分子標的治療薬の新規薬力学評価法―非小細胞肺癌のがん性胸膜炎をモデルとして

2014 Fiscal Year Annual Research Report

• Project/Area Number: 23501314
• Research Institution: Aichi Medical University
• Principal Investigator: 久保 昭仁 愛知医科大学, 医学部, 教授 (60416245)
• Project Period (FY): 2011-04-28 – 2015-03-31
• Keywords: 非小細胞肺癌 / 癌性胸膜炎 / 分子標的治療 / 薬力学 / 薬物動態 / FDG-PET / 化学療法 / サイトケラチン

Outline of Annual Research Achievements

【目的】非小細胞肺癌 (NSCLC) の癌性胸膜炎をモデルとする分子標的治療薬の薬力学評価系を確立すること。
【方法】NSCLCの癌性胸水および血液検体を用いて、分子標的治療における経時的な生体および腫瘍細胞の変化を解析し(薬力学)、同時に血液および胸水の薬物動態を評価する[PHarmacokinetic/PHarmacodynamic Assessment on Malignant Effusions (PHAME法)と命名]。18F-fluorodeoxyglucose-positron emission tomography (FDG-PET)を用いたイメージングによっても薬力学的検討を行う。
【結果と考察】癌性胸膜炎を合併したNSCLC患者を対象として上皮成長因子受容体(EGFR)阻害剤(ETKI) ゲフィチニブおよびエルロチニブの薬物動態および薬力学的検討を行ってきた。これまでに[1] 癌性胸膜炎がETKIの薬物動態・薬力学的評価系として優れていること報告し、メタボローム解析によって治療開始8時間後の胸水中ゲフィチニブ濃度および代謝物であるindoxyl sulfolic acidがゲフィチニブの主要な副作用である皮疹と関連することを明らかにした。[2] 進行NSCLC患者を対象に、従来の標準的殺細胞化学療法またはETKI治療時の薬力学評価をFDG-PETを用いたバイオイメージングによって行った。ETKIにおいて早期からFDG集積低下が認められ、腫瘍縮小効果、無増悪生存期間(PFS)、全生存期間とよく相関することを報告した。[3] NSCLCに高発現するサイトケラチン(CK)8を薬力学マーカーとして評価し、CK8が細胞浸潤を負に制御する一方で、血中CK8は予後不良因子であり、血中CK8は腫瘍量を反映することを報告した。

