Development of molecular-targeted therapeutic drugs for malignant glioma that enable reactivation of tumor immunity

• Project/Area Number: 20K09333
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56010:Neurosurgery-related
• Research Institution: Hokuriku University
• Principal Investigator: Takahashi Hisaaki 北陸大学, 薬学部, 教授 (20363228)
• Co-Investigator(Kenkyū-buntansha): 井上 明宏 愛媛大学, 医学部附属病院, 講師 (20593403)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2023: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
• Keywords: グリオーマ / 腫瘍幹細胞 / 腫瘍免疫 / Oct-3/4 / AMPK / TDO / IDO / 細胞周期 / cdc2 / 分子標的治療薬

Outline of Research at the Start

申請者がグリオーマ悪性化のマスター因子と考えるOct-3/4およびT細胞の機能的抑制に関わるTDO/IDOの発現を一気に抑制する化合物を、Oct-3/4、TDO、IDOの各プロモーターを用いたルシフェラーゼアッセイにより単離する。得られた候補化合物は癌細胞の浸潤や血管新生のみならず腫瘍免疫の再活性化までをも可能とする「万能型」化合物であり、現在実施されている標準治療との併用による治療効果の増強や標準治療を上回る新たな治療法の確立に向けた基盤構築が可能となる。

Outline of Final Research Achievements

This research aims to find a compound that suppresses Oct-3/4 expression and also suppresses anti-tumor immunity. The 24 candidate compounds have been obtained from a library of 640 compounds. When a secondary screening was performed, Compound F was obtained which had low cytotoxicity and exhibited a significant cell proliferation inhibitory effect. On the other hand, compound F did not inhibit cell proliferation of normal astrocytes. Therefore, when compound F was administered to a mouse glioma model, shrinkage of the formed glioma was observed. Docking simulation analysis has revealed that Compound F is an activator that binds to AMPK, and we would like to investigate a detailed study in the future.

Academic Significance and Societal Importance of the Research Achievements

グリオーマ治療においても免疫細胞の再活性化による腫瘍免疫治療薬が手術、放射線治療、化学療法に次ぐ「第4の柱」になりうるとして、国内外で研究開発が進められている。しかしながら、臨床試験段階ではあるものの有効性が報告されたものは少ない。
本研究結果は、免疫の中心的な役割を果たすT細胞の機能をOct-3/4が抑制し、グリオーマ細胞が宿主免疫システムから回避して増殖している可能性を示唆するものである。したがって、化合物Fは、Oct-3/4を抑制することで、浸潤、腫瘍幹細胞、腫瘍血管新生、薬剤耐性に加え、抗腫瘍免疫をも標的とし、停滞するグリオーマ治療の突破口になる可能性が期待される。

