Mutations in the RAS Pathway as Potential Precision Medicine Targets in Treatment of Rhabdomyosarcoma

• Project/Area Number: 17K10123
• 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: Kikuchi Ken 京都府立医科大学, 医学(系)研究科(研究院), 特任助教 (40453104)
• 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) ; 家原 知子 京都府立医科大学, 医学(系)研究科(研究院), 准教授 (20285266) ; 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: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
• Keywords: 横紋筋肉腫 / RAF-MEK阻害剤 / RAS変異 / MEK阻害剤 / RAS / プレシジョン医療

Outline of Final Research Achievements

Precision medicine strategies for treating rhabdomyosarcoma (RMS), a childhood malignancy, have not been developed. We examined the effect of selective dual RAF/MEK inhibitor on RMS cell lines. Among the eleven cell lines studied, one NRAS and two HRAS mutated cell lines were detected. RAF/MEK inhibitor inhibited the proliferation and growth in all of the RAS-mutated RMS cell lines, while it induced G1 cell cycle arrest in two of them. G1 cell cycle arrest was accompanied by p21 up-regulation and RB dephosphorylation. RAF/MEK inhibitor also suppressed the in vivo growth of RAS-mutated RMS tumor, and the mice showed improved survival.

Academic Significance and Societal Importance of the Research Achievements

本研究により開発された新しい治療方針・手法は、近年、本申請者らが協力して、インフラ整備と体制確立がなされた本邦の当該小児がんグループスタディの臨床試験において、臨床的にその有効性と安全性を検証し、さらにその結果は本邦の当該がん患児の治療の向上に貢献できると考えている。

Research Products

• [Journal Article] Mutations in the RAS pathway as potential precision medicine targets in treatment of rhabdomyosarcoma. (2019)
  • Author(s): Nakagawa N, Kikuchi K, Yagyu S, Miyachi M, Iehara T, Tajiri T, Sakai T, Hosoi H.
  • Journal Title: Biochem Biophys Res Commun Volume: 512 Issue: 3 Pages: 524-530
  • DOI: 10.1016/j.bbrc.2019.03.038
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Novel allosteric RAF/MEK inhibitor in the treatment of rhabdomyosarooma. (2018)
  • Author(s): Nakagawa N, Kikuchi K, Yagyu S, Iehara T, Sakai T, Hosoi H.
  • Organizer: 第60回日本小児血液・がん学会学術集会
• [Presentation] Mutation of Ras Pathway Should be a Target of Precision Medicine for Rhabdomyosarcoma (2017)
  • Author(s): N. nakagawa, K. Kikuchi, K. Nakamura, T. Tanaka, S. Yagyu, T. Iehara, T. Tajiri, T. Sakai, H. Hosoi
  • Organizer: 49th CONGRESS OF THE INTERNATIONAL SOCIETY OF PAEDIATRIC ONCOLOGY (SIOP)
  • Int'l Joint Research