Elucidation of the chemoresistance in pancreatic cancer and development of its tumor stroma targeting ADCs

• Project/Area Number: 15H04316
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: National Cancer Center Japan
• Principal Investigator: Yasunaga Masahiro 国立研究開発法人国立がん研究センター, 先端医療開発センター, ユニット長 (80450576)
• Research Collaborator: Matsumura Yasuhiro 国立研究開発法人国立がん研究センター, 先端医療開発センター, 分野長 (90209619) ; Manabe Shino 独立行政法人理化学研究所, 伊藤細胞制御化学, 専任研究員 (60300901)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000); Fiscal Year 2017: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2016: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2015: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000)
• Keywords: 抗体 / ADC / 膵臓がん / がん間質 / 間質バリア / DDS / 分子イメージング / ドラッグイメージング / 癌 / 間質 / ドラッグデリバリー

Outline of Final Research Achievements

(1) Pancreatic cancer model mice with a strong desmoplastic reaction similar to human pancreatic cancer was prepared. (2) We succeeded in developing a new drug imaging method by combining robot-controlled ESI (Electrospray ionization) method and an LC-MS apparatus. It has become possible to observe drug delivery within the tumor tissue with high sensitivity. (3) a) Anti-fibroblast / b) stellate and parietal cell / c) blood-vessel / d) blood and lymphoid vessel antibodies showed good tumor-stroma targeting within the tumor tissues. Regarding antibody-drug conjugates (ADCs), they were newly-produced and therapeutic experiments were conducted in the model of (1). A strong antitumor effect was observed in the order of a)b)c)d).(4) Anti-tissue factor/fibrin ADCs also showed therapeutic effect in the same mouse model.

