Role of NSD3 in regulation of cancer pathogenesis

NSD3 在癌症发病机制调节中的作用

• 批准号: 10633579
• 负责人: Or P. Gozani
• 金额: $ 66.07万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633579
• 关键词: 3q26; 8p11; Accounting; Biochemical; Cancer Etiology; Cancer Model; Cells; Cessation of life; Chromatin; Clinical; Clinical Trials; DNA methylation profiling; Data; Development; Diagnosis; Disease; Disease model; Drug Targeting; Enzymes; Epigenetic Process; Epitopes; Evolution; FGFR1 Gene Amplification; FGFR1 gene; Gene Amplification; Generations; Genes; Genetic; Genomic Segment; Goals; Heterogeneity; Histologic; Histone H3; Human; Knockout Mice; Lysine; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Medicine; Methylation; Methyltransferase; Modeling; Molecular; Mus; Mutation; Nature; Neoplasm Metastasis; Oncogenic; Outcome; Pathogenesis; Pathologic; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Penetrance; Pre-Clinical Model; Regulation; Research; Resolution; Role; Sampling; Squamous Cell Lung Carcinoma; System; TP53 gene; Technology; Testing; Therapeutic; Tumor Promotion; United States; Validation; Work; clinically actionable; driver mutation; drug candidate; epigenomics; experimental study; gain of function; histone methyltransferase; histone modification; human model; improved; in vivo; inhibitor; insight; mortality; mouse model; neoplastic cell; new therapeutic target; novel; novel strategies; novel therapeutics; overexpression; pre-clinical; recombinase; targeted treatment; therapeutic target; transcriptomic profiling; tumor; tumor heterogeneity; tumor initiation; tumor progression; tumorigenesis

ABSTRACT Our overarching goal is to elucidate the mode of action of and evaluate the therapeutic potential of the epigenetic regulatory factor NSD3 in the regulation of lung squamous cell carcinoma (LUSC) pathogenesis. Lung cancer is the most common cause of cancer-related mortality in the United States and worldwide, leading to over a 1.8 million deaths each year. LUSC is the second most common subtype of lung cancer, accounting for ~30% of all cases and tragically over 40,000 deaths each year in the US alone. While new targeted therapies have shown promise in other malignancies, unfortunately, to date, there are no approved targeted therapies for LUSC. Thus, there is a major unmet need to uncover new, clinically actionable, and compelling targets for the development of new medicines to ultimately treat this difficult disease. A central hypothesis to be tested here is that the histone H3 lysine 36 (H3K36) di-methyltransferase enzyme NSD3 is a promising epigenetic target for the treatment of LUSC. In preliminary work we found that NSD3, which is commonly amplified in LUSC, is a major driver of LUSC pathogenesis in mouse and human models of this cancer. In our proposal, we will investigate the role of the NSD3-H3K36me2 axis in lung cancer in vivo and explore the molecular and epigenetic basis of NSD3-driven tumorigenesis. In Aim 1 we investigate the role of NSD3 in LUSC pathogenesis. We have developed novel mouse models that recapitulate the most common genetic alterations in human LUSC, including NSD3 amplification, and incorporated an inducible dual-recombinase approach to allow study of multi-step tumorigenesis in vivo. This system will be used to dissect the specific functions for NSD3 in LUSC tumor initiation, progression, maintenance, and metastatic transition using conditional NSD3 gain-of-function and knockout mice. A multistep approach will also enable genetic validation of NSD3 as potential therapeutic target in advanced LUSC, a stage for which new therapies are urgently needed. In Aim 2 we will elucidate the epigenetic pathways reguated by the NSD3-H3K36me2 axis, utilizing new cutting-edge epigenomic technologies. We will also explore the role of NSD3 in promoting intratumoral heterogeneity in human and mouse models of LUSC at the single cell level. Together, this work will be the first to evaluate the therapeutic potential and mechanism-of-action of NSD3 in LUSC.

摘要 我们的首要目标是阐明的作用模式和评估的治疗潜力， 表观遗传调节因子NSD 3在肺鳞状细胞癌（LUSC）发病机制中的调节作用。肺 在美国和全世界，癌症是癌症相关死亡的最常见原因， a每年有180万人死亡。LUSC是第二种最常见的肺癌亚型，约占30%。 在所有的病例中，每年仅在美国就有超过40,000人死亡。虽然新的靶向疗法 尽管LUSC在其他恶性肿瘤中显示出前景，但不幸的是，迄今为止，还没有批准的LUSC靶向疗法。 因此，存在一个主要的未满足的需求，即发现新的、临床上可操作的和令人信服的靶点， 开发新的药物来最终治疗这种困难的疾病。这里要检验的一个中心假设是 组蛋白H3赖氨酸36（H3 K36）二甲基转移酶NSD 3是一个有前途的表观遗传靶点， LUSC的治疗在初步工作中，我们发现NSD 3，这是普遍扩增的LUSC，是一个重要的基因。 在这种癌症的小鼠和人类模型中，LUSC发病机制的主要驱动因素。在我们的建议中，我们将 研究NSD 3-H3 K36 me 2轴在体内肺癌中的作用，并探索其分子和表观遗传学机制。 NSD 3驱动的肿瘤发生的基础。 在目的1中，我们研究了NSD 3在LUSC发病机制中的作用。我们已经开发了新的小鼠模型 概括了人类LUSC中最常见的遗传改变，包括NSD 3扩增， 引入了诱导型双重组酶方法，以允许在体内研究多步骤肿瘤发生。这 系统将用于剖析NSD 3在LUSC肿瘤起始，进展， 使用条件性NSD 3功能获得性和敲除小鼠的维持和转移性转变。一个多步骤 该方法还将使NSD 3作为晚期LUSC的潜在治疗靶点的基因验证成为可能， 迫切需要新的治疗方法。在目标2中，我们将阐明表观遗传途径， NSD 3-H3 K36 me 2轴，利用新的尖端表观基因组技术。我们还将探讨 NSD 3在单细胞水平促进LUSC的人和小鼠模型中的肿瘤内异质性。 总之，这项工作将是第一个评估NSD 3在治疗糖尿病中的治疗潜力和作用机制的工作。 LUSC。