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Development of prodrug activator gene therapy combined with radiation therapy in glioblastoma

Research Project

Project/Area Number 16K10777
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

Takahashi Masamichi  国立研究開発法人国立がん研究センター, 中央病院, 医長 (10436454)

Co-Investigator(Kenkyū-buntansha) 平岡 圭  北海道大学, 医学研究院, 客員研究員 (10719587)
Project Period (FY) 2016-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywords膠芽腫 / 遺伝子治療 / 放射線治療 / ウイルスベクター / 脳腫瘍 / レトロウイルス
Outline of Final Research Achievements

We investigated the therapeutic efficacy of the combination of our prodrug activating gene therapy system using retroviral replicating vector (RRV) and radiation therapy in experimental glioblastoma models. RRV efficiently spread to almost all the cells in commercially available glioblastoma cell lines including U87 and radioresistant U87EGFRvIII cells, whereas only 50% of the cells were infected in patient-derived glioblastoma stem-like cells. In stability assay, RRV was shown to safely maintain its ability of infection even after the irradiation. In survival study, mice harboring brain tumor with U87EGFRvIII cells were treated with combination of RRV prodrug system and radiation therapy showed significant elongated survival time compared to other groups. In conclusion, our RRV prodrug gene therapy system efficiently enhanced the anti-tumor effect of radiation therapy in experimental glioblastoma. Improved infection to glioblastoma stem-like cells should be further investigated.

Academic Significance and Societal Importance of the Research Achievements

膠芽腫は最も予後不良の原発性悪性脳腫瘍の一つであり、新規治療法開発が切望されている。我々は本研究で、増殖型レトロウイルスベクター(RRV)を用いたプロドラッグシステムの放射線治療への増強効果について、膠芽腫細胞株を用いた基礎的研究、前臨床研究を行う事で検証した。その結果、RRVは膠芽腫細胞に広く感染して放射線照射を受けた後も安定してその感染能力を維持することが判明し、特にマウス脳腫瘍モデルにおいて効果的に放射線治療の抗腫瘍効果を増強させることが明らかとなった。これらの結果は現在論文として発表されるべく準備が進んでおり、将来的には膠芽腫患者を対象とした臨床応用が期待される。

Report

(5 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (10 results)

All 2020 2019 2018 2017

All Journal Article (9 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 7 results,  Open Access: 3 results) Book (1 results)

  • [Journal Article] Usefulness of carbon-11-labeled methionine positron-emission tomography for assessing the treatment response of primary central nervous system lymphoma2020

    • Author(s)
      Miyakita Yasuji、Ohno Makoto、Takahashi Masamichi、Kurihara Hiroaki、Katai Hitoshi、Narita Yoshitaka
    • Journal Title

      Japanese Journal of Clinical Oncology

      Volume: 50 Issue: 5 Pages: 512-518

    • DOI

      10.1093/jjco/hyaa010

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Eribulin penetrates brain tumor tissue and prolongs survival of mice harboring intracerebral glioblastoma xenografts2019

    • Author(s)
      Takahashi Masamichi、Miki Shunichiro、Fujimoto Kenji、Fukuoka Kohei、Matsushita Yuko、Maida Yoshiko、Yasukawa Mami、Hayashi Mitsuhiro、Shinkyo Raku、Kikuchi Kiyomi、Mukasa Akitake、Nishikawa Ryo、Tamura Kenji、Narita Yoshitaka、Hamada Akinobu、Masutomi Kenkichi、Ichimura Koichi
    • Journal Title

      Cancer Science

      Volume: 110 Issue: 7 Pages: 2247-2257

    • DOI

      10.1111/cas.14067

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A rare case of brain metastasis from poorly differentiated small bowel adenocarcinoma2019

    • Author(s)
      Yamazawa Erika、Honma Yoshitaka、Satomi Kaishi、Taniguchi Hirokazu、Takahashi Masamichi、Yoshida Akihiko、Tominaga Koji、Miyakita Yasuji、Ohno Makoto、Asanome Taku、Satomi Natsuko、Narita Yoshitaka
    • Journal Title

