The predictive biomarkers for antifolate anticancer drugs

2013 Fiscal Year Final Research Report

• Project/Area Number: 23591156
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Nagoya City University
• Principal Investigator: OGURI Tetsuya 名古屋市立大学, 医学(系)研究科(研究院), 准教授 (60363925)
• Project Period (FY): 2011 – 2013
• Keywords: 肺癌 / ペメトレキシド / ABCトランスポーター / 遺伝子多型 / thymidylate synthase / 予測バイオマーカー

Research Abstract

We found that the mechanisms of the synergistic interaction of pemetrexed (MTA) and cytotoxic nucleoside analogues are multifactorial, and that the chemotherapeutic activity of the combination of MTA and cytotoxic nucleoside analogues is synergistic with regard to the alteration of metanotbolic molecules.
In a search for biomarkers for study of the efficacy of MTA treatment, we examined the thymidylate synthase (TS) copy number in NSCLC cell lines and in clinical NSCLC samples treated with MTA with platinum drugs. Significant correlation was found between the TS copy number and the sensitivity for MTA in both lung cancer cell lines and clinical NSCLC samples. Our results suggest that TS copy number could be a predictive biomarker for MTA.
We also focus on ABCC11 polymorphism 538G>A, and established cell liens expressing human ABCC11, one carrying allele G and another carrying allele A. Moreover we now examine the relationship between ABCC11 polymorphism and resistance to MTA clinically.

Research Products

• [Journal Article] Thymidylate Synthase gene copy number as a predictive marker for response to pemetrexed treatment in lung adenocarcinoma (2013)
  • Author(s): Kasai D, Ozasa H, Oguri T, Miyazaki M, Uemura T, Takakuwa O, Kunii E, Ohkubo H, Maeno K, Niimi A
  • Journal Title: Anticancer Res Volume: 33 Pages: 1935-1940
  • Peer Reviewed
• [Journal Article] Preclinical rationale for synergistic interaction of pemetrexed and cytotoxic nucleoside analogues (2012)
  • Author(s): Oguri-T, Ozasa H, Uemura T, Takakuwa O, Kunii E, Kasai D, Ohkubo H, Miyazaki M, Maeno K, Sato S
  • Journal Title: Oncol Lett Volume: 4 Pages: 571-575
  • DOI: 10.3892/ol.2012.773
  • Peer Reviewed
• [Presentation] Significance of thymidylate synthase copy numbers for resistance to pemetrexed in lung cancer (2013)
  • Author(s): Kasai D, Oguri T, Ozasa H, Uemura T, Kunii E, Miyazaki M, Takakuwa O, Ohkubo H, Miyazaki M, Maeno K, Sato S
  • Organizer: 103th Annual Meeting of American Association of Cancer Research
  • Place of Presentation: Chicago、USA
  • Year and Date: 20130331-0404
• [Presentation] Thymidylate synthase gene copy number as a predictive marker for response to pemetrexed treatment in lung adenocarcinoma (2012)
  • Author(s): 笠井大嗣、小栗鉄也、小笹裕晃、上村剛大、國井英治、高桑修、大久保仁嗣、宮崎幹規、前野健、佐藤滋樹、新実彰男
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 東京
  • Year and Date: 20120919-21
• [Presentation] A SNP538(G>A) in ABCC11/MRP8 determines sensitivity for antimetabolites (2012)
  • Author(s): Uemura T, Oguri T, Ozasa H, Kasai D, Kunii E, Miyazaki M, Takakuwa O, Ohkubo H, Miyazaki M, Maeno K, Sato S
  • Organizer: 103th Annual Meeting of American Association of Cancer Research
  • Place of Presentation: Chicago、USA
  • Year and Date: 20120331-0404
• [Presentation] Pemetrexed治療効果予測因子としてのTS遺伝子増幅の有用性についての基礎的検討 (2011)
  • Author(s): 笠井大嗣、小栗鉄也,小笹裕晃,上村剛大,高桑修,國井英治,大久保久嗣,宮崎幹規,前野健,中村敦,佐藤滋樹
  • Organizer: 第52回日本肺癌学会
  • Place of Presentation: 大阪
  • Year and Date: 20111103-04