Merlin Signal in Glioma: Therapeutic Agents and Targets

恶性胶质瘤患者的预后仍然令人沮丧。用这个来治疗病人 为了更有效地治疗致命疾病，我们必须识别信号通路中常见的异常 它们是恶性胶质瘤侵袭性和抗药性的原因。梅林是一个 Band 4.1超家族蛋白质的成员。梅林基因的突变和缺失导致 神经纤维瘤病2型(NF2)，其特征是发展成神经鞘瘤， 脑膜瘤和室管膜瘤。在其他癌症中也发现了NF2基因的突变， 这表明梅林对多种癌症都很重要。我们最近已经证明了 Merlin在高级别胶质瘤中缺失或下调，而Merlin表达增加 显著抑制体内人脑胶质瘤的皮下和颅内生长。此外，我们 研究表明，Merlin的表达增加与激活Lats2肿瘤抑制信号有关 Wnt和c-Met致癌信号通路及其抑制。我们向大家展示了 Lats2、Canonical Wnt、RhoA和c-Met信号通路在脑胶质瘤生长中发挥重要作用 活着。根据这些结果，我们假设梅林是一个关键的负增长调节器 与人脑胶质瘤的发生和发展及Merlin的重要下游信号通路 是人脑胶质瘤细胞中的Lats2、Wnt和c-Met信号通路。我们进一步假设 说明Merlin可以在体内增敏胶质瘤细胞对化疗药物的反应。 为了检验这些假说，本文提出了两个具体目标。目标1是确定本质 恶性人脑胶质瘤中Merlin下游效应分子的激活 Lats2信号通路，并抑制Wnt和c-Met信号通路。目标2是提供一部小说 建立Merlin增敏胶质瘤反应的人脑胶质瘤治疗策略 细胞对体内化疗药物的敏感性。 拟议研究的结果将促进我们对Merlin的基本作用的理解 在胶质瘤进展中的信号转导，并将建立必要的下游信号通路 Merlin是抗胶质瘤治疗的主要靶点，并为未来进行临床前研究提供了强有力的基础 对抑制这些关键下游信号的现有药理制剂进行测试的研究 梅林之路。因此，该方案具有很高的生物学和临床应用价值。

The prognosis of patients with malignant gliomas remains dismal. To treat patients with this deadly disease more effectively, we must identify the common aberrations in the signaling pathways that are responsible for the invasive and drug-resistant nature of malignant gliomas. Merlin is a member of the Band 4.1 superfamily proteins. Mutations and deletions of merlin cause the neurofibromatosis type 2 (NF2), which is characterized by development of schwannomas, meningiomas, and ependymomas. Mutations of the NF2 gene have also been found in other cancers, suggesting that merlin is important for a variety of cancers. We have demonstrated recently that merlin is absent or down regulated in high-grade gliomas and that increased expression of merlin dramatically inhibits subcutaneous and intracranial growth of human gliomas in vivo. In addition, we demonstrated that increased expression of merlin is linked to activation the Lats2 tumor suppressorsignaling pathway and inhibition of Wnt and c-Met oncogenic signaling pathways. We showed that Lats2, canonical Wnt, RhoA, and c-Met signaling pathways play important roles in glioma growth in vivo. Based on these results, we hypothesize that merlin is a key negative regulator of the growth and progression of human gliomas and that the essential downstream signaling pathways of merlin are the Lats2, Wnt, and c-Met signaling pathways in human glioma cells. We further hypothesize that merlin can sensitize the response of glioma cells to the chemotherapeutic drugs in vivo. Two specific aims are proposed to test these hypotheses. Aim 1 is to determine the essential downstream effectors of merlin in malignant human gliomas by establishing that merlin activates Lats2 signaling and inhibits Wnt and c-Met signaling pathways. Aim 2 is to provide a novel therapeutic strategy for human gliomas by establishing that merlin sensitizes the response of glioma cells to chemotherapeutic drugs in vivo. Results from the proposed studies will advance our understanding in the essential role of merlin signaling in glioma progression and will establish that the essential downstream signaling pathways of merlin are prime targets for anti-glioma therapy and provide strong basis to conduct future preclinical studies to test the existing pharmacological agents that inhibit these essential downstream signaling pathways of merlin. Therefore, this proposal has high biological and clinical relevance