Targeted therapy for cancer stem-like cells of non-small cell lung cancers with inhibition of the cJun transcription factor

• Project/Area Number: 23591132
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Hokkaido University
• Principal Investigator: KINOSHITA Ichiro 北海道大学, 医学(系)研究科(研究院), 准教授 (40343008)
• Co-Investigator(Kenkyū-buntansha): SHIMIZU Yasushi 北海道大学, 大学病院, 助教 (10374513)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 肺癌 / 癌幹細胞 / ｃJun / EZH2 / 幹細胞 / cJun / HDAC / エピジェネティクス / 分子標的薬

Research Abstract

Sphere forming capacity under serum-free culture, indicative of cancer stem cells, were decreased by cJun inhibition in non-small lung cancer (NSCLC) cells, while sphere forming cells did not show enhanced tumorigenicity in SCID mice.
Meanwhile, an inhibitor of histone methyltransferase EZH2 involved in stem cell maintenance via epigenetic regulation suppressed growth of NSCLC cells. An inhibitor of histone deacetylase (HDAC), another epigenetic regulator, showed a synergistic growth suppressive effect with the EZH2 inhibitor. Combined epigenetic therapy with an EZH2 inhibitor and an HDAC inhibitor may represent an effective approach for NSCLCs.

Research Products

• [Journal Article] CD133 expression: a potential prognostic marker for non-small cell lung cancers (2014)
  • Author(s): Mizugaki H, Sakakibara-Konishi J, Kikuchi J, Moriya J, Hatanaka KC, Kikuchi E, Kinoshita I, Oizumi S, Dosaka-Akita H, Matsuno Y and Nishimura M
  • Journal Title: Int J Clin Oncol Volume: 19 Issue: 2 Pages: 254-259
  • DOI: 10.1007/s10147-013-0541-x
  • Peer Reviewed
• [Journal Article] Cancer stem-like cells derived from chemoresistant tumors have a unique capacity to prime tumorigenic myeloid cells. (2014)
  • Author(s): Yamashina T, Baghdadi M, Yoneda A, Kinoshita I, Suzu S, Dosaka-Akita H, Jinushi M.
  • Journal Title: Cancer Research Volume: 74 Issue: 10 Pages: 2698-2709
  • DOI: 10.1158/0008-5472.can-13-2169
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] TIM-4 glycoprotein-mediated degradation of dying tumor cells by autophagy leads to reduced antigen presentation and increased immune tolerance. (2013)
  • Author(s): Baghdadi M, Yoneda A, Yamashina T, Nagao H, Komohara Y, Nagai S, Akiba H, Foretz M, Yoshiyama H, Kinoshita I, Dosaka-Akita H, Takeya M, Viollet B, Yagita H, Jinushi M
  • Journal Title: Immunity Volume: 39 Issue: 6 Pages: 1070-1081
  • DOI: 10.1016/j.immuni.2013.09.014
  • Peer Reviewed
• [Journal Article] Updated Overall Survival Results from A Randomized Phase III Trial Comparing Gefitinib with Carboplatin-Paclitaxel for Chemo-Naive Non-Small Cell Lung Cancer with Sensitive EGFR Gene Mutations (NEJ002) (2013)
  • Author(s): Inoue A, Kobayashi K, Maemondo M, et al
  • Journal Title: Ann Oncol Volume: 24 Issue: 1 Pages: 54-9
  • DOI: 10.1093/annonc/mds214
  • Peer Reviewed
• [Journal Article] Epigenetic therapy with 3-deazaneplanocin A, an inhibitor of the histone methyltransferase EZH2, inhibits growth of non-small cell lung cancer cells (2012)
  • Author(s): Kikuchi J, Takashina T, Kinoshita I, Kikuchi E, Shimizu Y, Sakakibara-Konishi J, Oizumi S, Marquez VE, Nishimura M, Dosaka-Akita H
  • Journal Title: Lung Cancer Volume: 78 Issue: 2 Pages: 138-143
  • DOI: 10.1016/j.lungcan.2012.08.003
  • Peer Reviewed
• [Journal Article] Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. S. (2012)
  • Author(s): Chiba, M. Baghdadi, H. Akiba, H. Yoshiyama, I. Kinoshita, H. Dosaka-Akita, Y. Fujioka, Y. Ohba, J. V. Gorman, J. D. Colgan, M. Hirashima, T. Uede, A. Takaoka, H. Yagita and M. Jinushi.
  • Journal Title: Nat. Immunol. Volume: 13 Issue: 9 Pages: 832-842
  • DOI: 10.1038/ni.2376
  • Peer Reviewed
• [Journal Article] ATM-mediated DNA damage signals mediate immune escape through integrin αvβ3-dependent mechanisms. (2012)
  • Author(s): Jinushi M
  • Journal Title: Cancer Res Volume: 72 Issue: 1 Pages: 56-65
  • DOI: 10.1158/0008-5472.can-11-2028
  • Peer Reviewed
• [Journal Article] Minichromosome maintenance (MCM) protein 4 as a marker for proliferation and its clinical and clinicopathological significance in non-small cell lung cancer (2011)
  • Author(s): Kikuchi J, Kinoshita I, Shimizu Y, Kikuchi E, Takeda K, Aburatani H, Oizumi S, Konishi J, Kaga K, Matsuno Y, Birrer MJ, Nishimura M and Dosaka-Akita H
