Drag repositioning for malignant glioma targeting glioma stem cells

• Project/Area Number: 26293322
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Kanazawa University
• Principal Investigator: Nakada Mitsutoshi 金沢大学, 医学系, 教授 (20334774)
• Co-Investigator(Renkei-kenkyūsha): HIRAO Atsushi 金沢大学, がん進展制御研究所, 教授 (90343350) ; MINAMOTO Toshinari 金沢大学, がん進展制御研究所, 教授 (50239323)
• Research Collaborator: DONG Yu ; FURUTA Takuya ; SABIT Hemragul ; KITABAYASHI Tomohiro
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000); Fiscal Year 2016: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
• Keywords: グリオーマ / 幹細胞 / ドラッグリポジショニング / 脳神経疾患 / 化学療法

Outline of Final Research Achievements

Glioma stem cell (GSC)-targeted therapy is a promising approach to treat patients with glioblastoma (GBM). Here, we identified fluspirilene, a traditional antipsychotic drug, as a GSC-targeting agent, selected from thousands of existing drugs with the purpose of drug repositioning. We initially screened drug libraries for small-molecule compounds showing a greater efficacy in inhibiting the proliferation and survival of different GSC lines. Drugs already reported to show therapeutic effects against GBM or those under clinical trials were excluded from subsequent screening. Among the candidate drugs, fluspirilene demonstrated a significant inhibitory effect on the proliferation and invasion of glioma cells as well as in the model mice treated with the drug. These effects were associated with the inactivation of the signal transducer and activator of transcription 3 (STAT3). Redeveloping of fluspirilene is a promising approach for the treatment of GBM.

Research Products

• [Journal Article] Fluorescence intensity and bright spot analysis using a confocal microscope for photodynamic diagnosis of brain tumors (2017)
  • Author(s): T.Yoneyama, H.Kagawa, T.Watanabe, Y.Hayashi, M. Nakada
  • Journal Title: Photodiagnosis and Photodynamic Therapy Volume: 17 Pages: 13-21
  • DOI: 10.1016/j.pdpdt.2016.11.002
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Biological basis and clinical trial of glycogen synthase kinase-3β-targeted therapy by drug repositioning for glioblastoma (2016)
  • Author(s): Furuta T, Sabit H, Yu D, Miyashita K, Kinoshita M, Uchiyama N, Hayashi Y, Hayashi Y, Minamoto T, Nakada M
  • Journal Title: Oncotarget Volume: 8 Issue: 14 Pages: 22811-22824
  • DOI: 10.18632/oncotarget.15206
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 脳腫瘍に対するドラッグリポジショニング研究 (2016)
  • Author(s): 中田光俊
  • Journal Title: Neuro-Oncologyの進歩 Volume: 23 Pages: 1-8
  • NAID: 130005331332
  • Peer Reviewed
• [Journal Article] Critical neural networks in awake surgery for gliomas (2016)
  • Author(s): Kinoshita M, Miyashita K, Tsutsui T, Furuta T, Nakada M
  • Journal Title: Neurol Med Chir (Tokyo) Volume: 56 Pages: 674-686
  • NAID: 130005282105
  • Peer Reviewed
• [Journal Article] Volumetric growth analysis of an insular dysembryoplastic neuroepithelial tumor over a 10-year follow-up (2016)
  • Author(s): Uno T, Kinoshita M, Furuta T, Miyashita K, Sabit H, Nakada M
  • Journal Title: Surg Neurol Int Volume: 7 Issue: 45 Pages: 1154-1157
  • DOI: 10.4103/2152-7806.196931
  • Peer Reviewed
• [Journal Article] Force-Sensing Silicone Retractor for Attachment to Surgical Suction Pipes (2016)
  • Author(s): Tetsuyou Watanabe, Toshio Koyama, Takeshi Yoneyama and Mitsutoshi Nakada
  • Journal Title: Sensors Volume: 16(7) Issue: 7 Pages: 1133-1133
  • DOI: 10.3390/s16071133
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The role of AKT isoforms in glioblastoma: AKT3 delays tumor progression (2016)
  • Author(s): Joy A, Kapoor M, Georges J, Butler L, Chang Y, Li C, Crouch A, Smirnov I, Nakada M, Hepler J, Marty M, Feuerstein BG
  • Journal Title: J Neurooncol Volume: 130 Pages: 43-52
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Glycogen synthase kinase 3β is a pivotal mediator in cancer invasion and resistance to therapy. (2016)
  • Author(s): Domoto T, et al, Minamoto T.
