Elucidation of molecular mechanisms and development of novel therapeutic agents in pulmonary metastasis of osteosarcoma

• Project/Area Number: 19K16760
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Chiba Cancer Center (Research Institute)
• Principal Investigator: Kinoshita Hideyuki 千葉県がんセンター(研究所), 整形外科, 医長 (50797115)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2021: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2020: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
• Keywords: 骨肉腫 / レドックス / チオレドキシン (TXN) / PX-12 / TXN還元酵素 (TXNRD) / オーラノフィン (AUR) / 患者腫瘍組織移植モデル(PDX) / チオレドキシン (Trx) / Trx還元酵素 (TXNRD) / セレコキシブ / 肺転移 / アポトーシス / ASK1 / Trx

Outline of Research at the Start

骨肉腫の肺転移症例は極めて予後不良である. 周術期抗がん剤治療が標準治療となるが, 新規分子標的薬の早期開発が望まれる. 様々ながんのoncogeneであるApoptosis signalregulatingkinase 1 (ASK1)に着目し, 骨肉腫におけるASK1の関与の研究を立案した. 本研究の目的は骨肉腫モデルにおいてASK1の関与および阻害剤の効果を検討することである. 培養細胞では, 高肺転移骨肉腫細胞株・ヒト骨肉腫初代培養細胞を用いて増殖能・遊走能におけるASK1の機能を評価する. 動物実験では, ASK1欠損マウスで骨肉腫モデルを作成し, 腫瘍進展・肺転移の評価を行う.

Outline of Final Research Achievements

Osteosarcoma has a poor prognosis due to local progression and pulmonary metastasis, both of which must be controlled. In the current study, we focused on thioredoxin and thioredoxin reductase inhibitors, PX-12 and auranofin (AUR), to elucidate the involvement of oxidative and reductive (redox) regulation in osteosarcoma, respectively. PX-12 inhibited local progression and AUR also inhibited pulmonary metastasis. The combination of celecoxib and AUR was also examined to determine synergistic effects with other oxidative stress-inducing agents. The combination of celecoxib and AUR synergistically suppressed local progression of osteosarcoma. Patient-derived xenografts (PDX) models of osteosarcoma and chondrosarcoma were successfully generated and will be applied in future studies.

Academic Significance and Societal Importance of the Research Achievements

骨・軟部肉腫ではレドックス制御の報告は限られており，本研究のさらなる発展によりレドックス関連阻害剤の骨・軟部肉腫への応用が期待できる．また，AURはすでに本邦において承認されており，抗リウマチ薬としても用いられている安全性の高い内服薬である．近年，ドラッグリポジショニングが注目されており，今後AURの骨肉腫への効果がPDX等でも証明できれば，AURの臨床応用も早期可能であると考えられる．またPDXはヒトの病態に最も近いモデルであり，現在骨肉腫も含めた様々な骨・軟部肉腫のPDX作成を継続しており，今後のレドックス制御の解明を含め様々な研究の基盤になると考える．