  • Journal Title: Lung Cancer Volume: 72 Issue: 2 Pages: 229-237
  • DOI: 10.1016/j.lungcan.2010.08.020
  • Peer Reviewed
• [Journal Article] Expression of LGR5, an intestinal stem cell marker, during each stage of colorectal tumorigenesis (2011)
  • Author(s): Takeda K, Kinoshita I, Shimizu Y, Matsuno Y, Shichinohe T and Dosaka-Akita H
  • Journal Title: Anticancer Res Volume: 31 Pages: 263-270
  • Peer Reviewed
• [Journal Article] Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells (2011)
  • Author(s): Jinushi M, Chiba S, Yoshiyama H, Masutomi K, Kinoshita I, Dosaka-Akita H, Yagita H, Takaoka A, Tahara H.
  • Journal Title: Proc Natl Acad Sci USA Volume: 108巻 Issue: 30 Pages: 12425-30
  • DOI: 10.1073/pnas.1106645108
  • NAID: 10030575946
  • Peer Reviewed
• [Presentation] Pharmacologic disruption of polycomb group protein EZH2 via 3-Deazaneplanocin A inhibits growth of non-small cell lung cancer cells (2012)
  • Author(s): Kinoshita I
  • Organizer: 5th Asia Pacific Lung Cancer Conference
  • Place of Presentation: Hilton Fukuoka Sea Hawk, Fukuoka
  • Year and Date: 2012-11-26
• [Presentation] Role of polycomb group protein EZH2 in lung cancer (2012)
  • Author(s): Kinoshita I
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 教育文化会館, 札幌市
  • Year and Date: 2012-09-19
  • Invited
• [Presentation] Growth inhibition of non-small cell lung cancer cells by the histone methyltransferase ezh2 inhibitor 3-deazaneplanocin (2011)
  • Author(s): Kinoshita I
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場, 名古屋市
  • Year and Date: 2011-10-03
• [Presentation] Growth inhibition of non-small cell lung cancer cells by the histone methyltransferase ezh2 inhibitor 3-deazaneplanocin (2011)
  • Author(s): Kinoshita I
  • Organizer: 9th International Symposium for Future Drug Discovery and Medical Care
  • Place of Presentation: Hokkaido University, Sapporo
  • Year and Date: 2011-09-30
• [Presentation] Growth inhibition of non-small cell lung cancer cells by the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin (2011)
  • Author(s): 木下一郎，菊地順子，菊地英毅, 清水康, 榊原純, 大泉聡史, 西村正治, 秋田弘俊
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知）
• [Presentation] Growth inhibition of non-small cell lung cancer cells by the histone methyltransferase ezh2 inhibitor 3-deazaneplanocin (2011)
  • Author(s): Kinoshita I, Kikuchi J, Shimizu Y, Sakakibara-Konishi J, Oizumi S, Nishimura M, Dosaka-Akita H
  • Organizer: 9th International Symposium for Future Drug Discovery and Medical Care
  • Place of Presentation: 北海道大学（札幌市）
• [Presentation] Effects of combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin and the histone deacetylase inhibitor SAHA on non-small cell lung cancer cells
  • Author(s): Takashina T, Kinoshita I, Kikuchi J, Shimizu Y, Konishi JS, Oizumi S, Nishimura M and Dosaka-Akita H
  • Organizer: the 105th Annual Meeting of the American Association for Cancer Research
  • Place of Presentation: San Diego Conventon Center (San Diego)
• [Presentation] EZH2阻害薬とヒストン脱アセチル化酵素阻害薬の併用療法の非小細胞肺癌細胞に対する抗腫瘍効果の検討
  • Author(s): 高階太一、木下一郎、菊地順子、池澤靖元、榊原純、大泉聡史、西村正治、秋田弘俊
  • Organizer: 第54回日本肺癌学会総会
  • Place of Presentation: ホテルニューオータニ（東京）
• [Presentation] Effects of combined epigenetic therapy with EZH2 and HDAC inhibitors on NSCLC cells
  • Author(s): Takashina T, Kinoshita I, Kikuchi J, Kikuchi E, Shimizu Y, Sakakibara-Konishi J, Oizumi S, Nishimura M and Dosaka-Akita H
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜市）
• [Presentation] Role of polycomb group protein EZH2 in lung cancer
  • Author(s): Kinoshita I
  • Organizer: 第71会日本癌学会学術総会
  • Place of Presentation: 教育文化会館（札幌市）
  • Invited
• [Presentation] Pharmacologic disruption of polycomb group protein EZH2 via 3-Deazaneplanocin A inhibits growth of non-small cell lung cancer cells
  • Author(s): Kinoshita I
  • Organizer: 5th Asia Pacific Lung Cancer Conference
  • Place of Presentation: Hilton Fukuoka Sea Hawk (Fukuoka)
• [Presentation] ヒストンメチル化酵素EZH2阻害剤3-deazaneplanocin Aによる非小細胞肺癌細胞株に対する増殖抑制効果の検討
  • Author(s): 高階太一、木下一郎、菊地順子、菊地英毅、清水康、榊原純、大泉聡史、西村正治、秋田弘俊
  • Organizer: 第53回日本肺癌学会総会
  • Place of Presentation: 岡山コンベンションセンター（岡山市）
• [Remarks]
  • URL: http://medicaloncology.med.hokudai.ac.jp/