Molecular targeted therapy focusing invasion signaling in malignant glioma cell

聚焦恶性胶质瘤细胞侵袭信号的分子靶向治疗

• 批准号: 23592117
• 负责人: NAKADA MITSUTOSHI
• 金额: $ 3.33万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2013
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23592117/
• 关键词: グリオーマ; 分子標的療法; Akt; Notch; 増殖; 浸潤; GSK3β; テモゾロミド; 薬剤感受性; MGMT; 膠芽腫; シグナル伝達

We assessed the therapeutic possibility of inhibiting Notch and Akt in gliomas using the clinically available, selective small molecule inhibitors. Additionally, we investigated the molecular mechanisms of sensitization of glioblastoma (GBM) cells to temozolomide (TMZ) by GSK3beta inhibition. Notch and Akt inhibitors significantly inhibited cell growth, migration, and invasion in a dose-dependent manner. However, the effect of combination treatment did not exceed that of Akt inhibitor monotherapy in proliferation assay. Inhibition of invasion, further enhanced by combination therapy. Therefore, combination therapy may be effective for inhibiting invasion but not proliferation. GSK3beta inhibition enhanced TMZ effect. c-Myc binds to the MGMT promoter with consequent recruitment of DNMT3A, regulating the levels of MGMT promoter methylation. Therefore, GSK3beta inhibition enhances TMZ effect by silencing MGMT expression via c-Myc-mediated promoter methylation.

我们评估了使用临床上可用的选择性小分子抑制剂抑制胶质瘤中Notch和Akt的治疗可能性。此外，我们还研究了GSK3β抑制增敏胶质母细胞瘤(GBM)细胞对替莫唑胺(TMZ)的分子机制。Noch和Akt抑制剂以剂量依赖的方式显著抑制细胞的生长、迁移和侵袭。但在增殖实验中，联合用药的效果并不优于Akt抑制剂单独用药的效果。对侵袭的抑制，通过联合治疗进一步增强。因此，联合治疗可能对抑制侵袭有效，但对增殖无效。抑制GSK3β可增强TMZ效应。C-Myc与MGMT启动子结合，进而募集DNMT3A，调节MGMT启动子甲基化水平。因此，GSK3β抑制通过c-Myc介导的启动子甲基化抑制MGMT的表达，从而增强TMZ效应。

项目成果

PCDH10 is required for the tumorigenicity of glioblastoma cells

• DOI: 10.1016/j.bbrc.2013.12.138
• 发表时间: 2014-01-31
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Echizen, Kanae;Nakada, Mitsutoshi;Akiyama, Tetsu
• 通讯作者: Akiyama, Tetsu

膵臓癌治療剤

胰腺癌治疗剂

• 发表时间: 2013

金沢大学脳神経外科

金泽大学神经外科

Progressive adult primary glioblastoma in the medulla oblongata with an unmethylated MGMT promoter and without an IDH mutation

• DOI: 10.1007/s10014-012-0118-9
• 发表时间: 2013-07-01
• 期刊: BRAIN TUMOR PATHOLOGY
• 影响因子: 3.3
• 作者: Yoshikawa, Akifumi;Nakada, Mitsutoshi;Hamada, Jun-ichiro
• 通讯作者: Hamada, Jun-ichiro

Ligand-dependent EphB1 signaling suppresses glioma invasion and correlates with patient survival

配体依赖性 EphB1 信号传导抑制神经胶质瘤侵袭并与患者生存相关。

• DOI: 10.1093/neuonc/not128
• 发表时间: 2013-12-01
• 期刊: NEURO-ONCOLOGY
• 影响因子: 15.9
• 作者: Teng, Lei;Nakada, Mitsutoshi;Hamada, Jun-Ichiro
• 通讯作者: Hamada, Jun-Ichiro