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Development of G-quadruplex ligands that target cancer stem cells

Research Project

Project/Area Number 25290060
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypePartial Multi-year Fund
Section一般
Research Field Tumor therapeutics
Research InstitutionJapanese Foundation for Cancer Research

Principal Investigator

Seimiya Hiroyuki  公益財団法人がん研究会, がん化学療法センター分子生物治療研究部, 部長 (50280623)

Co-Investigator(Renkei-kenkyūsha) NAGASAWA Kazuo  東京農工大学, 大学院工学研究院生命工学専攻生命有機化学講座, 教授 (10247223)
MATSUSAKA Satoshi  公益財団法人がん研究会, がん研有明病院消化器化学療法科, 医長 (00372665)
Project Period (FY) 2013-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000)
Fiscal Year 2015: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2014: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2013: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Keywordsがん幹細胞 / テロメア / 分子標的 / DNA損傷 / グアニン4重鎖 / 神経膠腫 / 複製 / 創薬 / G4リガンド
Outline of Final Research Achievements

This study aims to develop G4 ligands that stabilize G-quadruplex (G4), a specialized structure of nucleic acids, and establish their anti-proliferative effects on cancer stem cells and the underlying molecular mechanisms. We found that G4 ligands, such as telomestatin and its derivative, X, preferentially attack the cancer stem cells of intractable glioblastoma (GSC). Our observations suggest that single-stranded DNA formed during replication and transcription causes G4 formation, which is targeted by G4 ligands. As a molecular mechanism that could explain the higher sensitivity of GSCs to G4 ligands, GSCs exhibited excessive response to the drug-induced replication stress. X inhibited the growth of GSC-derived tumors explanted in mice. These observations are fundamental achievement for development of G4 ligands as anticancer drugs.

Report

(4 results)
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Annual Research Report
  • 2013 Annual Research Report
  • Research Products

    (47 results)

All 2016 2015 2014 2013 Other

All Int'l Joint Research (2 results) Journal Article (16 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 16 results,  Acknowledgement Compliant: 5 results,  Open Access: 5 results) Presentation (25 results) (of which Int'l Joint Research: 7 results,  Invited: 15 results) Remarks (3 results) Patent(Industrial Property Rights) (1 results)

  • [Int'l Joint Research] University of Alabama at Birmingham(米国)

    • Related Report
      2015 Annual Research Report
  • [Int'l Joint Research] University of Cambridge(英国)

    • Related Report
      2015 Annual Research Report
  • [Journal Article] G-quadruplex ligand-induced DNA damage response coupled with telomere dysfunction and replication stress in glioma stem cells2016

    • Author(s)
      Hasegawa D, Okabe S, Okamoto K, Nakano I, Shin-Ya K, Seimiya H
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 471 Issue: 1 Pages: 75-81

    • DOI

      10.1016/j.bbrc.2016.01.176

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Senescence from glioma stem cell differentiation promotes tumor growth2016

    • Author(s)
      Rie Ouchi, Sachiko Okabe, Toshiro Migita, Ichiro Nakano, Hiroyuki Seimiya
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 470 Issue: 2 Pages: 275-281

    • DOI

      10.1016/j.bbrc.2016.01.071

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Report on the use of nonclinical studies in the regulatory evaluation of oncology drugs2016

    • Author(s)
      Hayakawa Y, Kawada M, Nishikawa H, Ochiya T, Saya H, Seimiya H, Yao Y, Hayashi M, Kai C, Matsuda A, Naoe T, Ohtsu A, Okazaki T, Saji H, Sata M, Sugimura H, Sugiyama Y, Toi M, Irimura T
    • Journal Title

      Cancer Sci

      Volume: 107(2) Issue: 2 Pages: 189-202

    • DOI

      10.1111/cas.12857

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Design, Synthesis and Evaluation of an L-Dopa-Derived Macrocyclic Hexaoxazole (6OTD) as a G-Quadruplex-Selective Ligand2015

    • Author(s)
      Takahiro Nakamura, Yue Ma, Keisuke Iida, Terumi Ohtake, Hiroyuki Seimiya, and Kazuo Nagasawa
    • Journal Title

      Heterocycles

      Volume: 92 Issue: 2 Pages: 305-315

    • DOI

      10.3987/com-15-13383

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Comprehensive transcriptomic analysis of molecularly targeted drugs in cancer for target pathway evaluation2015

    • Author(s)
      Mashima T, Ushijima M, Matsuura M, Tsukahara S, Kunimasa K, Furuno A, Saito S, Kitamura M, Soma-Nagae T, Seimiya H, Dan S, Yamori T, Tomida A
    • Journal Title