  • Journal Title: Cancer Sci Volume: 107 Issue: 10 Pages: 1363-72
  • DOI: 10.1111/cas.13028
  • NAID: 120005895690
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Establishment of anti-human ATRX monoclonal antibody AMab-6 (2016)
  • Author(s): Ogasawara S, Fujii Y, Kaneko MK, Oki H, Sabit H, Nakada M, Suzuki H, Ichimura K, Komori T, Kato Y
  • Journal Title: Monoclon Antib Immunodiagn Immunother Volume: 35 Pages: 254-258
  • Peer Reviewed
• [Journal Article] Tip60 regulates MT1-MMP transcription and invasion of glioblastoma cells through NF-κB pathway (2016)
  • Author(s): Takino T, Nakada M, Li Z, Yoshimoto T, Domoto T, Sato H
  • Journal Title: Clin Exp Metastasis Volume: 33 Pages: 45-52
  • NAID: 120005680038
  • Peer Reviewed
• [Journal Article] miR-150-5p and miR-133a suppress glioma cell proliferation and migration through targeting membrane-type-1 matrix metalloproteinase (2016)
  • Author(s): Sakr M, Takino T, Sabit H, Nakada M, Li Z, Sato H
  • Journal Title: Gene Volume: 587 Issue: 2 Pages: 155-162
  • DOI: 10.1016/j.gene.2016.04.058
  • Peer Reviewed
• [Journal Article] High efficacy of third generation EGFR inhibitor AZD9291 in a leptomeningeal carcinomatosis model with EGFR-mutant lung cancer cells (2016)
  • Author(s): Nanjo S, Ebi H, Arai S, Takeuchi S, Yamada T, Mochizuki S, Okada Y, Nakada M, Murakami T, Yano S.
  • Journal Title: Oncotarget Volume: 7(4) Issue: 4 Pages: 3847-3856
  • DOI: 10.18632/oncotarget.6758
  • NAID: 120005830568
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] MR spectroscopy to distinguish between supratentorial intraventricular subependymoma and central neurocytoma (2016)
  • Author(s): Ueda F, Aburano H, Ryu Y, Yoshie Y, Nakada M, Hayashi Y, Matsui O, Gabata T
  • Journal Title: Magn Reson Med Sci Volume: -
  • NAID: 130005797416
  • Peer Reviewed
• [Journal Article] Serine/Threonine kinase MLK4 determines Mesenchymal Identity in Glioma Stem Cells in an NFkB-dependent manner (2016)
  • Author(s): Kim SH, Ezhilarasan R, Chhipa R, Ladner K, Phillips E, Sparks A, Taylor D, Furuta T, Sabit H, Kurozumi K, Kuroiwa T, Akio A, Gallego-Perez1 D, Sulman EP, Cheng S, Lee J, Nakada M, Guttridge D, DasGupta B, Goidts V, Bhat KP, Walker J, Nakano I.
  • Journal Title: Cancer Cell Volume: 29 Issue: 2 Pages: 201-213
  • DOI: 10.1016/j.ccell.2016.01.005
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Chronic spatial working memory deficit associated with the superior longitudinal fasciculus: a study using voxel-based lesion-symptom mapping and intraoperative direct stimulation in the right prefrontal glioma surgery (2016)
  • Author(s): Kinoshita M, Nakajima R, Shinohara H, Miyashita K, Tanaka S, Okita H, Nakada M , Hayashi Y.
