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Efficient lysis of cancer-associated fibroblasts by next-generation reovirus and development of innovative cancer virotherapy

Research Project

Project/Area Number 17H04101
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Applied pharmacology
Research InstitutionOsaka University

Principal Investigator

SAKURAI FUMINORI  大阪大学, 薬学研究科, 准教授 (70370939)

Co-Investigator(Kenkyū-buntansha) 大河原 賢一  神戸薬科大学, 薬学部, 教授 (30291470)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000)
Fiscal Year 2019: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2018: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2017: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
Keywords腫瘍溶解性ウイルス / レオウイルス / Drug delivery system / 腫瘍ターゲティング / ナノ粒子 / 癌関連線維芽細胞 / リポソーム / 癌微小環境 / DDS / ナノ粒子製剤 / 癌 / ウイルス / 遺伝子 / 薬学 / ナノ材料
Outline of Final Research Achievements

Cancer-associated fibroblasts (CAF) are an important target for cancer therapy. I this study, we examined whether oncolytic reovirus mediated cytotoxic effects on mouse CAF. We demonstrated that reovirus induced apoptosis of mouse CAF. In addition, reovirus-mediated apoptosis of mouse tumor cells and CAF resulted in improvement of tumor accumulation of nanoparticle formulations following subsequent administration. Reovirus induced down-regulation of hypoxia inducible factor-1alpha (HIF-1alpha) in the tumor following administration, resulting in malignant transformation of tumors.

Academic Significance and Societal Importance of the Research Achievements

癌関連線維芽細胞は、癌治療の重要な治療標的であるが、癌細胞と癌関連線維芽細胞の両者に殺細胞効果を示す薬剤は開発されていない。本研究では、レオウイルスが癌細胞と癌関連線維芽細胞の両者に殺細胞効果を示すことを明らかにした。このような腫瘍溶解性ウイルスは他には報告されておらず、レオウイルスの特長であると言える。またレオウイルスは、種々の抗癌剤と併用するプロトコールが臨床でも用いられているが、本研究ではレオウイルスの前投与によりナノ粒子製剤の腫瘍集積性が向上することが示された。これまでレオウイルスが併用する薬剤の体内動態に及ぼす影響は報告されておらず、本研究は重要な情報を提供できるものと期待される。

Report

(4 results)
  • 2020 Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (31 results)

All 2021 2020 2019 2018 2017

All Journal Article (10 results) (of which Peer Reviewed: 10 results,  Open Access: 6 results,  Acknowledgement Compliant: 1 results) Presentation (21 results) (of which Invited: 2 results)

  • [Journal Article] Asymmetric profiles of infection and innate immunological responses in human iPS cell-derived small intestinal epithelial-like cell monolayers following infection with mammalian reovirus2021

    • Author(s)
      Inoue Chieko、Negoro Ryosuke、Takayama Kazuo、Mizuguchi Hiroyuki、Sakurai Fuminori
    • Journal Title

      Virus Research

      Volume: 296 Pages: 198334-198334

    • DOI

      10.1016/j.virusres.2021.198334

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Optimization of an E1A Gene Expression Cassette in an Oncolytic Adenovirus for Efficient Tumor Cell Killing Activity2021

    • Author(s)
      SAKURAI FUMINORI、NISHIMAE FUMITAKA、TAKAYAMA KOSUKE、MIZUGUCHI HIROYUKI
    • Journal Title

      Anticancer Research

      Volume: 41 Issue: 2 Pages: 773-782

    • DOI

      10.21873/anticanres.14829

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Efficient antitumor effects of a novel oncolytic adenovirus fully composed of species B adenovirus serotype 352021

    • Author(s)
      Ono Ryosuke、Takayama Kosuke、Sakurai Fuminori、Mizuguchi Hiroyuki
    • Journal Title

      Molecular Therapy - Oncolytics

      Volume: 20 Pages: 399-409

    • DOI

      10.1016/j.omto.2021.01.015

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Adenovirus Vector?Induced IL-6 Promotes Leaky Adenoviral Gene Expression, Leading to Acute Hepatotoxicity2020

    • Author(s)
      Shimizu Kahori、Sakurai Fuminori、Iizuka Shunsuke、Ono Ryosuke、Tsukamoto Tomohito、Nishimae Fumitaka、Nakamura Shin-ichiro、Nishinaka Toru、Terada Tomoyuki、Fujio Yasushi、Mizuguchi Hiroyuki
    • Journal Title