Research Products

• [Journal Article] Identification of CD44 as a Reliable Biomarker for Glioblastoma Invasion: Based on Magnetic Resonance Imaging and Spectroscopic Analysis of 5-Aminolevulinic Acid Fluorescence (2023)
  • Author(s): Inoue Akihiro、Ohnishi Takanori、Nishikawa Masahiro、Watanabe Hideaki、Kusakabe Kosuke、Taniwaki Mashio、Yano Hajime、Ohtsuka Yoshihiro、Matsumoto Shirabe、Suehiro Satoshi、Yamashita Daisuke、Shigekawa Seiji、Takahashi Hisaaki、Kitazawa Riko、Tanaka Junya、Kunieda Takeharu
  • Journal Title: Biomedicines Volume: 11 Issue: 9 Pages: 2369-2369
  • DOI: 10.3390/biomedicines11092369
  • Peer Reviewed / Open Access
• [Journal Article] A Narrative Review on CD44’s Role in Glioblastoma Invasion, Proliferation, and Tumor Recurrence (2023)
  • Author(s): Inoue Akihiro、Ohnishi Takanori、Nishikawa Masahiro、Ohtsuka Yoshihiro、Kusakabe Kosuke、Yano Hajime、Tanaka Junya、Kunieda Takeharu
  • Journal Title: Cancers Volume: 15 Issue: 19 Pages: 4898-4898
  • DOI: 10.3390/cancers15194898
  • Peer Reviewed / Open Access
• [Journal Article] What is the Best Preoperative Quantitative Indicator to Differentiate Primary Central Nervous System Lymphoma from Glioblastoma? (2023)
  • Author(s): Inoue Akihiro、Matsumoto Shirabe、Ohnishi Takanori、Miyazaki Yukihiro、Kinnami Shingo、Kanno Kazuhisa、Honda Takatsugu、Kurata Mie、Taniwaki Mashio、Kusakabe Kosuke、Suehiro Satoshi、Yamashita Daisuke、Shigekawa Seiji、Watanabe Hideaki、Kitazawa Riko、Kunieda Takeharu
  • Journal Title: World Neurosurgery Volume: 172 Pages: e517-e523
  • DOI: 10.1016/j.wneu.2023.01.065
  • Peer Reviewed
• [Journal Article] Quantitative measurement of peritumoral concentrations of glutamate, N-acetyl aspartate, and lactate on magnetic resonance spectroscopy predicts glioblastoma-related refractory epilepsy (2022)
  • Author(s): Nakamura Yawara、Inoue Akihiro、Nishikawa Masahiro、Ohnishi Takanori、Yano Hajime、Kanemura Yonehiro、Ohtsuka Yoshihiro、Ozaki Saya、Kusakabe Kosuke、Suehiro Satoshi、Yamashita Daisuke、Shigekawa Seiji、Watanabe Hideaki、Kitazawa Riko、Tanaka Junya、Kunieda Takeharu
  • Journal Title: Acta Neurochirurgica Volume: 164 Issue: 12 Pages: 3253-3266
  • DOI: 10.1007/s00701-022-05363-y
  • Peer Reviewed
• [Journal Article] Usefulness of intraoperative rapid immunohistochemistry in the surgical treatment of brain tumors (2022)
  • Author(s): Inoue Akihiro、Watanabe Hideaki、Kondo Takuya、Katayama Eiji、Miyazaki Yukihiro、Suehiro Satoshi、Yamashita Daisuke、Taniwaki Mashio、Kurata Mie、Shigekawa Seiji、Kitazawa Riko、Kunieda Takeharu
  • Journal Title: Neuropathology Volume: - Issue: 3 Pages: 209-220
  • DOI: 10.1111/neup.12864
  • Peer Reviewed
• [Journal Article] CD44 expression in the tumor periphery predicts the responsiveness to bevacizumab in the treatment of recurrent glioblastoma (2021)
  • Author(s): Nishikawa Masahiro、Inoue Akihiro、Ohnishi Takanori、Yano Hajime、Kanemura Yonehiro、Kohno Shohei、Ohue Shiro、Ozaki Saya、Matsumoto Shirabe、Suehiro Satoshi、Nakamura Yawara、Shigekawa Seiji、Watanabe Hideaki、Kitazawa Riko、Tanaka Junya、Kunieda Takeharu
  • Journal Title: Cancer Medicine Volume: 10 Issue: 6 Pages: 2013-2025
  • DOI: 10.1002/cam4.3767
  • Peer Reviewed / Open Access
• [Journal Article] Prediction of Glioma Stemlike Cell Infiltration in the Non?Contrast-Enhancing Area by Quantitative Measurement of Lactate on Magnetic Resonance Spectroscopy in Glioblastoma (2021)
  • Author(s): Inoue Akihiro、Nishikawa Masahiro、Ohnishi Takanori、Yano Hajime、Kanemura Yonehiro、Ohtsuka Yoshihiro、Ozaki Saya、Nakamura Yawara、Matsumoto Shirabe、Suehiro Satoshi、Yamashita Daisuke、Shigekawa Seiji、Watanabe Hideaki、Kitazawa Riko、Tanaka Junya、Kunieda Takeharu
  • Journal Title: World Neurosurgery Volume: 153 Pages: e76-e95
  • DOI: 10.1016/j.wneu.2021.06.044
  • Peer Reviewed
