NAD+ Pathway Signaling in Glioblastoma Tumor Growth and Therapy Resistance

摘要 胶质母细胞瘤是成人中最常见的原发性恶性脑肿瘤， 治疗，需要发现新的治疗策略。新出现的证据表明， 癌细胞独特的代谢谱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+）在肿瘤细胞中起着关键作用 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传导事件， 没有得到很好的理解。我们最近发现NAMPT的高表达，NAMPT是NAD+表达的限速步骤。 在胶质母细胞瘤肿瘤中，生物合成与患者的总生存率相关，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是必需的，表明NAMPT在胶质母细胞瘤细胞中的作用是重要的。 需要NAD+来维持恶性行为。我们还发现了一个NAD+依赖的转录因子， 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，我们将首先阐明连接NAD+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+生成的作用， 胶质母细胞瘤细胞关注NAMPT调节，并使用人肿瘤检查代谢相关性 样品最后，我们将研究NAMPT抑制在体内增强治疗功效的能力。 放射治疗，目前的护理标准的一个主要分支，并进一步描绘的机制， NAMPT决定了辐射反应性。该项目的直接目标是确定 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+通路导向的策略，以破坏胶质母细胞瘤的生长，并增加 目前治疗的有效性。

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.