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Generation of the MYCN/NCYM mouse model and the drug discovery for human neuroblastoma

Research Project

Project/Area Number 24249061
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionKyushu University (2014)
Chiba Cancer Center (Research Institute) (2012-2013)

Principal Investigator

NAKAGAWARA Akira  九州大学, 医学(系)研究科(研究院), 研究員 (50117181)

Co-Investigator(Kenkyū-buntansha) OOHIRA Miki  千葉県がんセンター(研究所), がんゲノム研究室, 室長 (20311384)
高取 敦志  千葉県がんセンター(研究所), 小児がん研究センター, 研究員 (40455390)
中村 洋子  千葉県がんセンター(研究所), がん先進治療開発研究室, 主席研究員 (60260254)
末永 雄介  千葉県がんセンター(研究所), がん先進治療開発研究室, 研究員 (80581793)
Co-Investigator(Renkei-kenkyūsha) TAKATORI Athushi  千葉県がんセンター(研究所), がん遺伝創薬研究室, 研究員 (40455390)
NAKAMURA Youko  千葉県がんセンター(研究所), がん予防センター, 主席研究員 (60260254)
SUENAGA Yusuke  千葉県がんセンター(研究所), 臨床ゲノム研究室, 研究員 (80581793)
Project Period (FY) 2012-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥45,110,000 (Direct Cost: ¥34,700,000、Indirect Cost: ¥10,410,000)
Fiscal Year 2014: ¥13,000,000 (Direct Cost: ¥10,000,000、Indirect Cost: ¥3,000,000)
Fiscal Year 2013: ¥12,870,000 (Direct Cost: ¥9,900,000、Indirect Cost: ¥2,970,000)
Fiscal Year 2012: ¥19,240,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥4,440,000)
Keywords創薬 / 神経芽腫 / in silico screening / TrkB / ALK / ShcC / NCYM / MYCN
Outline of Final Research Achievements

In this study, we developed new drugs against high-risk neuroblastoma. By targeting TrkB and ALK/ShcC proteins, we successfully identified more than several small chemical compounds that efficiently kill neuroblastoma cells. In addition, the candidate therapeutic monoclonal antibodies targeting NLRR1 were also generated. Furthermore, the NCYM/MYCN double transgenic mice we generated revealed to be suitable for screening new candidate drugs against high-risk human neuroblastoma.

Report

(4 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Annual Research Report
  • 2012 Annual Research Report
  • Research Products

    (41 results)

All 2015 2014 2013 2012

All Journal Article (35 results) (of which Peer Reviewed: 35 results,  Open Access: 15 results) Presentation (6 results) (of which Invited: 2 results)

  • [Journal Article] BMCC1, which is an interacting partner of BCL2, attenuates AKT activity, accompanied by apoptosis.2015

    • Author(s)
      Tatsumi Y, Takano R, Islam MS, Yokochi T, Itami M, Nakamura Y, Nakagawara A.
    • Journal Title

      Cell Death Dis.

      Volume: 6 Issue: 1 Pages: e1607-e1607

    • DOI

      10.1038/cddis.2014.568

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Revised risk estimation and treatment stratification of low- and intermediate-risk neuroblastoma patients by integrating clinical and molecular prognostic markers.2015

    • Author(s)
      Oberthuer A, Juraeva D, Hero B, Volland R, Carolina S, Schmidt R, Faldum A, Kahlert Y, Engesser A, Asgharzadeh S, Seeger RC, Ohira M, Nakagawara A, Scaruffi P, at all
    • Journal Title

      Clin Cancer Res.

