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Epigenetic analysis and drug development with cell-reprogramming technology in atypical teratoid/rhabdoid tumor

Research Project

Project/Area Number 19K09505
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 56010:Neurosurgery-related
Research InstitutionKyoto University

Principal Investigator

Arakawa Yoshiki  京都大学, 医学研究科, 講師 (20378649)

Co-Investigator(Kenkyū-buntansha) Thumkeo Dean  京都大学, 医学研究科, 特定准教授 (40372594)
平田 英周  金沢大学, がん進展制御研究所, 准教授 (40761937)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords非定型奇形腫様ラブドイド腫瘍 / リプログラミング / ヒト人工多能性幹細胞 / エピゲノム異常 / INI-1 / SMARCB1 / RAD21 / iPS / AT/RT / 転写ネットワーク / iPS / iPS細胞 / エピゲノム
Outline of Research at the Start

本研究では、INI-1不活化に伴うエピゲノム異常がAT/RTの発生メカニズムであるという作業仮説を立てる。そして、human induced pluripotent stem(hiPS)細胞からヒトAT/RT腫瘍モデルを樹立し、腫瘍起源細胞を同定すること、INI-1不活化に伴うエピゲノム異常、それに伴う転写ネットワーク異常を解明すること、治療ターゲットとなる新規標的分子を同定することを目的とする。本研究成果に基づいて、臨床応用を目指したAT/RTに対する新規治療開発研究へと推進する。

Outline of Final Research Achievements

The aim of this study was to develop a novel therapy by elucidating the epigenomic abnormalities of atypical teratoma/rhabdoid tumors (AT/RT) using reprogramming technology. Analysis of established hiPSCs TP53-/- and INI-1-/- cells identified the need of pluripotent stem cell-like gene expressions from INI-1 gene inactivation in AT/RT development, which is maintained by RAD21. Therefore, drug screening system against RAD21 with the established AT/RT cells from hiPSCs was developed to find specific inhibitors of RAD21. However, a specific RAD21 inhibitor was not to be found. Whole genome analysis of AT/RT revealed that the accumulation of genetic abnormalities from epigenomic aberrations is involved in AT/RT development.

Academic Significance and Societal Importance of the Research Achievements

INI-1不活化によるがん化では、p16-RB経路, WNT経路, sonic hedgehog経路、Polycomb経路などの関連が報告されてきた。SWI/SNF複合体の機能解析からクロマチンを基盤とするINI-1の新しいエピジェネティックな機構が示唆されていた。本研究では、INI-1不活化による新しいエピジェネティックな破綻機構として多能性幹細胞様遺伝子発現の維持を提唱した。さらに、INI-1遺伝子の体細胞変異からエピゲノム異常と遺伝子異常の蓄積がAT/RTの発生、悪性化機構に関わることを示したことは、AT/RTの新たな治療開発研究に大きく寄与するものである。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (19 results)

All 2021 2020 2019

All Journal Article (10 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 10 results,  Open Access: 7 results) Presentation (9 results) (of which Int'l Joint Research: 3 results)

  • [Journal Article] A randomized phase III study of short-course radiotherapy combined with Temozolomide in elderly patients with newly diagnosed glioblastoma; Japan clinical oncology group study JCOG1910 (AgedGlio-PIII)2021

    • Author(s)
      Arakawa Yoshiki、Sasaki Keita、Mineharu Yohei、Brain Tumor Study Group and Radiation Therapy Study Group of the Japan Clinical Oncology Group
    • Journal Title

      BMC Cancer

      Volume: 21 Issue: 1 Pages: 1-8

    • DOI

      10.1186/s12885-021-08834-0

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Infrequent RAS mutation is not associated with specific histological phenotype in gliomas2021

    • Author(s)
      Makino Yasuhide、Arakawa Yoshiki、Yoshioka Ema、Shofuda Tomoko、Minamiguchi Sachiko、Kawauchi Takeshi、Tanji Masahiro、Kanematsu Daisuke、Nonaka Masahiro、Okita Yoshiko、Kodama Yoshinori、Mano Masayuki、Hirose Takanori、Mineharu Yohei、Miyamoto Susumu、Kanemura Yonehiro
    • Journal Title

