滑膜肉腫幹細胞の同定と創薬基盤の確立

• Project/Area Number: 23390089
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Hokkaido University
• Principal Investigator: 田中 伸哉 北海道大学, 医学(系)研究科(研究院), 教授 (70261287)
• Co-Investigator(Kenkyū-buntansha): 西原 広史 北海道大学, 医学(系)研究科(研究院), 特任准教授 (50322805) ; 谷野 美智枝 北海道大学, 医学(系)研究科(研究院), 助教 (90360908)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Declined (Fiscal Year 2013)
• Budget Amount: ¥19,370,000 (Direct Cost: ¥14,900,000、Indirect Cost: ¥4,470,000); Fiscal Year 2013: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2012: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2011: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
• Keywords: 滑膜肉腫 / SYT-SSX / 分子標的薬 / 病理診断

Research Abstract

滑膜肉腫は若年成人の関節周辺に発生する悪性度の高い腫瘍であり有効な治療法は未だ確立されていない。
本研究では根源的な治療法を開発するため、滑膜肉腫幹細胞を同定し腫瘍発生機構・病態を解明し、発癌メカニズムに基づく治療薬開発の基盤技術を確立する。発癌機構の解析は、①肉腫幹細胞の分離とマーカー分子の同定、② 滑膜肉腫キメラ遺伝子SYT-SSXによるクロマチンリモデリング測定システムの開発、③滑膜肉腫の腫瘍化に必須のシグナル伝達分子Crkによる転移・浸潤メカニズムの解明、の3つを柱とする。治療薬剤のリード化合物の探索は独自に開発した1分子特異的シグナル抑制薬剤スクリーニング法、2分子結合FRETイメージング法、分子構造に基づくin silico分子設計法を用いて、スクリーニング法の基盤を確立する。候補となる化合物は申請者らが確立した滑膜肉腫モデルマウスを改良し、臨床応用の可能性を含めて有効性を評価する。
本研究では肉腫幹細胞、クロマチンリモデリング機構、HGF-Crkシグナルの3点に焦点をあて、SYT-SSXの癌化のメカニズムについて分子生物学的に包括的・総合的な理解を目指す。特に肉腫幹細胞はこれまで報告がほとんどなく、治療上極めて重要な発見となる。クロマチンリモデリングと発癌との関連については、近年急速に解析が発展している分野であるが、滑膜肉腫については癌化に必須であるSYT-SSXとhBRMとの結合は当研究室で発見されたものであり独創性が高い。