  • Journal Title: J Neurosurg Volume: ND
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Recurrent neomorphic mutations of MTOR in central nervous system and testicular germ cell tumors may be targeted for therapy (2016)
  • Author(s): Ichimura K, Fukushima S, Totoki Y, Matsushita Y, Otsuka A, Tomiyama A, Niwa T, Takami H, Nakamura T, Suzuki T, Fukuoka K, Yanagisawa T, Mishima K, Nakazato Y, Hosoda F, Narita Y, Shibui S, Yoshida A, Mukasa A, Saito N, Kumabe T, Kanamori M, Tominaga T, Kobayashi K, Shimizu S, Nagane M, Iuchi T, Nakada M, et al.
  • Journal Title: Acta Neuropathologica Volume: ND
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Acute progression of recurrent meningioma during luteinizing hormone-releasing hormone agonist treatment for prostate cancer. (2016)
  • Author(s): Tsutsui T, Miyashita K, Sabit H, Fukui I, Hayashi Y, Mizokami A, Ikeda H, Nagatani H, Nakada M
  • Journal Title: World Neurosurgery Volume: 印刷中 Pages: 670.e1-670.e6
  • DOI: 10.1016/j.wneu.2016.03.076
  • Peer Reviewed / Open Access
• [Journal Article] In vivo imaging models of bone and brain metastases and pleural carcinomatosis with a novel human EML4-ALK lung cancer cell line. (2015)
  • Author(s): Nanjo S, Yano S, et al.
  • Journal Title: Cancer Sci Volume: 106 Issue: 3 Pages: 244-52
  • DOI: 10.1111/cas.12600
  • NAID: 120005830611
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Strong therapeutic potential of γ-secretase inhibitor MRK003 for CD44-high and CD133-low glioblastoma initiating cells (2015)
  • Author(s): Tanaka S, Nakada M, Yamada D, Nakano I, Todo T, Ino Y, Hoshii T, Tadokoro Y, Ohta K, Ali MA, Hayashi Y, Hamada J, Hirao A.
  • Journal Title: J Neurooncol. Volume: 121 Issue: 2 Pages: 239
  • DOI: 10.1007/s11060-014-1630-z
  • Peer Reviewed / Open Access
• [Journal Article] Glycogen synthase kinase 3β sustains invasion of glioblastoma via the focal adhesion kinase, Rac1 and c-Jun N-terminal kinase-mediated pathway. (2015)
  • Author(s): Chikano Y, Domoto T, Furuta T, Sabit H, Kitano-Tamura A, Ilya V. Pyko, Takino T, Sai Y, Hayashi Y, Sato H, Miyamoto K, Nakada M, MinamotoT.
  • Journal Title: Molecular Cancer Therapeutics Volume: 14 Issue: 2 Pages: 564-574
  • DOI: 10.1158/1535-7163.mct-14-0479
  • Peer Reviewed / Open Access
• [Journal Article] Membrane-type 1 matrix metalloproteinase regulates fibronectin assembly and N-cadherin adhesion. (2014)
  • Author(s): Takino T, Yoshimoto T, Nakada M, Li Z, Domoto T, Kawashiri S, Sato H.
  • Journal Title: Biochem Biophys Res Commun. Volume: ４５０ Issue: 2 Pages: 1016-1020
  • DOI: 10.1016/j.bbrc.2014.06.100
  • NAID: 120005478703
  • Peer Reviewed
• [Journal Article] Epithelioid glioblastoma arising from pleomorphic xanthoastrocytoma with the BRAF V600E mutation. (2014)
  • Author(s): Tanaka S, Nakada M, Nobusawa S, Suzuki SO, Sabit H, Miyashita K, Hayashi Y.
