The KANK1 pathway may be a novel therapeutic target for ovarian clear cell carcinoma

• Project/Area Number: 16K11151
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Iwate Medical University
• Principal Investigator: ITAMOCHI Hiroaki 岩手医科大学, 医学部, 教授 (20314601)
• Co-Investigator(Kenkyū-buntansha): 小見 英夫 岩手医科大学, 医学部, 助教 (20382608) ; 利部 正裕 岩手医科大学, 医学部, 特任講師 (30382609) ; 佐藤 誠也 岩手医科大学, 医学部, 助教 (30621007) ; 杉山 徹 岩手医科大学, 医学部, 教授 (40162903) ; 竹内 聡 岩手医科大学, 医学部, 特任准教授 (60252772) ; 小島 淳美 岩手医科大学, 医学部, 講師 (60508753)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 卵巣明細胞癌 / Aurora kinase A / バイオマーカー / シスプラチン / 卵巣がん / 明細胞癌 / KANK1 / 卵巣癌 / 治療標的

Outline of Final Research Achievements

We examined the incidence of Aurora kinase A (Aurora-A) protein expression in ovarian clear cell carcinoma (OCCC) tumor tissues and its correlation with clinical parameters. In addition, we assessed the efficacy of ENMD-2076, an Aurora-A inhibitor, in combination with chemotherapeutic agents for the treatment of OCCC.
The expressions of Aurora-A protein were found in 96% of OCCC. Increased Aurora-A expression was associated with significantly worse overall survival of FIGO stages IC3 to IV patients (21% vs 77%). Multivariate analysis revealed that Aurora-A expression was an independent prognostic factor for stages IC3 to IV OCCC patients. Furthermore, synergistic effects were observed with ENMD-2076 in combination with cisplatin or SN-38 in 4 of the 6 tested cell lines. ENMD-2076 dramatically enhanced apoptosis and cell cycle arrest at the G2/M phase induced by cisplatin.
Aurora-A is a promising biomarker that is predictive of patient outcomes and a potential target for OCCC.

Academic Significance and Societal Importance of the Research Achievements

卵巣明細胞癌において、腫瘍組織中のAurora-A蛋白発現強度は有望な予後予測マ－カ－であることが示唆された。また、基礎的検討においてAurora-A阻害剤とシスプラチンとの併用療法の有効性が示唆された。
したがって、難治性卵巣癌の一つである明細胞癌において、Aurora-Aは重要なバイオマーカーであり、Aurora-A阻害剤は明細胞癌患者の予後を改善する可能性が示された。

Research Products

• [Journal Article] Inhibition of Aurora Kinase A Synergistically Enhances Cytotoxicity in Ovarian Clear Cell Carcinoma Cell Lines Induced by Cisplatin: A Potential Treatment Strategy. (2017)
  • Author(s): Chiba Y, Sato S, Itamochi H, Yoshino N, Fukagawa D, Kawamura H, Suga Y, Kojima-Chiba A, Muraki Y, Sugai T, Sugiyama T.
  • Journal Title: Int J Gynecol Cancer Volume: 8 Issue: 8 Pages: 1666-74
  • DOI: 10.1097/igc.0000000000001081
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Establishment and characterization of a novel uterine carcinosarcoma cell line, TU-ECS-1, with mutations of TP53 and KRAS. (2017)
  • Author(s): Chiba Y, Sato S, Itamochi H, Suga Y, Fukagawa T, Oumi N, Oishi T, Harada T, Sugai T, Sugiyama T
  • Journal Title: Human Cell Volume: 30 Issue: 2 Pages: 140-148
  • DOI: 10.1007/s13577-016-0154-6
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Molecular and genetic alterations in ovarian clear cell carcinoma. (2018)
  • Author(s): 佐藤誠也, 板持広明.
  • Organizer: 第60回日本婦人科腫瘍学会学術講演会
• [Presentation] Aurora-A inhibition synergistically enhances cisplatin induced cytotoxicity in ovarian clear cell carcinoma cell lines. (2017)
  • Author(s): Chiba Y, Sato S, Fukagawa D, Suga Y, Kagabu M, Chiba A, Takeuchi S, Itamochi H, Sugai T, Sugiyama T.
  • Organizer: 5th Biennial Meeting of Asian Society of Gynecologic Oncology
  • Int'l Joint Research
• [Presentation] 卵巣明細胞癌に対するAurora kinase A阻害剤を用いた至適併用化学療法の探索. (2017)
  • Author(s): 千葉洋平, 佐藤誠也, 板持広明, 杉山徹.
  • Organizer: 第76回日本癌学会学術総会