• [Journal Article] Hypoxia-induced phenotypic transition from highly invasive to less invasive tumors in glioma stem-like cells: Significance of CD44 and osteopontin as therapeutic targets in glioblastoma (2021)
  • Author(s): Nishikawa Masahiro、Inoue Akihiro、Ohnishi Takanori、Yano Hajime、Ozaki Saya、Kanemura Yonehiro、Suehiro Satoshi、Ohtsuka Yoshihiro、Kohno Shohei、Ohue Shiro、Shigekawa Seiji、Watanabe Hideaki、Kitazawa Riko、Tanaka Junya、Kunieda Takeharu
  • Journal Title: Translational Oncology Volume: 14 Issue: 8 Pages: 101137-101137
  • DOI: 10.1016/j.tranon.2021.101137
  • Peer Reviewed / Open Access
• [Journal Article] Chloride intracellular channel protein 2 is secreted and inhibits MMP14 activity, while preventing tumor cell invasion and metastasis (2021)
  • Author(s): Saya Ozaki, Akihiro Umakoshi, Hajime Yano, ............ Junya Tanaka
  • Journal Title: Neoplasia Volume: 23 Issue: 8 Pages: 754-765
  • DOI: 10.1016/j.neo.2021.06.001
  • Peer Reviewed / Open Access
• [Journal Article] Activated leukocyte cell adhesion molecule expression correlates with the WNT subgroup in medulloblastoma and is involved in regulating tumor cell proliferation and invasion (2020)
  • Author(s): Achiha T, Kijima N, Kodama Y, Kagawa N, Kinoshita M, Fujimoto Y, Nonaka M, Fukai J, Inoue A, Nishida N, Yamanaka T, Harada A, Mori K, Tsuyuguchi N, Uda T, Ishibashi K, Tomogane Y, Sakamoto D, Shofuda T, Yoshioka E, Kanematsu D, Mano M, Luu B, Taylor MD, Kanemura Y, Kishima H.
  • Journal Title: PLoS One Volume: 15 Issue: 12 Pages: e0243272-e0243272
  • DOI: 10.1371/journal.pone.0243272
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hypoxia-regulated expression of CD44 and osteopontin can change the phenotype of glioma stem-like cells from highly invasive to less invasive/proliferative tumors in glioblastoma (2020)
  • Author(s): Nishikawa M, Inoue A, Ohnishi T, Yano H, Ozaki S, Kanemura Y, Matsumoto S, Suehiro S, Ohtsuka Y, Kohno S, Ohue S, Shigekawa S, Watanabe H, Kitazawa R, Tanaka J, Kunieda T.
  • Journal Title: Cancer Med. Volume: 10 Pages: 2013-2025
  • DOI: 10.21203/rs.3.rs-72809/v1
  • Peer Reviewed / Open Access
• [Journal Article] Generation of CSF1-Independent Ramified Microglia-Like Cells from Leptomeninges In Vitro (2020)
  • Author(s): Tanaka J, Takahashi H, Yano H, Nakanishi H.
  • Journal Title: Cells Volume: 10 Issue: 1 Pages: 24-37
  • DOI: 10.3390/cells10010024
  • Peer Reviewed / Open Access
• [Presentation] 膠芽腫のSupra-total resectionを可能とする最新の手術支援技術：腫瘍浸潤領域に存在する腫瘍幹細胞の同定 (2023)
  • Author(s): 井上明宏、西川真弘、日下部公資、矢野元、末廣諭、山下大介、松本調、渡邉英昭、田中潤也、大西丘倫、國枝武治
  • Organizer: 日本脳神経外科学会 第82回学術総会
• [Presentation] 脳神経外科領域における術中迅速免疫組織診断の有用性 (2022)
  • Author(s): 井上明宏、片山英司、近藤拓弥、末廣諭、山下大介、重川誠二、渡邉英昭、北澤理子、國枝武治
  • Organizer: 第40回 日本脳腫瘍病理学会
• [Presentation] 膠芽腫摘出における真のGROSS TOTAL RESECTIONを獲得するための取り組み～浸潤部を見極める最適な手段とは～ (2022)
  • Author(s): 井上明宏、西川真弘、大西丘倫、矢野元、大塚祥浩、中村和、日下部公資、末廣諭、山下大介、渡邉英昭、田中潤也、國枝武治
  • Organizer: 日本脳神経外科学会 第81回学術総会
• [Presentation] 当院の膠芽腫摘出における腫瘍浸潤部を見極めるための取り組み (2022)
  • Author(s): 井上明宏、西川真弘、大塚祥浩、日下部公資、大西丘倫、矢野元、末廣諭、山下大介、渡邉英昭、田中潤也、國枝武治
  • Organizer: 第40回日本脳腫瘍学会学術集会
• [Presentation] 膠芽腫再発に関わるGlioma stem-like cellの分子病態：異なる酸素環境下でのCD44とOsteopontinの働きから (2021)
  • Author(s): 井上明宏、西川真弘、矢野元、北澤理子、大西丘倫、渡邉英昭、田中潤也、國枝武治
  • Organizer: 第39回 日本脳腫瘍病理学会
• [Presentation] 膠芽腫における効果的な Bevacizumab治療のためのバイオマーカーの同定：膠芽腫幹細胞マーカーCD44はBevacizumabの治療抵抗性を予測する (2021)
  • Author(s): 井上明宏、西川真弘、大西丘倫、矢野元、大塚祥浩、末廣諭、山下大介、渡邉英昭、田中潤也、國枝武治
  • Organizer: 日本脳神経外科学会 第80回学術総会
• [Presentation] Multicentric Gliomaとして発見されたEpithelioid Glioblastomaの1例 (2020)
  • Author(s): 井上明宏、末廣諭、福島万奈、北澤理子、渡邉英昭、國枝武治
  • Organizer: 第38回 日本脳腫瘍病理学会
• [Presentation] 膠芽腫摘出術におけるMethionine-PETの意義：Met 集積率と浸潤性腫瘍幹細胞の関連性 (2020)
  • Author(s): 井上明宏、末廣諭、尾崎沙耶、渡邉英昭、西川真弘、高野昌平、大西丘倫、大上史朗、渡邉英昭、國枝武治
  • Organizer: 第38回 日本脳腫瘍学会学術集会