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Development of innovative suicide gene virotherapy for disseminated cancer

Research Project

Project/Area Number 23K21450
Project/Area Number (Other) 21H03012 (2021-2023)
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeMulti-year Fund (2024)
Single-year Grants (2021-2023)
Section一般
Review Section Basic Section 55020:Digestive surgery-related
Research InstitutionHyogo Medical University

Principal Investigator

久保 秀司  兵庫医科大学, 医学部, 准教授 (10441320)

Co-Investigator(Kenkyū-buntansha) 中込 隆之  兵庫医科大学, 医学部, 教授 (80434950)
Project Period (FY) 2021-04-01 – 2025-03-31
Project Status Granted (Fiscal Year 2024)
Budget Amount *help
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2024: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Fiscal Year 2023: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2022: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2021: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Keywordsがんウイルス療法 / 増殖型レトロウイルスベクター / 自殺遺伝子 / 間葉系幹細胞 / 播種性癌
Outline of Research at the Start

がんの腹膜播種は腹腔内全体に腫瘍細胞が散布されるため根治が困難で、予後は極めて不良である。この腹膜播種がんに対する新規治療法として、我々がこれまでに開発したウイルス療法をさらに発展させた革新的技術を臨床に応用することを目指している。

Outline of Annual Research Achievements

1、腹水を伴う腹膜播種モデルの作製とMSCを媒体とした腫瘍へのRRV送達法の検証
ヌードマウスの腹腔内にmCherry標識したヒト悪性中皮腫細胞株(MSTO-211H/mCherry)を移植し、腹膜播種モデルを作製した。同細胞株は腹水を産生しないため、腹水を再現するため腫瘍細胞移植1週間後に10%ヒト血清/ PBSを1mL腹腔内投与した(隔日3回)。初回の血清投与直前にルシフェラーゼ発現RRVを感染させたMSCを腹腔内投与した(MSV/RRV群)。対照群として、PBS投与群、RRV群を設けた。in vivoイメージングにより、腫瘍内におけるRRV伝播効率を比較評価したところ、RRV群では腫瘍へのRRV伝達を認めなかったが、MSC/RRV群では高いRRV腫瘍伝達能を認めた。
2、腹水を伴う腹膜播種モデルにおける治療実験
上記同様のモデルを作製し、自殺遺伝子である酵母シトシン脱アミノ化酵素(CD)を発現するRRVを用い治療実験を行った。その結果、MSC/RRV群ではRRV群に比べ腫瘍シグナル減少、体重減少抑制、生存期間の延長のいずれの効果も有意に高かった。
3、高悪性度並びに腹水産生腫瘍細胞株の作製
腫瘍の形成能、増殖速度が早く、また腹水産生を伴うような悪性度の高い腫瘍細胞株を作製することを目指し、複数種のmCherry標識ヒト腫瘍細胞株を各々ヌードマウスの腹腔内に移植した後、腫瘍形成を認めたものについて、腫瘍から細胞を単離・培養し、再びヌードマウスの腹腔内に移植することを繰り返した(in vivo passage)。その結果、skov-3ヒト卵巣がん細胞株について、腫瘍生着率100%、増殖速度が約1.5倍、腹水産生率100%の細胞株(skov-3p)が作出できた。次年度はこの細胞株を用いた実験を行う予定である。

Current Status of Research Progress
Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

計画通り、腹膜播種マウスモデルでの有効性を示すことができた。また、腹水を産生するヒト腫瘍細胞株を作製できた。

Strategy for Future Research Activity

1、腹水を産生する腹膜播種モデルの作製とMSCを媒体とした腫瘍へのRRV送達法の検証
in vivo passageにより作出した腹水を産生する高悪性度ヒト卵巣がん細胞株 (skov-3p)を用いた腹水産生腹膜播種モデルを作製する。
2、腹水産生腹膜播種モデルにおけるMSCを媒体とした腫瘍へのRRV送達法の検証
上記1のモデル作製1週間後にルシフェラーゼ発現RRVを感染させたMSCを腹腔内投与する(MSV/RRV群)。対照群として、PBS投与群、RRV投与群を設ける。in vivoイメージングにより、腫瘍内におけるRRV伝播効率を比較評価する。
2、腹水産生腹膜播種モデルにおける治療実験
上記1のモデル作製1週間後に自殺遺伝子搭載RRVを感染させたMSCを腹腔内投与する(MSV/RRV群)。対照群として、PBS投与群、RRV群を設ける。抗腫瘍効果の判定には、体重、腹水量、in vivoイメージング解析結果、病理組織学的所見を比較検討する。また生存期間の差異についても検討する。