      Cancer Science

      Volume: in press Issue: 7 Pages: 909-920

    • DOI

      10.1111/cas.12682

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Predicting risk at the end of the end: Telomere G-tail as a biomarker2015

    • Author(s)
      Seimiya H
    • Journal Title

      EBioMedicine

      Volume: 2 Issue: 8 Pages: 802-803

    • DOI

      10.1016/j.ebiom.2015.07.006

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Design and Synthesis of a Berberine Dimer: A Fluorescent Ligand with High Affinity towards G-Quadruplexes2015

    • Author(s)
      M. Tera, T. Hirokawa, S. Okabe, K. Sugahara, H. Seimiya, K. Shimamoto
    • Journal Title

      Chemistry A European Journal

      Volume: 21 Issue: 41 Pages: 14519-14528

    • DOI

      10.1002/chem.201501693

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Telomeric repeat-containing RNA/G-quadruplex-forming sequences cause genome-wide alteration of gene expression in human cancer cells in vivo2015

    • Author(s)
      Hirashima K, Seimiya H
    • Journal Title

      Nucleic Acids Res

      Volume: 43 Issue: 4 Pages: 2022-2032

    • DOI

      10.1093/nar/gkv063

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] TRIB1 supports prostate tumorigenesis and tumor-propagating cell survival by regulation of endoplasmic reticulum chaperone expression2014

    • Author(s)
      Mashima T, Soma-Nagae T, Migita T, Kinoshita R, Iwamoto A, Yuasa T, Yonese J, Ishikawa Y, Seimiya H
    • Journal Title

      Cancer Res

      Volume: 74 Issue: 17 Pages: 4888-4897

    • DOI

      10.1158/0008-5472.can-13-3718

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] TRF1 ensures the centromeric function of Aurora-B and proper chromosome segregation2014

    • Author(s)
      Ohishi, T., Muramatsu, Y., Yoshida, H., Seimiya, H.
    • Journal Title

      Mol Cell Biol

      Volume: (in press) Issue: 13 Pages: 2464-2478

    • DOI

      10.1128/mcb.00161-14

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] TRF1 ensures the centromeric function of Aurora-B and proper chromosome segregation.2014

    • Author(s)
      Ohishi T, Muramatsu Y, Yoshida H, Seimiya H
    • Journal Title

      Mol Cell Biol

      Volume: in press

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Inhibition of ATP citrate lyase induces triglyceride accumulation with altered fatty acid composition in cancer cells.2014

    • Author(s)
      5.Migita T, Okabe S, Ikeda K, Igarashi S, Sugawara S, Tomida A, Soga T, Taguchi R, Seimiya H.
    • Journal Title

      Int J Cancer.

      Volume: 135 Issue: 1 Pages: 37-47

    • DOI

      10.1002/ijc.28652

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Telomere length influences cancer cell differentiation in vivo.2013

    • Author(s)
      Hirashima K, Migita T, Sato S, Muramatsu Y, Ishikawa Y, Seimiya H
    • Journal Title

      Mol Cell Biol

      Volume: 33 Issue: 15 Pages: 2988-2995

    • DOI

      10.1128/mcb.00136-13

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Evaluation of the interaction between long telomeric DNA and macrocyclic hexaoxazole (6OTD) dimer of a G-quadruplex ligand.2013

    • Author(s)
      Iida, K.
    • Journal Title

      Molecules

      Volume: 18 Issue: 4 Pages: 4328-4341

    • DOI

      10.3390/molecules18044328

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Inhibition of ATP citrate lyase induces an anticancer effect via reactive oxygen species: AMPK as a predictive biomarker for therapeutic impact2013

    • Author(s)
      Migita, T., Okabe, S., Ikeda, K., Igarashi, S., Sugawara, S., Tomida, A., Taguchi, R., Soga, T., Seimiya, H.
    • Journal Title

      Am J Pathol.

      Volume: 182 Issue: 5 Pages: 1800-1810

    • DOI

      10.1016/j.ajpath.2013.01.048

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Development of a gene expression database and related analysis programs for evaluation of anticancer compounds.2013

    • Author(s)
      Ushijima M, Mashima T, Tomida A, Dan S, Saito S, Furuno A, Tsukahara S, Seimiya H, Yamori T, Matsuura M.
    • Journal Title

      Cancer Sci.