Research Products

• [Journal Article] Ultra-sensitive detection of the pretreatment EGFR T790M mutation in non-small-cell lung cancer patients with an EGFR-activating mutation using picodroplet digital PCR. (2015)
  • Author(s): Watanabe M, Kawaguchi T, Isa S-I, Ando M, Tamiya A, Kubo A, Saka H, Takeo S, Adachi H, Tagawa T, Kakegawa S, Yamashita M, Kataoka K, Ichinose Y, Takeuchi Y, Sakamoto K, Matsumura A, Koh Y.
  • Journal Title: Clin Cancer Res Volume: in press Pages: in press
  • DOI: 10.1158/1078-0432.CCR-14-2151
  • Peer Reviewed
• [Journal Article] Therapeutic and Preventive Antiemetic Effect of Aprepitant in Japanese Patients with Thoracic Malignancies Who Truly Need It. (2015)
  • Author(s): Ito S, Tsukiyama I, Ando M, Katakami M, Hamanaka R, Kosaka K, Matsubara A, Nishimura M, Tanaka H, Asai N, Yokoe N, Takahashi A, Baba K, Matsuura K, Yamaguchi E, Kubo A.
  • Journal Title: Support Care Cancer Volume: 23 Pages: 905-12
  • DOI: 10.1007/s00520-014-2430-x
  • Peer Reviewed
• [Journal Article] Reply to G Spitzer, et al; F Zhou,et al; and B Biswas. (2015)
  • Author(s): Kawaguchi T, Ando M, Kubo A.
  • Journal Title: J Clin Oncol Volume: 33 Pages: 526-7
  • DOI: 10.1200/JCO.2014.58.5315
  • Peer Reviewed
• [Journal Article] The role of smoking status on the progression-free survival of non-small-cell lung cancer patients harboring activating epidermal growth factor (EGFR) mutations receiving first-line EGFR tyrosine kinase inhibitor: a meta-analysis of prospective randomized trials. (2015)
  • Author(s): Hasegawa Y, Ando M, Maemondo M, Yamamoto S, Isa S, Saka H, Kubo A, Kawaguchi T, Takada M, Rosell R, Kurata T, Ou SH.
  • Journal Title: The Oncologist Volume: 20 Pages: 1-9
  • DOI: 10.1634/theoncologist.2014-0285
  • Peer Reviewed
• [Journal Article] Metastatic embryonal carcinoma mimicking locally-advanced non-small cell lung cancer. (2015)
  • Author(s): Numanami H, Takahashi D, Takahashi E, Katsuda E, Kamei S, Naruse N, Baba K, Haniuda M, Yokoi T, Yamaguchi E, Kubo A.
  • Journal Title: Internal Medicine Volume: 54 Pages: 59-61
  • DOI: 10.2169/internalmedicine.54.2884
  • Peer Reviewed / Open Access
• [Journal Article] Long-term complete response in a patient with disseminated pulmonary pleomorphic carcinoma induced by cisplatin and gemcitabine. (2014)
  • Author(s): Tamiya A, Asami K, Shimizu S, Matusmura A, Isa S-I, Okishio K, Kitaichi M, Atagi S, Takada M, Kawaguchi T, Kubo A.
  • Journal Title: Internal Medicine Volume: 53 Pages: 2565-8
  • DOI: 10.2169/internalmedicine.53.2637
  • Peer Reviewed / Open Access
• [Journal Article] Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non-small cell lung cancer: Docetaxel and Erlotinib Lung cancer TriAl (DELTA). (2014)
  • Author(s): Kawaguchi T, Ando M, Asami K, Okano Y, Fukuda M, Nakagawa H, Ibata H, Kozuki T, Endo T, Tamura A, Kamimura M, Sakamoto K, Yoshimi M, Soejima Y, Tomizawa Y, Isa S, Takada M, Saka H, Kubo A.
  • Journal Title: J Clin Oncol Volume: 32 Pages: 1902-8
  • DOI: 10.1200/JCO.2013.52.4694
  • Peer Reviewed
• [Journal Article] Successful crizotinib re-challenge after crizotinib-induced organizing pneumonia in anaplastic lymphoma kinase-rearranged non-small cell lung cancer. (2014)
  • Author(s): Asai N, Yokoi T, Yamaguchi E, Kubo A.
  • Journal Title: Case Reports in Oncology Volume: 7 Pages: 681-4
  • DOI: 10.1159/000366516
  • Peer Reviewed
• [Journal Article] Successful crizotinib re-challenge after crizotinib-induced interstitial lung disease in patients with advanced non-small cell lung cancer. (2014)
  • Author(s): Asai N, Yamaguchi E, Kubo A.
  • Journal Title: Clin Lung Cancer Volume: 15 Pages: e33-5
  • DOI: 10.1016/j.cllc.2013.12.004
  • Peer Reviewed
• [Presentation] Updated overall survival (OS) results of randomized phase III trial of erlotinib (E) versus (v) docetaxel (D) as second or third line therapy in patients with advanced non-small cell lung cancer (NSCLC): Docetaxel and Erlotinib Lung cancer TriAl (DELTA). (2014)
  • Author(s): Ibata H, Ando M, Asami K, Okano Y, Fukuda M, Nakagawa H, Kozuki T, Endo T, Tamura A, Kamimura M, Sakamoto K, Yoshimi M, Soejima Y, Tomizawa Y, Isa S, Takada M, Saka H, Kubo A, Kawaguchi T.
  • Organizer: Annual Meeting of the American Society of Clinical Oncology
  • Place of Presentation: Chicago, IL, USA.
  • Year and Date: 2014-05-30 – 2014-06-03
• [Presentation] The role of smoking status on the progression-free survival of non-small-cell lung cancer patients harboring activating epidermal growth factor (EGFR) mutations receiving first-line EGFR tyrosine kinase inhibitor: a meta-analysis of prospective randomized trials. (2014)
  • Author(s): Hasegawa Y, Ando M, Maemondo M, Yamamoto S, Isa S, Saka H, Kubo A, Kawaguchi T, Takada M, Kurata T, Ou SH.
  • Organizer: Annual Meeting of the American Society of Clinical Oncology
  • Place of Presentation: Chicago, IL, USA.
  • Year and Date: 2014-05-30 – 2014-06-03