Report

(3 results)
  • 2023 Annual Research Report
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • Research Products

    (33 results)

All 2024 2023 2022 2021

All Journal Article (8 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 8 results,  Open Access: 8 results) Presentation (25 results) (of which Int'l Joint Research: 5 results)

  • [Journal Article] Targeted Suicide Gene Therapy with Retroviral Replicating Vectors for Experimental Canine Cancers2024

    • Author(s)
      Sonoda-Fukuda Emiko、Takeuchi Yuya、Ogawa Nao、Noguchi Shunsuke、Takarada Toru、Kasahara Noriyuki、Kubo Shuji
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 25 Issue: 5 Pages: 2657-2657

    • DOI

      10.3390/ijms25052657

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Therapeutic Efficacy of Prodrug Activator Gene Therapy Using Retroviral Replicating Vectors for Human Ovarian Cancer2023

    • Author(s)
      ISODA LISA、SONODA-FUKUDA EMIKO、FUJINO HIROAKI、TAKARADA TORU、HASEGAWA KOSEI、KASAHARA NORIYUKI、KUBO SHUJI
    • Journal Title

      Anticancer Research

      Volume: 43 Issue: 12 Pages: 5311-5317

    • DOI

      10.21873/anticanres.16734

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Retroviral Replicating Vectors Mediated Prodrug Activator Gene Therapy in a Gastric Cancer Model2023

    • Author(s)
      Fujino Hiroaki、Sonoda-Fukuda Emiko、Isoda Lisa、Kawabe Ayane、Takarada Toru、Kasahara Noriyuki、Kubo Shuji
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 24 Issue: 19 Pages: 14823-14823

    • DOI

      10.3390/ijms241914823

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Microglia Negatively Regulate the Proliferation and Neuronal Differentiation of Neural Stem/Progenitor Cells Isolated from Poststroke Mouse Brains2023

    • Author(s)
      Hirano Yoshinobu、Nakagomi Takayuki、Nakano-Doi Akiko、Kubo Shuji、Minato Yusuke、Sawano Toshinori、Sakagami Masafumi、Tsuzuki Kenzo
    • Journal Title

      Cells

      Volume: 12 Issue: 16 Pages: 2040-2040

    • DOI

      10.3390/cells12162040

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Transplantation of Human Brain-Derived Ischemia-Induced Multipotent Stem Cells Ameliorates Neurological Dysfunction in Mice After Stroke2023

    • Author(s)
      Nakagomi Takayuki、Nakano-Doi Akiko、Kubo Shuji、Sawano Toshinori、Kuramoto Yoji、Yamahara Kenichi、Matsuyama Tomohiro、Takagi Toshinori、Doe Nobutaka、Yoshimura Shinichi
    • Journal Title

      Stem Cells Translational Medicine

      Volume: 12 Issue: 6 Pages: 400-414

    • DOI

      10.1093/stcltm/szad031

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Different Contacted Cell Types Contribute to Acquiring Different Properties in Brain Microglial Cells upon Intercellular Interaction2023

    • Author(s)
      Nakano-Doi Akiko、Kubo Shuji、Sonoda Emiko、Taguchi Akihiko、Nakagomi Takayuki
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 24 Issue: 2 Pages: 1774-1774

    • DOI

      10.3390/ijms24021774

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] BAP1 depletion in human B-lymphoblast cells affects the production of innate immune cytokines and chemokines.2022

    • Author(s)
      Takagi-Kimura M, Tada A, Kijima T, Kubo S, Ohmuraya M, Yoshikawa Y
    • Journal Title

      Genes to Cells.

