Development of a new treatment based on the construction of expression database of giant cell tumor of bone

• Project/Area Number: 16K20070
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Orthopaedic surgery
• Research Institution: Juntendo University
• Principal Investigator: OKUBO TAKETO 順天堂大学, 医学部, 助教 (90732884)
• Research Collaborator: SUEHARA Yoshiyuki ; Saito Tsuyoshi ; Hayashi Takuo ; Kubota Daisuke ; Mukaihara Kenta ; Akaike Keisuke ; Tanabe Yu ; Ishii Midori ; Kurihara Taisei ; Sano Kei
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 骨巨細胞腫 / Denosumab / バイオマーカー / denosumab / 骨軟部腫瘍 / プロテオミクス / 遺伝子変異解析

Outline of Final Research Achievements

Giant cell tumors of bone (GCTB) are locally aggressive osteolytic bone tumors. Some studies have recently reported that denosumab is a novel and effective therapeutic option for GCTB. But, the prediction of treatment effect and the mechanism in GCTB are still unknown. Therefore, we constructed a profiling database of biological characteristics related to the grade of GCTB and the denosumab therapeutic response.
Histologically, the post-denosumab-treated samples were characterized by two lesions: SL-lesion, and FO-lesion. In this study, to clarify the differences in the protein expression between two lesions, we conducted comparative proteomic studies (12 pairs of pre- and post-denosumab treatment samples). We succeeded in constructing a protein expression database related to the fibro-osseous reactions by denosumab treatment. Based on the results, we also succeeded in determining the potential proteins that could be the biomarker for treatment evaluation and prognosis prediction.

Academic Significance and Societal Importance of the Research Achievements

骨巨細胞腫の新規治療薬であるDenosumabの治療反応性に関わる生物学的特徴のタンパク質プロファイリング・データベース構築と治療効果判定や予後予測のバイオマーカー候補となりうるタンパク質同定の成功の報告は世界初であり、今後の骨巨細胞腫の病態理解と治療法開発に道筋を示しうる有力な成果である。
本研究より開発されたバイオマーカーによりDenosumab治療の効果判定や予後予測が可能になるのみならず、データベースより同定されたタンパク質が骨巨細胞腫のさらなる新規治療薬開発に結びつく可能性もあり、骨巨細胞腫患者の治療成績向上に期待ができると考えている。

