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Molecular therapy for esophageal cancer targeting the p53 and the Hippo pathways

Research Project

Project/Area Number 17K10617
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Digestive surgery
Research InstitutionChiba Cancer Center (Research Institute)

Principal Investigator

TAGAWA Masatoshi  千葉県がんセンター(研究所), がん治療開発グループ, 特任研究員 (20171572)

Co-Investigator(Kenkyū-buntansha) 島田 英昭  東邦大学, 医学部, 教授 (20292691)
Project Period (FY) 2017-04-01 – 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 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywords食道がん / 遺伝子変異 / p53経路 / Hippo経路 / FAK経路 / 細胞障害活性 / DNA障害 / CP-31398 / FAK活性 / 細胞傷害活性 / MDM2分子 / p21分子誘導 / 細胞死 / MDM2 / MDM4 / DNA傷害 / 遺伝子 / 癌 / シグナル伝達 / バイオテクノロジー / 薬理学
Outline of Final Research Achievements

Esophageal carcinoma has frequent mutations in genes encoding p53 and several molecules in the Hippo pathway. This suggests that restoration of the p53 pathway and suppression of the elevated Hippo pathway are therapeutic strategies for the malignancy. We used agents which augmented p53 expression or suppressed several Hippo-linked pathways and examined whether these agents induced apoptotic cell death. The present study showed that small molecules activating p53 expression killed the tumor cells but the apoptosis induced was not always relevant to p53-mediated cell death. Among agents inhibiting elevated Hippo-linked pathways, an inhibitor for focal adhesion kinase effectively suppressed the growth and augmented p53 expression. A combinatory use of p53-activating agent and the FAK inhibitor synergistically suppressed the growth through augmenting p53 and dephosphorylating FAK levels. These data indicated that agents targeting the pathways are potentially useful for the treatments.

Academic Significance and Societal Importance of the Research Achievements

高齢者に多い食道がんは、周辺組織への進展が早いことも多く、進行がんは難治であり根治的治療は困難であることが多い。そこで、同疾患の遺伝子変異に基づいて、それを標的とした薬剤の開発は、従来の放射線治療、抗がん剤治療に引き続いて新たな治療の方向性となる。このような遺伝子変異を狙う薬物は、正常組織では同変異がないことから、有害事象が少なく当該疾患に特異的に作用すると想定され、また従来の治療法との併用が可能である。高齢化社会でのがん治療に向けて、また今後臨床応用されるゲノム研究の成果を生かす方向として、遺伝子変異に立脚した当該疾患の治療法が開発できる可能性を本研究では示している。

Report

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

    (10 results)

All 2020 2019 2018 2017

All Journal Article (4 results) (of which Peer Reviewed: 4 results,  Open Access: 3 results) Presentation (6 results) (of which Int'l Joint Research: 2 results,  Invited: 1 results)

  • [Journal Article] Combination of a p53-activating CP-31398 and an MDM2 or a FAK inhibitor produces growth suppressive effects in mesothelioma with wild-type p53 genotype.2020

    • Author(s)
      Zhong, B., Shingyoji, M., Hanazono, M., Nguye;n, T.T.T., Morinaga, T., Tada, Y., Hiroshima, K., Shimada, H. and Tagawa, M
    • Journal Title

      Apoptosis

      Volume: -

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A p53-stabilizing agent, CP-31398, induces p21 expression with increased G2/M phase through the YY1 transcription factor in esophageal carcinoma defective of the p53 pathway.2019

    • Author(s)
      Zhong, B., Shingyoji, M., Hanazono, M., Nguyen, T.T.T., Morinaga, T., Tada, Y., Hiroshima, K., Shimada, H. and Tagawa, M.
    • Journal Title

      Am. J. Cancer Res.

      Volume: 9 Pages: 79-93

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cytotoxicity of replication-competent adenoviruses powered by an exogenous regulatory region is not linearly correlated with the viral infectivity/gene expression or with the E1A-activating ability but is associated with the p53 genotypes2017

    • Author(s)
      Yamauchi Suguru、Zhong Boya、Kawamura Kiyoko、Yang Shan、Kubo Shuji、Shingyoji Masato、Sekine Ikuo、Tada Yuji、Tatsumi Koichiro、Shimada Hideaki、Hiroshima Kenzo、Tagawa Masatoshi
    • Journal Title

      BMC Cancer

      Volume: 17 Issue: 1 Pages: 622-622

    • DOI

      10.1186/s12885-017-3621-x

    • NAID

      120007134865

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] An image cytometric technique is a concise method to detect adenoviruses and host cell proteins and to monitor the infection and cellular responses induced2017

    • Author(s)
      Morinaga Takao、Nguyen Thao Thi Thanh、Zhong Boya、Hanazono Michiko、Shingyoji Masato、Sekine Ikuo、Tada Yuji、Tatsumi Koichiro、Shimada Hideaki、Hiroshima Kenzo、Tagawa Masatoshi
    • Journal Title

      Virology Journal

      Volume: 14 Issue: 1 Pages: 219-219

    • DOI

      10.1186/s12985-017-0888-0

    • NAID

      120007128796

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Increased p53 expression augments DNA damages and viral replications of p53-activating oncolytic adenoviruses through NF1 induction in mesothelioma with the wild-type p53 genotype.2019

    • Author(s)
      Masatoshi Tagawa, Yuji Tada, Hideaki Shimada, Kenzo Hiroshima.
    • Organizer
      12th Annual Conference of International Oncolytic Virus Conference
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Activation or suppression of immune responses for oncolytic virus therapy.2019

    • Author(s)
      Masatoshi Tagawa.
    • Organizer
      International Forum on Regulatory Sciences for Advanced Therapy Medical Products
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 核酸合成酵素非依存的なペメトレキセート耐性はAICARTを介したAMPKの活性化に関与している2018

    • Author(s)
      鐘博雅、関根郁夫、滝口裕一、グエン タオ、盛永敬郎、多田裕司、山口直人、田川雅敏
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Research-status Report
  • [Presentation] HSP90阻害剤は内因性p53発現を上昇させるが外因性p53発現をプロテアソーム活性で抑制する2018

    • Author(s)
      田川雅敏、盛永敬郎、鐘博雅、Nguyen Thi Thanh Thao、久保秀司、多田裕司、巽浩一郎、島田英昭、廣島健三、山口直人
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Research-status Report
  • [Presentation] A Wee1 kinase inhibitor increases apoptosis of replication-competent adenoviruses through induction of mitotic catastrophe and enhancement of viral replications2017

    • Author(s)
      Takao Morinaga, Thao Thi Thanh Nguyen, Boya Zhong, Shuji Kubo, Masato Shingyoji, Yuji Tada, Koichiro Tatsumi, Hideaki Shimada, Kenzo Hiroshima, Masatoshi Tagawa
    • Organizer
      23rd annual meeting of Japan Society of Gene Therapy
    • Related Report
      2017 Research-status Report
  • [Presentation] A role of Wee1 kinase in adenoviruses-induced cell death and viral replication2017

    • Author(s)
      盛永敬郎、グエン タオ、鐘博雅、久保秀司、関根郁夫、多田裕司、巽浩一郎、島田英昭、廣島健三、田川雅敏
    • Organizer
      第76回日本癌学会学術総会
    • Related Report
      2017 Research-status Report

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

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