Trial to establish new cancer stem cell targeting therapy utilizing drug repositioning

• Project/Area Number: 16K07160
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Yamagata University
• Principal Investigator: Okada Masashi 山形大学, 医学部, 講師 (70512614)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: がん幹細胞 / ドラッグリポジショニング / 適応拡大 / JNK / xenograft / 腫瘍発生 / 幹細胞性 / 癌幹細胞 / MLK

Outline of Final Research Achievements

We examined that the anti-cancer stem cell (CSC) activity of CEP1347, an MLK-JNK inhibitor which has a safety profile in humans. In vitro, CEP1347 induced differentiation and suppressed self-renewal and tumor initiation capacities of CSCs from glioblastoma, ovarian, and pancreatic cancer. In vivo, systemic administration of CEP1347 decreased tumor-initiating CSCs in established tumors in mice. Furthermore, the CEP1347 administration extended the survival of the glioblastoma orthotopic transplanted mice. Our findings suggest that CEP1347 is a promising candidate for cancer stem cell-targeting therapy.

Academic Significance and Societal Importance of the Research Achievements

腫瘍の発生及び維持には癌幹細胞の関与が指摘されており、様々な治療標的候補が報告されつつあるが、その克服は未だ困難である。本研究によりヒトに対して安全情報を持つMLK-JNK経路阻害薬CEP1347によって神経膠芽腫、膵癌、卵巣がんのがん幹細胞の制御が可能であることを明らかにした。これは、MLK-JNK経路ががん幹細胞の新たな治療標的として有望であることを示している。また、臨床試験済みの薬剤であり、ヒトに即座に応用可能なCEP1347が癌幹細胞標的薬として有効であることが示されたことも社会的にも意義あるものと考えられる。

