NAD+ Pathway Signaling in Glioblastoma Tumor Growth and Therapy Resistance

摘要 胶质母细胞瘤是成人最常见的原发恶性脑瘤，尽管有多种模式，但仍无法治愈。 治疗，有必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)在肿瘤细胞中起关键作用 新陈代谢，但NAD及其调节如何影响胶质母细胞瘤的功能相关信号事件 没有得到很好的理解。我们最近发现NAD中的限速步骤NAMPT的高表达 胶质母细胞瘤中的生物合成与患者的总体存活率低有关，并证明 NAMPT对原代胶质母细胞瘤细胞的自我更新和体内肿瘤生长是必不可少的，表明 NAD维持恶性行为的要求。我们还鉴定了一种依赖NAD的转录 转录因子E2F2介导的自我更新和克隆生存所需的程序 胶质母细胞瘤细胞。在这个项目中，我们将首先阐明NAD与NAD之间的分子机制 胶质母细胞瘤中E2F2依赖的转录程序。然后，我们将研究NAD世代在 胶质母细胞瘤细胞专注于NAMPT调节，并利用人类肿瘤检查代谢相关因素 样本。最后，我们将研究体内抑制NAMPT提高治疗效果的能力 放射治疗是当前护理标准的一个主要分支，并通过以下方式进一步描述其机制 哪个NAMPT规定了辐射响应性。该项目的直接目标是确定 胶质母细胞瘤中依赖NAD的代谢重编程的机制，长期目标是 开发新的NAD通路导向的策略来干扰胶质母细胞瘤的生长并增加 当前治疗方法的有效性。

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.