      BMC Cancer

      Volume: 21 Issue: 1 Pages: 1-14

    • DOI

      10.1186/s12885-021-08733-4

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Spinal cord astroblastoma with EWSR1-BEND2 fusion classified as HGNET-MN1 by methylation classification: a case report2021

    • Author(s)
      Tsutsui Takeyoshi、Arakawa Yoshiki、Makino Yasuhide、Kataoka Hiroharu、Mineharu Yohei、Naito Kentaro、Minamiguchi Sachiko、Hirose Takanori、Nobusawa Sumihito、Nakano Yoshiko、Ichimura Koichi、Haga Hironori、Miyamoto Susumu
    • Journal Title

      Brain Tumor Pathology

      Volume: 38 Issue: 4 Pages: 283-289

    • DOI

      10.1007/s10014-021-00412-3

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Prognostic stratification for IDH-wild-type lower-grade astrocytoma by Sanger sequencing and copy-number alteration analysis with MLPA2021

    • Author(s)
      Makino Yasuhide、Arakawa Yoshiki、Yoshioka Ema、Shofuda Tomoko、Kawauchi Takeshi、Terada Yukinori、Tanji Masahiro、Kanematsu Daisuke、Mineharu Yohei、Miyamoto Susumu、Kanemura Yonehiro
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 1-12

    • DOI

      10.1038/s41598-021-93937-8

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Temozolomide and etoposide combination for the treatment of relapsed osteosarcoma2020

    • Author(s)
      Akazawa Ryo、Umeda Katsutsugu、Saida Satoshi、Kato Itaru、Hiramatsu Hidefumi、Sakamoto Akio、Arakawa Yoshiki、Sumiyoshi Shinji、Okamoto Takeshi、Moritake Hiroshi、Adachi Souichi、Takita Junko
    • Journal Title

      Japanese Journal of Clinical Oncology

      Volume: 50 Issue: 8 Pages: 948-952

    • DOI

      10.1093/jjco/hyaa070

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Genetic analysis in patients with newly diagnosed glioblastomas treated with interferon-beta plus temozolomide in comparison with temozolomide alone2020

    • Author(s)
      Natsume A, Nagane M, Wakabayashi T, et al.
    • Journal Title

      J Neurooncol

      Volume: May 4 Issue: 1 Pages: 17-27

    • DOI

      10.1007/s11060-020-03505-9

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Hierarchical Cluster and Region of Interest Analyses Based on Mass Spectrometry Imaging of Human Brain Tumours2020

    • Author(s)
      Hiratsuka Takuya、Arakawa Yoshiki、Yajima Yuka、Kakimoto Yu、Shima Keisuke、Yamazaki Yuzo、Ikegami Masahiro、Yamamoto Takushi、Fujiwake Hideshi、Fujimoto Koichi、Yamada Norishige、Tsuruyama Tatsuaki
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 1-11

    • DOI

      10.1038/s41598-020-62176-8

    • NAID

      120006823932

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinical characteristics, treatment, and survival outcome in pediatric patients with atypical teratoid/rhabdoid tumors: a retrospective study by the Japan Children’s Cancer Group2020

    • Author(s)
      Yamasaki Kai、Kiyotani Chikako、Terashima Keita、Watanabe Yuko、Kanamori Masayuki、Koga Yuhki、Hata Nobuhiro、Iwasaki Fuminori、Goto Hiroaki、Koh Katsuyoshi、Kurihara Jun、Tokunaga Shinya、Arakawa Yoshiki、Hasegawa Daiichiro、Kosaka Yoshiyuki、Hara Junichi
    • Journal Title

      Journal of Neurosurgery: Pediatrics

      Volume: 25 Issue: 2 Pages: 111-120

    • DOI

      10.3171/2019.9.peds19367

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Brain MRI with Quantitative Susceptibility Mapping: Relationship to CT Attenuation Values2020

    • Author(s)
      Oshima S, Fushimi Y, Okada T, Takakura K, Liu C, Yokota Y, Arakawa Y, Sawamoto N, Miyamoto S, Togashi K
    • Journal Title