      Volume: 104(3) Issue: 3 Pages: 360-368

    • DOI

      10.1111/cas.12071

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Presentation] TERRA G-quadruplex as a potential modifier of cancer behavior2016

    • Author(s)
      Hiroyuki Seimiya
    • Organizer
      The 13th Korea-Japan Joint Symposium on Cancer and Ageing Research
    • Place of Presentation
      Jeju, Korea
    • Year and Date
      2016-02-25
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] A preferential growth inhibitory activity of a G-quadruplex ligand against glioma stem cells2016

    • Author(s)
      Takahiro Nakamura, Sachiko Okabe, Keisuke Iida, Takao Yamori, Kazuo Shin-ya, Ichiro Nakano, Kazuo Nagasawa and Hiroyuki Seimiya
    • Organizer
      The 13th Korea-Japan Joint Symposium on Cancer and Ageing Research
    • Place of Presentation
      Jeju, Korea
    • Year and Date
      2016-02-25
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] New mode-of-action of anticancer effects of G-quadruplex ligands2016

    • Author(s)
      Reina Kojima, Keiji Okamoto, Sachiko Okabe, Takahiro Nakamura, Kazuo Nagasawa, and Hiroyuki Seimiya
    • Organizer
      The 13th Korea-Japan Joint Symposium on Cancer and Ageing Research
    • Place of Presentation
      Jeju, Korea
    • Year and Date
      2016-02-25
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Senescence from cancer stem cell differentiation promotes tumor growth in glioblastoma2016

    • Author(s)
      Rie Ouchi, Sachiko Okabe, Toshiro Migita, Ichiro Nakano, Hiroyuki Seimiya
    • Organizer
      The 10th AACR-JCA Joint Conference on Breakthroughs in Cancer Research: From Biology to Therapeutics
    • Place of Presentation
      Hawaii, USA
    • Year and Date
      2016-02-16
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Glioma stem cell-selective antitumor effect of a novel G-quadruplex ligand2015

    • Author(s)
      Takahiro Nakamura, Sachiko Okabe, Keisuke Iida, Takao Yamori, Kazuo Shin-ya, Ichiro Nakano, Kazuo Nagasawa and Hiroyuki Seimiya
    • Organizer
      The 20th Japanese Foundation for Cancer Research-International Symposium on Cancer Chemotherapy
    • Place of Presentation
      Daiba, Tokyo
    • Year and Date
      2015-12-09
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 神経膠腫幹細胞に対するグアニン四重鎖リガンドの制がん作用機序2015

    • Author(s)
      長谷川大記、岡部幸子、中野伊知郎、新家一男、清宮啓之
    • Organizer
      BMB2015
    • Place of Presentation
      兵庫県神戸市
    • Year and Date
      2015-12-01
    • Related Report
      2015 Annual Research Report
  • [Presentation] Senescence derived from glioma stem cell differentiation and its implication in the tumor progression2015

    • Author(s)
      Rie Ouchi, Sachiko Okabe, Toshiro Migita, Ichiro Nakano, Hiroyuki Seimiya
    • Organizer
      BMB2015
    • Place of Presentation
      兵庫県神戸市
    • Year and Date
      2015-12-01
    • Related Report
      2015 Annual Research Report
  • [Presentation] G-quadruplex: a potential modifier of cancer behavior and a therapeutic target for glioma stem cells2015

    • Author(s)
      清宮啓之
    • Organizer
      慶應義塾大学理工学部セミナー
    • Place of Presentation
      神奈川県横浜市
    • Year and Date
      2015-10-28
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] がん分子標的創薬をめぐる最近の話題2015

    • Author(s)
      清宮啓之
    • Organizer
      第74回日本癌学会学術総会モーニングレクチャー
    • Place of Presentation
      愛知県名古屋市
    • Year and Date
      2015-10-08
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] Growth inhibition mechanisms for a telomestatin derivative against glioma stem cells2015

    • Author(s)
      中村貴大、岡部幸子、飯田圭介、新家一男、長澤和夫、清宮啓之
    • Organizer
      第74回日本癌学会学術総会
    • Place of Presentation
      愛知県名古屋市
    • Year and Date
      2015-10-08
    • Related Report
      2015 Annual Research Report
  • [Presentation] テロメスタチン誘導体による神経膠腫幹細胞の増殖抑制メカニズム2015

    • Author(s)
      中村貴大、岡部幸子、飯田圭介、矢守隆夫、新家一男、長澤和夫、清宮啓之
    • Organizer
      第19回日本がん分子標的治療学会学術集会
    • Place of Presentation
      愛媛県松山市
    • Year and Date
      2015-06-10
    • Related Report
      2015 Annual Research Report
  • [Presentation] TERRA G-quadruplex as a potential modifier of the genome-wide gene expression and cancer behavior in vivo2015

    • Author(s)
      Hiroyuki Seimiya
    • Organizer
      5th International Meeting on Quadruplex Nucleic Acids
    • Place of Presentation
      Bordeaux、France
    • Year and Date
      2015-05-26
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] G-quadruplex: a potential modifier of cancer behavior and a therapeutic target for glioma stem cells2015

