Merlin Signal in Glioma: Therapeutic Agents and Targets

胶质瘤中的 Merlin 信号：治疗药物和靶点

• 批准号: 7672177
• 负责人: Qin Yu
• 金额: $ 34.9万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7672177
• 关键词: Actins; Apoptotic; Biological; Carmustine; Cells; Cytoskeleton; Deletion Mutation; Development; Disease; Drug resistance; Ependymoma; Fibromatoses; Future; Genes; Glioma; Growth; Human; In Vitro; Link; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Membrane Proteins; Molecular; Mutation; Nature; Neurilemmoma; Neurofibromatosis 2; Neurofibromin 2; Oncogenic; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Proteins; Resistance; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Time; Tumor Suppressor Proteins; base; chemotherapeutic agent; chemotherapy; clinically relevant; in vivo; inhibitor/antagonist; meetings; member; meningioma; novel; novel therapeutics; outcome forecast; preclinical study; research study; response; subcutaneous; success; temozolomide; tumor

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

恶性胶质瘤患者的预后仍然很差。用这个治疗病人 为了更有效地治疗致命疾病，我们必须确定信号通路中的常见畸变， 恶性神经胶质瘤的侵袭性和耐药性。梅林是一个 属于Band 4.1超家族蛋白。merlin基因的突变和缺失会导致 2型神经纤维瘤病（NF 2），其特征在于神经鞘瘤的发展， 脑膜瘤和室管膜瘤。在其他癌症中也发现了NF 2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， merlin在高级别胶质瘤中缺失或下调， 在体内显著抑制皮下和颅内人胶质瘤生长。另外我们 表明merlin表达的增加与Lats 2肿瘤抑制信号的激活有关， 途径和抑制Wnt和c-Met致癌信号传导途径。我们发现 Lats 2、经典Wnt、RhoA和c-Met信号通路在胶质瘤生长中起重要作用。 vivo.基于这些结果，我们假设merlin是生长的关键负调节因子， 和人类神经胶质瘤的进展，以及merlin的重要下游信号通路， 是人类神经胶质瘤细胞中的Lats 2、Wnt和c-Met信号通路。我们进一步假设 Merlin可在体内增敏胶质瘤细胞对化疗药物的反应。 提出了两个具体的目标来测试这些假设。目标1是确定基本的 恶性人脑胶质瘤中merlin下游效应子的研究 Lats 2信号传导并抑制Wnt和c-Met信号传导途径。目标2是提供一种新颖的 通过确立Merlin对胶质瘤反应的增敏作用来治疗人脑胶质瘤的策略 细胞对化疗药物的反应。 从拟议的研究结果将推进我们的理解梅林的重要作用 神经胶质瘤进展中的信号传导，并将建立神经胶质瘤的重要下游信号传导途径。 merlin是抗胶质瘤治疗的主要靶点，为将来进行临床前研究提供了强有力的基础。 测试抑制这些必需下游信号传导的现有药理学试剂的研究 Merlin的路径因此，该提议具有很高的生物学和临床相关性