The Role of Signaling Pathways in Brain Tumors in Mice

描述（由申请人提供）：本基金拟比较和对比神经胶质瘤和髓母细胞瘤的基因工程小鼠模型，以研究这些肿瘤中血管周围龛（PVN）的干细胞样细胞。我们将研究PVN细胞使用什么信号通路来响应用于人类的标准治疗。Akt、一氧化氮、音速刺猬和notch通路在这些细胞中都很活跃。我们的初步数据表明，替马唑胺和辐射都激活了这些途径中的一些，从而增强了占据PVN的细胞的干细胞特征。干细胞特性的增加通过多种机制与对放射和化学疗法的抗性相关。一个目标是确定这些途径之间的因果关系作为治疗反应的一部分。这些肿瘤中的多药耐药性主要是由于ABCG 2（CNS干细胞标志物）的活性，并与这些肿瘤对化疗的耐药性有关。ABCG2功能也作为对治疗的响应而增强。这一事实对神经胶质瘤的标准治疗（替马唑胺与同步放疗）具有重大影响，因为替马唑胺和放疗均可诱导ABCG 2，而替马唑胺是ABCG 2的底物。因此，我们的另一个目标是通过可用的小分子抑制剂可以阻断的信号通路将ABCG 2的激活与治疗联系起来。最终，我们希望创造一个合理的鸡尾酒疗法，将最大限度地减少神经胶质瘤和髓母细胞瘤血管周围小生境细胞中干细胞特性和多药耐药性的增强。

DESCRIPTION (provided by applicant): This grant proposes to compare and contrast genetically engineered mouse models of gliomas and medulloblastomas to investigate the stem-like cells of the perivascular niches (PVN) in these tumors. We will investigate what signaling pathways cells of the PVN use to respond to standard therapy used for humans. The Akt, nitric oxide, sonic hedgehog, and notch pathways are all active in these cells. Our preliminary data indicates that both temazolamide and radiation activate some of these pathways with resultant enhancement of stem cell character for cells occupying the PVN. Increased stem cell character is associated with resistance to both radiation and chemotherapy by multiple mechanisms. One goal is to determine the causal relationship between these pathways as a part of therapeutic response. Multi-drug resistance in these tumors is primarily due to activity of ABCG2 (a CNS stem cell marker), and is linked to the resistance of these tumors to chemotherapy. ABCG2 function is enhanced as a response to therapy as well. This fact has a substantial impact on the standard of care for gliomas (temazolamide with concurrent radiation) as both temazolamide and radiation induce ABCG2 and temazolamide is a substrate for ABCG2. Our additional goal is therefore to link the activation of ABCG2 to therapy through signaling pathways that could be blocked by available small molecule inhibitors. Eventually we hope to create a rational cocktail of therapy that would minimize the enhancement of stem cell character and multi-drug resistance in cells of the perivascular niche in gliomas and medulloblastomas.