Developement of new therapy for high-grade sarcoma focused on dephosphorylation disorder

• Project/Area Number: 17H07098
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Orthopaedic surgery
• Research Institution: Juntendo University
• Principal Investigator: AKAIKE KEISUKE 順天堂大学, 医学部, 非常勤助教 (60801719)
• Research Collaborator: SAITO tsuyoshi ; SUEHARA yoshiyuki ; HAYASHI takuo ; KURIHARA taisei ; SANO kei
• Project Period (FY): 2017-08-25 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 高悪性骨軟部腫瘍 / 特異的融合遺伝子 / 網羅的タンパク質解析 / 胞巣型横紋筋肉腫 / 脱リン酸化酵素 / PP2A / FTY720 / SET / 高悪性骨軟部肉腫 / driver-oncogene / 脱リン酸化異常 / Phosphatase / PPP2R1A / 脱リン酸化 / 悪性骨軟部肉腫

Outline of Final Research Achievements

We performed proteomic analyses of Alveolar rhabdomyosarcoma (ARMS) to determine proteins profiles regulated by PAX3-FOXO1, and PPP2R1A was determined to play a critical functional role in the setting of ARMS. We also evaluated the function of PPP2R1A, suggesting that PPP2R1A still has a tumor suppressive function in ARMS cells and PPP2R1A is a negatively regulated by PAX3-FOXO1 in ARMS In addition, the activation of PP2A - part of which was encoded by PPP2R1A - by FTY720 treatment in ARMS cell lines inhibited cell growth.

Academic Significance and Societal Importance of the Research Achievements

本研究は、難治性の骨軟部肉腫に対して、生命予後の改善に貢献する新規治療法開発を進める臨床的意義の高い研究である。これまで分子標的治療薬の開発は主にリン酸化に関連する“kinase”に焦点が当てられてきたが、もう一つの中心である“Phosphatase”については基礎的な研究が後れを取っている。未だ予後不良である多数の骨軟部肉腫ではPP2Aを含んだ脱リン酸化異常についての報告はなく、本研究結果を基に既存のPP2Aを含んだ脱リン酸化賦活剤の臨床応用に成功すれば、新薬の開発を待つことなく生命予後が改善する事が期待され、骨軟部肉腫患者へ大きく貢献できる。

Research Products

• [Journal Article] PPP2R1A regulated by PAX3/FOXO1 fusion contributes to the acquisition of aggressive behavior in PAX3/FOXO1-positive alveolar rhabdomyosarcoma. (2018)
  • Author(s): Keisuke Akaike, Yoshiyuki Suehara, Shinji Kohsaka, Takuo Hayashi, Yu Tanabe, Saiko Kazuno, Kenta Mukaihara, Midori Ishii, Taisei Kurihara, Youngji Kim, Taketo Okubo, Yasuhide Hayashi, Kazuya Takamochi, Fumiyuki Takahashi, Kazuo Kaneko, Marc Ladanyi, Tsuyoshi Saito
  • Journal Title: Oncotarget Volume: 印刷中
  • Peer Reviewed / Open Access