Research Products

• [Journal Article] Clavicula Pro Humero Reconstruction for Malignant Tumor of the Proximal Humerus in Children and Adults (2022)
  • Author(s): Kinoshita H, Kamoda H, Hagiwara Y, Ishii T, Ohtori S, Yonemoto T.
  • Journal Title: Anticancer Res. Volume: 42(4) Issue: 4 Pages: 2139-2144
  • DOI: 10.21873/anticanres.15696
  • Peer Reviewed
• [Journal Article] Prognostic Factors for Survival in Patients With High-grade Chondrosarcoma. (2022)
  • Author(s): Kinoshita H, Kamoda H, Hagiwara Y, Ishii T, Ohtori S, Yonemoto T.
  • Journal Title: Cancer Diagn Progn. Volume: 2(6) Issue: 6 Pages: 681-685
  • DOI: 10.21873/cdp.10159
  • Peer Reviewed / Open Access
• [Journal Article] Effectiveness of Salvage Knee Rotationplasty on Sarcoma Around the Knee in Adolescents and Young Adults. (2021)
  • Author(s): Kinoshita H, Yonemoto T, Kamoda H, Hagiwara Y, Tsukanishi T, Inoue M, Terakawa F, Ohtori S, Ishii T.
  • Journal Title: Anticancer Res Volume: 41(2) Issue: 2 Pages: 1041-1046
  • DOI: 10.21873/anticanres.14860
  • Peer Reviewed
• [Journal Article] Poor efficacy of postoperative radiotherapy in infiltrative high-grade soft tissue sarcomas. (2021)
  • Author(s): Kinoshita H, Yonemoto T, Kamoda H, Hagiwara Y, Tsukanishi T, Inoue M, Terakawa F, Ohtori S, Ishii T.
  • Journal Title: Anticancer Res Volume: 41(8) Issue: 8 Pages: 4027-4032
  • DOI: 10.21873/anticanres.15202
  • Peer Reviewed
• [Journal Article] The thioredoxin reductase inhibitor auranofin suppresses the pulmonary metastasis of osteosarcoma, but not local progression. (2021)
  • Author(s): Kinoshita H, Shimozato O, Ishii T, Kamoda H, Hagiwara Y, Tsukanishi T, Ohtori S, Yonemoto T.
  • Journal Title: Anticancer Res Volume: 41(10) Issue: 10 Pages: 4947-4955
  • DOI: 10.21873/anticanres.15308
  • Peer Reviewed
• [Journal Article] Doxorubicin Combined With Ifosfamide for Sarcoma Induces Muscle Atrophy and Sleep Disruption. (2021)
  • Author(s): Kinoshita H, Hagiwara Y, Kamoda H, Hagiwara Y, Tsukanishi T, Ishii T, Ohtori S, Yonemoto T.
  • Journal Title: Anticancer Res Volume: 41(12) Issue: 12 Pages: 6273-6278
  • DOI: 10.21873/anticanres.15448
  • Peer Reviewed
• [Journal Article] The Thioredoxin-1 Inhibitor, PX-12, Suppresses Local Osteosarcoma Progression. (2021)
  • Author(s): Kinoshita H, Shimozato O, Kamoda H, Hagiwara Y, Tsukanishi T, Ishii T, Ohtori S, Yonemoto T.
  • Journal Title: Anticancer Res Volume: 41(12) Issue: 12 Pages: 6013-6021
  • DOI: 10.21873/anticanres.15420
  • Peer Reviewed
• [Journal Article] Successful Neurological Recovery with Multimodality Therapy without Surgery for Spinal Metastases from Advanced Gastric Cancer (2020)
  • Author(s): Kinoshita H, Kamoda H, Ishii T, Hagiwara Y, Tsukanishi T, Orita S, Inage K, Hirosawa N, Ohtori S, Yonemoto T.
  • Journal Title: Case Rep Orthop. Volume: 2020 Pages: 4753027-4753027
  • DOI: 10.1155/2020/4753027
  • Peer Reviewed / Open Access
• [Journal Article] Freeze-Dried Platelet-Rich Plasma Induces Osteoblast Proliferation via Platelet-Derived Growth Factor Receptor-Mediated Signal Transduction (2020)