      Volume: 21(8) Issue: 8 Pages: 1904-1915

    • DOI

      10.1158/1078-0432.ccr-14-0817

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] NCYM, a Cis-antisense gene of MYCN, encodes a de novo evolved protein that inhibits GSK3β resulting in the stabilization of MYCN in human neuroblastomas.2014

    • Author(s)
      Suenaga Y, Islam SM, Alagu J, Kaneko Y, Kato M, Tanaka Y, Kawana H, Hossain S, Matsumoto D, Yamamoto M, Shoji W, Itami M, Shibata T, Nakamura Y, Ohira M, Haraguchi S, Takatori A, Nakagawara A.
    • Journal Title

      PLoS Genet

      Volume: 10 Issue: 1 Pages: 1-14

    • DOI

      10.1371/journal.pgen.1003996

    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Neuroblastoma in older children, adolescents and young adults. A report from the International Neuroblastoma Risk Group Project.2014

    • Author(s)
      Mosse YP, Deyell RJ, Berthold F, Nakagawara A, Ambros PF, Monclair T, Cohn SL, Pearson AD, London WB, Matthay KK.
    • Journal Title

      Pediatr. Blood Cancer

      Volume: 61 Issue: 4 Pages: 627-635

    • DOI

      10.1002/pbc.24777

    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of novel candidate compounds targeting TrkB to induce apoptosis in neuroblastoma.2014

    • Author(s)
      Nakamura Y, Suganami A, Fukuda M, Md. Kamrul Hasan, Yokochi T, Takatori A, Satoh S, Hoshino T, Tamura Y, Nakagawara A.
    • Journal Title

      Cancer Medcine

      Volume: 3 Issue: 1 Pages: 25-35

    • DOI

      10.1002/cam4.175

    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Two cases of neuroblastoma comprising two distinct clones.2014

    • Author(s)
      Yamazaki F, Nakazawa A, Osumi T, Shimojima N, Tanaka T, Nakagawara A, Shimada H.
    • Journal Title

      Pediatr. Blood Cancer

      Volume: 61 Issue: 4 Pages: 760-762

    • DOI

      10.1002/pbc.24779

    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Novel 1p tumour suppressor Dnmt1-associated protein 1 regulates MYCN/ataxia telangiectasia mutated/p53 pathway.2014

    • Author(s)
      Yamaguchi Y, Takenobu H, Ohira M, Nakazawa A, Yoshida S, Akita N, Shimozato O, Iwama A, Nakagawara A, Kamijo T.
    • Journal Title

      Eur J Cancer

      Volume: 50 Issue: 8 Pages: 1555-1565

    • DOI

      10.1016/j.ejca.2014.01.023

    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Metastatic Neuroblastoma Confined to Distant Lymph Nodes (stage 4N) Predicts Outcome in Patients With Stage 4 Disease: A Study From the International Neuroblastoma Risk Group Database.2014

    • Author(s)
      Morgenstern DA, London WB, Stephens D, Volchenboum SL, Hero B, Di Cataldo A, Nakagawara A, Shimada H, Ambros PF, Matthay KK, Cohn SL, Pearson AD, Irwin MS.
    • Journal Title

      J. Clin. Oncol.

      Volume: 32 Issue: 12 Pages: 1228-1235

    • DOI

      10.1200/jco.2013.53.6342

    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] RASSF1A methylation may have two biological roles in neuroblastoma tumorigenesis depending on the ploidy status and age of patients2014

    • Author(s)
      Haruta M, Kamijo T, Nakagawara A, Kaneko Y
    • Journal Title

      Cancer Lett

      Volume: 348 Issue: 1-2 Pages: 167-176

    • DOI

      10.1016/j.canlet.2014.03.022

    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Flotillin-1 regulates oncogenic signaling in neuroblastoma cells by regulating ALK membrane association.2014

    • Author(s)
      Tomiyama A, Uekita T, Kamata R, Sasaki K, Takita J, Ohira M, Nakagawara A, Kitanaka C, Mori K, Yamaguchi H, Sakai R.
    • Journal Title

      Cancer Res.

      Volume: 74(14) Issue: 14 Pages: 3790-3801

    • DOI

      10.1158/0008-5472.can-14-0241

    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Significance of clinical and biologic features in stage 3 neuroblastoma: A report from the International Neuroblastoma Risk Group project.2014

    • Author(s)
      Meany HJ, London WB, Ambros PF, Matthay KK, Monclair T, Simon T, Garaventa A, Berthold F, Nakagawara A, Cohn SL, Peason ADJ, Park JR.
    • Journal Title

      Pediatr Blood Cancer.