Research Products

• [Journal Article] Spironolactone, a Classic Potassium-Sparing Diuretic, Reduces Survivin Expression and Chemosensitizes Cancer Cells to Non-DNA-Damaging Anticancer Drugs (2019)
  • Author(s): Sanomachi Tomomi、Suzuki Shuhei、Togashi Keita、Sugai Asuka、Seino Shizuka、Okada Masashi、Yoshioka Takashi、Kitanaka Chifumi、Yamamoto Masahiro
  • Journal Title: Cancers Volume: 11 Issue: 10 Pages: 1550-1550
  • DOI: 10.3390/cancers11101550
  • Peer Reviewed / Open Access
• [Journal Article] Brexpiprazole Reduces Survivin and Reverses EGFR Tyrosine Kinase Inhibitor Resistance in Lung and Pancreatic Cancer (2019)
  • Author(s): Tomomi Sanomachi, Shuhei Suzuki, Keita Togashi, Shizuka Seino, Takashi Yoshioka, Chifumi Kitanaka , Masashi Okada, Masahiro Yamamoto
  • Journal Title: Anticancer Res Volume: 9 Issue: 9 Pages: 4817-4828
  • DOI: 10.21873/anticanres.13667
  • Peer Reviewed
• [Journal Article] Brexpiprazole, a Serotonin-Dopamine Activity Modulator, Can Sensitize Glioma Stem Cells to Osimertinib, a Third-Generation EGFR-TKI, via Survivin Reduction (2019)
  • Author(s): Suzuki Shuhei、Yamamoto Masahiro、Sanomachi Tomomi、Togashi Keita、Sugai Asuka、Seino Shizuka、Yoshioka Takashi、Kitanaka Chifumi、Okada Masashi
  • Journal Title: Cancers Volume: 11 Issue: 7 Pages: 947-947
  • DOI: 10.3390/cancers11070947
  • Peer Reviewed / Open Access
• [Journal Article] In vitro and in vivo Anti-Tumor Effects of Brexpiprazole, a Newly-Developed Serotonin-Dopamine Activity Modulator With an Improved Safety Profile (2019)
  • Author(s): Shuhei Suzuki, Masahiro Yamamoto, Keita Togashi, Tomomi Sanomachi, Asuka Sugai, Shizuka Seino, Takashi Yoshioka, Chifumi Kitanaka, Masashi Okada
  • Journal Title: Oncotarget Volume: 37 Issue: 37 Pages: 3547-3558
  • DOI: 10.18632/oncotarget.26949
  • Peer Reviewed / Open Access
• [Journal Article] AS602801 Sensitizes Ovarian Cancer Stem Cells to Paclitaxel by Down-regulating MDR1. (2019)
  • Author(s): Yamamoto M, Suzuki S, Togashi K, Sanomachi T, Seino S, Kitanaka C, Okada M.
  • Journal Title: Anticancer Res. Volume: 39 Issue: 2 Pages: 609-617
  • DOI: 10.21873/anticanres.13154
  • Peer Reviewed
• [Journal Article] AS602801, an Anticancer Stem Cell Candidate Drug, Reduces Survivin Expression and Sensitizes A2780 Ovarian Cancer Stem Cells to Carboplatin and Paclitaxel. (2018)
  • Author(s): Yamamoto M, Suzuki S, Togashi K, Sanomachi T, Seino S, Kitanaka C, Okada M.
  • Journal Title: Anticancer Res. Volume: 38 Issue: 12 Pages: 6699-6706
  • DOI: 10.21873/anticanres.13038
  • Peer Reviewed
• [Journal Article] Involvement of GLUT1-mediated glucose transport and metabolism in gefitinib resistance of non-small-cell lung cancer cells. (2018)
  • Author(s): Suzuki S, Okada M, Takeda H, Kuramoto K, Sanomachi T, Togashi K, Seino S, Yamamoto M, Yoshioka T, Kitanaka C.
  • Journal Title: Oncotarget. Volume: 9 Issue: 66 Pages: 32667-32679
  • DOI: 10.18632/oncotarget.25994
  • Peer Reviewed / Open Access
• [Journal Article] AS602801, an Anti-Cancer Stem Cell Drug Candidate, Suppresses Gap-junction Communication Between Lung Cancer Stem Cells and Astrocytes. (2018)
  • Author(s): Kuramoto K, Yamamoto M, Suzuki S, Sanomachi T, Togashi K, Seino S, Kitanaka C, Okada M.
  • Journal Title: Anticancer Res. Volume: 38 Issue: 9 Pages: 5093-5099
  • DOI: 10.21873/anticanres.12829
  • Peer Reviewed
• [Journal Article] A Small-molecule Kinase Inhibitor, CEP-1347, Inhibits Survivin Expression and Sensitizes Ovarian Cancer Stem Cells to Paclitaxel. (2018)
  • Author(s): Togashi K, Okada M, Yamamoto M, Suzuki S, Sanomachi T, Seino S, Yamashita H, Kitanaka C.
  • Journal Title: Anticancer Res. Volume: 38 Issue: 8 Pages: 4535-4542
  • DOI: 10.21873/anticanres.12757
  • Peer Reviewed
• [Journal Article] Repositioning CEP-1347, a chemical agent originally developed for the treatment of Parkinson's disease, as an anti-cancer stem cell drug. (2017)