  • Journal Title: Brain Tumor Pathology Volume: 31 Issue: 3 Pages: 172-6
  • DOI: 10.1007/s10014-014-0192-2
  • Peer Reviewed
• [Presentation] 既存薬による膠芽腫に対する新規化学療法 (2016)
  • Author(s): 中田光俊，董宇、北林朋宏、淑瑠ヘムラサビット、古田拓也、平尾敦
  • Organizer: 第34回日本脳腫瘍学会
  • Place of Presentation: 甲府、甲府富士屋ホテル
  • Year and Date: 2016-12-04
• [Presentation] Drug repositioning targeting glioma stem cells (2016)
  • Author(s): Nakada M, Dong Y, Kitabayashi Y, Sabit H, Furuta T, Hirao A
  • Organizer: Society for Neuro-Onology 21st Annual Meeting 2016
  • Place of Presentation: Scottsdale Fairmont Princess Hotel, Scottsdale, Arizona, USA
  • Year and Date: 2016-11-17
  • Int'l Joint Research
• [Presentation] 脳腫瘍に対するドラッグリポジショニングの試み (2016)
  • Author(s): 中田光俊
  • Organizer: 第9回香川県脳腫瘍学術講演会
  • Place of Presentation: 高松、ホテルクレメント高松
  • Year and Date: 2016-10-28
  • Invited
• [Presentation] 既存薬の応用による膠芽腫に対する新規化学療法 (2016)
  • Author(s): 中田光俊、董宇、北林朋宏、淑瑠ヘムラサビット、古田拓也、平尾敦
  • Organizer: 第75回日本脳神経外科学会総会
  • Place of Presentation: 福岡、福岡国際会議場・福岡サンパレス・マリンメッセ福岡
  • Year and Date: 2016-09-29
• [Presentation] Screening of existing drugs to target glioma stem cells (2016)
  • Author(s): Nakada M, Dong Y, Kitabayashi Y, Sabit H, Furuta T, Hirao A
  • Organizer: 13th Asian Society for Neuro-Oncology (ASNO) Meeting
  • Place of Presentation: Sheraton on the Park, Sydney, Australia
  • Year and Date: 2016-09-11
  • Int'l Joint Research
• [Presentation] 悪性グリオーマ浸潤の分子生物学 (2016)
  • Author(s): 中田光俊
  • Organizer: 第17回日本分子脳神経外科学会
  • Place of Presentation: 東京、帝京大学板橋キャンパス本部棟
  • Year and Date: 2016-08-26
• [Presentation] グリオーマ幹細胞を標的とした新規化学療法の開発 (2015)
  • Author(s): 中田光俊，董宇、北林朋宏、淑瑠ヘムラサビット、古田拓也、平尾敦
  • Organizer: 第74回日本脳神経外科学会総会
  • Place of Presentation: ロントン札幌（札幌）
  • Year and Date: 2015-10-14
• [Presentation] 既存薬スクリーニングによる悪性グリオーマ治療薬の探索 (2015)
  • Author(s): 中田光俊
  • Organizer: 第9回奈良脳腫瘍研究会
  • Place of Presentation: スイスホテル南海大阪（大阪）
  • Year and Date: 2015-10-09
  • Invited
• [Presentation] Existing approved drug with anti-glioma effect and drug safety test in vivo (2015)
  • Author(s): 董宇, 北林朋宏, 古田拓也, 平尾敦, 中田光俊
  • Organizer: 第16回日本分子脳神経外科学会
  • Place of Presentation: アクトシティ浜松コングレスセンター（浜松）
  • Year and Date: 2015-08-28
• [Presentation] 既存医薬品による悪性グリオーマ新規治療法の開発 (2015)
  • Author(s): 中田光俊
  • Organizer: 第26回熊本脳神経外科夏季セミナープログラム
  • Place of Presentation: 阿蘇医療センター（熊本）
  • Year and Date: 2015-08-01
  • Invited
• [Presentation] 抗悪性グリオーマ作用を有する既存薬剤のスクリーニング (2015)
  • Author(s): 中田光俊
  • Organizer: 第21回北海道脳腫瘍治療研究会
  • Place of Presentation: 日本生命札幌ビル（札幌）
  • Year and Date: 2015-06-27