Research Products

• [Int'l Joint Research] Memorial Sloan-Kettering Cancer Center(米国)
• [Journal Article] Squamous cell carcinoma arising from chronic osteomyelitis massively expanding into the medullary cavity: A case report. (2019)
  • Author(s): Kurihara T, Suehara Y, Akaike K, Hayashi T, Okubo T, Kim Y, Takagi T, Kaneko K, Yao T, Saito T
  • Journal Title: Human Pathology Case reports Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Fibrocartilaginous mesenchymoma of the tibia with predominant microcystic features: A case report and literature review (2019)
  • Author(s): Saito T, Motoi T, Suehara Y, Takagi T, Okubo T, Kurihara T, Hayashi T, Kudo T, Maruyama Y, Kaneko K, YaoT.
  • Journal Title: Human Pathology Case reports Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Proteomic signatures corresponding to the SS18/SSX fusion gene in synovial sarcoma. (2018)
  • Author(s): Ishii M, Suehara Y, Sano K, Kohsaka S, Hayashi T, Kazuno S, Akaike K, Mukaihara K, Kim Y, Okubo T, Takamochi K, Takahashi F, Kaneko K, Saito T.
  • Journal Title: Oncotarget Volume: 9(101) Issue: 101 Pages: 37509-37519
  • DOI: 10.18632/oncotarget.26493
  • Peer Reviewed / Open Access
• [Journal Article] The first study on locomotive syndrome in lower amputees. (2018)
  • Author(s): Sano K, Suehara Y, Tanabe Y, Okubo T, Kim Y, Ishii M, Kawasaki T, Terakado A, Akaike K, Mukaihara K, Kubota D, Okubo N, Maruyama Y, Saito T, Kaneko K.
  • Journal Title: J Adv Med Med Res. Volume: 27 Pages: 1-10
  • Peer Reviewed
• [Journal Article] PPP2R1A regulated by PAX3/FOXO1 fusion contributes to the acquisition of aggressive behavior in PAX3/FOXO1-positive alveolar rhabdomyosarcoma. (2018)
  • Author(s): Akaike K, Suehara Y, Kohsaka S, Hayashi T, Tanabe Y, Kazuno S, Mukaihara K, Toda-Ishii M, Kurihara T, Kim Y, Okubo T, Hayashi Y, Takamochi K, Takahashi F, Kaneko K, Ladanyi M, Saito T.
  • Journal Title: Oncotarget Volume: 9(38) Issue: 38 Pages: 25206-25215
  • DOI: 10.18632/oncotarget.25392
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] KCTD12 is negatively regulated by Kit in gastrointestinal stromal tumors. (2018)
  • Author(s): Suehara Y, Akaike K, Mukaihara K, Kurisaki-Arakawa A, Kubota D, Okubo T, Mitomi H, Mitani K, Takahashi M, Toda-Ishii M1, Kim Y, Tanabe Y, Takagi T, Hayashi T, Mogushi K, Kaneko K, Yao T, Saito T.
  • Journal Title: Oncotarget Volume: 9(43) Issue: 43 Pages: 27016-27026
  • DOI: 10.18632/oncotarget.25469
  • Peer Reviewed / Open Access
• [Journal Article] IRE1α-XBP1 inhibitors exerted anti-tumor activities in Ewing's sarcoma. (2018)
  • Author(s): Tanabe Y, Suehara Y, Kohsaka S, Hayashi T, Akaike K, Mukaihara K, Kurihara T, Kim Y, Okubo T, Ishii M, Kazuno S, Kaneko K, Saito T.
  • Journal Title: Oncotarget Volume: 9(18) Issue: 18 Pages: 14428-14443
  • DOI: 10.18632/oncotarget.24467
  • Peer Reviewed / Open Access
• [Journal Article] An The development of the short-form “25-question Geriatric Locomotive Function Scale”. (2018)
  • Author(s): Tanabe Y, Suehara Y Kim Y, Nojiri S, Okubo T, Ishii M, Kawasaki T, Matsuoka K, Akaike K, Mukaihara K, Okubo N, Saito T, Kaneko K.
  • Journal Title: Journal of Advances in Medicine and Medical Research Volume: 10 Issue: 10 Pages: 1-13
  • DOI: 10.9734/jammr/2018/40196
  • Peer Reviewed / Open Access
• [Journal Article] Cabozantinib and dastinib exert anti-tumor activity in alveolar soft part sarcoma (2017)
  • Author(s): Mukaihara K, Tanabe Y, Kubota D, Akaike K, Hayashi T, Mogushi K, Hosoya M, Sato S,Kobayashi E, Okubo T, Kohsaka S, Saito T, Kaneko K, Suehara Y.
  • Journal Title: PLoS One Volume: 12(9) Issue: 9 Pages: 0185321-0185321
  • DOI: 10.1371/journal.pone.0185321
  • Peer Reviewed / Open Access
• [Journal Article] Protein Expression Profiling of Giant Cell Tumors of Bone Treated with Denosumab. (2016)