      Volume: 27 (12) Issue: 12 Pages: 731-740

    • DOI

      10.1111/gtc.12988

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Assessment of circulating microRNA specific for patients with familial adenomatous polyposis2021

    • Author(s)
      Yamano T, Kubo S, Sonoda E, Kominato T, Kimura K, Yasuhara M, Kataoka K, Son J, Babaya A, Takenaka Y, Matsubara T, Beppu N, Ikeda M
    • Journal Title

      PLoS One

      Volume: 16 Issue: 5 Pages: 250072-250072

    • DOI

      10.1371/journal.pone.0250072

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Retroviral replicating vector-mediated prodrug-activator gene therapy achieved highly efficient tumor transduction and antitumor efficacy in experimental human gastric cancer2023

    • Author(s)
      Shuji Kubo, Hiroaki Fujino, Noriyuki Kasahara, Emiko Sonoda
    • Organizer
      26th annual meeting of the American society of gene & cell therapy
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Retroviral replicating vector-mediated prodrug-activator gene therapy for canine cancers2023

    • Author(s)
      Emiko Sonoda, Shunsuke Noguchi, Noriyuki Kasahara, Shuji Kubo
    • Organizer
      26th annual meeting of the American society of gene & cell therapy
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Prodrug activator gene therapy using retroviral replicating vectors and mesenchymal stem cells in an experimental model of human malignant mesothelioma2023

    • Author(s)
      Shuji Kubo, Noriyuki Kasahara, Emiko Sonoda
    • Organizer
      16th International Conference of the International Mesothelioma Interest Group
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Suicide gene therapy using retroviral replicating vectors for gastric cancer2023

    • Author(s)
      Shuji Kubo, Hiroaki Fujino, Noriyuki Kasahara, Emiko Sonoda-Fukuda
    • Organizer
      第29回日本遺伝子細胞治療学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Cell death-inducing cancer virotherapy for canine malignancies using retroviral replicating vector2023

    • Author(s)
      Emiko Sonoda-Fukuda, Toru Takarada, Shunsuke Noguchi, Noriyuki Kasahara, Shuji Kubo
    • Organizer
      第29回日本遺伝子細胞治療学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] イヌ悪性腫瘍に対して増殖型レトロウイルスベクターを用いた自殺遺伝子療法2023

    • Author(s)
      福田(園田)絵観子、野口俊助、笠原典之、久保秀司
    • Organizer
      第82回日本癌学会学術総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Therapeutic efficacy of prodrug activator gene therapy using retroviral replicating vectors in experimental human ovarian cancer2023

    • Author(s)
      Shuji Kubo, Lisa Isoda, Noriyuki Kasahara, Emiko Sonoda-Fukuda
    • Organizer
      30th annual congress of the European society of gene & cell therapy
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Therapeutic efficacy of prodrug-activator gene therapy by retroviral replicating vectors for canine cancers2023

    • Author(s)
      Emiko Sonoda-Fukuda, Shunsuke Noguchi, Noriyuki Kasahara, Shuji Kubo
    • Organizer
      30th annual congress of the European society of gene & cell therapy
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 播種性がん治療を目指した増殖型レトロウイルスベクター新規輸送法の開発2023

    • Author(s)
      久保秀司、竹内雄哉、小川奈桜、笠原典之、福田(園田)絵観子
    • Organizer
      第1回日本ウイルス療法学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 増殖型レトロウイルスベクターを用いたイヌ悪性腫瘍に対する細胞死誘導型がんウイルス療法2023

    • Author(s)
      福田(園田)絵観子、寳田徹、野口俊助、笠原典之、久保秀司
    • Organizer
      第1回日本ウイルス療法学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 卵巣がんに対する増殖型レトロウイルスベクターを用いた細胞死誘導型ウイルス療法2023

    • Author(s)
      小川奈桜、磯田莉沙、福田 (園田) 絵観子、竹内雄哉、寳田徹、長谷川幸清、笠原典之、久保秀司
    • Organizer
      第46回日本分子生物学会年会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 抗がんウイルス新規輸送法の播種性がん治療への応用2023

    • Author(s)
      竹内雄哉、福田(園田)絵観子、小川奈桜、笠原典之、久保秀司
    • Organizer
      第46回日本分子生物学会年会
    • Related Report
      2023 Annual Research Report
  • [Presentation] イヌ悪性腫瘍に対する増殖型レトロウイルスベクターを用いた細胞死誘導型がんウイルス療法2023