Current Status of Research Progress

Reason

翌年度、交付申請を辞退するため、記入しない。

Strategy for Future Research Activity

翌年度、交付申請を辞退するため、記入しない。

Research Products

• [Journal Article] STAT3 inhibition overcomes temozolomide resistance in glioblastoma by downregulating MGMT expression. (2012)
  • Author(s): Kohsaka, S., Wang, L.,Yachi, K.,Mahabir, R.,Narita, T.,Itoh, T.,Tanino, M.,Kimura, T.,Nishihara H.,Tanaka, S.
  • Journal Title: Mol Cancer Ther. Volume: 11 Pages: 1289-1299
  • NAID: 120005228738
  • Peer Reviewed
• [Journal Article] CD133 negatively regulates tumorigenicity via AKT pathway in synovial sarcoma. (2012)
  • Author(s): Kimura, T.,Wang, L.,Tabu, K.,Nishihara, H.,Mashita, Y.,Kikuchi, N.,Tanino, M.,Hiraga, H.,Tanaka, S.
  • Journal Title: Cancer invest Volume: 30 Pages: 390-397
  • NAID: 120005228733
  • Peer Reviewed
• [Journal Article] Prognostic implication of histological oligodendroglial tumor component: clinicopathological analysis of 111 cases of malignant gliomas. (2012)
  • Author(s): Kanno, H.,Nishihara, H.,Narita, T.,Yamaguchi, S.,Kobayashi, H.,Tanino, M.,Kimura, T.,Terasaka S.,Tanaka, S.
  • Journal Title: PLoS One. Volume: 7 Issue: 7 Pages: e41669-e41669
  • DOI: 10.1371/journal.pone.0041669
  • NAID: 120004650825
  • Peer Reviewed
• [Journal Article] CRKL plays a pivotal role in tumorigenesis of head and neck squamous cell carcinoma through the regulation of cell adhesion. (2012)
  • Author(s): Yanagi, H.,Wang , L.,Nishihara, H.,Kimura, T.,Tanino, M.,Yanagi, T.,Fukuda, S.,Tanaka, S.
  • Journal Title: Biochem Biophys Res Commun. Volume: 418 Pages: 104-109
  • NAID: 120005183147
  • Peer Reviewed
• [Journal Article] Expression of O6-methylguanine DNA methyltransferase (MGMT) and immunohistochemical analysis of 12 pineal parenchymal tumors. (2012)
  • Author(s): Kanno, H.,Nishihara, H.,Oikawa, M.,Ozaki, Y.,Murata, J.,Sawamura, Y.,Kato, M.,Kubota, K.,Tanino, M. Kimura, T.,Nagashima, K.,Itoh, T.,Tanaka, S.
  • Journal Title: Neuropathology Volume: 32 Issue: 6 Pages: 647-653
  • DOI: 10.1111/j.1440-1789.2012.01315.x
  • NAID: 120005356854
  • Peer Reviewed
• [Journal Article] Toll-like receptor 3 signaling converts tumor-supporting myeloid cells to tumoricidal effectors. (2012)
  • Author(s): Shime, H.,Matsumoto, M.,Oshiumi, H.,Tanaka, S.,Nakane, A.,Iwakura, Y.,Tahara, H.,Inoue, N.,Seya, T.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 109 Pages: 2066-2071
  • Peer Reviewed
• [Journal Article] TRIM67 negatively regulates Ras activity through degradation of 80K-H and induces neuritogenesis. (2012)
  • Author(s): Yaguchi, H.,Okumura, F.,Takahashi, H.,Kano, T.,Kameda, H.,Uchigashima, M.,Tanaka, S.,Watanabe, M. Sasaki, H.,Hatakeyama, S.
  • Journal Title: J Biol Chem. Volume: 287 Pages: 12050-12059
  • Peer Reviewed
• [Journal Article] “CRK” Atlas of Genetics and Cytogenetics in Oncology and Haematology (2012)
  • Author(s): Shinya Tanaka.
  • Journal Title: Atlas of Genetics and Cytogenetics in Oncology and Haematology Volume: 17p13.3 Pages: 1324647-1359561
  • Peer Reviewed
• [Journal Article] Roles for Crk in Cancer Metastasis and Invasion. (2012)
  • Author(s): Masumi Tsuda and Shinya Tanaka.
  • Journal Title: Genes & Cancer Volume: 3 Issue: 5-6 Pages: 334-340
  • DOI: 10.1177/1947601912458687
  • Peer Reviewed
• [Journal Article] Regulation of MGMT and application for the therapy to attenuate the chemoresistance. (2012)
  • Author(s): Shinji Kohsaka, Hiromi Kanno, Shinya Tanaka.
  • Journal Title: Nihon Rinsho. Volume: 8 Pages: 346-352
• [Journal Article] STAT3 inhibition overcomes temozolomide resistance in glioblastoma by downregulating MGMT expression. (2012)
  • Author(s): Kohsaka, S., Wang, L.,Yachi, K.,Mahabir, R.,Narita, T.,Itoh, T.,Tanino, M.,Kimura, T.,Nishihara,H.,Tanaka, S
  • Journal Title: Mol Cancer Ther Volume: 11 Pages: 1289-1299
  • NAID: 120005228738
  • Peer Reviewed
• [Journal Article] CD133 negatively regulates tumorigenicity via AKT pathway in synovial sarcoma (2012)
  • Author(s): Kimura, T.,Wang, L.,Tabu, K.,Nishihara, H.,Mashita, Y.,Kikuchi, N.,Tanino, M.,Hiraga, H.,Tanaka, S.
  • Journal Title: Cancer invest Volume: 30 Pages: 390-397
  • NAID: 120005228733
  • Peer Reviewed
• [Journal Article] Regulation of MGMT and application for the therapy to attenuate the chemoresistance. (2012)
  • Author(s): Shinji Kohsaka, Hiromi Kanno, Shinya Tanaka.
  • Journal Title: Nihon Rinsho Volume: 8 Pages: 346-352
• [Presentation] dentification and analysis of synovial sarcoma initiating cells. (2012)
  • Author(s): Taichi Kimura, Lei Wang, Mishie Tanino, Hiroshi Nishihara, Shinya Tanaka
  • Organizer: Cold Spring Harbor Laboratory Meeting; Mechanisms and Models of Cancer
  • Place of Presentation: Cold Spring Harbor laboraory(USA)
• [Presentation] Molecular and pathological analysis of malignant glioma: from tissues to therapeutic reagents (2012)
  • Author(s): Shinya Tanaka, Shinji Kohsaka, Kouich Tabu, Lei Wang, Masumi Tsuda, Taichi Kimura, Mishie Tanino, Hiroshi Nishihara, Hiromichi Kimura
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌（北海道）
• [Presentation] Prognostic PDGFR-beta expression in tumor stroma of pancreatic adenocarcinoma. (2012)
  • Author(s): Hiroshi Nishihara, Sayaka Yuzawa, Mitsunobu Kano, Shinya Tanaka
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌（北海道）
• [Presentation] Clinicopathological analysis for angiocentric, angiodestructive lymphoproliferative disorder of central nervous system (2012)
  • Author(s): Hiroshi Nishihara, Teruki Yanagi and Shinya Tanaka
  • Organizer: 17th Annual Scientific Meeting and Education Day of the Society for Neuro-oncology
  • Place of Presentation: Washington DC HIlton Hotel(USA)
• [Presentation] Identification and analysis of synovial sarcoma initiating cells. (2012)
  • Author(s): Taichi Kimura, Lei Wang, Mishie Tanino, Hiroshi Nishihara, Shinya Tanaka
  • Organizer: Cold Spring Harbor Laboratory Meeting; Mechanisms and Models of Cancer
  • Place of Presentation: Cold Spring Harbor Laboratory(USA)
• [Presentation] Clinicopathological analysis for angiocentric, angiodestructive lymphoproliferative disorder of central nervous system (2012)
  • Author(s): Hiroshi Nishihara, Teruki Yanagi and Shinya Tanaka
  • Organizer: 17th Annual Scientific Meeting and Education Day of the Society for Neuro-oncology
  • Place of Presentation: Washington DC Hilton Hotel (USA)