Comprehensive evaluation and analysis of therapeutic agents utilizing desmoid-type fibromatosis PDC

• Project/Area Number: 18K15313
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Aichi Cancer Center Research Institute
• Principal Investigator: Hamada Shunsuke 愛知県がんセンター(研究所), がん病態生理学分野, 研究員 (90747289)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: デスモイド型線維腫症 / CTNNB1変異 / Wntシグナル / Patient-Derived Cell / CTNNB1遺伝子 / WNT/β-catenin系シグナル / CTNNB1遺伝 / Patient-derived Cell

Outline of Final Research Achievements

TNNB1 mutations were identified in tumor tissue from desmoid fibromatosis, and these tumor cells were isolated and cultured. The tumor cells with S45F mutation, which is considered to have a poor clinical prognosis, showed stronger nuclear migration of β-catenin than cells with other mutations. We selected candidate drugs by drug screening as novel therapeutic agents, but the inhibitory effect of each drug, including existing drugs, was relatively low in S45F mutant cells. The expression profile of Wnt signaling genes also differed from that of other mutant cells, suggesting that these genes may be involved in the unique clinical course of S45F mutant tumors, including high drug resistance and recurrence rates.

Academic Significance and Societal Importance of the Research Achievements

デスモイド型線維腫症においてCTNNB1遺伝子変異はそれ自体が診断的意義を持つと同時に、その変異型が臨床的な術後再発率や薬物治療効果と相関することが報告されており、近年実臨床においても診断や治療方針の決定に有用なツールとなってきている。本研究では治療抵抗性のS45F変異型腫瘍の臨床的特徴と、細胞の分子生物学的性質について相関性が示された。今後さらに解析を進めることで、治療抵抗性の症例に対してより治療効果の高い薬剤の開発や、他の変異型を含めたより厳密な治療マーカーの確立化などが期待される。

Research Products

• [Journal Article] Risk factors of local recurrence after surgery in extraabdominal desmoid-type fibromatosis: A multicenter study in Japan (2020)
  • Author(s): Nishida Y, Hamada S, Kawai A, Kunisada T, Ogose A, Matsumoto Y, Ae K, Toguchida J, Ozaki T, Hirakawa A, Motoi T, Sakai T, Kobayashi E, Gokita T, Okamoto T, Matsunobu T, Shimizu K, Koike H.
  • Journal Title: CANCER SCIENCE Volume: 111 Issue: 8 Pages: 2935-2942
  • DOI: 10.1111/cas.14528
  • Peer Reviewed / Open Access
• [Journal Article] Desmoid with biweekly methotrexate and vinblastine shows similar effects to weekly administration: A phase II clinical trial (2020)
  • Author(s): Nishida Yoshihiro, Hamada Shunsuke, Urakawa Hiroshi, Ikuta Kunihiro, Sakai Tomohisa, Koike Hiroshi, Ito Kan, Emoto Ryo, Ando Yuichi, Matsui Shigeyuki
  • Journal Title: CANCER SCIENCE Volume: 111 Issue: 11 Pages: 4187-4194
  • DOI: 10.1111/cas.14626
  • Peer Reviewed / Open Access
• [Journal Article] Is tumour location a prognostic factor for pharmacological treatment in patients with desmoid-type fibromatosis? a systematic review (2020)
  • Author(s): Koike Hiroshi, Hamada Shunsuke, Sakai Tomohisa, Shimizu Koki, Yoshida Masahiro, Nishida Yoshihiro
  • Journal Title: JAPANESE JOURNAL OF CLINICAL ONCOLOGY Volume: 50 Issue: 9 Pages: 1032-1036
  • DOI: 10.1093/jjco/hyaa078
  • Peer Reviewed / Open Access
• [Journal Article] Is mutation analysis of beta-catenin useful for the diagnosis of desmoid-type fibromatosis? A systematic review (2020)
  • Author(s): Sakai Tomohisa, Hamada Shunsuke, Koike Hiroshi, Shimizu Koki, Yoshida Masahiro, Nishida Yoshihiro
  • Journal Title: JAPANESE JOURNAL OF CLINICAL ONCOLOGY Volume: 50 Issue: 9 Pages: 1037-1042
  • DOI: 10.1093/jjco/hyaa080
  • Peer Reviewed / Open Access
• [Journal Article] MRI characteristics predict the efficacy of meloxicam treatment in patients with desmoid‐type fibromatosis (2019)
  • Author(s): Shimizu Koki、Hamada Shunsuke、Sakai Tomohisa、Ito Shinji、Urakawa Hiroshi、Arai Eisuke、Ikuta Kunihiro、Koike Hiroshi、Ishiguro Naoki、Nishida Yoshihiro
  • Journal Title: Journal of Medical Imaging and Radiation Oncology Volume: 63 Issue: 6 Pages: 751-757
  • DOI: 10.1111/1754-9485.12940
  • Peer Reviewed / Open Access
• [Journal Article] Is immunohistochemical staining for β-catenin the definitive pathological diagnostic tool for desmoid-type fibromatosis? A multi-institutional study (2019)
  • Author(s): Koike Hiroshi、Nishida Yoshihiro、Kohno Kei、Shimoyama Yoshie、Motoi Toru、Hamada Shunsuke、Kawai Akira、Ogose Akira、Ozaki Toshifumi、Kunisada Toshiyuki、Matsumoto Yoshihiro、Matsunobu Tomoya、Ae Keisuke、Gokita Tabu、Sakai Tomohisa、Shimizu Koki、Ishiguro Naoki
  • Journal Title: Human Pathology Volume: 84 Pages: 155-163
  • DOI: 10.1016/j.humpath.2018.09.018
  • Peer Reviewed / Open Access