Development of Oct-3/4 targeting drug for malignant glioma treatment

• Project/Area Number: 15K10324
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Hokuriku University (2016-2018); Asahikawa Medical College (2015)
• Principal Investigator: Takahashi Hisaaki 北陸大学, 薬学部, 教授 (20363228)
• Co-Investigator(Kenkyū-buntansha): 田中 潤也 愛媛大学, 医学系研究科, 教授 (70217040) ; 竹内 文也 旭川医科大学, 医学部, 准教授 (30281835)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
• Keywords: 膠芽腫 / グリオーマ / Oct-3/4 / 化合物スクリーニング / 腫瘍幹細胞 / 浸潤 / 薬剤耐性 / MGMT / テモゾロミド / DNAメチル化 / ABCトランスポーター

Outline of Final Research Achievements

Malignant gliomas are the most common, infiltrative, and lethal primary brain tumors. Accumulating evidence shows that the expression level of Oct-3/4, a self-renewal regulator in stem cells, is positively correlated with the progression of malignant glioma, such as cancer stemness, invasion, tumor angiogenesis, and chemoresistance. These finding suggests that suppression of Oct-3/4 might have a potential for solving all problems of glioma treatment. In this study, we established GFP expressing T98G cells under Oct-3/4 promoter, and 1,142 compounds were investigated by detecting the attenuation of fluorescence intensity on these cells. We found one compound in the candidate compounds for its potential use in malignant glioma treatment.

Academic Significance and Societal Importance of the Research Achievements

悪性グリオーマは根治が極めて困難な疾患であり、既存の分子標的薬も有効な治療効果をあげているとは言い難い。本研究の特色は、申請者らが継続して行ってきた一連の研究成果（悪性グリオーマにおけるOct-3/4の役割）に基づき、分子標的薬でありながら「万能型」でもある新しい治療薬の開発を目指した点である。1,134種類の化合物の中から得られた候補化合物はOct-3/4発現抑制による悪性グリオーマの治療効果が期待できることに加えて、既に治療薬として国内外で使用されていることから、開発コストの大幅な削減も期待でき、その社会的意義は大きいと考えられる。