    • Author(s)
      Hiroyuki Seimiya
    • Organizer
      Developmental Therapeutics Branch, National Cancer Institute, Special DTB Seminar
    • Place of Presentation
      Bethesda, USA
    • Year and Date
      2015-04-23
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] グアニン4重鎖を標的としたがん創薬2015

    • Author(s)
      清宮啓之
    • Organizer
      愛媛大学医学部分子病態医学セミナー
    • Place of Presentation
      愛媛県東温市
    • Year and Date
      2015-04-03
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] G-quadruplex, a potential modifier of cancer behavior and a target for the therapeutic intervention2015

    • Author(s)
      清宮啓之
    • Organizer
      国際高等研究所研究プロジェクト「クロマチン・デコーディング」2014年度第1回研究会
    • Place of Presentation
      国際高等研究所(京都府・木津川市)
    • Year and Date
      2015-03-19
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] グアニン4重鎖リガンドによる神経膠腫幹細胞のターゲティング2015

    • Author(s)
      清宮啓之
    • Organizer
      日本癌学会シンポジウム/共同利用・共同研究拠点シンポジウム「がん幹細胞・微小環境・分子標的~がん進展制御への挑戦」
    • Place of Presentation
      石川県立音楽堂交流ホール(石川県・金沢市)
    • Year and Date
      2015-01-22
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] G-quadruplex as a therapeutic target for glioma stem cells2014

    • Author(s)
      Seimiya H
    • Organizer
      The 19th Japan-Korea Cancer Research Workshop
    • Place of Presentation
      Jeju (Korea)
    • Year and Date
      2014-11-29
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] G-quadruplex, a potential modifier of cancer behavior and a therapeutic target for glioma stem cells2014

    • Author(s)
      Seimiya H
    • Organizer
      The 4th Japan-France Cancer Workshop
    • Place of Presentation
      関西セミナーハウス(京都府・京都市)
    • Year and Date
      2014-11-19
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Telomeres and G-quadruplexes as targets for cancer therapy2014

    • Author(s)
      Seimiya, H.
    • Organizer
      Kangwon National University Research Seminar
    • Place of Presentation
      Gangwon-Do, Korea
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] TRF1 ensures proper chromosome segregation in mitosis.2013

    • Author(s)
      Seimiya, H
    • Organizer
      Cold Spring Harbor Laboratory Meeting on Telomeres & Telomerase
    • Place of Presentation
      Cold Spring Harbor, NY, USA
    • Related Report
      2013 Annual Research Report
  • [Presentation] グアニン4重鎖リガンドによる神経膠腫幹細胞のターゲティング2013

    • Author(s)
      清宮啓之
    • Organizer
      第17回日本がん分子標的治療学会学術集会
    • Place of Presentation
      京都
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] G4リガンドによるがん幹細胞のターゲティング2013

    • Author(s)
      清宮啓之
    • Organizer
      第47回愛媛大学分子病態医学セミナー
    • Place of Presentation
      松山
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Targeted therapy of glioma stem cells with G-quadruplex ligands2013

    • Author(s)
      Seimiya, H
    • Organizer
      第72回日本癌学会学術総会
    • Place of Presentation
      横浜
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] 抗がん剤探索アプローチの変遷と最近の話題2013

    • Author(s)
      清宮啓之
    • Organizer
      第72回日本癌学会学術総会
    • Place of Presentation
      横浜
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Telomere length influences cancer cell differentiation in vivo2013

    • Author(s)
      Seimiya, H
    • Organizer
      3rd GDRI French Japanese Cancer Meeting
    • Place of Presentation
      Toulouse, France
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Remarks] 研究室ホームページ

    • URL

      http://www.jfcr.or.jp/chemotherapy/department/molecular_biotherapy/index.html

    • Related Report
      2015 Annual Research Report 2014 Annual Research Report
  • [Remarks] がん幹細胞の治療抵抗性と標的分子

    • URL

      http://www.jfcr.or.jp/chemotherapy/department/molecular_biotherapy/research/003.html

    • Related Report
      2014 Annual Research Report
  • [Remarks] 研究室ホームページ

    • URL

      http://www.jfcr.or.jp/chemotherapy/department/molecular_biotherapy/index.html

    • Related Report
      2013 Annual Research Report
  • [Patent(Industrial Property Rights)] 神経膠腫幹細胞を標的とするグアニン四重鎖リガンド2014

    • Inventor(s)
      長澤和夫、清宮啓之、飯田圭介、中村貴大
    • Industrial Property Rights Holder
      東京農工大学、(公財)がん研究会
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2014-229221
    • Filing Date
      2014-11-11
    • Related Report
      2014 Annual Research Report

URL: 

Published: 2013-05-21   Modified: 2022-01-31  

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