Research Products

• [Journal Article] Imaging mass spectrometry for the precise design of antibody-drug conjugates. (2016)
  • Author(s): 1.Fujiwara Y, Furuta M, Manabe S, Koga Y, Yasunaga M, Matsumura Y
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 24954-24954
  • DOI: 10.1038/srep24954
  • Peer Reviewed / Open Access
• [Journal Article] Tumour imaging by the detection of fibrin clots in tumour stroma using an anti-fibrin Fab fragment. (2016)
  • Author(s): Obonai T, Fuchigami H, Furuya F, Kozuka N, Yasunaga M, Matsumura Y.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 23613-23613
  • DOI: 10.1038/srep23613
  • Peer Reviewed / Open Access
• [Journal Article] Feasibility study of the Fab fragment of a monoclonal antibody against tissue factor as a diagnostic tool. (2016)
  • Author(s): Tsumura R, Sato R, Furuya F, Koga Y, Yamamoto Y, Fujiwara Y, Yasunaga M, Matsumura Y.
  • Journal Title: Int J Oncol. Volume: 47 Issue: 6 Pages: 2107-2114
  • DOI: 10.3892/ijo.2015.3210
  • Peer Reviewed
• [Journal Article] Antitumor effect of antitissue factor antibody-MMAE conjugate in human pancreatic tumor xenografts. (2015)
  • Author(s): Koga Y, Manabe S, Aihara Y, Sato R, Tsumura R, Iwafuji H, Furuya F, Fuchigami H, Fujiwara Y, Hisada Y, Yamamoto Y, Yasunaga M, Matsumura Y.
  • Journal Title: Int J Cancer. Volume: 137 Issue: 6 Pages: 1457-1466
  • DOI: 10.1002/ijc.29492
  • Peer Reviewed
• [Presentation] Development of antibody-drug conjugates against refractory cancer (2017)
  • Author(s): Masahiro Yasunaga
  • Organizer: Protein & Peptide Conference 2017
  • Place of Presentation: Fukuoka, Japan
  • Int'l Joint Research / Invited
• [Presentation] Development of ADC utilizing molecular imaging (2016)
  • Author(s): Masahhiro Yasunaga, Shino Manabe, Atushi Tsuji, Masaru Furuta, Koretsugu Ogata, Yuki Fujiwara, Yoshikazu Koga, Yasuhiro Matsumura
  • Organizer: Antibody Engineering & Therapeutics
  • Place of Presentation: San Diego, USA
  • Year and Date: 2016-12-13
  • Int'l Joint Research
• [Presentation] 分子イメージングを駆使した難治性がんに対するantibody-drug conjugateの開発 (2016)
  • Author(s): 安永正浩、眞鍋史乃、辻厚至、古田大、緒方是嗣、高島大輝、藤原悠起、古賀宣勝、佐賀恒夫、松村保広
  • Organizer: 日本分子イメージング学会
  • Place of Presentation: 神戸
• [Presentation] 難治性がんに対するantibody-drug conjugate（ADC)の開発 (2016)
  • Author(s): 安永正浩、眞鍋史乃、辻厚至、古田大、緒方是嗣、高島大輝、藤原悠起、古賀宣勝、佐賀恒夫、松村保広
  • Organizer: 日本DDS学会学術集会
  • Place of Presentation: 静岡
• [Presentation] Development of antibody-drug conjugate against refractory cancer by utilizing molecular imaging (2016)
  • Author(s): 安永正浩、松村保広
  • Organizer: 日本微小循環学会
  • Place of Presentation: 東京
• [Presentation] 抗体DDS (2016)
  • Author(s): 安永正浩
  • Organizer: 情報計算化学生物学会2016年大会・分子ロボティクス研究会シンポジウム
  • Place of Presentation: 東京
  • Invited
• [Presentation] Development of CAST therapy by utilizing molecular imaging (2016)
  • Author(s): Masahhiro Yasunaga, Shino Manabe, Atushi Tsuji, Masaru Furuta, Koretsugu Ogata, Yuki Fujiwara, Yoshikazu Koga, Yasuhiro Matsumura.
  • Organizer: World Molecular Imaging Congress
  • Place of Presentation: New York, USA
  • Int'l Joint Research
• [Presentation] Developmental strategy of CAST (Cancer stromal targeting) therapy (2015)
  • Author(s): Yasunaga M, Manabe S, Matsumura Y.
  • Organizer: Antibody Engineering & Therapeutics
  • Place of Presentation: USA・San Diego
  • Year and Date: 2015-12-09
  • Int'l Joint Research / Invited
• [Presentation] Visualisation of drug delivery and EPR effect by using microscopic mass spectrometry (2015)
  • Author(s): 安永正浩、古田大、緒方是嗣、藤原悠起、古賀宣勝、松村保広
  • Organizer: 日本癌学会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-09
• [Presentation] Molecular imaging of drug delivery by using high resolution microscopic mass spectrometry (2015)
  • Author(s): Yasunaga M, Furuta M, Ogata K, Fujiwara Y, Koga Y, Matsumura Y.
  • Organizer: World Molecular Imaging Congress
  • Place of Presentation: USA・Honolulu
  • Year and Date: 2015-09-05
  • Int'l Joint Research
• [Book] 抗体薬物複合体(ADC)の設計開発・第７章ADC設計のための分子イメージングの有用性 (2016)
  • Author(s): 安永正浩
  • Total Pages: 10
  • Publisher: シーエムシー出版
• [Book] BIO Clinica (2015)
  • Author(s): 安永正浩、眞鍋史乃、松村保広
  • Total Pages: 6
  • Publisher: 北隆館
• [Remarks] 国立がん研究センター 先端医療開発センター 新薬開発分野 スタッフプロフィール
  • URL: http://epoc.ncc.go.jp/about/staff/yasunaga.php
• [Remarks] 東京大学大学院新領域創成科学研究科 連携講座 がん先端生命科学分野 教員紹介
  • URL: https://www.youtube.com/watch?v=-w41XuptYWw&feature=youtu.be
• [Remarks] 東京大学大学院新領域創成科学研究科 連携講座 がん先端生命科学分野 教員紹介
  • URL: https://www.youtube.com/watch?v=-w41XuptYWw