Identification of anti-cancer targets based on synthetic lethality between paralogous genes

• Project/Area Number: 23701110
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Clinical oncology
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: OGIWARA Hideaki 独立行政法人国立がん研究センター, 研究所, 研究員 (40568953)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2011: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: SWI/SNF / BRG1 / 合成致死 / クロマチンリモデリング / 分子標的治療 / CBP / アセチル化酵素 / ヒストン修飾 / ヒストンアセチル化

Research Abstract

BRG1 gene is mutated or lost in 10% of lung adenocarcinoma. We found that BRM, BRG1 paralogous gene, is essential for BRG1 deficient cancer cells, that is, BRM is synthetically lethal with BRG1. Our research indicated that molecular target inhibitor for BRM is a candidate of anti-cancer agent for the cancer patient with BRG1 deficiency. Now, we started the development of BRM inhibitor to lead to translational research.

Research Products

• [Journal Article] SWI/SNF Factors Required for Cellular Resistance to DNA Damage Include ARID1A and ARID1B and Show Interdependent Protein Stability (2014)
  • Author(s): Watanabe R, Ui A, Kanno S, Ogiwara H, Nagase T, Kohno T, Yasui A
  • Journal Title: Cancer Res. Volume: 74 Pages: 2465-2475
  • Peer Reviewed
• [Journal Article] C646, a selective small molecule inhibitor of histone acetyltransferase p300, radiosensitizes lung cancer cells by enhancing mitotic catastrophe (2014)
  • Author(s): Oike T, Komachi M, Ogiwara H, Amornwichet N, Saitoh Y, Torikai K, Kubo N, Nakano T, Kohno T
  • Journal Title: Radiother Oncol. Volume: (In press)
  • Peer Reviewed
• [Journal Article] Druggable Oncogene Fusions in Invasive Mucinous Lung Adenocarcinoma (2014)
  • Author(s): Nakaoku T, Tsuta K, Ichikawa H, Shiraishi K, Sakamoto H, Enari M, Furuta K, Shimada Y, Ogiwara H, Watanabe SI, Nokihara H, Yasuda K, Hiramoto M, Nammo T, Ishigame T, Schetter AJ, Okayama H, Harris CC, Kim YH, Mishima M, Yokota J, Yoshida T, Kohno T
  • Journal Title: Clin Cancer Res. Volume: (In press)
  • Peer Reviewed
• [Journal Article] Fine-tuning of DNA damage-dependent ubiquitination by OTUB2 supports the DNA repair pathway choice (2014)
  • Author(s): Kato K, Nakajima K, Ui A, Muto-Terao Y, Ogiwara H, Nakada S
  • Journal Title: Mol Cell. Volume: 53 Pages: 617-630
  • Peer Reviewed
• [Journal Article] Molecular Mechanisms Underlying Oncogenic RET Fusion in Lung Adenocarcinoma (2014)
  • Author(s): Mizukami T, Shiraishi K, Shimada Y, Ogiwara H, Tsuta K, Ichikawa H, Sakamoto H, Kato M, Shibata T, Nakano T, Kohno T
  • Journal Title: J Thorac Oncol. Volume: 9 Pages: 622-630
  • Peer Reviewed
• [Journal Article] Chromatin-regulating proteins as targets for cancer therapy (2014)
  • Author(s): Oike T, Ogiwara H, Amornwichet N, Nakano T, Kohno T
  • Journal Title: J Radiat Res. Volume: (In press)
  • Peer Reviewed
• [Journal Article] Possible involvement of LKB1-AMPK signaling in non-homologous end joining (2014)
  • Author(s): Ui A, Ogiwara H, Nakajima S, Kanno S, Watanabe R, Harata M, Okayama H, Harris CC, Yokota J, Yasui A, Kohno T
  • Journal Title: Oncogene. Volume: 33 Pages: 1640-1648
  • Peer Reviewed
• [Journal Article] Chromatin-regulating proteins as targets for cancer therapy. (2014)
  • Author(s): Oike T, Ogiwara H, Amornwichet N, Nakano T, Kohno T.
  • Journal Title: J Radiat Res. Volume: 未定
  • Peer Reviewed
• [Journal Article] Possible involvement of LKB1-AMPK signaling in non-homologous end joining. (2014)
  • Author(s): Ui A, Ogiwara H, Nakajima S, Kanno S-I, Watanabe R, Harata M, Okayama H, Harris CC, Yokota J, Yasui A and Kohno T
  • Journal Title: Oncogene Volume: 33 Issue: 13 Pages: 1640-1648
  • DOI: 10.1038/onc.2013.125
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Inactivating mutations in SWI/SNF chromatin remodeling genes in human cancer (2013)
