Study of specific gene expression in intractable childhood cancer and growth suppression and differentiation inducing effect of HDAC inhibitors

• Project/Area Number: 17K10122
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Iehara Tomoko 京都府立医科大学, 医学(系)研究科(研究院), 准教授 (20285266)
• Co-Investigator(Kenkyū-buntansha): 柳生 茂希 京都府立医科大学, 医学(系)研究科(研究院), 助教 (10572547) ; 細井 創 京都府立医科大学, 医学(系)研究科(研究院), 教授 (20238744) ; 菊地 顕 京都府立医科大学, 医学(系)研究科(研究院), 特任助教 (40453104) ; 宮地 充 京都府立医科大学, 医学(系)研究科(研究院), 助教 (40584983)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 小児がん / HDAC阻害剤 / アポトーシス / 神経芽腫 / 横紋筋肉腫 / 小児腫瘍

Outline of Final Research Achievements

Introduction: We investigated whether the novel HDAC inhibitor YM753 has an antitumor effect on rhabdomyosarcoma and neuroblastoma in cell lines and in animal models.　Methods: The rhabdomyosarcoma and neuroblastoma cell lines were used. The antitumor effect and mechanism were examined. A xenograft mouse model was prepared to examine the antitumor effects. Results: This drug induced cell death in rhabdomyosarcoma and neuroblastoma cell lines. Induction of apoptosis was confirmed, showing G2/M phase arrest. The tumor cells showed G2/M phase arrest, confirming apoptosis induction. In addition, p21 expression induction, histone acetylation, and Cleaved caspase-3 induction were confirmed. In a mouse model, it suppressed tumor growth. In neuroblastoma it also induced differentiation. Discussion: From these results of culture experiments and animal experiments, it was effective as a novel therapeutic agent for rhabdomyosarcoma and neuroblastoma.

Academic Significance and Societal Importance of the Research Achievements

新規 HDAC 阻害剤 YM753 が、横紋筋肉腫、神経芽腫に対して、培養細胞および動物実験モデルで抗腫瘍効果を検討した。細胞株およびマウスモデルにおいては、腫瘍増殖を抑制した。神経芽腫では、分化も誘導した。これらの細胞培養実験、動物実験の結果から、横紋筋肉腫、神経芽腫の新規治療薬として有効であると考えられた。現在phase 1試験が米国で実施されていることから、小児がん領域での本薬剤の臨床応用が期待される。

Research Products

• [Journal Article] OBP;801, a novel histone deacetylase inhibitor, induces M;phase arrest and apoptosis in rhabdomyosarcoma cells. (2019)
  • Author(s): Tomoyasu C, Kikuchi K, Kaneda D, Yagyu S, Miyachi M, Tsuchiya K, Iehara T, Sakai T, Hosoi H
  • Journal Title: Oncol Rep Volume: 41(1) Pages: 643-649
  • DOI: 10.3892/or.2018.6813
  • Peer Reviewed / Open Access
• [Presentation] 横紋筋肉腫における新規ヒストン脱アセチル化酸素阻害剤OBP-801の抗腫瘍効果 (2018)
  • Author(s): 菊地顕，友安千紘，中村加世子，柳生茂希，宮地充，勝見良樹，土屋邦彦，家原知子，酒井敏行，細井 創
  • Organizer: 第121回日本小児科学会学術集会
• [Presentation] The novel histone deacetylase inhibitor OBP-801 induces apoptosis in neuroblastoma tumor cells (2018)
  • Author(s): Daisuke Kaneda, Ken Kikuchi, Kayoko Nakamura, Shigeki Yagyu, Tomoko Iehara, Toshiyuki Sakai, Hajime Hosoi
  • Organizer: Advances in Neuroblastoma research
  • Int'l Joint Research
• [Presentation] The novel histone deacetylase inhibitor OBP-801 induces apoptosis in neuroblastoma tumor cells (2018)
  • Author(s): Daisuke Kaneda, Ken Kikuchi, Kayoko Nakamura, Shigeki Yagyu, Tomoko Iehara, Toshiyuki Sakai, Hajime Hosoi
  • Organizer: Advances in NEうろbぁs苫Research
  • Int'l Joint Research
• [Presentation] 横紋筋肉腫における新規ヒストン脱メチル化酵素阻害剤の抗腫瘍効果と分子機構の解析 (2018)
  • Author(s): 菊地顕、友安千紘、中村加世子、柳生茂希、宮地充、家原知子、酒井敏行、細井創
  • Organizer: 第121回日本小児科学会学術集会