      Surgical Neurology International

      Volume: 10 Pages: 256-256

    • DOI

      10.25259/sni_413_2019

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Survival benefits of hypofractionated radiotherapy combined with temozolomide or temozolomide plus bevacizumab in elderly patients with glioblastoma aged > 75 years2019

    • Author(s)
      Ohno Makoto、Miyakita Yasuji、Takahashi Masamichi、Igaki Hiroshi、Matsushita Yuko、Ichimura Koichi、Narita Yoshitaka
    • Journal Title

      Radiation Oncology

      Volume: 14 Issue: 1 Pages: 200-200

    • DOI

      10.1186/s13014-019-1389-7

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Assessment of the Diagnostic Utility of Serum MicroRNA Classification in Patients With Diffuse Glioma2019

    • Author(s)
      Ohno Makoto、Matsuzaki Juntaro、Kawauchi Junpei、Aoki Yoshiaki、Miura Junichiro、Takizawa Satoko、Kato Ken、Sakamoto Hiromi、Matsushita Yuko、Takahashi Masamichi、Miyakita Yasuji、Ichimura Koichi、Narita Yoshitaka、Ochiya Takahiro
    • Journal Title

      JAMA Network Open

      Volume: 2 Issue: 12 Pages: 1916953-1916953

    • DOI

      10.1001/jamanetworkopen.2019.16953

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Prediction of IDH and TERT promoter mutations in low-grade glioma from magnetic resonance images using a convolutional neural network2019

    • Author(s)
      Fukuma Ryohei、Yanagisawa Takufumi、Kinoshita Manabu、他
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 0-0

    • DOI

      10.1038/s41598-019-56767-3

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Therapeutic activity of retroviral replicating vector-mediated prodrug activator gene therapy for pancreatic cancer.2018

    • Author(s)
      Inoko K, Hiraoka K, Inagaki A, Takahashi M, Kushibiki T, Hontani K, Takano H, Sato S, Takeuchi S, Nakamura T, Tsuchikawa T, Shichinohe T, Gruber HE, Jolly DJ, Kasahara N, Hirano S.
    • Journal Title

      Cancer Gene Ther

      Volume: epub ahead of print Issue: 7-8 Pages: 184-195

    • DOI

      10.1038/s41417-018-0020-7

    • Related Report
      2018 Research-status Report 2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Toca 511 gene transfer and treatment with the prodrug, 5-fluorocytosine, promotes durable antitumor immunity in a mouse glioma model2017

    • Author(s)
      Mitchell Leah A.、Lopez Espinoza Fernando、Mendoza Daniel、Kato Yuki、Inagaki Akihito、Hiraoka Kei、Kasahara Noriyuki、Gruber Harry E.、Jolly Douglas J.、Robbins Joan M.
    • Journal Title

      Neuro-Oncology

      Volume: 19 Issue: 7 Pages: 930-939

    • DOI

      10.1093/neuonc/nox037

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Retroviral replicating vector-mediated gene therapy achieves long-term control of tumor recurrence and leads to durable anticancer immunity.2017

    • Author(s)
      Hiraoka K, Inagaki A, Kato Y, Huang TT, Mitchell LA, Kamijima S, Takahashi M, Matsumoto H, Hacke K, Kruse CA, Ostertag D, Robbins JM, Gruber HE, Jolly DJ, Kasahara N
    • Journal Title

      Neuro-Oncology

      Volume: 印刷中 Issue: 7 Pages: 918-929

    • DOI

      10.1093/neuonc/nox038

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Book] 先端治療技術の実用化と開発戦略(核酸医薬、免疫療法、遺伝子治療、細胞医薬品)2017

    • Author(s)
      高橋雅道
    • Total Pages
      480
    • Publisher
      技術情報協会
    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2021-02-19  

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