An Efficacy of polyphenols for Il13Ra2-positive advanced pancreatic cancer

• Project/Area Number: 18K07332
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Juntendo University
• Principal Investigator: FUJISAWA Toshio 順天堂大学, 医学部, 先任准教授 (50627346)
• Co-Investigator(Kenkyū-buntansha): 伊佐山 浩通 順天堂大学, 医学部, 教授 (70376458)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: IL-13Ra2 / 膵癌 / EUS-FNA / 緑茶ポリフェノール / 浸潤・転移 / 予後 / 抗癌剤効果予測 / バイオマーカー / IL-13Rα2 / 浸潤 / 転移 / Gemcitabine / 化学療法 / ポリフェノール / 膵臓癌 / gemcitabine / 予測因子 / 浸潤転移 / 動物モデル / epigenetics / エピジェネティクス / 神経浸潤 / IL-13 receptor alpha2 / Histone修飾 / HDAC inhibitor

Outline of Final Research Achievements

Since only about 20% of patients with pancreatic cancer can undergo surgery, we investigated whether the expression of IL-13Ra2 could be evaluated using biopsy specimens obtained by EUS-FNA when pancreatic cancer is diagnosed. In more than 90% of cases, the expression was consistent when compared with surgical specimens, and the expression of IL-13Ra2 was also evaluable in EUS-FNA. When EUS-FNA samples were used to compare the low and high expression groups of IL-13Ra2 in 132 new pancreatic cancer patients, progression-free survival and overall survival were significantly shorter in the low expression group. Furthermore, we found that IL-13Ra2 attenuated the effect of gemcitabine and was involved in the metabolic pathway of gemcitabine and the growth of tumor blood vessels. In addition, animal studies have shown that small molecules containing green tea polyphenols can be used to suppress the expression of IL-13Ra2 and improve the prognosis of IL-13Ra2-positive pancreatic cancer.

Academic Significance and Societal Importance of the Research Achievements

前回の科研費を用いた研究で、IL-13Ra2が膵癌の進展を促進し予後を悪化させることを見出したが、今回の研究ではIL-13Ra2が予後を悪化させるメカニズムを詳細に検討した。更に膵癌診断時に用いるEUS-FNA検体を用いてIL-13Ra2の発現が評価できることが分かったため、予後や化学療法の効果判定のバイオマーカーや治療のターゲットとして活用しうる。今後はIL-13Ra2による治療法の選択やIL-13Ra2を抑制することによる化学療法の効果改善を評価していく予定である。膵癌は未だ最難治癌であり、IL-13Ra2の治療応用が膵癌の予後の改善に貢献すると確信している。

