NAD+ Pathway Signaling in Glioblastoma Tumor Growth and Therapy Resistance

胶质母细胞瘤肿瘤生长和治疗耐药性中的 NAD 通路信号传导

基本信息

批准号：
10194624
负责人：
Albert Hong-Jae Kim
金额：
$ 45.47万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10194624
关键词：
Adult Anabolism Behavior Biochemical Biological Cell Cycle Progression Cell Nucleus Cell Survival Cells Combined Modality Therapy Cues DNA Damage DNA Repair Data Dependence Drug Targeting E2F2 transcription factor Effectiveness Enzymes Event Exhibits Generations Genetic Genetic Transcription Glioblastoma Goals Growth Human In Vitro Ionizing radiation Link Maintenance Malignant - descriptor Malignant neoplasm of brain Mediating Mediator of activation protein Metabolic Metabolic Pathway Metabolism Molecular NADP Nicotinamide adenine dinucleotide Nuclear Pathway interactions Patients Pharmacology Play Process Production Radiation Radiation Tolerance Radiation therapy Regulation Reporting Resistance Role Sampling Signal Pathway Signal Transduction Specimen System TNF gene Treatment Efficacy Tumorigenicity Up-Regulation Validation Xenograft Model arm base cancer cell cancer type cell growth cofactor combat human disease in vivo insight loss of function metabolic profile nicotinamide phosphoribosyltransferase novel novel therapeutic intervention overexpression pre-clinical programs promoter radiation resistance response self-renewal standard of care translational impact tumor tumor growth tumor heterogeneity tumor metabolism tumor microenvironment tumorigenic

项目摘要

ABSTRACT Glioblastoma, the most common primary malignant brain tumor in adults, remains incurable despite multimodal therapy, necessitating the discovery of new therapeutic strategies. Emerging evidence indicates that the unique metabolic profile of cancer cells interfaces with signal transduction and transcriptional programs to stimulate malignant behavior. Nicotinamide adenine dinucleotide (NAD+) plays a pivotal role in cancer cell metabolism, but how NAD+ and its regulation impacts functionally relevant signaling events in glioblastoma has not been well understood. We recently found that high expression of NAMPT, the rate-limiting step in NAD+ biosynthesis, in glioblastoma tumors is associated with poor overall survival in patients and demonstrated that NAMPT is essential for self-renewal and in vivo tumor growth in primary glioblastoma cells, indicating a requirement for NAD+ to maintain malignant behavior. We also identified a NAD+-dependent transcriptional program mediated by transcription factor E2F2, which is required for the self-renewal and clonogenic survival of glioblastoma cells. In this project, we will first elucidate the molecular mechanisms that link NAD+ to the E2F2-dependent transcriptional program in glioblastoma. We will then examine the role of NAD+ generation in glioblastoma cells focusing on NAMPT regulation, with examination of metabolic correlates using human tumor samples. Finally, we will investigate the ability of NAMPT inhibition in vivo to enhance the therapeutic efficacy of radiation therapy, a major arm of the current standard-of-care, and further delineate the mechanism by which NAMPT dictates radiation responsiveness. The immediate goal of this project is to identify the mechanisms of NAD+-dependent metabolic reprogramming in glioblastoma, with the long-term goal of developing novel NAD+ pathway-directed strategies to disrupt glioblastoma growth and increase the effectiveness of current therapies.

抽象的胶质母细胞瘤是成人最常见的原发性恶性脑肿瘤，尽管采用多种模式，但仍然无法治愈治疗，需要发现新的治疗策略。新出现的证据表明癌细胞独特的代谢特征与信号转导和转录程序相互作用刺激恶性行为。烟酰胺腺嘌呤二核苷酸 (NAD+) 在癌细胞中发挥着关键作用代谢，但是 NAD+ 及其调节如何影响胶质母细胞瘤中功能相关的信号事件没有得到很好的理解。我们最近发现 NAMPT 的高表达，NAD+ 的限速步骤胶质母细胞瘤中的生物合成与患者总体生存率较差有关，并证明 NAMPT 对于原代胶质母细胞瘤细胞的自我更新和体内肿瘤生长至关重要，这表明 NAD+维持恶性行为的必要条件。我们还发现了 NAD+ 依赖性转录由转录因子 E2F2 介导的程序，这是自我更新和克隆生存所必需的胶质母细胞瘤细胞。在这个项目中，我们将首先阐明将 NAD+ 与胶质母细胞瘤中 E2F2 依赖性转录程序。然后我们将研究 NAD+ 生成在胶质母细胞瘤细胞专注于 NAMPT 调节，并使用人类肿瘤检查代谢相关性样品。最后，我们将研究体内抑制NAMPT以增强治疗效果的能力放射治疗是当前标准护理的一个主要部分，并进一步描述了其机制 NAMPT 决定了辐射响应性。该项目的近期目标是确定胶质母细胞瘤中 NAD+ 依赖性代谢重编程的机制，长期目标是开发新的 NAD+ 通路导向策略来破坏胶质母细胞瘤生长并增加当前疗法的有效性。