Targeting Brain Tumor Stem Cells In The Hypoxic Microenvironment

在缺氧微环境中靶向脑肿瘤干细胞

• 批准号: 10071001
• 负责人: Eli E Bar
• 金额: $ 30.8万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10071001
• 关键词: Targeting; Brain; Tumor; Stem; Cells

 DESCRIPTION (provided by applicant): Locally reduced oxygen levels are a feature of many malignancies, particularly those which grow rapidly. One cancer in which hypoxia-induced necrosis and neovascularization is central to pathological diagnosis is glioblastoma the most common malignant brain tumor. Hypoxic regions are frequent in glioblastoma, and increased levels of tumor hypoxia have been associated with worse clinical outcomes. In this proposal, we focus on functionally important links between hypoxia, the monocarboxylate transporter-4 (MCT4), and Notch and their role in promoting the growth and survival of stem-like glioma cells (GSC) in malignant brain tumors for which there is no cure. In the first aim we determine how Notch is regulated by MCT4. In Aim 2, we will study the relationship between Notch and GSC in the hypoxic microenvironment. Finally, in Aim 3 we will focus on potential mechanism by which MCT4 may regulate GSC radiation sensitivity. These studies build directly on recent work from our group linking hypoxia, Notch, and MCT4 to stem cell induction and address the role of MCT4 in mediating critical aspects of the hypoxic response. An important component of our strategy is using novel constructs to manipulate and measure the molecular response to hypoxia and Notch signaling. We hope that these studies will lay the foundation for direct translation into clinical therapeutic trials.

 描述(申请人提供)：局部氧气水平降低是许多恶性肿瘤的特征，尤其是那些生长迅速的肿瘤。最常见的恶性脑肿瘤--胶质母细胞瘤是一种以缺氧引起的坏死和新生血管为中心的肿瘤。低氧区域在胶质母细胞瘤中很常见，肿瘤低氧水平的增加与较差的临床结果相关。在这项研究中，我们将重点放在低氧、单羧酸转运体-4(MCT4)和Notch之间在功能上的重要联系，以及它们在促进干细胞样脑胶质瘤细胞(GSC)生长和存活中的作用，这些肿瘤目前还无法治愈。在第一个目标中，我们确定Notch是如何由MCT4调节的。在目标2中，我们将研究缺氧微环境中Notch与GSC的关系。最后，在目标3中，我们将重点介绍MCT4调节GSC辐射敏感性的潜在机制。这些研究直接建立在我们团队最近的工作基础上，将低氧、Notch和MCT4与干细胞诱导联系起来，并解决了MCT4在调节低氧反应的关键方面的作用。我们策略的一个重要组成部分是使用新的结构来操纵和测量分子对缺氧和Notch信号的反应。我们希望这些研究将为直接转化为临床治疗试验奠定基础。

项目成果

Disruption of the monocarboxylate transporter-4-basigin interaction inhibits the hypoxic response, proliferation, and tumor progression.

• DOI: 10.1038/s41598-017-04612-w
• 发表时间: 2017-06-27
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Voss DM;Spina R;Carter DL;Lim KS;Jeffery CJ;Bar EE
• 通讯作者: Bar EE

MCT4 regulates de novo pyrimidine biosynthesis in GBM in a lactate-independent manner.

MCT4 以不依赖于乳酸的方式调节 GBM 中的从头嘧啶生物合成。

• DOI: 10.1093/noajnl/vdz062
• 发表时间: 2020
• 期刊: Neuro-oncology advances
• 作者: Spina,Raffaella;Voss,DillonM;Yang,Xiaohua;Sohn,JasonW;Vinkler,Robert;Schraner,Julianna;Sloan,Anthony;Welford,ScottM;Avril,Norbert;Ames,HeatherM;Woodworth,GraemeF;Bar,EliE
• 通讯作者: Bar,EliE

Atracurium Besylate and other neuromuscular blocking agents promote astroglial differentiation and deplete glioblastoma stem cells.

• DOI: 10.18632/oncotarget.6314
• 发表时间: 2016-01-05
• 期刊: Oncotarget
• 作者: Spina R;Voss DM;Asnaghi L;Sloan A;Bar EE
• 通讯作者: Bar EE