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髄膜腫微小環境におけるSiglec-15を標的とした治療開発

Research Project

Project/Area Number 22K16663
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 56010:Neurosurgery-related
Research InstitutionOita University

Principal Investigator

札場 博貴  大分大学, 医学部, 助教 (00772930)

Project Period (FY) 2022-04-01 – 2026-03-31
Project Status Granted (Fiscal Year 2023)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2025: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2024: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2023: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2022: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Keywords髄膜腫 / Siglec-15
Outline of Research at the Start

髄膜腫に対する免疫チェックポイント阻害療法はいまだ開発途上であるが、近年新たな治療標的として、Siglec-15が報告された。Siglec-15とPD-L1は相互排他的な発現傾向を示し、抗PD-1抗体療法後の再発固形腫瘍患者に対する抗Siglec-15抗体療法の有効性が臨床試験で示唆されている。本研究では、髄膜腫の腫瘍微小環境におけるSiglec-15の意義を探索し、治療標的となりうるか検証する。本研究を通して、髄膜腫への新たな治療展開に導く前臨床試験を行う。

Outline of Annual Research Achievements

Siglecはシアル酸と結合する細胞表面タンパク質であり、Siglec-15はPD-L1と類似した免疫調整機構を持つ。Siglec-15は、腫瘍細胞や腫瘍関連マクロファージに発現する新たな免疫チェックポイント分子であり、また、Siglec-15とPD-L1は相互排他的な発現傾向を示す。
本年度は髄膜腫の50切除検体のSiglec-15発現を免疫組織化学染色で検証した。悪性髄膜腫7検体のうち6例でPD-L1発現の発現がない一方、Siglec-15は強発現していた。また、髄膜腫細胞株に関して、Western blottingでSiglec-15、PD-L1発現を検証した。生存曲線を評価したが、現在のサンプル数では有意な結果は得られなかった。
また、ヒト由来の悪性髄膜腫細胞株2種(HKBMM,IOMM-Lee)とマウス由来の悪性髄膜腫細胞株(MGS2)を検証したところ、IOMM-Leeにおいて、PD-L1に加え、Siglec-15の発現も確認された。PD-1/PD-L1経路阻害と抗Siglec-15療法を併用することにより、強い抗腫瘍効果が得られる可能性が示唆された。一方、MGS2では、Siglec-15はわずかに発現がある一方、PD-L1のタンパク発現はみられなかった。動物モデルにおける評価は、次年度に向けた課題である。

Current Status of Research Progress
Current Status of Research Progress

3: Progress in research has been slightly delayed.

Reason

動物モデル作成において、条件検討を行っており、治療実験に移行できていないため。

Strategy for Future Research Activity

MGS2のマウス脳腫瘍モデルにおける、腫瘍微小環境を評価し、治療実験に移行できるか検証する。

Report

(2 results)
  • 2023 Research-status Report
  • 2022 Research-status Report
  • Research Products

    (9 results)

All 2024 2023 2022

All Journal Article (8 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 8 results,  Open Access: 5 results) Presentation (1 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Chimeric oncolytic adenovirus to break away from neutralizing antibodies2024

    • Author(s)
      Sanchez Gil Judit、Fudaba Hirotaka、Wakimoto Hiroaki
    • Journal Title

      Molecular Therapy

      Volume: 32 Issue: 4 Pages: 875-877

    • DOI

      10.1016/j.ymthe.2024.03.017

    • Related Report
      2023 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Clinicopathologic analysis of pineal parenchymal tumors of intermediate differentiation: a multi-institutional cohort study by the Kyushu Neuro-Oncology Study Group2023

    • Author(s)
      Yamashita Shinji、Takeshima Hideo、Hata Nobuhiro、Fudaba Hirotaka、(著者省略)、Sangatsuda Yuhei、Yoshimoto Koji、Hanaya Ryousuke、Mukasa Akitake、Suzuki Kohei、Yamamoto Junkoh、Negoto Tetsuya、Nakamura Hideo、Momii Yasutomo、Fujiki Minoru、Abe Hiroshi、Masuoka Jun、Abe Tatsuya、Matsuo Takayuki、Ishiuchi Shogo
    • Journal Title

