Copper ions are promising therapeutic target against ATP7B positive uterine leiomyosarcoma

• Project/Area Number: 17K11278
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Osaka University
• Principal Investigator: Matsuzaki Shinya 大阪大学, 医学部附属病院, 助教 (00467565)
• Co-Investigator(Kenkyū-buntansha): 上田 豊 大阪大学, 医学系研究科, 講師 (10346215) ; 岩宮 正 大阪大学, 医学系研究科, 助教 (40790936) ; 小林 栄仁 大阪大学, 医学系研究科, 助教 (50614773) ; 吉野 潔 産業医科大学, 医学部, 教授 (90362730)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 婦人科腫瘍学 / プラチナ耐性 / 子宮平滑筋肉腫 / プラチナ製剤 / ATP7B / 婦人科腫瘍 / 肉腫

Outline of Final Research Achievements

Platinum resistance is a major concern in leiomyosarcoma (LMS) treatment. The role of ATP7B in LMS resistance to platinum drugs was investigated both in vitro and in vivo. Western blot analysis of SK-LMS-1 cells (leiomyosarcoma cell line) revealed strong ATP7B expression. ATP7B silencing with siRNA resulted in a significantly reduced cisplatin half-maximal inhibitory concentration value. Immunohistochemistry showed the overexpression of ATP7B in 11 of 14 clinical LMS samples (78.6%). A permanent SK-LMS-ATP7B-suppressed cell line (SK-LMS-7B cells) was generated and tumor-xenografted mice were produced via inoculation with SK-LMS-1 parent or SK-LMS-7B cells. Cisplatin exhibited a significant antitumor effect in xenografts of SK-LMS-7B cells compared with those of SK-LMS-1 parent cells. Copper sulfate (CuSO4) was identified as a preferential inhibitor of ATP7B expression both in vitro and in vivo.

Academic Significance and Societal Importance of the Research Achievements

本研究は難治性疾患である子宮平滑筋肉腫の予後を改善させうる研究成果を示した。本研究で解析を行ったATP7Bは子宮平滑筋肉腫のみならず、他の婦人科癌や癌腫においても発現を認めると予想され本研究でえられた成果は他の癌種にも用いることができると考えられる。本研究ではプラチナ耐性に着目したが、ATP7Bを発現する腫瘍では銅イオンを併用して投与することで必要なプラチナ製剤の量を減少させ、副作用を軽減させうることも可能だと考えられる。銅イオンは人体に安全に投与できる量も知られており、比較的早期に臨床応用ができると考えられ、今後の癌の治療に速やかに応用されると期待される点で社会的意義は大きいと考えられる。