      Volume: 61(11) Issue: 11 Pages: 1932-1939

    • DOI

      10.1002/pbc.25134

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinical, biological, and prognostic differences on the basis of primary tumor site in neuroblastoma: a report from the international neuroblastoma risk group project.2014

    • Author(s)
      Vo KT, Matthay KK, Neuhaus J, London WB, Hero B, Ambros PF, Nakagawara A, Miniati D, Wheeler K, Pearson ADJ, Cohn SL, DuBois SG.
    • Journal Title

      J Clin Oncol.

      Volume: 32(28) Issue: 28 Pages: 3169-3176

    • DOI

      10.1200/jco.2014.56.1621

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Intracellular fragment of NLRR3 (NLRR3-ICD) stimulates ATRA-dependent neuroblastoma differentiation.2014

    • Author(s)
      Akter J, Takatori A, Islam MS, Nakazawa A, Ozaki T, Nagase H, Nakagawara A.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 453(1) Issue: 1 Pages: 86-93

    • DOI

      10.1016/j.bbrc.2014.09.065

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Receptor-type protein tyrosine phosphatasedirectly dephosphorylates CD133 and regulates downstream AKT activation2014

    • Author(s)
      Shimozato O, Souda H
    • Journal Title

      Oncogene

      Volume: 34(15) Issue: 15 Pages: 1-12

    • DOI

      10.1038/onc.2014.141

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] RUNX3 interacts with MYCN and facilitates protein degradation in neuroblastoma.2013

    • Author(s)
      Yu F, Gao W, Yokochi T, Suenaga Y, Ando K, Ohira M, Nakamura Y, Nakagawara A.
    • Journal Title

      Oncogene

      Volume: 33 Issue: 20 Pages: 2601-2609

    • DOI

      10.1038/onc.2013.221

    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cell culture and Drosophila model systems define three classes of anaplastic lymphoma kinase mutations in neuroblastoma.2013

    • Author(s)
      Chand D, Yamazaki Y, Ruuth K, Schönherr C, Martinsson T, Kogner P, Attiyeh EF, Maris J, Morozova O, Marra MA, Ohira M, Nakagawara A, Sandström PE, Palmer RH, Hallberg B.
    • Journal Title

      Dis Model Mech.

      Volume: 6 Pages: 373-82

    • DOI

      10.1242/dmm.010348

    • Related Report
      2013 Annual Research Report 2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Epithelial mesenchymal transition-related gene expression as a new prognostic marker for neuroblastoma.2013

    • Author(s)
      Nozato M, Komuro H et al.
    • Journal Title

      International Journal of Oncology

      Volume: 42 Issue: 1 Pages: 134-140

    • DOI

      10.3892/ijo.2012.1684

    • Related Report
      2013 Annual Research Report 2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A MYCN-amplified cell line derived from a long-term event-free survivor among our sixteen established neuroblastoma cell lines.2013

    • Author(s)
      Sugimoto T, Gotoh T, Yagyu S, Kuroda H, Iehara T, Hosoi H, Ohta S, Ohira M, Nakagawara A.
    • Journal Title

      Cancer Lett

      Volume: 331 Issue: 1 Pages: 115-121

    • DOI

      10.1016/j.canlet.2012.12.011

    • Related Report
      2013 Annual Research Report 2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Novel adaptor protein Shf interacts with ALK receptor and negatively regulates its downstream signals in neuroblastoma.2013

    • Author(s)
      Takagi D
    • Journal Title

      Cancer Sci

      Volume: 104 Issue: 5 Pages: 563-572

    • DOI

      10.1111/cas.12115

    • Related Report
      2013 Annual Research Report 2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Temozolomide suppresses MYC via activation of TAp63 to inhibit progression of human glioblastoma.2013

    • Author(s)
      Yamaki T, Suenaga Y, Iuchi T, Alagu J, Takatori A, Itami M, Araki A, Ohira M, Inoue M, Kageyama H, Yokoi S, Saeki N, Nakagawara A.
    • Journal Title

      Sci Rep.