Research Products

• [Journal Article] Significance of Glioma Stem-Like Cells in the Tumor Periphery That Express High Levels of CD44 in Tumor Invasion, Early Progression, and Poor Prognosis in Glioblastoma. (2018)
  • Author(s): Masahiro Nishikawa, Akihiro Inoue, Takanori Ohnishi, Shohei Kohno, Shiro Ohue, Shirabe Matsumoto, Satoshi Suehiro, Daisuke Yamashita, Saya Ozaki, Hideaki Watanabe, Hajime Yano, Hisaaki Takahashi, Riko Kitazawa, Junya Tanaka, Takeharu Kunieda
  • Journal Title: Stem Cells International Volume: 23 Pages: 5387041-5387041
  • DOI: 10.1155/2018/5387041
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Truncated CD200 stimulates tumor immunity leading to fewer lung metastases in a novel Wistar rat metastasis model (2018)
  • Author(s): Kuwabara Jun、Umakoshi Akihiro、Abe Naoki、Sumida Yutaro、Ohsumi Shota、Usa Eika、Taguchi Kana、Choudhury Mohammed E.、Yano Hajime、Matsumoto Shirabe、Kunieda Takeharu、Takahashi Hisaaki、Yorozuya Toshihiro、Watanabe Yuji、Tanaka Junya
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 496 Issue: 2 Pages: 542-548
  • DOI: 10.1016/j.bbrc.2018.01.065
  • Peer Reviewed / Open Access
• [Journal Article] Blood vessels expressing CD90 in human and rat brain tumors (2016)
  • Author(s): Akihiro Inoue, Junya Tanaka, Hisaaki Takahashi, Shohei Kohno, Shiro Ohue, Akihiro Umakoshi, Katsuhiro Gotoh, Takanori Ohnishi
  • Journal Title: Neuropathology Volume: 36 Issue: 2 Pages: 168-180
  • DOI: 10.1111/neup.12244
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The hypnotic bromovalerylurea ameliorates 6-hydroxydopamine-induced dopaminergic neuron loss while suppressing expression of interferon regulatory factors by microglia (2016)
  • Author(s): Hiromi Higaki, Mohammed Emamussalehin Choudhury, Chisato Kawamoto, Keisuke Miyamoto, Afsana Islam, Yurika Ishii, Kazuya Miyanishi, Haruna Takeda, Naoto Seo, Kana Sugimoto, Hisaaki Takahashi, Hajime Yano and Junya Tanaka
  • Journal Title: Neurochemistry International Volume: 99 Pages: 158-168
  • DOI: 10.1016/j.neuint.2016.06.013
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Treadmill exercise ameliorates ischemia-induced brain edema while suppressing Na+/H+ exchanger 1 expression (2016)
  • Author(s): Ryutaro Nishioka, Kana Sugimoto, Hitomi Aono, Ayano Mise, Mohammed E. Choudhury, Kazuya Miyanishi, Afsana Islam, Takahiro Fujita, Haruna Takeda, Hisaaki Takahashi, Hajime Yano, Junya Tanaka
  • Journal Title: Experimental Neurology Volume: 277 Pages: 150-161
  • DOI: 10.1016/j.expneurol.2015.12.016
  • Peer Reviewed / Open Access
• [Journal Article] Postnatal interleukin-1beta administration after experimental prolonged febrile seizures enhances epileptogenesis in adulthood (2015)
  • Author(s): Fukuda, M, Ishii, E, et al.
  • Journal Title: Metab Brain Dis Volume: in press Issue: 3 Pages: 813-819
  • DOI: 10.1007/s11011-014-9648-7
  • Peer Reviewed
• [Journal Article] The Ameliorative Effects of a Hypnotic Bromvalerylurea in Sepsis (2015)
  • Author(s): Kikuchi S, Nishihara T, Kawasaki S, Abe N, Kuwabara J, Choudhury ME, Takahashi H, Yano H, Nagaro T, Watanabe Y, Aibiki M, Tanaka J
  • Journal Title: Biochem Biophys Res Commun. Volume: 459 Issue: 2 Pages: 319-326
  • DOI: 10.1016/j.bbrc.2015.02.111
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] CD200+ and CD 200- macrophages accumulated in ischemic lesions of rat brain: The two populations cannot be classified as either M1 or M2 macrophages (2015)
  • Author(s): Shirabe Matsumoto, Junya Tanaka, Hajime Yano, Hisaaki Takahashi, Kana Sugimoto, Shiro Ohue, Akihiro Inoue, Hitomi Aono, Akari Kusakawa, Hideaki Watanabe, Yoshiaki Kumon, Takanori Ohnishi
  • Journal Title: Journal of Neuroimmunology Volume: 282 Pages: 7-20
  • DOI: 10.1016/j.jneuroim.2015.03.013
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] miR-340 acts as atumor suppressor in tumorigenesis of human glioma-initiating cells by targeting plasminogen activator, tissue. (2015)
  • Author(s): Yamashita D, Kondo T, Ohue S, Takahashi H, Ishikawa M, Matoba R, Suehiro A, Inoue A, Kohno S, Harada H, Tanaka J, Ohnishi T
  • Journal Title: Cancer Research Volume: 75 Pages: 1123-1133
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Anti-inflammatory effects of noradrenaline on LPS-treated microglial cells: Suppression of NFκB nuclear translocation and subsequent STAT1 phosphorylation. (2015)
  • Author(s): Ishii Y, Yamaizumi A, Kawakami A, Islam A, Choudhury ME, Takahashi H, Yano H, Tanaka J
  • Journal Title: Neurochem Int. Volume: 90 Pages: 56-66
  • DOI: 10.1016/j.neuint.2015.07.010
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Oct-3/4 promotes tumor angiogenesis through VEGF production in glioblastoma (2014)
  • Author(s): Takahashi H, Inoue A, Kawabe Y, et al.
  • Journal Title: Brain Tumor Pathology Volume: ３２ Issue: 1 Pages: 31-40
  • DOI: 10.1007/s10014-014-0203-3
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Oct-3/4 modulates the drug-resistant phenotype of glioblastoma cells through expression of ATP binding cassette transporter G2 (2014)
  • Author(s): Hosokawa Y, Takahashi H, Inoue A, et al.
  • Journal Title: Biochimica et Biophysica Acta Volume: １８５０ Issue: 6 Pages: 1197-1205
  • DOI: 10.1016/j.bbagen.2015.01.017
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Oct-3/4を介したMGMT遺伝子発現調節とDNMT1の関連性 (2017)
  • Author(s): 井上明宏、高野昌平、大上史朗、高橋寿明、田中潤也、大西丘倫、國枝武治
  • Organizer: 第35回 日本脳腫瘍病理学会
• [Presentation] 膠芽腫におけるOct-3/4を介したMGMT遺伝子発現調節とDNMT1の関連性 (2017)
  • Author(s): 井上明宏、高野昌平、西川真弘、末廣諭、高橋寿明、田中潤也、國枝武治
  • Organizer: 日本脳神経外科学会 第76回学術総会
• [Presentation] 膠芽腫におけるMGMT発現調節機構に対するOct-3/4を介したエピジェネティクスの制御 (2016)
  • Author(s): 井上明宏、大上史朗、岩田真治、河野兼久、高野昌平、大西丘倫、高橋寿明、田中潤也
  • Organizer: 日本脳神経外科学会 第75回学術総会
  • Place of Presentation: 福岡
  • Year and Date: 2016-09-29
• [Presentation] Oct-3/4のMGMT発現調節機構への関与 (2016)
  • Author(s): 井上明宏、高野昌平、大上史朗、大西丘倫、高橋寿明、田中潤也
  • Organizer: 第34回 日本脳腫瘍病理学会
  • Place of Presentation: 東京
  • Year and Date: 2016-05-27
• [Presentation] 腫瘍幹細胞の病態生理学：腫瘍制御の技術基盤を目指して (2015)
  • Author(s): 高橋寿明
  • Organizer: 日本病態生理学会
  • Place of Presentation: 愛媛
  • Year and Date: 2015-07-31
  • Invited
• [Remarks] 北陸大学
  • URL: http://acoffice.jp/hruhp/KgApp?kyoinId=ymdggkymggy