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Clinical application and biomarker of CHK1 inhibitor-mediated cell death

Research Project

Project/Area Number 18K07246
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 50010:Tumor biology-related
Research InstitutionResearch Institute for Clinical Oncology Saitama Cancer Center (2020-2021)
Showa University (2018-2019)

Principal Investigator

Ando Kiyohiro  地方独立行政法人埼玉県立病院機構埼玉県立がんセンター(臨床腫瘍研究所), 臨床腫瘍研究所, 副部長 (10455389)

Co-Investigator(Kenkyū-buntansha) 末永 雄介  千葉県がんセンター(研究所), 発がん研究グループ 発がん制御研究部, 研究員 (80581793)
Project Period (FY) 2018-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
KeywordsCHK1阻害剤 / 神経芽腫 / DNA損傷応答 / CEP131 / FGFR2 / MEK阻害剤 / DNA-PK阻害剤 / MYCN / DNA損傷修復 / CHK1 / MEK / ERK / neuroblastoma / kinase inhibitor / FGFR2 / ATM / DNA-PK / p63 / CHP134 / 10q loss / checkpoint kinase 1
Outline of Final Research Achievements

Selective inhibitors of checkpoint kinase 1 (CHK1) are undergoing clinical evaluation for various human malignancies. We reported that ATM inhibitor and DNA-PK inhibitor potentiated CHK1 inhibitor-mediated cell death in neuroblastoma cell line. Furthermore, the decreased expression of fibroblast growth factor receptor 2 (FGFR2) was causally related to CHK1 sensitivity. Since FGFR2 activated MEK/ERK pathway for cell proliferation, our data suggested that loss of FGFR2 expression might be possible utilization for determination of CHK1 inhibitor sensitivity in patients with neuroblastoma, whereas the increase expression of FGFR2 might be a candidate biomarker for combination therapy with MEK inhibitor.

Academic Significance and Societal Importance of the Research Achievements

CHK1阻害剤は、非臨床において高い抗腫瘍効果が示されているにもかかわらず、臨床試験の結果はいまだ十分でないことから、治療応用には感受性遺伝子の同定が急務である。本研究では、CHK1の機能阻害に対してATMまたはDNA-PKのDNA損傷修復機構及びFGFR2の細胞増殖効果が補完的に働くことが明らかとなった。この成果は、がん細胞におけるCHK1の機能的役割に新しい知見を与える学術的意義が高いと考えられ、またこれらの感受性に関連するがん細胞の遺伝子背景は、効果予測および適応決定の指標として今後の適切なCHK1阻害剤の臨床試験デザインに有用であり、また併用治療薬の選択に臨床的意義が高いと考える。

Report

(5 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (8 results)

All 2021 2020 2019 2018

All Journal Article (4 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 4 results,  Open Access: 2 results) Presentation (4 results)

  • [Journal Article] FGFR2 loss sensitizes MYCN‐amplified neuroblastoma CHP134 cells to CHK1 inhibitor?induced apoptosis2021

    • Author(s)
      Ando Kiyohiro、Ohira Miki、Takada Ichiro、Cazares‐Ordonez Verna、Suenaga Yusuke、Nagase Hiroki、Kobayashi Shinichi、Koshinaga Tsugumichi、Kamijo Takehiko、Makishima Makoto、Wada Satoshi
    • Journal Title

      Cancer Science

      Volume: 113 Issue: 2 Pages: 587-596

    • DOI

      10.1111/cas.15205

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy?2021

    • Author(s)
      Ando Kiyohiro、Nakagawara Akira
    • Journal Title

      Biomolecules

      Volume: 11 Issue: 5 Pages: 750-750

    • DOI

      10.3390/biom11050750

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Co-Inhibition of the DNA Damage Response and CHK1 Enhances Apoptosis of Neuroblastoma Cells2019

    • Author(s)
      Ando Kiyohiro、Nakamura Yohko、Nagase Hiroki、Nakagawara Akira、Koshinaga Tsugumichi、Wada Satoshi、Makishima Makoto
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 20 Issue: 15 Pages: 3700-3700

    • DOI

      10.3390/ijms20153700

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] TAp63 represses transcription of MYCN/NCYM gene and its high levels of expression are associated with favorable outcome in neuroblastoma2019

    • Author(s)
      Suenaga Yusuke、Yamamoto Mami、Sakuma Tetsushi、Sasada Manabu、Fukai Fumio、Ohira Miki、Yamaguchi Yohko、Yamamoto Takashi、Ando Kiyohiro、Ozaki Toshinori、Nakagawara Akira
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 518 Issue: 2 Pages: 311-318

    • DOI

      10.1016/j.bbrc.2019.08.052

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Presentation] CHK1阻害剤はFGFR2-MEK-ERK経路の抑制に相乗的に神経芽腫の増殖を抑制する2021

    • Author(s)
      安藤清宏
    • Organizer
      第80回日本癌学会学術総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] FGFR2の欠失はCHK1阻害剤が誘導する細胞死の感受性を増強する2020

    • Author(s)
      安藤清宏、大平美紀、末永雄介、上條岳彦、永瀬浩喜、小林真一、和田聡
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Research-status Report
  • [Presentation] MDM2はp53とcentrosome-associated family proteinとの結合によりCHK1阻害剤感受性を増強する2019

    • Author(s)
      安藤清宏
    • Organizer
      第61回 日本小児血液・がん学会
    • Related Report
      2019 Research-status Report
  • [Presentation] checkpoint abrogationを応用した神経芽腫治療の可能性2018

    • Author(s)
      安藤清宏
    • Organizer
      第60回 日本小児血液・がん学会学術総会
    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2023-01-30  

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