Establishment of novel therapeutic system for renal cell carcinoma by pahrmacogenomics and transcriptomics

• Project/Area Number: 15K10573
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: Yamagata University
• Principal Investigator: Tsuchiya Norihiko 山形大学, 医学部, 教授 (70282176)
• Co-Investigator(Kenkyū-buntansha): 成田 伸太郎 秋田大学, 医学部, 准教授 (40396552) ; 黄 明国 秋田大学, 医学(系)研究科(研究院), 助教 (60448503) ; 藤山 信弘 秋田大学, 医学部, 助教 (90603275)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 腎細胞癌 / 薬物動態 / 遺伝子多型 / 分子標的薬 / エクソソーム / マイクロRNA / サイトカイン / ファーマコゲノミクス / トランスクリプトミクス / 薬力学 / 血中濃度 / バイオマーカー

Outline of Final Research Achievements

We analyzed pharmacokinetics and polymorphisms of 8 genes in 46 patients with metastatic RCC (mRCC) who were treated with axitinib. Axitinib level in patients with UGT1A1 poor metabolisers were signifcantly higher than others. The overall survival (OS) in patients with C0>5 ng/mL was signifcantly better than that in others. Genetic polymorphisms in UGT1A1 were signifcantly associated with the plasma axitinib level.
Furthermore, we measured serum concentrations of 34 cytokines in 44 mRCC patients treated with axitinib. PFS and OS of those patients in whom serum PAI-1 level decreased after the treatment was significantly extended. The multivariate analysis showed that declined serum PAI-1 after the treatment was a independent predictive marker of PFS and OS.

Research Products

• [Journal Article] Contribution of UGT1A1 genetic polymorphisms related to axitinib pharmacokinetics to safety and efficacy in patients with renal cell carcinoma. (2018)
  • Author(s): Igarashi R, Inoue T, Fujiyama N, Tsuchiya N, Numakura K, Kagaya H, Saito M, Narita S, Satoh S, Niioka T, Miura M, Habuchi T.
  • Journal Title: Med Oncol. Volume: 35(51) Issue: 4 Pages: 51-58
  • DOI: 10.1007/s12032-018-1113-8
  • Peer Reviewed / Open Access
• [Journal Article] Inverse relationship between insulin receptor expression and progression in renal cell carcinoma. (2017)
  • Author(s): Takahashi M, Inoue T, Huang M, Numakura K, Tsuruta H, Saito M, Maeno A, Nakamura E, Narita S, Tsuchiya N, Habuchi T.
  • Journal Title: Oncol Rep. Volume: 37 Issue: 5 Pages: 2929-2941
  • DOI: 10.3892/or.2017.5552
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Clinical effects of single nucleotide polymorphisms on drug-related genes in Japanese metastatic renal cell carcinoma patients treated with sunitinib (2017)
  • Author(s): Numakura K, Tsuchiya N, Kagaya H, Takahashi M, Tsuruta H, Inoue T, Narita S, Huang M, Satoh S, Niioka T, Miura M, Habuchi T
  • Journal Title: Anticancer Drugs Volume: 28 Issue: 1 Pages: 97-103
  • DOI: 10.1097/cad.0000000000000425
  • Peer Reviewed
• [Presentation] Contribution of genetic polymorphisms related to axitinib pharmacokinetics to the clinical safety and efficacy in patients with advanced renal cell carcinoma (2017)
  • Author(s): Igarashi R, Tsuchiya N, Inoue T, Fujiyama N, Numakura K, Tsuruta H, Kagaya H, Maeno A, Saito M, Narita S, Nioka T, Miura M, Satoh S, Habuchi T
  • Organizer: American Urological Association 2017 Annual Meeting
  • Int'l Joint Research
• [Presentation] 転移性腎癌の逐次治療におけるSunitinibおよびAxitinib血中濃度の比較と遺伝子多型の関与 (2017)
  • Author(s): 井上高光, 五十嵐龍馬, 沼倉一幸, 藤山信弘, 鶴田大, 齋藤満, 成田伸太郎, 三浦昌朋, 佐藤滋, 土谷順彦, 羽渕友則
  • Organizer: 第105回日本泌尿器科学会総会
• [Presentation] 転移性腎癌におけるアキシチニブの治療効果を予測する血清バイオマーカーの探索 (2017)
  • Author(s): 本間直子, 土谷順彦, 井上高光, 鶴田大, 前野淳, 沼倉一幸, 成田伸太郎, 齋藤満, 佐藤滋, 羽渕友則
  • Organizer: 第105回日本泌尿器科学会総会
• [Presentation] 進行性腎癌患者の遺伝子多型とアキシチニブ血中濃度および有害事象との関連解析 (2016)
  • Author(s): 五十嵐 龍馬
  • Organizer: 第54回日本癌治療学会学術集会
  • Place of Presentation: パシフィコ横浜、横浜
  • Year and Date: 2016-10-20
• [Presentation] 進行性腎癌におけるアキシチニブの効果予測を目的とした血清バイオマーカーの探索 (2016)
  • Author(s): 喜早 祐介
  • Organizer: 第32回日本DDS学会学術集会
  • Place of Presentation: 静岡県コンベンションアーツセンター、静岡
  • Year and Date: 2016-06-30
• [Presentation] Exosomal miRNAs and serum cytokines as predictors for treatment outcome in patients with metastatic renal cell carcinoma treated with axitinib (2016)
  • Author(s): Naoko Honma
  • Organizer: Annual meeting of american urological association 2016
  • Place of Presentation: San Diego Convention Center, San Diego, USA
  • Year and Date: 2016-05-06
  • Int'l Joint Research
• [Presentation] Association between plasma concentration of axitinib and treatment outcome in advanced renal cell carcinoma patients (2015)
  • Author(s): Norihiko Tsuchiya, et al.
  • Organizer: The 110th Annual Meeting of the American Urological Association
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2015-05-15
  • Int'l Joint Research