創薬シーズ探索のための「Cancer Cell Informatics」の開発と応用

2007 Fiscal Year Annual Research Report

• Project/Area Number: 17390032
• Research Institution: Japanese Foundation For Cancer Research
• Principal Investigator: 矢守 隆夫 Japanese Foundation For Cancer Research, 癌化学療法センター・分子薬理部, 部長 (60200854)
• Co-Investigator(Kenkyū-buntansha): 旦 慎吾 財団法人癌研究会, 癌科学療法センター分子薬理部, 研究員 (70332202)
• Keywords: Cancer Cell Informatics / 分子標的予測 / がん / がん細胞パネル / PI3K / 薬剤感受性 / 抗がん剤探索 / データベース

Research Abstract

がん細胞パネルについて化合物感受性情報とゲノム情報を集積し、化合物とその分子標的の対応関係の予測ならびに抗がん剤分子薬理研究に有用な情報を得るための基盤情報システム(Cancer Cell Infomatics、CCIと略)の構築と応用を行った。
1、CCIの構築本研究の中心となるJFCR39(9臓器由来のがん39株からなるがん細胞パネル)について新たに123種の阻害剤に対する感受性情報を取得した。JFCR45(胃がん21株、肝がん12株、乳がん12株からなるがん細胞パネル)について新たにGeneChipを用いゲノムワイドな遺伝子発現情報を取得した。以上の惰報を、昨年度作成した化合物感受性情報とゲノム情報の統合データベース(DRAMA)に加えた。DRAMAに登録された各々の化合物、遺伝子およびその産物は、いずれもがん細胞パネルを介したフィンガープリント(FPと略、詳細は調書参照)として描出される。FPの類似性を評価するプログラム(COMAPREおよびBIOCOMPARE)をバージョンアップした。FPの相互比較により、分子標的に共通性のある化合物の組み合わせ、あるいは、ミサイルと標的の関係にある化合物と遺伝子産物の組み合わせを予測することが本研究の狙いである。本年度もDRAMAのデータ量は着実に増加し、予測能力が向上した。
2、CCIの成果と応用CCIを155種の毒性化学物質評価に応用した。評価可能であった90化合物をFPに基づきクラスター解析した結果、同一クラスターに属するものは共通の作用メカニズムをもつ傾向が見られた。よって、CCIは毒性化学物質の作用メカニズム予測にも有用と考えられる。一方、CCIによって新たなメカニズムを持つことが示唆される新規抗がん剤候補物質が見出された。
次年度はDRAMAをさらに充実させ本研究を発展させる計画である。

Research Products

• [Journal Article] Synthesis of hybrid acetogenins,alpha,beta-unsaturated-gamma-lactone-free nitrogen-containing heterocyclic analogues,and their cytotoxicity against human cancer cell lines (2008)
  • Author(s): Kojima N, Fushimi T, Maezaki N, Tanaka T, Yamori T.
  • Journal Title: Bioorg Med Chem Lett. (in press)
  • Peer Reviewed
• [Journal Article] Synthesis and pharmacological evaluation of the novel pseudo-symmetrical tamoxifen derivatives as anti-tumor agents (2008)
  • Author(s): Shiina I, Sano Y, Nakata K, Kikuchi T, Sasaki A, Ikekita M, Nagahara Y, Hasome Y, Yamori T, Yamazaki K.
  • Journal Title: Biochem Pharmacol 75(5) Pages: 1014-1026
  • Peer Reviewed
• [Journal Article] Motif-programmed artificial protein induces apoptosis in several cancer cells by disrupting mitochondria (2008)
  • Author(s): Saito H, Minamisawa T, Yamori T, Shiba K.
  • Journal Title: Cancer Sci. 99(2) Pages: 398-406
  • Peer Reviewed
• [Journal Article] Anticancer mechanisms of YC-1 in human lung cancer cell line,NCI-H226 (2008)
  • Author(s): Chen CJ, Hsu MH, Huang LJ, Yamori T, Chung JG, Lee FY, Teng CM, Kuo SC.
  • Journal Title: Biochem Pharmacol 75(2) Pages: 360-368
  • Peer Reviewed
• [Journal Article] Proteomics-based identification of biomarkers for predicting sensitivety to a PI3-kinase inhibitor in cancer (2007)
  • Author(s): Akashi T, Nishimura Y, Wakatabe R, Shiwa M, Yamori T.
  • Journal Title: Biochemical and biophysical research communications 352(2) Pages: 514-521
  • Peer Reviewed
• [Journal Article] A novel method for analyzing phosphoproteins using SELDI-TOF MS in combination with a series of recombinant proteins (2007)
  • Author(s): Akashi T, Yamori T.
