Targeting Brain Tumor Stem Cells In The Hypoxic Microenvironment

 描述（由申请人提供）：局部氧水平降低是许多恶性肿瘤的特征，特别是那些快速生长的恶性肿瘤。其中缺氧诱导的坏死和新血管形成是病理诊断的中心的一种癌症是胶质母细胞瘤，其是最常见的恶性脑肿瘤。胶质母细胞瘤中常出现缺氧区，肿瘤缺氧水平升高与临床结局恶化相关。在这项提案中，我们专注于缺氧，单羧酸转运蛋白-4（MCT 4）和Notch之间的功能重要联系，以及它们在促进恶性脑肿瘤中干细胞样胶质瘤细胞（GSC）生长和存活中的作用，这些恶性脑肿瘤无法治愈。在第一个目标中，我们确定Notch如何被MCT 4调节。目的二：研究缺氧微环境下Notch与GSC的关系。最后，在目标3中，我们将关注MCT 4可能调节GSC辐射敏感性的潜在机制。这些研究直接建立在我们小组将缺氧、Notch和MCT 4与干细胞诱导联系起来的最新工作基础上，并解决了MCT 4在介导缺氧反应关键方面的作用。我们的策略的一个重要组成部分是使用新的结构来操纵和测量缺氧和Notch信号传导的分子反应。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。

 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.