ヒト神経芽腫ＭＹＣＮ／ＮＣＹＭマウスモデル構築による大規模分子標的創薬

2014 Fiscal Year Annual Research Report

• Project/Area Number: 24249061
• Research Institution: Kyushu University
• Principal Investigator: 中川原 章 九州大学, 医学(系)研究科(研究院), 研究員 (50117181)
• Co-Investigator(Kenkyū-buntansha): 大平 美紀 千葉県がんセンター(研究所), その他部局等, 研究員 (20311384)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 神経芽腫 / TrkB / ALK / ShcC / 創薬

Outline of Annual Research Achievements

小児がんの治癒率が７０％を越す中、今なお最も難治性の高リスク神経芽腫に対する新しい治療薬の開発は喫緊の課題である。インシリコ・オートドック・スクリーニング法を用いて、TrkB受容体のBDNF結合領域を標的とする３００万個の低分子化合物から、７個の阻害剤の同定し、さらにIC-50の低い２個の構造から類推して新規化合物５個を作製した。次に、マウスを用いた神経芽腫ゼノグラフトでin vivo増殖抑制を確認した。また、神経芽腫細胞株でp53の強い活性化が認められた。さらに同様の方法で、我々が見いだしたNCYM蛋白に対する阻害剤を探索すべく、標的部位のデザイン作製を始めた。
一方、高リスク神経芽腫に高発現するNLRR1新規膜蛋白質に対する増殖抑制性単クローン抗体を大量に作製し、ヒト神経芽腫ゼノグラフトにおいて抗体が腫瘍に蓄積すること、腫瘍の増殖を抑制することを確認した。さらに、ヒト神経芽腫組織において、NLRR1とALKが異なる腫瘍細胞群に発現していることを見いだした。したがって、NLRR1抗体を用いた治療と、ALK阻害剤の併用療法が神経芽腫においては重要と考えられた。
MYCNオンコジンの cis-antisense geneであるNCYM遺伝子は、ヒトおよびチンパンジーのみにしか無い蛋白質であり、GSK3bを阻害することによってMYCN蛋白質の安定化を図ることを見出したが、今回、Calpainを介してMyc蛋白質のcleavageを促進し細胞死を抑制していることを明らかにした。したがって、NCYMの機能がさらに明らかとなり、NCYMに対する阻害剤の開発が、とくに神経芽腫においてはより重要となって来た。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [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 Pages: e1607.
  • DOI: 10.1038/cddis.2014.568.
  • 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) Pages: 1904-1915
  • DOI: 10.1158/1078-0432.CCR-14-0817.
  • Peer Reviewed / Open Access
• [Journal Article] Receptor-type protein tyrosine phosphatase κdirectly dephosphorylates CD133 and regulates downstream AKT activation. (2015)
  • Author(s): Shimozato O, Waraya M, Nakashima K, Soda H, Takiguchi N, Yamamoto H, Takenobu H, Uehara H, Ikeda E, Matsushita S, Kubo N, Nakagawara A, Ozaki T, Kamijo T.
  • Journal Title: Oncogene. Volume: 34(15) Pages: 1949-1960
  • DOI: 10.1038/onc.2014.141.
  • Peer Reviewed / Open Access
• [Journal Article] NCYM, a cis-antisense gene of MYCN, encodes a de novo evoluted protein that inhibits GSK3b resulting in the stabilization of MYCN in human neuroblastoma. (2014)
  • Author(s): Suenaga Y, Islam SMR, Alagu J, Kaneko Y, Kato M, Tanaka Y, Kawana H, Hossain S, Matsumoto D, Yamamoto M, Shoji W, Itami M, Shibta T, Nakamura Y, Ohira M, Haraguchi S, Takatori A, Nakagawara A.
  • Journal Title: PLoS Genet. Volume: 10(1) Pages: e1003996
  • DOI: 10.1371/journal.pgen.1003996.
  • Peer Reviewed / Open Access
• [Journal Article] RUNX3 interacts with MYCN and facilitates protein degradation in neuroblastoma. (2014)
  • Author(s): Yu F, Gao W, Yokochi T, Suenaga Y, Ando K, Ohira M, Nakamura Y, Nakagawara A.
  • Journal Title: Oncogene Volume: 33(20) Pages: 2601-2609
  • DOI: 10.1038/onc.2013.221.
  • 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(4) Pages: 627-635
  • DOI: 10.1002/pbc.24777.
  • 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, Hasan MK, Yokochi T, Takatori A, Sato S, Hoshino T, Tamura Y, Nakagawara A.
  • Journal Title: Cancer Med. Volume: 3(1) Pages: 25-35
  • DOI: 10.1002/cam4.175.
  • Peer Reviewed / Open Access
• [Journal Article] Two cases of neuroblastoma comprising two distinct clones. (2014)
  • Author(s): Yamazaki F, Nakazawa A, Shimojima N, Tanaka T, Nakagawara A, Shimada H.
  • Journal Title: Pediatr Blood Cancer. Volume: 61(4) Pages: 760-762
  • DOI: 10.1002/pbc.24779.
  • Peer Reviewed / Open Access
• [Journal Article] Novel 1p tumor suppressor DMAP1 regulates MYCN/ATM/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(8) Pages: 1555-1565
  • DOI: 10.1016/j.ejca.2014.01.023.
  • Peer Reviewed / Open Access
• [Journal Article] Metastatic neuroblastoma confined to distant lymph nodes (stage 4N) predeicts outcome in patients with stage 4 disease: A study from the International Neuroblastoma Risk Group Database. (2014)
  • Author(s): Morgenstern DA, London WA, Stephens D, Volchenboum S, Hero B, Cataldo AD, Nakagawara A, Shimada H, Ambros P, Matthay KK, Cohn SL, Peason ADJ, Irwin MS.
  • Journal Title: J Clin Oncol. Volume: 20 Pages: 1228-1235
  • DOI: 10.1200/JCO.2013.53.6342.
  • Peer Reviewed / Open Access
• [Journal Article] RASSF1A methylation may have two biological roles on neuroblastoma tumorigenesis depending on the ploidy status and age of patients. (2014)
  • Author(s): Haruta M, Kamijo T, Nakagawara A, Kaneko Y.
  • Journal Title: Cancer Lett. Volume: 348(1-2) Pages: 167-176
  • DOI: 10.1016/j.canlet.2014.03.022.
  • 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) Pages: 3790-3801
  • DOI: 10.1158/0008-5472.CAN-14-0241.
  • 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) Pages: 1932-1939
  • DOI: 10.1002/pbc.25134.
  • 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) Pages: 3169-3176
  • DOI: 10.1200/JCO.2014.56.1621.
  • 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) Pages: 86-93
  • DOI: 10.1016/j.bbrc.2014.09.065.
  • Peer Reviewed / Open Access
• [Presentation] Reducing inequalities in childhood cancer : Experience from Asia (2014)
  • 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
  • Invited
• [Presentation] JCCG and COG: Global challenge for the future of pediatric hematology and oncology (2014)
  • 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
  • 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
• [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
• [Presentation] NEURONAL LEUCINE RICH REPEAT PROTEIN1(NLRR1)SUPPRESSES NGF/TRKA SIGNAL IN NEUROBLASTOMA (2014)
  • 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
• [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