  • Journal Title: Proteomics 7(14) Pages: 2350-2354
  • Peer Reviewed
• [Journal Article] Variation in cytostatic constituents of a sponge-derived Gymnascella dankaliensis by manipulating the carbon source (2007)
  • Author(s): Amagata T, Tanaka M, Yamada T, Doi M, Minoura K, Ohishi H, YamoriT, Numata A.
  • Journal Title: Journal of natural products 70(11) Pages: 1731-1740
  • Peer Reviewed
• [Journal Article] Enantioselective Total Synthesis of(+)-Ottelione A,(-)-Ottelione B,(+)-3-epi-Ottelione A and Preliminary Evaluation of Their Antitumor Activity (2007)
  • Author(s): Araki H, Inoue M, Suzuki T, Yamori T, Kohno M, Watanabe K, Abe H, Katoh T.
  • Journal Title: Chemistry 13(35) Pages: 9866-9881
  • Peer Reviewed
• [Journal Article] Synthesis and structure-activity relationships of taxuyunnanine C derivatives as multidrug resistance modulator in MDR cancer cells (2007)
  • Author(s): Hasegawa T, Bai J, Dai J, Bai L, Sakai J, Nishizawa S, Bai Y, Kikuchi M, Abe M, Yamori T, TomidaA, Tsuruo T, Hirose K, Ando M.
  • Journal Title: Bioorganic&medicinal chemistry letters 17(13) Pages: 3722-3728
  • Peer Reviewed
• [Journal Article] Application of in vivo ESR/spin-probe technique to monitor tumor in vivo in mouse footpad (2007)
  • Author(s): Ichikawa K, Sakabe E, Kuninobu K, Yamori T, Tsuruo T, Yao T, Tsuneyoshi M, Utsumi H.
  • Journal Title: Antioxidants&redox signaling 9(10) Pages: 1699-1707
  • Peer Reviewed
• [Journal Article] Comparative profiling of the gene expression for estrogen responsiveness in cultured human cell lines (2007)
  • Author(s): Inoue A, Seino Y, Terasaka S, Hayashi S, Yamori T, Tanji M, Kiyama R.
  • Journal Title: Toxicol In Vitro 21(4) Pages: 741-752
  • Peer Reviewed
• [Journal Article] Development and characterization of a model of liver metastasis using human colon cancer HCT-116 cells (2007)
  • Author(s): Ishizu K, Sunose N, Yamazaki K, Tsuruo T, Sadahiro S, Makuuchi H, Yamori T.
  • Journal Title: Biological&pharmaceutical bulletin 30(9) Pages: 1779-1783
  • Peer Reviewed
• [Journal Article] Marine diterpenoids with a briarane skeleton from the Okinawan soft coral Pachyclavularia violacea (2007)
  • Author(s): Ito H, Iwasaki J, Sato Y, Aoyagi M, Iguchi K, Yamori T.
  • Journal Title: Chemical&pharmaceutical bulletin 55(12) Pages: 1671-1676
  • Peer Reviewed
• [Journal Article] ZSTK474 is an ATP-competitive inhibitor of class I phosphatidylinosito 13 kinase isoforms (2007)
  • Author(s): Kong D, Yamori T.
  • Journal Title: Cancer science 98(10) Pages: 1638-1642
  • Peer Reviewed
• [Journal Article] Sesquiterpenoids and flavonoids from the aerial parts of Tithonia diversifolia and their cytotoxic activity (2007)
  • Author(s): Kuroda M, Yokosuka A, Kobayashi R, Jitsuno M, Kando H, Nosaka K, Ishii H, Yamori T, Mimaki Y.
  • Journal Title: Chemical&pharmaceutical bulletin 55(8) Pages: 1240-1244
  • Peer Reviewed
• [Journal Article] Urukthapelstatin A, a novel cytotoxic substance from marine-derived Mechercharimyces asporophorigenens YM11-542.I.Fermentation,isolation and biological activities (2007)
  • Author(s): Matsuo Y, Kanoh K, Yamori T, Kasai H, Katsuta A, Adachi K, Shin-Ya K, Shizuri Y.
  • Journal Title: The Journal of antibiotics 60(4) Pages: 251-255
  • Peer Reviewed
• [Journal Article] A novel candidate compound with urethane structure for anticancer drug development (2007)
  • Author(s): Matsuoka A, Isama K, Tanimura S, Kohno M, Yamori T.
