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がんにおけるNotchシグナル異常の解析とこれを標的とした抗腫瘍療法開発研究

Research Project

Project/Area Number 20015010
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionUniversity of Tsukuba

Principal Investigator

千葉 滋  University of Tsukuba, 大学院・人間総合科学研究科, 教授 (60212049)

Co-Investigator(Kenkyū-buntansha) 坂田 麻実子 (柳元 麻実子)  筑波大学, 大学院・人間総合科学研究科, 講師 (80451805)
Project Period (FY) 2008 – 2009
Project Status Completed (Fiscal Year 2009)
Budget Amount *help
¥11,000,000 (Direct Cost: ¥11,000,000)
Fiscal Year 2009: ¥5,500,000 (Direct Cost: ¥5,500,000)
Fiscal Year 2008: ¥5,500,000 (Direct Cost: ¥5,500,000)
Keywordsがん / Notch / 腫瘍 / 分子標的 / 白血病 / 血管新生
Research Abstract

(1)前年までの共同研究で、Notchシグナル下流の核内複合体(Notch-RBP-Jκ-MAM)を標的として、in silicoスクリーニングで得られた候補低分子化合物から、低濃度で腫瘍増殖抑制効果を示す化合物が同定されていた。これをもとに、研究協力者・細田らが合成した誘導体の中から、Notchシグナル阻害活性とin vivo抗腫瘍活性を有する化合物をスクリーニングした。その結果、いずれの活性も強い化合物が複数同定された。今後さらに、製薬に向けた共同研究を進める。
(2)Delta4-Fcは、腫瘍血管形成の異常を誘導する作用を介して抗腫瘍作用を発揮することがすでに証明され(Nature 444 : 1083-7, 2006)、臨床応用が期待されている。一方われわれは、前年までにヒトDelta1-Fcを抗腫瘍薬として製剤化するための研究開発を進めてきた。今年度、ヒト細胞株TH1080をヌードマウス皮下に移植して腫瘍を形成させたのち、マウスDelta1-FcあるいはDelta4-Fcを腹腔内に投与して、両者の効果を比較検討した。Delta4-Fcは、20mg/kgの隔日投与で明瞭な腫瘍増大抑制効果を認め、報告された結果が再現された。一方、Deltal-Fcも20mg/kgを隔日投与することにより、Delta4-Fcと同等の腫瘍増大抑制効果を認めた。Delta4-Fc同様に、競合によって血管内皮細胞のNotch受容体シグナルを抑制し、内皮stalk細胞の過剰なtip細胞への分化を誘導して、結果的に腫瘍血管形成を阻害することによる抗腫瘍効果であるかについては、現在までに結論を得ていない。今後明らかにする必要がある。

Report

(2 results)
  • 2009 Annual Research Report
  • 2008 Annual Research Report
  • Research Products

    (16 results)

All 2010 2009 2008

All Journal Article (14 results) (of which Peer Reviewed: 14 results) Presentation (2 results)

  • [Journal Article] Notch2 signaling is required for potent anti-tumor immunity in vivo2010

    • Author(s)
      Sugumito K, Maekawa Y, Kitamura A, Nishida J, Koyanagi A, Yagita H, Kojima H, Chiba S, Shimada M, Yasutomo K.
    • Journal Title

      Journal of Immunology (印刷中)

      Pages: 4673-4678

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Hes1 immortalizes committed progenitors and plays a role in blast crisis transition in chronic myelogenous leukemia2010

    • Author(s)
      Nakahara F, Sakata-Yanagimoto M, Komeno Y, Kato N, Uchida T, Haraguchi K, Kumano K, Harada Y, Harada H, Kitaura J, Ogawa S, Kurokawa M, Kitamura T, Chiba S.
    • Journal Title

      Blood 115

      Pages: 2878-2881

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Dual antitumor mechanisms of Notch signaling inhibitor in a T cell acute lymph oblastic leukemia xenograft model2009

    • Author(s)
      Masuda S, Kumano K, Suzuki T, Tomita T, Iwatsubo T, Natsugari H, Tojo A, Shibutani M, Mitsumori K, Hanazono Y, Ogawa S, Kurokawa M, Chiba S.
    • Journal Title

      Cancer Science 100

      Pages: 2444-2450

    • NAID

      10027198807

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Gain-of-function of mutated c-Cbl tumor suppressor associated with myeloid neoplasms having 11q UPD2009