  • Author(s): Oike T, Ogiwara H, Nakano T, Yokota J, Kohno T
  • Journal Title: Jpn J Clin Oncol. Volume: 43 Pages: 849-855
  • Peer Reviewed
• [Journal Article] Curcumin suppresses multiple DNA damage response pathways and has potency as a sensitizer to PARP inhibitor (2013)
  • Author(s): Ogiwara H, Ui A, Shiotani B, Zou L, Yasui A, Kohno T
  • Journal Title: Carcinogenesis. Volume: 34 Pages: 2486-2497
  • Peer Reviewed
• [Journal Article] A synthetic lethality-based strategy to treat cancers harboring a genetic deficiency in the chromatin remodeling factor BRG1 (2013)
  • Author(s): Oike T, Ogiwara H, Tominaga Y, Ito K, Ando O, Tsuta K, Mizukami T, Shimada Y, Isomura H, Komachi M, Furuta K, Watanabe S, Nakano T, Yokota J, Kohno T
  • Journal Title: Cancer Res. Volume: 73 Pages: 5508-5518
  • Peer Reviewed
• [Journal Article] A synthetic lethality-based strategy to treat cancers harboring a genetic deficiency in the chromatin remodeling factor BRG1. (2013)
  • Author(s): Oike T, Ogiwara H, Tominaga Y, Ito K, Ando O, Tsuta K, Mizukami T, Shimada Y, Isomura H, Komachi M, Furuta K, Watanabe SI, Nakano T, Yokota J, Kohno T
  • Journal Title: Cancer Res Volume: 73 Issue: 17 Pages: 5508-5518
  • DOI: 10.1158/0008-5472.can-12-4593
  • Peer Reviewed
• [Journal Article] Inactivating mutations in SWI/SNF chromatin remodeling genes in human cancer. (2013)
  • Author(s): Oike T, Ogiwara H, Nakano T, Kohno T
  • Journal Title: Jpn J Clin Oncol Volume: 43 Issue: 9 Pages: 849-855
  • DOI: 10.1093/jjco/hyt101
  • Peer Reviewed
• [Journal Article] Curcumin suppresses multiple DNA damage response pathways and has potency as a sensitizer to PARP inhibitor. (2013)
  • Author(s): Ogiwara H, Ui A, Shiotani B, Zou L, Yasui A, Kohno T
  • Journal Title: Carcinogenesis Volume: 34 Issue: 11 Pages: 2486-2497
  • DOI: 10.1093/carcin/bgt240
  • Peer Reviewed
• [Journal Article] CBP and p300 histone acetyltransferases contribute to homologous recombination by transcriptionally activating the BRCA1 and RAD51 genes (2012)
  • Author(s): Ogiwara H
  • Journal Title: PLoS One Volume: 7 Issue: 12 Pages: e52810-e52810
  • DOI: 10.1371/journal.pone.0052810
  • Peer Reviewed
• [Journal Article] Garcinol, a histone acetyltransferase inhibitor, radiosensitizes cancer cells by inhibiting non-homologous end joining. (2012)
  • Author(s): Oike T
  • Journal Title: Int J Radiat Oncol Biol Phys Volume: 84(3) Issue: 3 Pages: 815-821
  • DOI: 10.1016/j.ijrobp.2012.01.017
  • Peer Reviewed
• [Journal Article] Histone acetylation by CBP and p300 at double-strand break sites facilitates SWI/SNF chromatin remodeling and the recruitment of non-homologous end joining factors. (2011)
  • Author(s): Ogiwara H et al
  • Journal Title: Oncogene Volume: 30 Issue: 18 Pages: 2135-2146
  • DOI: 10.1038/onc.2010.592
  • Peer Reviewed
• [Journal Article] Essential factors for incompatible DNA end joining at chromosomal DNA double strand breaks in vivo (2011)
  • Author(s): Ogiwara H
  • Journal Title: PLoS One Volume: 6 Issue: 12 Pages: e28756-e28756
  • DOI: 10.1371/journal.pone.0028756
  • Peer Reviewed
• [Journal Article] PALF acts as both a single-stranded DNA endonuclease and a single-stranded DNA 3’-exonuclease and can participate in DNA end joining in a biochemical system. (2011)
  • Author(s): Li S et al
  • Journal Title: J Biol Chem Volume: 286 Pages: 36368-36377
  • Peer Reviewed
• [Presentation] Personalized Medicine of Lung Adenocarcinoma Based on Genetic Alterations (2013)
  • Author(s): Takashi Kohno Ph D, Hideaki Ogiwara Ph D, Tatsuji Mizukami MD
  • Organizer: 原研・国際キックオフシンポジウム
  • Year and Date: 2013-11-28
• [Presentation] DNA切断修復と発がん・がん治療 (2013)
  • Author(s): 河野隆志、荻原秀明、尾池貴洋、水上達治、白石航也
  • Organizer: 日本放射線影響学会第56回大会
  • Year and Date: 2013-10-19