      The Journal of Immunology

      Volume: 206 Issue: 2 Pages: 410-421

    • DOI

      10.4049/jimmunol.2000830

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Systemically Administered Reovirus-Induced Downregulation of Hypoxia Inducible Factor-1a in Subcutaneous Tumors2019

    • Author(s)
      Takuma Hotani, Hiroyuki Mizuguchi, Fuminori Sakurai
    • Journal Title

      Molecular Therapy Oncolytics

      Volume: 12 Pages: 162-172

    • DOI

      10.1016/j.omto.2018.12.012

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A MicroRNA Derived from Adenovirus Virus-Associated RNAII Promotes Virus Infection via Posttranscriptional Gene Silencing.2019

    • Author(s)
      Wakabayashi K., Machitani M., Tachibana M., Sakurai F., Mizuguchi H.
    • Journal Title

      J. Virol.

      Volume: 93 Issue: 2

    • DOI

      10.1128/jvi.01265-18

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Antibodies against adenovirus fiber and penton base proteins inhibit adenovirus vector-mediated transduction in the liver following systemic administration.2018

    • Author(s)
      Tomita K., Sakurai F., Iizuka S., Hemmi M., Wakabayashi K., Tachibana M., Katayama K., Kamada H., Mizuguchi H.
    • Journal Title

      Sci. Rep.

      Volume: 8 Issue: 1 Pages: 12315-12315

    • DOI

      10.1038/s41598-018-30947-z

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Oncolytic Reovirus InhibitsImmunosuppressive Activity of Myeloid-Derived Suppressor Cells in a TLR3-Dependent Manner.2018

    • Author(s)
      Katayama Y, Tachibana M, Kurisu N, Oya Y, Terasawa Y, Goda H, Kobiyama K, Ishii KJ, Akira S, Mizuguchi H, Sakurai F.
    • Journal Title

      The Journal of Immunology

      Volume: 200 Issue: 8 Pages: 2987-2999

    • DOI

      10.4049/jimmunol.1700435

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cationic liposome-mediated delivery of reovirus enhances the tumor cell-killing efficiencies of reovirus in reovirus-resistant tumor cells2017

    • Author(s)
      Fuminori Sakurai, Syunsuke Inoue, Tadataka Kaminade, Takuma Hotani, Yuki Katayama, Eri Hosoyamada, Yuichi Terasawa, Masashi Tachibana, Hiroyuki Mizuguchi
    • Journal Title

      International Journal of Pharmaceutics

      Volume: 524 Issue: 1-2 Pages: 238-247

    • DOI

      10.1016/j.ijpharm.2017.04.006

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Type I interferons impede short-hairpin RNA-mediated RNA interference via inhibition of dicer-mediated processing to small interfering RNA.2017

    • Author(s)
      Machitani M., Sakurai F., Wakabayashi K., Takayama K., Tachibana M., Mizuguchi H.
    • Journal Title

      Mol. Ther. Nucleic Acids,

      Volume: 6 Pages: 173-182

    • DOI

      10.1016/j.omtn.2016.12.007

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] 腫瘍溶解性ウイルス製剤であるレオウイルスによる肝臓の脱線維化機構の解明2021

    • Author(s)
      石神育歩、木部友貴、井上俊介、水口裕之、櫻井文教
    • Organizer
      日本薬学会第141年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] TGF-b受容体阻害剤SB431542は、オフターゲット効果により肝癌細胞におけるレオウイルスの感染を阻害する2021

    • Author(s)
      種昻なお実、上撫忠孝、水口裕之、櫻井文教
    • Organizer
      日本薬学会第141年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] レオウイルスによる免疫細胞の腫瘍内浸潤促進機構の解明に向けた基礎的検討2021

    • Author(s)
      江口真帆, 石神育歩, 立花雅史, 水口裕之, 櫻井文教
    • Organizer
      日本薬学会第141年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 異なる血清型のアデノウイルスを基盤とした新規腫瘍溶解性アデノウイルスの開発と機能評価2021

    • Author(s)
      小野良輔、高山耕輔、櫻井文教、水口裕之
    • Organizer
      日本薬学会第141年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 新規制限増殖型アデノウイルスを用いた高効率な末梢循環腫瘍細胞の検出に関する検討2021

    • Author(s)
      池本星南、櫻井文教、高山耕輔、岡部隆宏、住吉一誠、十合晋作、水口裕之
    • Organizer
      日本薬学会第141年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 腫瘍溶解性ウイルス製剤であるReovirusによる肝線維化抑制機構の解明2020

