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Elucidation of the inhibitory mechanism of metastasis in bony malignant tumors to realize the early clinical application of FAK inhibitor

Research Project

Project/Area Number 19K08255
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52050:Embryonic medicine and pediatrics-related
Research InstitutionUniversity of Miyazaki

Principal Investigator

Moritake Hiroshi  宮崎大学, 医学部, 教授 (40336300)

Project Period (FY) 2019-04-01 – 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 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords骨肉腫 / ユーイング肉腫 / 転移 / RNAシーケンス / FAK / IGF-IR / 肺転移 / 骨原発悪性腫瘍 / 転移抑制 / インテグリン
Outline of Research at the Start

骨肉腫およびユーイング肉腫(ES)は小児・若年成人に多い骨原発悪性腫瘍であるが、転移例の予後は極めて不良でその対策は急務である。
申請者はFAKとIGF-IRの二重チロシンキナーゼ阻害剤を用いることで骨肉腫およびES細胞の増殖、転移能を抑制することを明らかにしたが、その機序については明らかになっていない。
本研究ではxenograftおよびPDX(Patient-derived xenograft)モデルを用いて
1)小児骨原発悪性腫瘍の転移能を有する細胞分画の同定とFAK活性の評価
2)転移を制御する上流分子の同定とFAK阻害療法の開発
を行い、転移阻害剤として臨床応用するための基礎研究を行う。

Outline of Final Research Achievements

We showed that TAE226, a dual inhibitor of FAK and IGF-IR, has a drastic inhibitory effect on metastasis in Ewing sarcoma. Furthermore, the molecular biological mechanism underlying the effect and the synergetic effect of various anticancer drugs was revealed. We established a mouse model of pulmonary metastasis using the osteosarcoma 143B cell line. RNA from primary and metastatic sites was extracted from mice and two patients, respectively. We compared the expression profile between primary and metastatic sites by RNA sequencing and extracted the 10 most-common genes among high-expression genes at metastatic sites. We then established sgRNA-based knockdown 143B cells for 10 genes and introduced these cells to tibias of immunocompromised mice. One gene showed an inhibitory effect on computed tomography and pathological evaluations at four weeks after inoculation, suggesting its relation to pulmonary metastatic machinery in osteosarcoma.

Academic Significance and Societal Importance of the Research Achievements

骨原発腫瘍の転移例に対する治療成績の向上は認められていない。今回ユーイング肉腫で見出されたFAKとIGF-IR抑制による転移抑制メカニズム解明は、Novartis社の同薬剤TAE226の開発中止決定は誠に残念であるが、別のルートから臨床応用に繋がっていくことに期待したい。骨肉腫に関しても既存の化学療法の組み合わせでは限界があり、病態メカニズムからアプローチする新規薬剤に期待が集まる。本研究により、現在候補として再現性を確認している遺伝子が標的遺伝子として確定すれば、創薬に繋がり骨肉腫転移症例の予後改善に期待できる。

Report

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

    (3 results)

All 2019

All Journal Article (1 results) (of which Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (2 results)

  • [Journal Article] TAE226, a dual inhibitor of focal adhesion kinase and insulin-like growth factor-I receptor, is effective for Ewing sarcoma.2019

    • Author(s)
      Moritake H, Saito Y, Sawa D, Sameshima N, Yamada A, Kinoshita M, Kamimura S, Konomoto T, Nunoi H.
    • Journal Title

      Cancer Medicine

      Volume: 8 Issue: 18 Pages: 7809-7821

    • DOI

      10.1002/cam4.2647

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 小児希少疾患の克服に向けて病態から考える2019

    • Author(s)
      盛武 浩
    • Organizer
      第171回日本小児科学会鹿児島地方会
    • Related Report
      2019 Research-status Report
  • [Presentation] TAE226, a dual inhibitor of focal adhesion kinase and insulin-like growth factor-I receptor, is an effective treatment for Ewing sarcoma2019

    • Author(s)
      Moritake H, Saito Y, Sameshima N, Yamada A, Kinoshita M, Kamimura S, Konomoto T, Nunoi H
    • Organizer
      51th Congress of the international society of paediatric oncology
    • Related Report
      2019 Research-status Report

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

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