  • Journal Title: Current drug discovery technologies 4(2) Pages: 69-76
  • Peer Reviewed
• [Journal Article] Absolute quantification of four isoforms of the class I phosphoinositide-3-kinase catalytic subunit by real-time RT-PCR (2007)
  • Author(s): Nakamura H, Dan S, Akashi T, Unno M, Yamori T.
  • Journal Title: Biological&pharmaceutical bulletin 30(6) Pages: 1181-1184
  • Peer Reviewed
• [Journal Article] Evaluation of Action Mechanisms of Toxic Chemicals Using JFCR39,a Panel of Human Cancer Cell Lines (2007)
  • Author(s): Nakatsu N, Nakamura T, Yamazaki K, Sadahiro S, Makuuchi H, Kanno J, Yamori T.
  • Journal Title: Mol Pharmacol 72(5) Pages: 1171-1180
  • Peer Reviewed
• [Journal Article] Identification of JTP-70902,a p15(INK4b)-inductive compound,as a novel MEK1/2 inhibitor (2007)
  • Author(s): Yamaguchi T, Yoshida T, Kurachi R, Kakegawa J, Hori Y, Nanayama T, Hayakawa K, Abe H, Takagi K, Matsuzaki Y, Koyama M, Yogosawa S, Sowa Y, Yamori T, Tajima N, Sakai T.
  • Journal Title: Cancer science 98(11) Pages: 1809-1816
  • Peer Reviewed
• [Journal Article] Iaziovianin A,a new isoflavone,from the leaves of Ateleia glazioviana and its cytotoxic activity against human cancer cells (2007)
  • Author(s): Yokosuka A, Haraguchi M, Usui T, Kazami S, Osada H, Yamori T, Mimaki Y.
  • Journal Title: Bioorganic&medicinal chemistry letters 17(11) Pages: 3091-3094
  • Peer Reviewed
• [Presentation] Cancer Cell Informaticsとは〜その分子標的治療薬の創薬への応用〜 (2008)
  • Author(s): 矢守 隆夫
  • Organizer: 北里大学薬学部公開シンポジウム
  • Place of Presentation: 北里大学
  • Year and Date: 2008-02-22
• [Presentation] Informatics-guided identification of candidates for new drug,target and biomarker based on JFCR39 (2007)
  • Author(s): Yamori T.
  • Organizer: 66-th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama
  • Year and Date: 20071003-05
• [Presentation] Proteomic screening for signaling proteins involved in PI3-kinase pathways by using SELDT-TOF MS (2007)
  • Author(s): Akashi T, Yaguchi S, Yamorit.
  • Organizer: 66-th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama
  • Year and Date: 20071003-05
• [Presentation] Promoter methylation of WRN gene in cancer (2007)
  • Author(s): Okui M, Yamori T, Nakagawa K, Ishikawa Y.
  • Organizer: 66-th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama
  • Year and Date: 20071003-05
• [Presentation] ZSTK474 inhibits class I PI3 kinase isoforms competitively with ATP (2007)
  • Author(s): Kong D, Yaguchi S, Yamori T.
  • Organizer: 66-th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama
  • Year and Date: 20071003-05
• [Presentation] MELl cooperates with c-ski to repress TGF-beta signal in gingastric cancer cells (2007)
  • Author(s): Takahata M, Koinuma D, inazawa J, Yamori T, Miyazawa K, Miyazono K, Imamura T.
  • Organizer: 66-th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama
  • Year and Date: 20071003-05
• [Presentation] PI3K inhibitor,down-regulates CDC25A and induces G_1,phase cell cycle arrest in human cancer cells (2007)
  • Author(s): Dan S, Mukai Y, Yaguchi S, Yamori T.
  • Organizer: 66-th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama
  • Year and Date: 20071003-05
• [Presentation] PIK3CA mutations in JFCR-39 human cancer cell lines. (2007)
  • Author(s): Sugita H, Dan S, Nakamura H, Yamori T.