Research Products

• [Int'l Joint Research] Food and Drug Administration(米国)
• [Int'l Joint Research] US Food and Drug Administration(米国)
• [Int'l Joint Research] Food and Drug Administration(米国)
• [Int'l Joint Research] Food and Drug Administrations(米国)
• [Journal Article] Clinical Practice Guidelines for Pancreatic Cancer 2022 from the Japan Pancreas Society: a synopsis (2023)
  • Author(s): Takuji Okusaka, Masafumi Nakamura, Masahiro Yoshida, Masayuki Kitano, Yoshinori Ito, Nobumasa Mizuno, Keiji Hanada, Masato Ozaka, Chigusa Morizane, Yoshifumi Takeyama, Toshio Fujisawa et. al
  • Journal Title: International Journal of Clinical Oncology Volume: 28 Issue: 4 Pages: 493-511
  • DOI: 10.1007/s10147-023-02317-x
  • Peer Reviewed / Open Access
• [Journal Article] Pancreatic Adenocarcinoma With Strong Expression of Interleukin-13 Receptor α2 Shows a Poor Response to Gemcitabine-Based Chemotherapy. (2022)
  • Author(s): Tomishima K, Fujisawa T, Fukumura Y, Ushio M, Fukuma T, Takahashi S, Takasaki Y, Suzuki A, Ito K, Ishii S, Yao T, Nagahara A, Isayama H.
  • Journal Title: Pancreas Volume: 51 Issue: 9 Pages: 1133-1139
  • DOI: 10.1097/mpa.0000000000002151
  • Peer Reviewed / Open Access
• [Journal Article] IL-13Rα2 Is a Biomarker of Diagnosis and Therapeutic Response in Human Pancreatic Cancer (2021)
  • Author(s): Fujisawa T, Joshi BH, Takahashi S, Takasaki Y, Suzuki A, Ito K, Ochiai K, Tomishima K, Ishii S, Puri RK, Isayama H.
  • Journal Title: Diagnostics Volume: 11 Issue: 7 Pages: 1140-1140
  • DOI: 10.3390/diagnostics11071140
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Novel Role of Interleukin 13 Receptor alpha2 in Perineural Invasion and Its Association With Poor Prognosis of Patients With Pancreatic Ductal Adenocarcinoma (2020)
  • Author(s): Toshio Fujisawa, Takeshi Shimamura, Kaku Goto, Ryo Nakagawa, Ryosuke Muroyama, Yoshinori Ino, Hajime Horiuchi, Itaru Endo, Shin Maeda, Yasushi Harihara, Atsushi Nakajima,, Nobuyuki Matsuhashi, Naoya Kato, Hiroyuki Isayama, Ankit Puri, Akiko Suzuki, Ian Bellayr, Pamela Leland, Bharat H Joshi, Raj K Puri
  • Journal Title: Cancers Volume: 12 Issue: 5 Pages: 1294-1294
  • DOI: 10.3390/cancers12051294
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Immunotherapy for Pancreatic Cancer (2020)
  • Author(s): Toshio Fujisawa, Hiroyuki Isayama
  • Journal Title: Juntendo Medical Journal Volume: 66 Issue: 3 Pages: 238-244
  • DOI: 10.14789/jmj.2020.66.JMJ20-LN02
  • NAID: 130007867030
  • ISSN: 2187-9737, 2188-2126
  • Peer Reviewed / Open Access
• [Presentation] 膵癌抗癌剤治療におけるIL-13 receptorα2 発現による効果予測と感受性低下機序の解明 (2023)
  • Author(s): 藤澤聡郎, 冨嶋享, 伊佐山浩通.
  • Organizer: 第109回日本消化器病学会総会
• [Presentation] 膵癌の化学療法選択においてIL-13 receptorα2発現の示す意義. (2022)
  • Author(s): 冨嶋 享
  • Organizer: U45消化器疾患 イノベーションカンファレンス ~サイエンスでつながる次世代の会~
  • Invited
• [Presentation] 癌精巣抗原IL-13Rα2の膵癌における役割と分子標的治療法の開発. (2022)
  • Author(s): 藤澤 聡郎
  • Organizer: 第６回がんブレインストーミング研究会
  • Invited
• [Presentation] 膵癌EUS-FNA検体で評価し得たIL-13 receptor&alpha2発現と化学療法効果について. (2022)
  • Author(s): 冨嶋享, 藤澤聡郎, 伊佐山浩通, 福村由紀.
  • Organizer: 第103回日本消化器内視鏡学会総会
• [Presentation] 膵癌の化学療法選択においてIL-13 receptorα2発現の示す意義. (2022)
  • Author(s): 冨嶋享, 藤澤聡郎, 伊佐山浩通.
  • Organizer: 第108回日本消化器病学会総会
• [Presentation] PANCREATIC ADENOCARCINOMA WITH STRONG EXPRESSION OF IL-13RA2 SHOWS A POOR RESPONSE TO GEMCITABINE-BASED CHEMOTHERAPY. (2022)
  • Author(s): Ko Tomishima, Toshio Fujisawa, Hiroyuki Isayama
  • Organizer: United-European Gastrointestinal Week
  • Int'l Joint Research
• [Presentation] 膵癌EUS-FNA検体で評価し得たIL-13 receptor a2発現と化学療法効果について (2022)
  • Author(s): 冨嶋 享、藤澤 聡郎、伊佐山 浩通、福村 由紀
  • Organizer: 第103回 日本消化器内視鏡学会総会
• [Presentation] 膵癌の化学療法の選択においてIL-13 receptor a2発現の示す意義 (2022)
  • Author(s): 冨嶋 享、藤澤 聡郎、伊佐山 浩通
  • Organizer: 第108回 日本消化器病学会総会
• [Remarks] Dr. Puri's site
  • URL: https://www.linkedin.com/in/raj-puri-m-d-ph-d-19383430