      Radiology

      Volume: 294 Issue: 3 Pages: 600-609

    • DOI

      10.1148/radiol.2019182934

    • NAID

      120007026444

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Human Pluripotent Stem Cell-Derived Tumor Model Uncovers the Embryonic Stem Cell Signature as a Key Driver in Atypical Teratoid/Rhabdoid Tumor2019

    • Author(s)
      Terada Yukinori、Jo Norihide、Arakawa Yoshiki、Sakakura Megumi、Yamada Yosuke、Ukai Tomoyo、Kabata Mio、Mitsunaga Kanae、Mineharu Yohei、Ohta Sho、Nakagawa Masato、Miyamoto Susumu、Yamamoto Takuya、Yamada Yasuhiro
    • Journal Title

      Cell Reports

      Volume: 26 Issue: 10 Pages: 2608-2621

    • DOI

      10.1016/j.celrep.2019.02.009

    • NAID

      120006578965

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 脳腫瘍に対する光線力学的治療の治療成績から見た課題2021

    • Author(s)
      荒川芳輝
    • Organizer
      LASER WEEK IN TOKYO Ⅱ
    • Related Report
      2021 Annual Research Report
  • [Presentation] The late intracranial adverse events occur more frequently in the patients with intracranial germinomas treated with high dose radiotherapy2021

    • Author(s)
      Yoshiki Arakawa, Etsuko Yamamoto, Katsutsugu Umeda, Yohei Mineharu, Megumi Uto, Junko Takita, Takashi Mizowaki, Susumu Miyamoto
    • Organizer
      26th Annual Meeting and Education Day of the Society for Neuro-Oncology
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 第17回日本Awake Surgery学会全国アンケート調査から見えた覚醒下手術の現状と課題2020

    • Author(s)
      荒川芳輝 溝田敏幸 福井彩香 川田将義 米澤淳 川内豪 山本悦子 山尾幸広 峰晴陽平 菊池隆幸 古川恵子 宮本享
    • Organizer
      日本脳神経外科学会 第79回学術総会
    • Related Report
      2020 Research-status Report
  • [Presentation] 本邦における小児脳腫瘍診療の向上を目指す多角的アプローチ2020

    • Author(s)
      荒川芳輝 山崎夏維 寺島慶太 山本哲哉 中村英夫 五味玲 中野嘉子 金村米博 市村幸一 義岡孝子 瀧本哲也 平戸純子 坂本博昭 西川亮 原純一 JCCG脳腫瘍委員会
    • Organizer
      日本脳神経外科学会 第79回学術総会
    • Related Report
      2020 Research-status Report
  • [Presentation] 京都大学病院におけるがんゲノムプロファイリング検査の現状2020

    • Author(s)
      荒川芳輝 須賀淳子 寺田行範 丹治正大 峰晴陽平 武藤学 宮本享
    • Organizer
      第38回日本脳腫瘍学会学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] 実質性脳腫瘍に対する内視鏡手術における術前シミュレーションの役割2020

    • Author(s)
      荒川芳輝 姜裕 中島公平 丹治正大 峰晴陽平 山尾幸広 菊池隆幸 宮本享
    • Organizer
      第38回日本脳腫瘍学会学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] Retrospective analysis of the combined treatment of vincristine, ACNU, carboplatin and interferon-β plus radiotherapy (VAC-feron-R)in patients with diffuse astrocytoma2020

    • Author(s)
      Yoshiki Arakawa, Yasuhide Makino, Takeshi Kawauchi, Masaharu Tanji, Yohei Mineharu, Yonehiro Kanemura, Susumu Miyamoto
    • Organizer
      The 25th Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Embryonic stem cell signature drives atypical teratoid/rhabdoid tumor development in human pluripotent stem cell-derived tumor model2019

    • Author(s)
      Yoshiki Arakawa, Yukinori Terada, Norihide Jo, Yohei Mineharu, Susumu Miyamoto, Yasuhiro Yamada
    • Organizer
      24th Annual Meeting of the Society for Neuro-Oncology
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] 多能性ネットワークがAT/RTの形成と腫瘍の悪性度を促進している2019

    • Author(s)
      寺田 行範,城 憲秀,荒川 芳輝,峰晴 陽平,宮本 享,山田 泰広
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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