    • Author(s)
      Sanada M, Suzuki T, Shih LY, Otsu M, Kato M, Yamazaki S, Tamura A, Honda H, Sakata-Yanagimoto M, Kumano K, Oda H, Yamagata T, Takita J, Gotoh N, Nakazaki K, Kawamata N, Onodera M, Nobuyoshi M, Hayashi Y, Harada H, Kurokawa M, Chiba S, Mori H, Ozawa K, Omine M, Hirai H, Nakauchi H, Koeffler HP, Ogawa S.
    • Journal Title

      Nature 460

      Pages: 904-908

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Derivation of functional mature neutrophils from human embryonic stem cells2009

    • Author(s)
      Yokoyama Y, Suzuki T, Sakata-Yanagimoto M, Kumano K, Higashi K, Takato T, Kurokawa M, Ogawa S, Chiba S.
    • Journal Title

      Blood 113

      Pages: 6584-6592

    • NAID

      120007131544

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Frequent inactivation of A20 in B-cell lymphomas2009

    • Author(s)
      Kato M, Sanada M, Kato I, Sato Y, Takita J, Takeuchi K, Niwa A, Chen Y, Nakazaki K, Nomoto J, Asakura Y, Muto S, Tamura A, Iio M, Akatsuka Y, Hayashi Y, Mori H, Igarashi T, Kurokawa M, Chiba S, Mori S, Ishikawa Y, Okamoto K, Tobinai K, Nakagama H, Nakahata T, Yoshino T, Kobayashi Y, Ogawa S.
    • Journal Title

      Nature 459

      Pages: 712-716

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Gain-of-function mutations and copy number increases of Notch2 in diffuse large B-cell lymphoma2009

    • Author(s)
      Lee S-y, Kumano K, Nakazaki K, Sanada M, Matsumoto A, Yamamoto C, Nannya Y, Suzuki R, Ota S, Ota Y, Izutsu K, Sakata-Yanagimoto M, Hangaishi A, Yagita H, Fukayama M, Seto M, Kurokawa M, Ogawa S, Chiba S.
    • Journal Title

      Cancer Science 100

      Pages: 920-926

    • NAID

      10025145854

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Notch Activation Induces the Generation of Functional NK Cells from Human Cord Blood CD34-Positive Cells Devoid of IL-152009

    • Author(s)
      Haraguchi K, Suzuki T, Koyama N, Kumano K, Nakahara F, Matsumoto A, Yokoyama Y, Sakata-Yanagimoto M, Masuda S, Takahashi T, Kamijo A, Takahashi K, Takanashi M, Okuyama Y, Yasutomo K, Sakano S, Yagita H, Kurokawa M, Ogawa S, Chiba S.
    • Journal Title

      Journal of Immunology 182

      Pages: 6168-6178

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Fbxw7 acts as a critical fail-safe against premature loss of hematopoietic stem cells and development of T-ALL2008

    • Author(s)
      松岡佐保子, 他
    • Journal Title

      Genes & Development 22

      Pages: 986-991

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Dendritic cell-mediated NK cell activation is controlled by Jagged2-Notch interaction2008

    • Author(s)
      木嶋美香、他
    • Journal Title

      National Academy of Science, USA 105

      Pages: 7010-7015

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Coordinated regulation of transcription factors through Notch2 is an important mediator of mast cell fate2008

    • Author(s)
      坂田(柳元)麻実子、他
    • Journal Title

      National Academy of Science, USA 105

      Pages: 7839-7844

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Evi-1 is a critical regulator for hematopoietic stem cells and transformed leukemic tells2008

    • Author(s)
      合山進、他
    • Journal Title

      Cell Stem Cell 3

      Pages: 207-220

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Notch 2 integrates signaling by the transcription factors RBP-J and CREBI to promote T cell cytotoxicity2008

    • Author(s)
      前川洋一、他
    • Journal Title

      Nature Immunology 9

      Pages: 1140-1147

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Notch signaling confers antigen-presenting cell functions on mastcells2008

    • Author(s)
      中野信浩, 他
    • Journal Title

      Journal of Allergy and Clinical Immunology 123

      Pages: 74-81

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Presentation]2010

    • Author(s)
      千葉滋
    • Organizer
      日本再生医療学会
    • Place of Presentation
      広島
    • Year and Date
      2010-03-19
    • Related Report
      2009 Annual Research Report
  • [Presentation] Dual antitumor mechanisms of Notch signaling inhibitor in axenograft model2008

    • Author(s)
      千葉滋
    • Organizer
      Notch and Cancer
    • Place of Presentation
      ギリシャ、アテネ
    • Year and Date
      2008-10-06
    • Related Report
      2008 Annual Research Report

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Published: 2008-04-01   Modified: 2018-03-28  

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