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Elucidation of regulated mechanism in controlling purine metabolism through PI3K/mTOR pathway in small cell lung cancer

Research Project

Project/Area Number 17K07189
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Tumor biology
Research InstitutionNational Cancer Center Japan

Principal Investigator

Makinoshima Hideki  国立研究開発法人国立がん研究センター, 先端医療開発センター, ユニット長 (30510573)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Keywords肺小細胞がん / PI3K/mTOT経路 / プリンヌクレオチド / 核酸代謝 / PI3K/mTOR経路 / プリン塩基 / 癌
Outline of Final Research Achievements

To elucidate the metabolic pathway by which PI3K/mTOR regulates purine biosynthesis in small-cell lung carcinoma cell (SCLC), we conducted this research. I almost achieved the initially planned goals. There are two types of purine nucleotide biosynthesis pathways, a de novo pathway and a salvage pathway. The PI3K/mTOR pathway positively regulates the new synthesis pathway, and it seems that the SCLC cell lines which have high salvage pathway activity seems to be resistant to PI3K/mTOR inhibitors. The important outcome of this research is establishment of a defective SCLC cell line of HPRT1 gene, which is an enzyme that exists in the purine nucleotide recycling pathway. Moreover, it is the construction of an experimental system for measuring the biosynthesis ratio derived from either de novo or salvage route using SCLC cells. It is expected that these research results will be useful for research on SCLC.

Academic Significance and Societal Importance of the Research Achievements

肺小細胞がんは、肺がんの15%程度の症例数であるが、進行が速く、治療抵抗性が臨床上問題となっている。近年新たな治療法が開発されず、新規の治療標的の同定が必要である。本研究では、PI3K/mTOR阻害剤の感受性と代謝産物のプロファイルを解析し、PI3K/mTOR阻害剤の臨床研究と並行し、代謝産物由来のバイオマーカー探索も行った。今後、新規治療法の開発に発展する研究が期待できる。さらに、この科研費を用いたことが記載されている論文が少なくとも3報発表することができ、社会的な意義も大きかったと感じている。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (7 results)

All 2019 2018

All Journal Article (6 results) (of which Peer Reviewed: 4 results,  Open Access: 4 results) Presentation (1 results)

  • [Journal Article] Extraction of Aqueous Metabolites From Cultured Adherent Cells for Metabolomic Analysis by Capillary Electrophoresis-Mass Spectrometry2019

    • Author(s)
      Ami Maruyama, Kenjiro Kami, Kazunori Sasaki, Hajime Sato, Yuzo Sato, Katsuya Tsuchihara, Hideki Makinoshima
    • Journal Title

      J Vis Exp

      Volume: 148 Issue: 148 Pages: 59551-59551

    • DOI

      10.3791/59551

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Extraction of aqueous metabolites from cultured adherent cells for metabolomic analysis by capillary electrophoresis-mass spectrometry2019

    • Author(s)
      Ami Maruyama, Kenjiro Kami, Kazunori Sasaki, Hajime Sato, Yuzo Sato, Katsuya Tsuchihara and Hideki Makinoshima
    • Journal Title

      J. Exp. Vis.

      Volume: in press

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genetic profiling-based prognostic prediction of patients with advanced small-cell lung cancer in large scale analysis2018

    • Author(s)
      Udagawa Hibiki、Umemura Shigeki、Murakami Isao、Mimaki Sachiyo、Makinoshima Hideki、Ishii Genichiro、Miyoshi Tomohiro、Kirita Keisuke、Matsumoto Shingo、Yoh Kiyotaka、Niho Seiji、Tsuchihara Katsuya、Goto Koichi
    • Journal Title

      Lung Cancer

      Volume: 126 Pages: 182-188

    • DOI

      10.1016/j.lungcan.2018.11.014

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Metabolic Characterization of Antifolate Responsiveness and Non-responsiveness in Malignant Pleural Mesothelioma Cells.2018

    • Author(s)
      Sato Y, Matsuda S, Maruyama A, Nakayama J, Miyashita T, Udagawa H, Umemura S, Yanagihara K, Ochiai A, Tomita M, Soga T, Tsuchihara K, Makinoshima H.
    • Journal Title

      Front Pharmacol.

      Volume: 9 Pages: 1129-1129

    • Related Report
      2018 Research-status Report
  • [Journal Article] Metabolic Determinants of Sensitivity to Phosphatidylinositol 3-Kinase Pathway Inhibitor in Small-Cell Lung Carcinoma.2018

    • Author(s)
      Makinoshima H, Umemura S, Suzuki A, Nakanishi H, Maruyama A, Udagawa H, Mimaki S, Matsumoto S, Niho S, Ishii G, Tsuboi M, Ochiai A, Esumi H, Sasaki T, Goto K, Tsuchihara K.
    • Journal Title

      Cancer Res.

      Volume: 78 Pages: 2179-2190

    • Related Report
      2018 Research-status Report
  • [Journal Article] Metabolic determinants of sensitivity to phosphatidylinositol 3-kinase pathway inhibitor in small-cell lung carcinoma2018

    • Author(s)
      Makinoshima H et al.
    • Journal Title

      Cancer Research

      Volume: - Issue: 9 Pages: 2179-2190

    • DOI

      10.1158/0008-5472.can-17-2109

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] がん細胞における核酸サルベージ経路の重要性2019

    • Author(s)
      牧野嶋 秀樹
    • Organizer
      核酸代謝鶴岡カンファレンス
    • Related Report
      2019 Annual Research Report

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Published: 2017-04-28   Modified: 2021-02-19  

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