      Volume: 3 Issue: 1 Pages: 1160-1160

    • DOI

      10.1038/srep01160

    • Related Report
      2013 Annual Research Report 2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Stronger prognostic power of the CpG island methylator phenotype than methylation of individual genes in neuroblastomas2013

    • Author(s)
      Asada K, Watanabe N, Nakamura Y, Ohira M, Westermann F, Schwab M, Nakagawara A, Ushijima T.
    • Journal Title

      Jpn J Clin Oncol

      Volume: 43 Issue: 6 Pages: 641-645

    • DOI

      10.1093/jjco/hyt058

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Apoptotic cell death in neuroblastoma.2013

    • Author(s)
      Li Y, Nakagawara A.
    • Journal Title

      Cells

      Volume: 2 Issue: 2 Pages: 432-459

    • DOI

      10.3390/cells2020432

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Dependence receptor UNC5D mediates nerve growth factor depletion-induced neuroblastoma regression.2013

    • Author(s)
      Zhu Y, Li Y, Haraguchi S, Yu M, Ohira M, Ozaki T, Nakagawa A, Ushijima T, Isogai E, Koseki H, Nakamura Y, Kong C, Mehlen P, Arakawa H, Nakagawara A.
    • Journal Title

      J Clin Invest.

      Volume: 123 Issue: 7 Pages: 2935-47

    • DOI

      10.1172/jci65988

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] ALK is a MYCN target gene and regulates cell migration and invasion in neuroblastoma.2013

    • Author(s)
      Hasan MK, Nafady A, Takatori A, Kishida S, Ohira M, Suenaga Y, Hossain S, Akter J, Ogura A, Nakamura Y, Kadomatsu K, Nakagawara A.
    • Journal Title

      Sci Rep

      Volume: 3 Issue: 1 Pages: 3450-3450

    • DOI

      10.1038/srep03450

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] NFBD1/MDC1 is phosphorylated by PLK1 and controls G2/M transition through the regulation of a TOPOIIα-mediated decatenation checkpoint.2013

    • Author(s)
      Ando K, Ozaki T, Hirota T, Nakagawara A.
    • Journal Title

      PLoS One

      Volume: e82744 Issue: 12 Pages: 0-0

    • DOI

      10.1371/journal.pone.0082744

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Runt-related Transcription Factor 1 (RUNX1) Stimulates Tumor Suppressor p53 in Response to DNA Damage Through Complex Formation and Acetylation.2013

    • Author(s)
      Wu D, Nakagawara A. et.al.
    • Journal Title

      J. Biol. Chem.

      Volume: 288 Issue: 2 Pages: 1353-1364

    • DOI

      10.1074/jbc.m112.402594

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Co-chaperon DnaJC7/TPR2 enhances p53 stability and activity through blocking the complex formation between p53 and MDM2.2013

    • Author(s)
      Kubo N, Wu D, Yoshihara Y, Sang M, Nakagawara A, Ozaki T.
    • Journal Title

      Biochem. Biophys. Res. Commun.

      Volume: 430 Issue: 3 Pages: 1034-1039

    • DOI

      10.1016/j.bbrc.2012.11.121

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Runt-related transcription factor 2 (RUNX2) inhibits p53- dependent apoptosis through the collaboration with HDAC6 in response to DNA damage.2013

    • Author(s)
      Ozaki T, Wu D, Sugimoto H, Nagase H, Nakagawara A.
    • Journal Title

      Cell Death Dis.

      Volume: e610 Issue: 4 Pages: e610-e610

    • DOI

      10.1038/cddis.2013.127

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Stronger Prognostic Power of the CpG Island Methylator Phenotype than Methylation of Individual Genes in Neuroblastomas.2013

    • Author(s)
      Asada K, Nakagawara A, Ushijima T. et. al.
    • Journal Title

      Jpn. J. Clin. Oncol.

