The Development of Novel Therapy Targeting Differentiation in Bone and Soft Tissue Sarcomas

• Project/Area Number: 19K09589
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56020:Orthopedics-related
• Research Institution: National Cancer Center Japan
• Principal Investigator: Kobayashi Eisuke 国立研究開発法人国立がん研究センター, 中央病院, 医長 (40365292)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 肉腫 / 分化 / 脱分化 / 滑膜肉腫 / 軟骨肉腫 / 脱分化型軟骨肉腫 / TNIK / 骨肉腫 / 新規治療開発

Outline of Research at the Start

肉腫は未だ治療に難渋することが臨床上の大きな問題点である。また免疫療法含めて、新規の有効な薬剤の開発が過去35年肉腫でほとんどない。本研究は肉腫のBreakthrough therapyの開発のため、Wntシグナル調節因子であるTRAF2 and NCK-interacting protein kinase (TNIK)および肉腫ではしばしば認められる脱分化という悪性化メカニズムの２つに着目し、新規薬剤の臨床応用を目指すことが目的である。

Outline of Final Research Achievements

Two studies were conducted to develop therapeutic agents focusing on sarcoma differentiation: First, the Wint signaling regulator TRAF2 and NCK-interacting protein kinase (TNIK) were examined for their usefulness as therapeutic targets in sarcoma. The second is the clinical application of a novel drug focusing on the malignant transformation mechanism of sarcoma, i.e., dedifferentiation. Focusing on the mechanism of chondrosarcoma dedifferentiation, we were able to prove a new form of chondrosarcoma dedifferentiation by genetic analysis.

Academic Significance and Societal Importance of the Research Achievements

希少がんである肉腫では治療開発が進まず、医師主導での研究で見つかった有望なシーズを臨床応用に繋げることが求められている。今回の研究は滑膜肉腫や軟骨肉腫など、予後不良かつ治療選択のすくない肉腫において新たな視点で治療開発に応用できる可能性を有した結果を得ることができた。学術的にも社会的にも極めて意義深いと考える。脱分化に関しては引き続きの研究を継続中である。

Research Products

• [Journal Article] Direct conversion of osteosarcoma to adipocytes by targeting TNIK (2021)
  • Author(s): Hirozane Toru、Masuda Mari、Sugano Teppei、Sekita Tetsuya、Goto Naoko、Aoyama Toru、Sakagami Takato、Uno Yuko、Moriyama Hideki、Sawa Masaaki、Asano Naofumi、Nakamura Masaya、Matsumoto Morio、Nakayama Robert、Kondo Tadashi、Kawai Akira、Kobayashi Eisuke、Yamada Tesshi
  • Journal Title: JCI Insight Volume: 6 Issue: 3
  • DOI: 10.1172/jci.insight.137245
  • Peer Reviewed / Open Access
• [Journal Article] Feasibility of Targeting Traf2-and-Nck-Interacting Kinase in Synovial Sarcoma (2020)
  • Author(s): Sekita Tetsuya、Yamada Tesshi、Kobayashi Eisuke、Yoshida Akihiko、Hirozane Toru、Kawai Akira、Uno Yuko、Moriyama Hideki、Sawa Masaaki、Nagakawa Yuichi、Tsuchida Akihiko、Matsumoto Morio、Nakamura Masaya、Nakayama Robert、Masuda Mari
  • Journal Title: Cancers Volume: 12 Issue: 5 Pages: 1258-1258
  • DOI: 10.3390/cancers12051258
  • Peer Reviewed / Open Access
• [Journal Article] A clinical comparison between dedifferentiated low-grade osteosarcoma and conventional osteosarcoma (2019)
  • Author(s): Toki S.、Kobayashi E.、Yoshida A.、Ogura K.、Wakai S.、Yoshimoto S.、Yonemori K.、Kawai A.
  • Journal Title: The Bone & Joint Journal Volume: 101-B Issue: 6 Pages: 745-752
  • DOI: 10.1302/0301-620x.101b6.bjj-2018-1207.r1
  • Peer Reviewed / Open Access
• [Presentation] 原発巣と異なる部位に異時性脱分化が生じた軟骨肉腫の症例：ゲノム解析による脱分化の証明 (2022)
  • Author(s): 関田哲也 小林英介
  • Organizer: 第37回日本整形外科学会基礎学術集会
• [Presentation] 滑膜肉腫に対するTNIK阻害剤の有効性 (2019)
  • Author(s): 関田哲也、山田哲司、小林英介、増田万里
  • Organizer: 第39回日本分子マーカー研究会
• [Presentation] Clinical Outcome of Dedifferentiated Low-grade Osteosarcoma (2019)
  • Author(s): E. Kobayashi, S. Toki, A. Yoshida, A. Kawai
  • Organizer: 20th General Meeting of the International Society of Limb Salvage