  • Organizer: 66-th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama
  • Year and Date: 20071003-05
• [Presentation] PI3キナーゼを標的とする新規分子標的薬候補ZSTK474 (2007)
  • Author(s): 矢守 隆夫
  • Organizer: 第16回日本がん転移学会総会
  • Place of Presentation: 富山
  • Year and Date: 20070709-10
• [Presentation] 新規PI3キナーゼ阻害剤ZSTK474による抗腫瘍効果の分子機構の解析 (2007)
  • Author(s): 旦 慎吾, 向井 由美子, 矢口 信一, 矢守 隆夫
  • Organizer: 第11回がん分子標的治療研究会総会
  • Place of Presentation: 大阪
  • Year and Date: 20070705-06
• [Presentation] 新規PI3K阻害剤ZSTK474の分子薬理機序の解析 (2007)
  • Author(s): 孔 徳新, 矢守 隆夫
  • Organizer: 第11回がん分子標的治療研究会総会
  • Place of Presentation: 大阪
  • Year and Date: 20070705-06
• [Presentation] 山菜のシゲト(モミジガサ)から単離されたピサボラン型セスキテルペ'ンエンドパーオキサイドの抗癌活性 (2007)
  • Author(s): 西川 耕司, 山田 京平, 土屋 英子, 矢守 隆夫, 木村 賢一
  • Organizer: 第11回がん分子標的治療研究会総会
  • Place of Presentation: 大阪
  • Year and Date: 20070705-06
• [Presentation] Identification of candidates for new drug,target and biomarker by mining data sets from a panel of human cancer cell lines:JFCR39 (2007)
  • Author(s): Yamori T.
  • Organizer: MBI Chemogenomics Workshop
  • Place of Presentation: Ohio,USA
  • Year and Date: 20070508-10
• [Presentation] Epigenetic silencing of the RecQ helicase genes in Japanese lung cancer (2007)
  • Author(s): Okui M, Ishikawa Y, Yamori T, Nakagawa K.
  • Organizer: The 98-th Am Assoc Cancer Res(AACR)Annual Meeting
  • Place of Presentation: Los Angeles,CA,U.S.A.
  • Year and Date: 20070414-18
• [Presentation] Proteomic screening for biomarkers for predicting sensitivity to anticancer drugs by using SELDI-TOF MS (2007)
  • Author(s): Akashi T, Nishimura Y, Shiwa M, Yamori T.
  • Organizer: The 98-th Am Assoc Cancer Res(AACR)Annual Meeting
  • Place of Presentation: Los Angeles,CA,U.S.A.
  • Year and Date: 20070414-18
• [Presentation] EGFR signal pathways selectively activated in lung adenocarcinoma (2007)
  • Author(s): Hiramatsu M, Ninomiya H, Inamura K, Okui M, Satoh Y, Fujiwara M, Yamori T, Kitagawa T, Ishikawa Y.
  • Organizer: The 98-th Am Assoc Cancer Res(AACR)Annual Meeting
  • Place of Presentation: Los Angeles,CA,U.S.A.
  • Year and Date: 20070414-18
• [Book] 新規PI3キナーゼ阻害剤ZSTK474の抗がん活性 (2007)
  • Author(s): 矢口 信一, 矢守 隆夫
  • Total Pages: 22-26
  • Publisher: 細胞The CELL
• [Book] 分子標的治療薬の開発と発展 (2007)
  • Author(s): 矢守 隆夫
  • Total Pages: 63-67
  • Publisher: 日本病院薬剤師会雑誌
• [Book] クリニカルプラクティス (2007)
  • Author(s): 矢守 隆夫
  • Total Pages: 231-232
  • Publisher: 分子標的治療薬
• [Book] Cancer Cell Informaticsとケミカルバイオロジー (2007)
  • Author(s): 矢守 隆夫
  • Total Pages: 1690-1695
  • Publisher: 蛋白質核酸酵素
• [Book] 分子標的治療薬とは (2007)
  • Author(s): 矢守 隆夫
  • Total Pages: 1819-1824
  • Publisher: 月刊薬事
• [Book] 特集・制がん剤の分子標的スクリーニング成績「化学療法基盤情報支援班」報告-制がん候補物質のスクリーニング成績・第12報- (2007)
  • Author(s): 矢守 隆夫, 上原 至雅, 吉田 稔, 井上 正哉, 清宮 啓之, 水上 民夫, 川田 学, 長田 裕之, 松浦 正明
  • Total Pages: 112-144
  • Publisher: 癌と化学療法
• [Book] 特集・制がん剤の分子標的スクリーニング成績「新しい戦略による抗がん剤のスクリーニングのための委員会」報告-制がん候補物質のスクリーニング成績・第11報- (2007)
  • Author(s): 矢守 隆夫, 安藤 俊夫, 上原 至雅, 小野 真弓, 河野 通明, 済木 育夫, 内藤 幹彦, 早川 洋一, 鶴尾 隆, 吉田 稔, 杉本 芳一, 馬島 哲夫
  • Total Pages: 1-111
  • Publisher: 癌と化学療法
• [Patent(Industrial Property Rights)] PI3キナーゼ阻害剤の効果判定方法 (2007)
  • Inventor(s): 明石 哲行、矢守 隆夫、岡村 睦美
  • Industrial Property Rights Holder: 財団法人癌研究会
  • Industrial Property Number: 特願2007-218234
  • Filing Date: 2007-08-24