    • Author(s)
      福田(園田)絵観子、寳田徹、野口俊助、笠原典之、久保秀司
    • Organizer
      第46回日本分子生物学会年会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Suicide gene therapy for canine malignancies by using retroviral replicating vectors2022

    • Author(s)
      Emiko Sonoda, Hiroaki Fujino, Ayane Kawabe, Toru Takarada, Shunsuke Noguchi, Noriyuki Kasahara, Shuji Kubo
    • Organizer
      第28回日本遺伝子細胞治療学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Suicide gene therapy for canine cancers with retroviral replicating vectors2022

    • Author(s)
      Emiko Sonoda, Hiroaki Fujino, Ayane Kawabe, Toru Takarada, Shunsuke Noguchi, Noriyuki Kasahara, Shuji Kubo
    • Organizer
      第81回日本癌学会学術総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Retroviral replicating vector-mediated prodrug-activator gene therapy for gastric cancer2022

    • Author(s)
      Shuji Kubo, Hiroaki Fujino, Noriyuki Kasahara, Emiko Sonoda
    • Organizer
      The 14th International Oncolytic Virotherapy Conference (IOVC2022)
    • Related Report
      2022 Annual Research Report
  • [Presentation] Prodrug-activator gene therapy for canine cancers with retroviral replicating vectors2022

    • Author(s)
      Emiko Sonoda, Shunsuke Noguchi, Noriyuki Kasahara, Shuji Kubo
    • Organizer
      The 14th International Oncolytic Virotherapy Conference (IOVC2022)
    • Related Report
      2022 Annual Research Report
  • [Presentation] Development of human mesenchymal stem cells as tumor-homing cellular carriers for retroviral replicating vectors2022

    • Author(s)
      Yuya Takeuchi, Emiko Sonoda, Ayane Kawabe, Hiroaki Fujino, Noriyuki Kasahara, Shuji Kubo
    • Organizer
      第45回日本分子生物学会年会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Retroviral replicating vector-mediated suicide gene therapy for osteosarcoma2022

    • Author(s)
      Ayane Kawabe, Hiroaki Fujino, Emiko Sonoda, Toru Takarada, Noriyuki Kasahara, Shuji Kubo
    • Organizer
      第45回日本分子生物学会年会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Suicide gene therapy by retroviral replicating vectors for canine malignancies2022

    • Author(s)
      Emiko Sonoda, Hiroaki Fujino, Ayane Kawabe, Toru Takarada, Shunsuke Noguchi, Noriyuki Kasahara, Shuji Kubo
    • Organizer
      第45回日本分子生物学会年会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Suicide gene therapy for ovarian cancer using retroviral replicating vector2021

    • Author(s)
      Emiko Sonoda, Lisa Isoda, Hiroaki Fujino, Ayane Kawabe, Kosei Hasegawa, Noriyuki Kasahara, Shuji Kubo
    • Organizer
      第27回日本遺伝子細胞治療学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 増殖型レトロウイルスを用いた卵巣癌に対する自殺遺伝子治療2021

    • Author(s)
      久保 秀司、藤野 宏晃、川邉 彩音、園田 絵観子
    • Organizer
      日本人類遺伝学会第66回大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Suicide gene therapy by retroviral replicating vectors for canine malignancies2021

    • Author(s)
      園田絵観子,藤野宏晃,川邉彩音,寳田徹,野口俊助,笠原典之,久保秀司
    • Organizer
      第44回日本分子生物学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Retroviral replicating vector-mediated suicide gene therapy for osteosarcoma2021

    • Author(s)
      川邉 彩音、藤野 宏晃、園田 絵観子、寳田 徹、笠原典之、久保 秀司
    • Organizer
      第44回日本分子生物学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Suicide Gene Therapy Using Retroviral Replicating Vectors for Gastric Cancer2021

    • Author(s)
      藤野 宏晃、園田 絵観子、磯田 莉沙、川邉 彩音、寳田 徹、笠原典之、久保 秀司
    • Organizer
      第44回日本分子生物学会年会
    • Related Report
      2021 Annual Research Report

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Published: 2021-04-28   Modified: 2024-12-25  

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