• [Presentation] Curcumin suppresses multiple DNA damage response pathways and has potency as sensitizer to PARP inhibitor (2013)
  • Author(s): Hideaki Ogiwara, Ayako Ui, Bunsho Shiotani, Lee Zou, Akira Yasui, Takashi Kohno
  • Organizer: 第72回日本癌学会学術総会
  • Year and Date: 2013-10-05
• [Presentation] Curcumin suppresses multiple DNA damage response pathways and has potency as sensitizer to PARP inhibitor (2013)
  • Author(s): Hideaki Ogiwara1, Ayako Ui2, Bunsho Shiotani3, Lee Zou3, Akira Yasui2, Takashi Kohno1
  • Organizer: The 72nd Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: パシフィコ横浜
• [Presentation] Personalized Medicine of Lung Adenocarcinoma Based on Genetic Alterations (2013)
  • Author(s): Takashi Kohno Ph D1,2, Hideaki Ogiwara Ph D1, Tatsuji Mizukami MD1
  • Organizer: 原研・国際キックオフシンポジウム
  • Place of Presentation: 長崎大学医学部良順会館ボードインホール
  • Invited
• [Presentation] ヒストンアセチル化酵素CBP/p300は、相同組換え修復遺伝子BRCA1およびRAD51の転写活性化を制御する (2012)
  • Author(s): 荻原 秀明
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
• [Presentation] 発がんに関わるDNA切断修復・クロマチンリモデリング機構 (2012)
  • Author(s): 河野隆志
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
• [Presentation] Garcinol, a Histone Acetyltransferase Inhibitor, Radiosensitezes Cancer Cells by Inhibiting Non-homologous End Joining (2012)
  • Author(s): Oike T
  • Organizer: ASTRO’S 54th ANNUAL MEETING
  • Place of Presentation: Boston USA
• [Presentation] Curcumin, a novel inhibitor of ATR-CHK1 pathway, suppresses homologous recombination and DNA damage checkpoint and enhances sensitivity to PARP inhibitors (2011)
  • Author(s): Ogiwara H. et al
  • Organizer: AACR-NCI-EORTC International Conference Molecular targets and cancer Therapeutics
  • Place of Presentation: San Francisco, USA
• [Presentation] Curcumin enhances the sensitivity to PARP inhibitors by suppression of homologous recombination and DNA damage checkpoint through inhibition of ATR-CHK1 pathway (2011)
  • Author(s): Ogiwara H. et al
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: Yokohama
• [Presentation] Garcinol, a Histone Acetyltransferase Inhibitor, Radiosensitezes Cancer Cells by Inhibiting Non-homologous End Joining (2011)
  • Author(s): Oike T. et al
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: Yokohama
• [Presentation] Involvement of LKB1 tumor suppressor protein in non-homologous end joining repair against DNA double strand breaks (2011)
  • Author(s): Ui A. et al
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: Yokohama
• [Presentation] Chromatin remodeling factors influencing DNA double-strand break repair and transcription (2011)
  • Author(s): Yasui A. et al
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: Yokohama
• [Presentation] Curcumin, a novel sensitizer for PARP inhibitor-based cancer therapy, working by suppression of homologous recombination and DNA damage checkpoint through inhibition of the ATR-CHK1 pathway (2011)
  • Author(s): Ogiwara H. et al
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: Nagoya
• [Presentation] Radio-sensitization of human lung cancer cells using histone acetyltranferase (HAT) inhibitors (2011)
  • Author(s): Oike T. et al
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: Nagoya
• [Remarks] ゲノム生物学研究分野
  • URL: http://www.ncc.go.jp/jp/nccri/divisions/genome_biology/index.html
• [Remarks] 分子診断・個別化医療開発グループ ゲノム生物学研究分野
  • URL: http://www.ncc.go.jp/jp/nccri/divisions/genome_biology/index.html
• [Patent(Industrial Property Rights)] P300を阻害する化合物によるがんの治療への応答性を予測する方法 (2014)
  • Inventor(s): 河野隆志・荻原秀明
  • Industrial Property Rights Holder: 河野隆志・荻原秀明
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-032928
  • Filing Date: 2014-02-24
• [Patent(Industrial Property Rights)] 癌の治療への応答性を予測する方法 (2013)
  • Inventor(s): 河野隆志・蔦幸治
  • Industrial Property Rights Holder: 河野隆志・蔦幸治
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-147061
  • Filing Date: 2013-07-12