      Volume: Epub ahead of print

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Kruppel-like factor 4 (KLF4) suppresses neuroblastoma cell growth and determines non-tumorigenic lineage differentiation.2012

    • Author(s)
      Shum CK, Lau ST, Tsoi LL, Chan LK, Yam JW, Ohira M, Nakagawara A, Tam PK, Ngan ES.
    • Journal Title

      Oncogene

      Volume: advance online publication Issue: 35 Pages: 4086-4099

    • DOI

      10.1038/onc.2012.437

    • Related Report
      2013 Annual Research Report 2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Inhibitory role of E2F-1 in the regulation of tumor suppressor p53 during DNA damage response2012

    • Author(s)
      Yoshihara Y, Nakagawara A, et.al.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 421 Issue: 1 Pages: 57-63

    • DOI

      10.1016/j.bbrc.2012.03.108

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Molecular and genetic bases of neuroblastoma2012

    • Author(s)
      Kamijo T, Nakagawara A
    • Journal Title

      Int J Clin Oncol.

      Volume: 17 Issue: 3 Pages: 190-195

    • DOI

      10.1007/s10147-012-0415-7

    • NAID

      10030951290

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] NLRR1 enhances EGF-mediated MYCN induction in neuroblastoma and accelerates tumor growth in vivo.2012

    • Author(s)
      Hossain S
    • Journal Title

      Cancer Res

      Volume: 72 Issue: 17 Pages: 4587-4596

    • DOI

      10.1158/0008-5472.can-12-0943

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Towards a turning point of neuroblastoma therapy.2012

    • Author(s)
      Tonini GP, Nakagawara A, Berthold F.
    • Journal Title

      Cancer Lett.

      Volume: 326 Issue: 2 Pages: 128-134

    • DOI

      10.1016/j.canlet.2012.08.017

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Segmental chromosomal alterations have prognostic impact in neuroblastoma: a report from the INRG project.2012

    • Author(s)
      Schleiermacher G, Nakagawara A, Pearson AD. et. al.
    • Journal Title

      Br. J. Cancer

      Volume: 107 Issue: 8 Pages: 1418-1422

    • DOI

      10.1038/bjc.2012.375

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Presentation] Reducing inequalities in childhood cancer : Experience from Asia2014

    • Author(s)
      A.Nakagawara
    • Organizer
      2014 WORLD CENCER CONGRESS
    • Place of Presentation
      オーストラリア
    • Year and Date
      2014-12-04
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] JCCG and COG: Global challenge for the future of pediatric hematology and oncology2014

    • Author(s)
      中川原 章
    • Organizer
      第56回日本小児血液・がん学会
    • Place of Presentation
      岡山
    • Year and Date
      2014-11-28
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] A NEUROBLASTOMA RISK CLASSIFICATION MODEL FOR DEVELOPING COUNTRIES : A STDY FROM THE INTERNATIONAL NEUROBLASTOMA(NB)RISK GROUP(INRG)2014

    • Author(s)
      W.London
    • Organizer
      46th Congress of the International Society of Paediatric Oncology
    • Place of Presentation
      カナダ
    • Year and Date
      2014-10-24 – 2014-10-25
    • Related Report
      2014 Annual Research Report
  • [Presentation] CHARACTERTICS OF IMAGE DEFINED RISK FACTORS(IDRFS) IN PATIENTS ENROLLED THE LOW RISK PROTOCOL(JNB-L-10)FROM THE JAPANESE NEUROBLASTOMA STUDY GROUP(JNBSG)2014

    • Author(s)
      A.Yoneda
    • Organizer
      46th Congress of the International Society of Paediatric Oncology
    • Place of Presentation
      カナダ
    • Year and Date
      2014-10-24 – 2014-10-25
    • Related Report
      2014 Annual Research Report
  • [Presentation] NEURONAL LEUCINE RICH REPEAT PROTEIN1(NLRR1)SUPPRESSES NGF/TRKA SIGNAL IN NEUROBLASTOMA2014

    • Author(s)
      M.Fukuda
    • Organizer
      46th Congress of the International Society of Paediatric Oncology
    • Place of Presentation
      カナダ
    • Year and Date
      2014-10-24 – 2014-10-25
    • Related Report
      2014 Annual Research Report
  • [Presentation] MYCN/ATM/p53経路を制御する 1p がん抑制2014

    • Author(s)
      上條 岳彦
    • Organizer
      第73回日本癌学会学術総会
    • Place of Presentation
      横浜
    • Year and Date
      2014-09-25
    • Related Report
      2014 Annual Research Report

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Published: 2013-05-15   Modified: 2019-07-29  

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