  • Author(s): Mukaihara K, Suehara Y, Kohsaka S, Akaike K, Tanabe Y, Kubota D, Ishii M, Fujimura T, Kazuno S, Okubo T, Takagi T, Yao T, Kaneko K, Saito T.
  • Journal Title: PLoS One Volume: 10 Issue: 2 Pages: e0148401-e0148401
  • DOI: 10.1371/journal.pone.0148401
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] An Outpatient-based Survey on the Recognition of Locomotive Syndrome in Japan: The Results of three Years of Surveys. (2016)
  • Author(s): Tanabe Y, Suehara Y, Okubo T, Kim Y, Ishii M,Kawasaki T, Matsuoka K, Akaike K, Mukaihara K, Kubota D, Okubo N, Maruyama Y, Saito T, Kaneko K.
  • Journal Title: British Journal of Medicine & Medical Research. Volume: 15(9) Issue: 9 Pages: 1-9
  • DOI: 10.9734/bjmmr/2016/26127
  • Peer Reviewed / Open Access
• [Journal Article] Clinicopathological effects of protein phosphatase 2, regulatory subunit A, alpha mutations in gastrointestinal stromal tumors (2016)
  • Author(s): Ishii M, Akaike K, Suehara Y, Mukaihara K, Kubota K , Kohsaka S, Okubo T, Mitani K, Mogushi K, Takagi T, Kaneko K, Yao T, Saito T.
  • Journal Title: Modern Pathology. Volume: 29 Issue: 11 Pages: 1424-1432
  • DOI: 10.1038/modpathol.2016.138
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A comparative study of 2 screening tools for locomotive syndrome (the “Loco-check” and the “GLFS-25”): An orthopedic outpatient-based survey. (2016)
  • Author(s): Kim Y, Suehara Y, Ishii M, Kawasaki T, Matsuoka K, Okubo T, Okubo N, Tanabe Y, Akaike K, Mukaihara K, Kubota D, Maruyama Y, Saito T, Kaneko K.
  • Journal Title: British Journal of Medicine & Medical Research Volume: 17(5) Issue: 5 Pages: 1-13
  • DOI: 10.9734/bjmmr/2016/28194
  • Peer Reviewed / Open Access
• [Presentation] Metabolic fluctuations in adriamycin-resistant osteosarcomas using metabolomic approaches (2019)
  • Author(s): Sasa K, Suehara Y, Akaike K, Hayashi T, Taka H, Youngji K, Okubo T, Kaneko K, Saito T
  • Organizer: the 65th Annual Meeting of the Orthopaedic Research Society
  • Int'l Joint Research
• [Presentation] IRE1α-XBP1 Inhibitor exerts antiyumor activity in osteosarcoma. (2019)
  • Author(s): Kurihara T, Suehara Y, Hayashi T, Akaike K, Okubo T, Kim Y, Kaneko K, Saito T
  • Organizer: the 65th Annual Meeting of the Orthopaedic Research Society
  • Int'l Joint Research
• [Presentation] Comprehensive mRNA-based screen for tyrosine kinase fusions and a de novo alternative transcription initiation site in soft tissue sarcomas. (2018)
  • Author(s): Suehara Y, Kohsaka S, Kurisaki A, Akaike K, Hayashi T, Mogushi K, Okubo T, Kim Y, Sato S, Kobayashi E, Kaneko K, Mano H, Saito T
  • Organizer: European Society For Medical Oncology ASIA, Nov 23-25th 2018
  • Int'l Joint Research
• [Presentation] IRE1α-XBP1 Inhibitor exerts antiyumor activity in osteosarcoma. (2018)
  • Author(s): Kurihara T, Suehara Y, Hayashi T, Akaike K, Okubo T, Kim Y, Kaneko K, Saito T
  • Organizer: Connective Tissue Oncology Society, 23th Annual Meeting, November 14 - 17, 2018, Roma, Italy
  • Int'l Joint Research
• [Presentation] Locomotive Syndrome in Lower Amputees: A Comparative Study with Orthopedic Patients. (2017)
  • Author(s): Tanabe Y, Suehara Y, Terakado A, Okubo T, Kim Y, Ishii M, Uehara H, Maruyama Y, Saito T, Kaneko K.
  • Organizer: 19th, International Symposium on Limb Salvage, May 10-12th, 2017, Kanazawa Japan
  • Int'l Joint Research
• [Presentation] Large skin ulcer due to a subcutaneous orthopedic implant after bevacizumab therapy: A case report. (2017)
  • Author(s): Suehara Y, Kubota D, Kato S, Akaike K, Tanabe Y, Okubo T, Kim Y, Saito T, Kaneko K.
  • Organizer: 19th, International Symposium on Limb Salvage, May 10-12th, 2017, Kanazawa Japan
  • Int'l Joint Research