Effectively Targeting Notch in Hypoxic Brain Tumor Cells

描述（由申请人提供）：由于肿瘤细胞对标准疗法的抗性，胶质母细胞瘤（GBM）患者无法治愈。干细胞样肿瘤亚群似乎对大多数治疗特别难治，并且越来越清楚的是，特定的肿瘤亚群可能与肿瘤的生长有关。 微环境可以促进干细胞特性和化学抗性。然而，对新兴靶向治疗如何与其他药物和肿瘤微环境相互作用的理解不足限制了它们的发展。该项目的长期目标是开发Notch抑制剂作为胶质母细胞瘤和其他恶性脑肿瘤的有效新疗法。该提案的目的是阐明Notch如何与肿瘤微环境和其他治疗方法相互作用，以便通路抑制剂可以有效地用于临床。Notch通路是生成和维持非肿瘤性神经干细胞所必需的，在GBM癌症干细胞（CSC）中也起着关键作用。已经表明，血管周围微环境通过激活Notch信号传导促进CSC，并且目前正在使用许多靶向血管的药剂。随着肿瘤相关血管被移除，GBM和其他肿瘤向缺氧表型转变，并且不太清楚Notch如何在这种微环境中发挥作用。在该提议中待检验的中心假设是Notch不仅在血管周围小生境中，而且在缺氧微环境中是GBM分化和治疗反应的关键介质。事实上，新出现的数据表明，缺氧肿瘤细胞可以概括许多定义血管周围生态位的分子特征，并且Notch诱导干细胞样表型并在这种情况下调节对传统化疗的反应。前两个具体目标集中在理解Notch如何在缺氧GBM细胞中被激活，并确定Notch阻断是否可以逆转缺氧促进的CSC和治疗抗性的增加。第二个两个具体的目标集中在Notch抑制，放射和替莫唑胺化疗之间的相互作用，并研究一种新的机制，Notch阻断可以敏感GBM这种常用的烷化剂。这些研究将确定Notch活性在缺氧胶质瘤细胞中是如何调节的，并建立在缺氧微环境中CSC诱导和侵袭性肿瘤行为中对Notch的需求。他们还将研究一种新的表观遗传机制，通过这种机制，该途径可以调节MGMT表达和替莫唑胺敏感性。这些结果都具有很高的临床意义，并将对开发一种靶向胶质母细胞瘤CSC的新药物产生直接影响。

DESCRIPTION (provided by applicant): No cures exist for patients with glioblastoma (GBM) due to the resistance of tumor cells to standard therapies. Stem-like tumor subpopulations seem especially refractory to most treatments, and it is becoming increasingly clear that specific tumor microenvironments can promote stem cell properties and chemoresistance. However, poor understanding of how emerging targeted therapies interact with other agents and the tumor microenvironment has limited their development. The long-term goal of the project is to develop Notch inhibitors as effective new therapies for glioblastoma and other malignant brain tumors. The objective of this proposal is to elucidate how Notch interacts with the tumor microenvironment and other treatments so pathway inhibitors can be effectively used in the clinic. The Notch pathway, which is required for generation and maintenance of non-neoplastic neural stem cells, also plays a key role in GBM cancer stem cells (CSC). It has been shown that the perivascular microenvironment promotes CSC through activation of Notch signaling, and a number of agent targeting blood vessels are currently in use. As tumor-associated blood vessels are removed, GBM and other tumors shift towards a hypoxic phenotype, and it is less clear how Notch will function in this microenvironment. The central hypothesis to be tested in this proposal is that Notch is a key mediator of GBM differentiation and therapeutic response not just in the perivascular niche, but also in the hypoxic microenvironment. Indeed, emerging data suggest that hypoxic tumor cells can recapitulate many of the molecular features which define the perivascular niche, and that Notch induces a stem-like phenotype and modulates the response to traditional chemotherapy in this context. The first two specific aims focus on understanding how Notch is activated in hypoxic GBM cells, and determining if Notch blockade can reverse the increase in CSC and treatment resistance promoted by hypoxia. The second two specific aims focus on the interaction between Notch inhibition, radiation, and temozolomide chemotherapy, and investigate a novel mechanism by which Notch blockade can sensitize GBM to this commonly used alkylating agent. These studies will determine how Notch activity is regulated in hypoxic glioma cells, and to establish a requirement for Notch in CSC induction and aggressive tumor behavior in the hypoxic microenvironment. They will also examine a novel epigenetic mechanism by which the pathway can modulate MGMT expression and temozolomide sensitivity. These results are all of high clinical relevance, and will have a direct impact on the development of a novel agent targeting CSC in glioblastoma.