  • Author(s): Kinoshita H, Orita S, Inage K, Fujimoto K, Shiga Y, Abe K, Inoue M, Norimoto M, Umimura T, Ishii T, Yonemoto T, Kamoda H, Tsukanishi T, Akazawa T, Ohtori S
  • Journal Title: Asian Spine J. Volume: 14(1) Issue: 1 Pages: 1-8
  • DOI: 10.31616/asj.2019.0048
  • Peer Reviewed / Open Access
• [Journal Article] Giant protruding high grade undifferentiated pleomorphic sarcoma arising in a keloid scar on the abdominal wall. (2020)
  • Author(s): Kinoshita H, Tsukanishi T, Ishii T, Kamoda H, Hagiwara Y, Orita S, Inage K, Hirosawa N, Ohtori S, Yonemoto T.
  • Journal Title: Case Rep Dermatol Med. Volume: 2020 Pages: 4898965-4898965
  • DOI: 10.1155/2020/4898965
  • Peer Reviewed / Open Access
• [Journal Article] Successful treatment of a massive desmoplastic fibroma of the ilium without surgery: A case report with long-term follow-up (2020)
  • Author(s): Kinoshita H, Ishii T, Kamoda H, Tsukanishi T, Orita S, Inage K, Ohtori S, Yonemoto T.
  • Journal Title: Case Rep Orthop. Volume: 2020 Pages: 5380598-5380598
  • DOI: 10.1155/2020/5380598
  • Peer Reviewed / Open Access
• [Journal Article] Synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome with purely osteolytic, not osteosclerotic, lesions mimicking a malignant tumor. (2020)
  • Author(s): Kinoshita H, Ishii T, Kamoda H, Hagiwara Y, Tsukanishi T, Orita S, Inage K, Hirosawa N, Ohtori S, Yonemoto T.
  • Journal Title: Case Rep Reumato. Volume: 2020 Pages: 6316921-6316921
  • DOI: 10.1155/2020/6316921
  • Peer Reviewed / Open Access
• [Journal Article] Skeletal Muscle Cell Oxidative Stress as a Possible Therapeutic Target in a Denervation-Induced Experimental Sarcopenic Model (2019)
  • Author(s): Kinoshita H, Orita S, Inage K, Yamauchi K, Abe K, Inoue M, Norimoto M, Umimura T, Eguchi Y, Fujimoto K, Shiga Y, Kanamoto H, Aoki Y, Furuya T, Suzuki M, Akazawa T, Takahashi K, Ohtori S.
  • Journal Title: Spine Volume: 44 Issue: 8 Pages: 446-455
  • DOI: 10.1097/brs.0000000000002891
  • Peer Reviewed
• [Journal Article] Successful total en bloc spondylectomy of the L3 vertebra with a paravertebral giant cell tumor following preoperative treatment with denosumab. (2019)
  • Author(s): Kinoshita H, Orita S, Yonemoto T, Ishii T, Iwata S, Kamoda H, Tsukanishi T, Inage K, Abe K, Inoue M, Norimoto M, Umimura T, Fujimoto K, Shiga Y, Kanamoto H, Furuya T, Takahashi K, Ohtori S.
  • Journal Title: J Med Case Rep. Volume: 13(1) Issue: 1 Pages: 116-116
  • DOI: 10.1186/s13256-019-2029-4
  • Peer Reviewed
• [Journal Article] Muscle Invasive Dermatofibroma Clinically Mimicking a Malignant Tumor. (2019)
  • Author(s): Kinoshita H, Ishii T, Kamoda H, Tsukanishi T, Orita S, Inage K, Ohtori S, Yonemoto T.
  • Journal Title: Case Rep Dermatol Med. Volume: 2019 Pages: 4503272-4503272
  • DOI: 10.1155/2019/4503272
  • Peer Reviewed / Open Access
• [Journal Article] Giant protruding nodular fasciitis of the anterior chest wall clinically mimicking a soft tissue sarcoma. (2019)
  • Author(s): Kinoshita H, Yonemoto T, Kamoda H, Tsukanishi T, Orita S, Inage K, Hirosawa N, Ohtori S, Ishii T.
  • Journal Title: Case Rep Orthop. Volume: 2019 Pages: 4174985-4174985