  • Invited
• [Presentation] 既存薬剤を使用する悪性グリオーマの化学療法 (2015)
  • Author(s): 中田光俊
  • Organizer: 第19回新潟脳腫瘍研究会
  • Place of Presentation: 朱鷺メッセ（新潟）
  • Year and Date: 2015-06-19
  • Invited
• [Presentation] ドラッグ・リポジショニングによる悪性脳腫瘍に対する新規化学療法 (2015)
  • Author(s): 中田光俊
  • Organizer: 第1回先端脳腫瘍治療シンポジウム
  • Place of Presentation: トラストシティカンファレンス（仙台）
  • Year and Date: 2015-06-10
  • Invited
• [Presentation] 既存薬剤を使用した悪性グリオーマの新たな治療戦略 (2015)
  • Author(s): 中田光俊
  • Organizer: 脳腫瘍治療セミナー
  • Place of Presentation: 新宿NSビル（東京）
  • Year and Date: 2015-06-05
  • Invited
• [Presentation] 脳腫瘍学におけるドラッグリポジショニング (2015)
  • Author(s): 中田光俊
  • Organizer: 第10回脳腫瘍の基礎シンポジウム
  • Place of Presentation: 日本大学病院（東京）
  • Year and Date: 2015-04-25
  • Invited
• [Presentation] グリオーマ幹細胞に対して抗腫瘍効果を有する既存医薬品の探索 (2014)
  • Author(s): 中田光俊，董宇，北林朋宏，古田拓也，宮下勝吉，木下雅史，平尾敦，林裕
  • Organizer: 第32回日本脳腫瘍学会
  • Place of Presentation: シェラトン・グランデ・トーキョーベイ・ホテル（千葉）
  • Year and Date: 2014-11-30 – 2014-12-02
• [Presentation] ドラッグリポジショニングによる膠芽腫に対する新規化学療法 (2014)
  • Author(s): 中田光俊
  • Organizer: Temozolomide Forum in HIROSHIMA 2014
  • Place of Presentation: ホテルグランヴィア広島（広島）
  • Year and Date: 2014-11-07
  • Invited
• [Presentation] ドラッグリポジショニングを指向したグリオーマ幹細胞に対する既存薬剤スクリーニング (2014)
  • Author(s): 中田光俊，董宇，北林朋宏，古田拓也，平尾敦，林裕
  • Organizer: 第73回日本脳神経外科学会総会
  • Place of Presentation: グランドプリンスホテル新高輪（東京）
  • Year and Date: 2014-10-09 – 2014-10-11
• [Presentation] Screening of existing approved drugs for inhibiting glioma stem cell proliferation (2014)
  • Author(s): 董宇, 中田光俊, 北林朋宏, 古田拓也, 平尾敦, 林裕
  • Organizer: 第15回日本分子脳神経外科学会
  • Place of Presentation: 大手門パルズ（山形）
  • Year and Date: 2014-09-25 – 2014-09-26
• [Presentation] 右前頭葉Grade II, IIIグリオーマに対する覚醒下手術による高次脳機能温存の検証 (2014)
  • Author(s): 中田光俊，中嶋理帆，宮下勝吉，木下雅史，沖田浩一，田中慎吾，林裕
  • Organizer: 第19回日本脳腫瘍の外科学会
  • Place of Presentation: 東京ドームホテル（東京）
  • Year and Date: 2014-09-12 – 2014-09-13
• [Presentation] 再発膠芽腫に対するベバシズマブ治療効果予測因子同定の試み (2014)
  • Author(s): 中田光俊、田中慎吾、古田拓也、淑瑠ヘムラサビット、宮下勝吉、林裕
  • Organizer: 第32回日本脳腫瘍病理学会
  • Place of Presentation: あわぎんホール（徳島）
  • Year and Date: 2014-05-23 – 2014-05-24
• [Remarks] 金沢大学脳神経外科
  • URL: http://neurosurgery.w3.kanazawa-u.ac.jp/
• [Patent(Industrial Property Rights)] 脳腫瘍治療組成物 (2015)
  • Inventor(s): 中田光俊、平尾敦
  • Industrial Property Rights Holder: 中田光俊、平尾敦
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-05-07
• [Patent(Industrial Property Rights)] 医療行為に用いるデバイス・外科用器具 (2014)
  • Inventor(s): 中田光俊
  • Industrial Property Rights Holder: 中田光俊
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-04-04