Research Products

• [Journal Article] Copper ions are novel therapeutic agents for uterine leiomyosarcoma (2020)
  • Author(s): Kakuda M, Matsuzaki S, Ueda Y, Shiomi M, Matsuzaki S, Kimura T, Fujita M, Egawa-Takata T, Kobayashi E, Serada S, Yoshino K, Naka T, Kimura T
  • Journal Title: Am J Obstet Gynecol Volume: 222 Issue: 1 Pages: 64.e1-64.e16
  • DOI: 10.1016/j.ajog.2019.07.030
  • Peer Reviewed / Open Access
• [Journal Article] LSR Antibody Therapy Inhibits Ovarian Epithelial Tumor Growth by Inhibiting Lipid Uptake (2018)
  • Author(s): Hiramatsu K, Serada S, Enomoto T, Takahashi Y, Nakagawa S, Nojima S, Morimoto A, Matsuzaki S, Yokoyama T, Takahashi T, Fujimoto M, Takemori H, Ueda Y, Yoshino K, Morii E, Kimura T, Naka T
  • Journal Title: Cancer Res Volume: 78 Issue: 2 Pages: 516-27
  • DOI: 10.1158/0008-5472.can-17-0910
  • Peer Reviewed / Open Access
• [Journal Article] Combination chemotherapy with irinotecan and gemcitabine for taxane/platinum-resistant/refractory ovarian and primary peritoneal cancer: a multicenter phase I/II trial (GOGO-Ov 6) (2017)
  • Author(s): Yoshino K, Kamiura S, Yokoi T, Nakae R, Fujita M, Takemura M, Adachi K, Wakimoto A, Nishizaki T, Shiki Y, Tsutsui T, Kanda Y, Kobayashi E, Hashimoto K, Mabuchi S, Ueda Y, Sawada K, Tomimatsu T, Kimura T
  • Journal Title: Cancer Chemother Pharmacol Volume: 80 Issue: 6 Pages: 1239-47
  • DOI: 10.1007/s00280-017-3468-5
  • Peer Reviewed / Open Access
• [Presentation] 2',4'bridged nucleic acid antisense for Annexin A4 Improve platinum drug resistance of ovarian clear cell carcinoma (2017)
  • Author(s): Nakagawa S, Yoshino K, Kakubari R, Matsuzaki S, Okazawa A, Matsuzaki S, Kobayashi E, Ueda Y, Naka T, Kimura T
  • Organizer: 第69回日本産科婦人科学会学術講演会
• [Presentation] 【ワークショップ】Novel strategy to overcome platinum resistance＜優秀演題賞＞ (2017)
  • Author(s): Kakuda M, Matsuzaki S, Nakae R, Tanaka Y, Iwamiya T, Okazawa A, Kobayashi E, Ueda Y, Yoshino K, Kimura T
  • Organizer: 第69回日本産科婦人科学会学術講演会
• [Presentation] Key role of Notch-ASCL1 pathway for trans-differentiation in a mixed small cell carcinoma/adenocarcinoma of uterine cervix (2017)
  • Author(s): Kubota S, Kiyohara Y, Okazawa A, Matsuzaki S, Kobayashi E, Ueda Y, Yoshino K, Kimura T, Inoue M
  • Organizer: 第69回日本産科婦人科学学会学術講演会
• [Presentation] 当科における子宮平滑筋肉腫に対するゲムシタビン/ドセタキセル併用療法の有用性についての検討＜優秀ポスター賞＞ (2017)
  • Author(s): 中江瑠璃子 岡澤晶子 柿ヶ野藍子 岩宮正 小玉美智子 松崎慎哉 小林栄仁 橋本香映 馬淵誠士 上田豊 澤田健二郎 冨松拓治 吉野潔 木村正
  • Organizer: 第59回日本婦人科腫瘍学会学術講演会
• [Presentation] アネキシンA4に対するアンチセンス核酸は卵巣明細胞癌の薬剤耐性を改善させる (2017)
  • Author(s): 角張玲沙 中川慧 世良田聡 松崎慎哉 上田豊 吉野潔 笠原勇矢 小比賀聡 仲哲治 木村正
  • Organizer: 第59回日本婦人科腫瘍学会学術講演会
• [Presentation] Antisense oligonucleotide of Annexin A4 improved platinum resistance in ovarian clear cell cancer (2017)
  • Author(s): Kakubari R, Serada S, Nakagawa S, Matuzaki S, Ueda Y, Yoshino K, Naka T, Kimura T
  • Organizer: 第76回日本癌学会学術集会
• [Presentation] Novel strategy to overcome platinum resistance in leiomyosarcoma (LMS); blocking ATP7B by copper ion (2017)
  • Author(s): Kakuda M, Matsuzaki S, Nakae R, Tanaka Y, Iwamiya T, Okazawa A, Kobayashi E, Ueda Y, Yoshino K, Kimura T
  • Organizer: The 69th Annual Congress of the Japanese Society of Obstetrics and Gynecology
  • Int'l Joint Research
• [Book] Advances in Medicine and Biology (2017)
  • Author(s): Otake A, Ueda Y, Matsuzaki S, Yoshino K, Kimura T
  • Publisher: Nova Science Publishers
  • ISBN: 9781536120691