  • DOI: 10.1155/2019/4174985
  • Peer Reviewed / Open Access
• [Presentation] Development of novel therapeutic agents targeting redox regulation system in osteosarcoma (2022)
  • Author(s): Kinoshita H
  • Organizer: European Calcified Tissue Society (ECTS) 2022
  • Int'l Joint Research
• [Presentation] Synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome with purely osteolytic, not osteosclerotic, lesions mimicking a malignant tumor (2022)
  • Author(s): Kinoshita H
  • Organizer: European Calcified Tissue Society (ECTS) 2022
  • Int'l Joint Research
• [Presentation] レドックス制御を標的とする 骨肉腫新規治療薬の開発および 分子機序解明 (2022)
  • Author(s): 木下英幸 ，石井猛，鴨田博人，萩原洋子， 塚西敏則， 米本司
  • Organizer: 第5回日本サルコーマ治療研究学会学術集会
• [Presentation] 転移性脊髄圧迫に対する 椎弓切除術の術後歩行機能獲得に 及ぼす予測因子の検討 (2022)
  • Author(s): 木下英幸 ，鴨田 博人，萩原洋子， 大鳥精司， 米本司
  • Organizer: 第55回日本整形外科学会骨・軟部腫瘍学術集会
• [Presentation] レドックス制御を標的とする 骨肉腫新規治療薬の開発および 分子機序解明 (2022)
  • Author(s): 木下英幸 ，石井猛，鴨田博人，萩原洋子， 塚西敏則， 米本司
  • Organizer: 第95回日本整形外科学会学術総会
• [Presentation] The evaluation of bone union activity of freeze-dried platelet-rich plasma (2021)
  • Author(s): Kinoshita H, Orita S, Inage K, Shiga Y, Ohtori S.
  • Organizer: European Calcified Tissue Society (ECTS)
  • Int'l Joint Research
• [Presentation] Effectiveness of salvage knee rotationplasty on sarcoma around the knee in adolescents and young adults (2021)
  • Author(s): Kinoshita H, Yonemoto T, Kamoda H, Hagiwara Y, Tsukanishi T, Ishi T.
  • Organizer: European Calcified Tissue Society (ECTS)
  • Int'l Joint Research
• [Presentation] Skeletal muscle cell oxidative stress as a possible therapeutic target for sarcopenia (2021)
  • Author(s): Kinoshita H, Orita S, Inage K, and Ohtori S.
  • Organizer: European Calcified Tissue Society (ECTS)
  • Int'l Joint Research
• [Presentation] レドックス制御を標的とする骨肉腫新規治療薬の開発および分子機序解明 (2021)
  • Author(s): 木下英幸
  • Organizer: 日本整形外科学会 骨軟部腫瘍学術集会
• [Presentation] The evaluation of bone union activity of freeze-dried platelet-rich plasma (2020)
  • Author(s): Kinoshita H, Orita S, Inage K, Shiga Y, Ohtori S.
  • Organizer: American Society for Bone and Mineral Research (ASBMR)
  • Int'l Joint Research
• [Presentation] Successful total en bloc spondylectomy of the L3 vertebra with a paravertebral giant cell tumor following preoperative treatment with denosumab (2019)
  • Author(s): Kinoshita H, Yonemoto T, Kamoda H, Hagiwara Y, Tsukanishi T, Ishi T
  • Organizer: International Society of Limb Salvage (2019 Athens,Greece)
  • Int'l Joint Research
• [Presentation] Giant muscle invasive dermatofibroma clinically mimicking a malignant tumor (2019)
  • Author(s): Kinoshita H, Yonemoto T, Kamoda H, Hagiwara Y, Tsukanishi T, Ishi T
  • Organizer: International Society of Limb Salvage (2019 Athens,Greece)
  • Int'l Joint Research
• [Presentation] Skeletal muscle cell oxidative stress as a possible therapeutic target for sarcopenia (2019)
  • Author(s): Kinoshita H, Yonemoto T, Kamoda H, Hagiwara Y, Tsukanishi T, Ishi T
  • Organizer: International Society of Limb Salvage (2019 Athens,Greece)
  • Int'l Joint Research