      Journal of Neuro-Oncology

      Volume: 162 Issue: 2 Pages: 425-433

    • DOI

      10.1007/s11060-023-04310-w

    • Related Report
      2023 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Multidrug chemotherapy, whole-brain radiation and cytarabine therapy for primary central nervous system lymphoma in elderly patients with dose modification based on geriatric assessment: study protocol for a phase II, multicentre, non-randomised study2023

    • Author(s)
      Yamasaki Fumiyuki、Fudaba Hirotaka、Asano Kenichiro、(著者省略)、Yasutomo Momii、Kawasaki Yukari、Kakuta Kiyohide、Katayama Kosuke、Tanaka Kazuhiro、Nagashima Hiroaki、Tsukamoto Yoshihiro、Ideguchi Makoto、Nishizaki Takafumi、Kurozumi Kazuhiko、Hosoya Tomohiro、Akita Tomoyuki、Kambe Atsushi
    • Journal Title

      BMJ Open

      Volume: 13 Issue: 4 Pages: e071350-e071350

    • DOI

      10.1136/bmjopen-2022-071350

    • Related Report
      2023 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Monophasic-quadri-burst stimulation robustly activates bilateral swallowing motor cortices2023

    • Author(s)
      Fujiki Minoru、Hata Nobuhiro、Anan Mitsuhiro、Matsushita Wataru、Kawasaki Yukari、Fudaba Hirotaka
    • Journal Title

      Frontiers in Neuroscience

      Volume: 17 Pages: 1163779-1163779

    • DOI

      10.3389/fnins.2023.1163779

    • Related Report
      2023 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Quantitative GABA magnetic resonance spectroscopy as a measure of motor learning function in the motor cortex after subarachnoid hemorrhage2023

    • Author(s)
      Sugita Kenji、Anan Mitsuhiro、Matsuta Hiroyuki、Shimomura Tsuyoshi、Fudaba Hirotaka、Hata Nobuhiro、Fujiki Minoru
    • Journal Title

      Frontiers in Neurology

      Volume: 14 Pages: 1173285-1173285

    • DOI

      10.3389/fneur.2023.1173285

    • Related Report
      2023 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Oncolytic virus therapy for malignant gliomas: entering the new era2023

    • Author(s)
      Fudaba Hirotaka、Wakimoto Hiroaki
    • Journal Title

      Expert Opinion on Biological Therapy

      Volume: 23 Issue: 3 Pages: 269-282

    • DOI

      10.1080/14712598.2023.2184256

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] High D-Dimer Concentration Is a Significant Independent Prognostic Factor in Patients with Acute Large Vessel Occlusion Undergoing Endovascular Thrombectomy2022

    • Author(s)
      Hisamitsu Yoshinori、Kubo Takeshi、Fudaba Hirotaka、Sugita Kenji、Fujiki Minoru、Ide Satomi、Kiyosue Hiro、Hori Yuzo
    • Journal Title

      World Neurosurgery

      Volume: 160 Pages: e487-e493

    • DOI

      10.1016/j.wneu.2022.01.052

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Mycotic pseudoaneurysm in the internal carotid artery secondary to cranial base abscess diagnosed with optic neuritis: a case report2022

    • Author(s)
      Aso Daigo、Fudaba Hirotaka、Hisamitsu Yoshinori、Kubo Takeshi、Fujiki Minoru
    • Journal Title

      British Journal of Neurosurgery

      Volume: - Pages: 1-4

    • DOI

      10.1080/02688697.2022.2090503

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Presentation] Oncolytic Herpes Simplex Virus Combinations with DNA Damage Response Inhibitors to Treat Glioblastoma2023

    • Author(s)
      Hirotaka Fudaba, Robert L. Martuza, and Samuel D. Rabkin
    • Organizer
      The 15th International Oncolytic Virotherapy Conference
    • Related Report
      2023 Research-status Report
    • Int'l Joint Research

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Published: 2022-04-19   Modified: 2024-12-25  

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