  • Author(s): Okada M, Takeda H, Sakaki H, Kuramoto K, Suzuki S, Sanomachi T, Togashi K, Seino S, Kitanaka C.
  • Journal Title: Oncotarget. Volume: 8 Issue: 55 Pages: 94872-94882
  • DOI: 10.18632/oncotarget.22033
  • Peer Reviewed / Open Access
• [Journal Article] Antitumor activity of gemcitabine against high-grade meningioma in vitro and in vivo. (2017)
  • Author(s): Takeda H, Okada M, Kuramoto K, Suzuki S, Sakaki H, Sanomachi T, Seino S, Yoshioka T, Hirano H, Arita K, Kitanaka C.
  • Journal Title: Oncotarget. Volume: 8 Issue: 53 Pages: 90996-91008
  • DOI: 10.18632/oncotarget.18827
  • Peer Reviewed / Open Access
• [Journal Article] Olanzapine, an Atypical Antipsychotic, Inhibits Survivin Expression and Sensitizes Cancer Cells to Chemotherapeutic Agents. (2017)
  • Author(s): Sanomachi T, Suzuki S, Kuramoto K, Takeda H, Sakaki H, Togashi K, Seino S, Yoshioka T, Okada M, Kitanaka C.
  • Journal Title: Anticancer Res. Volume: 37 Issue: 11 Pages: 6177-6188
  • DOI: 10.21873/anticanres.12067
  • Peer Reviewed
• [Journal Article] Licochalcone A specifically induces cell death in glioma stem cells via mitochondrial dysfunction. (2017)
  • Author(s): Kuramoto K, Suzuki S, Sakaki H, Takeda H, Sanomachi T, Seino S, Narita Y, Kayama T, Kitanaka C, Okada M.
  • Journal Title: FEBS Open Bio. Volume: 7 Issue: 6 Pages: 835-844
  • DOI: 10.1002/2211-5463.12226
  • Peer Reviewed / Open Access
• [Journal Article] Rho-Associated Protein Kinase (ROCK) Inhibitors Inhibit Survivin Expression and Sensitize Pancreatic Cancer Stem Cells to Gemcitabine. (2016)
  • Author(s): Takeda H, Okada M, Suzuki S, Kuramoto K, Sakaki H, Watarai H, Sanomachi T, Seino S, Yoshioka T, Kitanaka C.
  • Journal Title: Anticancer Res. Volume: 12 Issue: 12 Pages: 6311-6318
  • DOI: 10.21873/anticanres.11227
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Aripiprazole, an Antipsychotic and Partial Dopamine Agonist, Inhibits Cancer Stem Cells and Reverses Chemoresistance. (2016)
  • Author(s): Suzuki S, Okada M, Kuramoto K, Takeda H, Sakaki H, Watarai H, Sanomachi T, Seino S, Yoshioka T, Kitanaka C.
  • Journal Title: Anticancer Res. Volume: 10 Issue: 10 Pages: 5153-5161
  • DOI: 10.21873/anticanres.11085
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Impact of H3K27 Demethylase Inhibitor GSKJ4 on NSCLC Cells Alone and in Combination with Metformin. (2016)
  • Author(s): Watarai H, Okada M, Kuramoto K, Takeda H, Sakaki H, Suzuki S, Seino S, Oizumi H, Sadahiro M, Kitanaka C.
  • Journal Title: Anticancer Res. Volume: 11 Issue: 11 Pages: 6083-6092
  • DOI: 10.21873/anticanres.11198
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The novel JNK inhibitor AS602801 inhibits cancer stem cells in vitro and in vivo. (2016)
  • Author(s): Okada M, Kuramoto K, Takeda H, Watarai H, Sakaki H, Seino S, Seino M, Suzuki S, Kitanaka C.
  • Journal Title: Oncotarget Volume: 19 Issue: 19 Pages: 27021-27032
  • DOI: 10.18632/oncotarget.8395
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] がん幹細胞におけるJNKの役割 (2019)
  • Author(s): 岡田 雅司、北中 千史
  • Organizer: 第92回生化学会大会
• [Presentation] The novel JNK inhibitor AS602801 inhibits cancer stem cells in vitro and in vivo (2017)
  • Author(s): Masashi Okada, Shuhei Suzuki, Manabu Seino, Hiroyuki Takeda and Chifumi Kitanaka
  • Organizer: 日本癌学会年会
• [Presentation] がん幹細胞におけるJNK経路の機能解析 (2017)
  • Author(s): 岡田 雅司、鈴木 修平、倉元 謙太、武田 弘幸、清野 静香、北中 千史
  • Organizer: 生命科学系学会合同年次大会
• [Presentation] グルコース代謝の抑制はがん幹細胞の 幹細胞性維持および腫瘍創始能を抑制する (2016)
  • Author(s): 岡田雅司, 北中 千史
  • Organizer: 放射線影響学会
  • Place of Presentation: JMSアステールプラザ（広島市）
  • Year and Date: 2016-10-26
  • Invited
• [Presentation] Targeting the facilitative glucose transporter GLUT1 inhibits the self-renewal and tumor-initiating capacity of cancer stem cells (2016)
  • Author(s): Masashi Okada, Shuhei Suzuki, Manabu Seino, Hiroyuki Takeda, and Chifumi Kitanaka
  • Organizer: 日本癌学会 年会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2016-10-06