are to understand the fundamental mechanisms that drive TCL pathogenesis and promote their resistance to currently available therapies. In doing so, we hope to develop rationally designed therapeutic strategies that will overcome the challenge of chemotherapy resistance and improve outcomes for patients afflicted with these TCL. Our overall objectives in this application are to evaluate the role of Notch signaling in T-cell lymphomagenesis and to identify the requirements for optimal GATA-3 DNA binding and transcriptional regulation. These will be achieved by addressing our central hypothesis that Notch and GATA-3 promote TCL progression and resistance to chemotherapy. In addition to being well- grounded in our own preliminary data, our central hypothesis is entirely consistent with our current understanding of the genetic landscape and molecular pathogenesis of the TCL and has significant therapeutic implications.

项目摘要 快速的疾病进展和化疗耐药性疾病是最常见的疾病之一。 常见 T 细胞淋巴瘤 (TCL)，其中大多数患者最终将死于进行性进展 诊断后三年内患病。只有少数（≤10%）患者能够获得持久缓解 使用新药，因为促进 TCL 进展和化疗耐药的机制很差 尚未确定克服这些问题的理解和治疗策略。我们最近证明了 T- 细胞转录因子 GATA-3 识别出分子、遗传和临床上独特的 TCL 子集， 对化疗具有高度抵抗力。我们还证明了 Notch 激活在 TCL 中很普遍， 初步研究表明，Notch 阻断可抑制 TCL 增殖和 Notch 靶基因 GATA-3 的表达。 研究。遗传和药理学功能丧失（和功能获得）策略在 基因多样化的 TCL 细胞，随后证明 GATA-3 直接赋予对 TCL 细胞的耐药性 以细胞自主方式进行化疗。此外，淋巴瘤相关巨噬细胞（LAM） 肿瘤微环境（TME）促进化疗耐药，GATA-3依赖性细胞因子调节 它们的功能极化，突出了 GATA-3 依赖性的额外非细胞自主机制 化疗耐药。因此，迫切需要确定调节 GATA-3 表达的因子并 在这些咄咄逼人的TCL中发挥作用。在缺乏这些知识的情况下，治疗方法的发展 损害 GATA-3 依赖性转录调控并改善这些 TCL 预后的策略 仍将难以捉摸。我们的长期目标是了解推动 TCL 发展的基本机制 发病机制并促进他们对现有疗法的抵抗力。在此过程中，我们希望能够发展 合理设计的治疗策​​略将克服化疗耐药性的挑战 改善患有这些 TCL 的患者的预后。我们在此应用程序中的总体目标是评估 Notch 信号传导在 T 细胞淋巴瘤发生中的作用并确定最佳 GATA-3 的要求 DNA 结合和转录调控。这些将通过解决我们的中心假设来实现： Notch 和 GATA-3 促进 TCL 进展和化疗耐药。除了身体健康之外—— 基于我们自己的初步数据，我们的中心假设与我们当前的完全一致 了解 TCL 的遗传景观和分子发病机制，具有重要的治疗意义 影响。