    • Author(s)
      石神育歩、井上俊介、木部友貴、水口裕之、櫻井文教
    • Organizer
      第27回肝細胞研究会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Efficient antitumor effects of a novel oncolytic adenovirus fully composed of species B2 adenovirus serotype 352020

    • Author(s)
      Ryosuke Ono, Fuminori Sakurai, Hiroyuki Mizuguchi
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] アデノウイルスベクターによる投与後早期の肝障害誘導メカニズムの解明2020

    • Author(s)
      櫻井文教、清水かほり、飯塚俊輔、小野良輔、塚本智仁、西前文敬、西中徹、寺田知行、水口裕之
    • Organizer
      第36回日本DDS学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 腫瘍溶解性ウイルスであるレオウイルスの前投与によるリポソーム製剤の腫瘍ターゲティング向上に関する検討2018

    • Author(s)
      平田聖也、上撫忠孝、大河原賢一、水口裕之、櫻井文教
    • Organizer
      第68回日本薬学会近畿支部大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Reovirus induces down-regulation of HIF-1alpha in subcutaneous tumors following systemic administration2018

    • Author(s)
      Takuma Hotani, Hiroyuki Mizuguchi, Fuminori Sakurai
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 腫瘍溶解性ウイルスであるレオウイルスは、全身投与後、癌組織中のHIF-1alpha量を低減させる2018

    • Author(s)
      櫻井文教、宝谷拓磨、水口裕之
    • Organizer
      第16回がんとハイポキシア研究会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 腫瘍溶解性ウイルスであるレオウイルスは、癌関連線維芽細胞に感染し死滅させる2018

    • Author(s)
      栗栖望、上撫忠孝、水口裕之、櫻井文教
    • Organizer
      第16回がんとハイポキシア研究会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Reovirus induces down-regulation of HIF-1alpha in the subcutaneous tumors following intravenous administration2018

    • Author(s)
      Fuminori Sakurai, Takuma Hotani, Hiroyuki Mizuguchi
    • Organizer
      第24回日本遺伝子細胞治療学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] ウイルスを基盤とした遺伝子治療薬の臨床開発の現状と今後の展望2018

    • Author(s)
      櫻井文教
    • Organizer
      日本薬学会第138年会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 腫瘍溶解性ウイルスであるレオウイルスの癌関連線維芽細胞における細胞死誘導メカニズムに関する検討2018

    • Author(s)
      栗栖望、上撫忠孝、水口裕之、櫻井文教
    • Organizer
      日本薬学会第138年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 腫瘍溶解性ウイルスであるレオウイルスの前投与によるPEG修飾リポソームの腫瘍集積性の向上に関する検討2017

    • Author(s)
      櫻井文教、平田聖也、上撫忠孝、大河原賢一、水口裕之
    • Organizer
      第33回日本DDS学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Elucidation of mechanism of reovirus-mediated down-regulation of hypoxia-inducible factor-1alpha in tumor cells2017

    • Author(s)
      Fuminori Sakurai, Takuma Hotani, Hiroyuki Mizuguchi
    • Organizer
      第23回日本遺伝子細胞治療学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Highly efficient biallelic genome editing of human ES/iPS cells using a CRISPR/Cas9 system2017

    • Author(s)
      Kazuo Takayama, Fuminori Sakurai, Hiroyuki Mizuguchi
    • Organizer
      第23回日本遺伝子細胞治療学会学術集会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 腫瘍溶解性ウイルスであるレオウイルスは、皮下腫瘍におけるHIF-1alphaの分解を促進させる2017

    • Author(s)
      櫻井文教、寳谷琢磨、立花雅史、水口裕之
    • Organizer
      第15回がんとハイポキシア研究会
    • Related Report
      2017 Annual Research Report
  • [Presentation] レオウイルスの癌関連線維芽細胞に対する殺細胞効果に関する検討2017

    • Author(s)
      栗栖望、上撫忠孝、水口裕之、櫻井文教
    • Organizer
      第17回遺伝子デリバリー研究会シンポジウム
    • Related Report
      2017 Annual Research Report
  • [Presentation] Reovirus-mediated down-regulation of HIF-1alpha in subcutaneous tumors following systemic administration2017

    • Author(s)
      Takuma Hotani, Masashi Tachibana, Hiroyuki Mizuguchi, Fuminori Sakurai
    • Organizer
      第76回日本癌学会学術総会
    • Related Report
      2017 Annual Research Report

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Published: 2017-04-28   Modified: 2022-01-27  

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