Microglia facilitate glioma progression through the Pyk2 and FAK signaling

小胶质细胞通过 Pyk2 和 FAK 信号传导促进神经胶质瘤进展

• 批准号: 9279824
• 负责人: Lilia Kucheryavykh
• 金额: $ 33.08万
• 依托单位: UNIVERSIDAD CENTRAL DEL CARIBE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9279824
• 关键词: Ablation; Area; Biological Assay; Brain; Bromodeoxyuridine; C57BL/6 Mouse; Cells; Cellular biology; Clinical; Combined Modality Therapy; Data; Diagnosis; Effectiveness; Environment; Excision; Glioblastoma; Glioma; Growth; Human; ITGAM gene; Immune; Impairment; In Vitro; Investigation; Kinetics; Malignant - descriptor; Malignant neoplasm of brain; Medical; Microglia; Modeling; Molecular; Mus; Nature; Operative Surgical Procedures; Outcome; Outcome Study; PTK2 gene; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Primary Cell Cultures; Process; Property; Recurrence; Regulation; Relapse; Resected; Resistance; Role; Sampling; Signal Pathway; Signal Transduction; Small Interfering RNA; System; Techniques; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Translating; Treatment Efficacy; Treatment Protocols; Tumor Cell Invasion; Use Effectiveness; Validation; Western Blotting; animal mortality; chemotherapy; combinatorial; cytotoxic; experimental study; glioma cell line; healing; implantation; improved; in vivo; inhibitor/antagonist; knock-down; migration; mouse model; outcome forecast; release factor; targeted treatment; temozolomide; therapy design; therapy resistant; tumor; tumor growth; tumor progression

Glioblastoma tumors carry an exceptionally poor prognosis with median survival of approximately one year following diagnosis. Treatment resistance and invasive nature of glioma tumors negates the effectiveness of current medical approaches. Microglia infiltrate most gliomas and release factors which influence tumor growth and invasion. It was shown that soluble factors, released by microglia activate migration, proliferation, and resistance to applied chemotherapy in cultured glioma cell lines. Previously we demonstrated that microglia promote dispersal of glioma cells through the Pyk2 signaling pathway. Our preliminary data show that pharmacological inhibition of Pyk2/FAK in glioma cells reduce proliferation and increase cytotoxic effect of temozolomide in the presence of microglia. We hypothesize that microglia release factors to promote migration, proliferation, chemotherapy resistance, and tumor recurrence through the Pyk2/FAK pathways. The use of Pyk2/FAK blockers will reduce the microglial effect on tumor growth, dispersal, recurrence, and resistance to therapy. Combinatorial therapies utilizing Pyk2/FAK inhibitors together with chemotherapeutic compounds have the potential to provide significant treatment benefits. In the present study, we will utilize resected human glioblastoma tissues and cell biology approaches to investigate the intracellular mechanisms exploited to promote microglia-activated glioma invasiveness and proliferation. We will also examine, in a murine model, the effectiveness of supplementing traditional chemotherapeutic glioblastoma treatment with a Pyk2/FAK blocker on tumor growth and recurrence. To test our hypothesis we propose the following specific aims: Specific Aim #1: To test the hypothesis that microglia activate migration, invasion and proliferation of glioma cells through Pyk2 and FAK intracellular pathways. Specific Aim #2: To investigate combined effect of temozolomide (TMZ) and the Pyk2/FAK blocker PF- 562271 on tumor growth and animal mortality. Specific aim #3: To investigate the effectiveness of combined treatment with TMZ and PF-562271 on glioma recurrence after tumor resection. Validation of our hypothesis will provide a platform for developing therapeutic strategies aimed at elimination of the microglial component on glioma growth and recurrence and, thereby, increasing treatment efficacy.

胶质母细胞瘤预后极差，中位生存期约为一年 诊断后。胶质瘤的治疗抗性和侵袭性否定了化疗的有效性。 目前的医疗方法。小胶质细胞浸润大多数胶质瘤并释放影响肿瘤生长的因子 和入侵。结果表明，小胶质细胞释放的可溶性因子激活了迁移、增殖和增殖， 培养的胶质瘤细胞系对应用化疗的抗性。之前我们证明了小胶质细胞 通过Pyk 2信号通路促进胶质瘤细胞的扩散。初步数据显示， 神经胶质瘤细胞中Pyk 2/FAK的药理学抑制降低了增殖并增加了细胞毒性作用， 替莫唑胺在存在小胶质细胞的情况下。我们假设小胶质细胞释放因子， 通过Pyk 2/FAK途径的迁移、增殖、化疗抗性和肿瘤复发。的 使用Pyk 2/FAK阻断剂将减少小胶质细胞对肿瘤生长、扩散、复发的影响， 对治疗的抵抗利用Pyk 2/FAK抑制剂与化疗药物一起的组合疗法 化合物具有提供显著治疗益处的潜力。 在本研究中，我们将利用切除的人胶质母细胞瘤组织和细胞生物学方法， 研究用于促进小胶质细胞激活的胶质瘤侵袭性的细胞内机制， 增殖我们还将在小鼠模型中研究补充传统的 使用Pyk 2/FAK阻断剂的化学治疗胶质母细胞瘤对肿瘤生长和复发的影响。 为了检验我们的假设，我们提出以下具体目标： 具体目标#1：检验小胶质细胞激活胶质瘤迁移、侵袭和增殖的假设 细胞通过Pyk 2和FAK细胞内途径。 具体目标#2：研究替莫唑胺（TMZ）和Pyk 2/FAK阻滞剂PF-1的联合作用。 562271对肿瘤生长和动物死亡率的影响。 具体目标#3：研究TMZ和PF-562271联合治疗胶质瘤的有效性 肿瘤切除后复发。 验证我们的假设将提供一个平台，以制定治疗策略，旨在消除 小胶质细胞组分对胶质瘤生长和复发的影响，从而提高治疗效果。