Synthetic lethality induced by arctigenin through engineering tumor tissue microenvironment

• Project/Area Number: 16K14619
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: Tokyo University of Science
• Principal Investigator: Esumi Hiroyasu 東京理科大学, 研究推進機構生命医科学研究所, 教授 (70160364)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 低酸素 / 微少環境 / vascular normalization / synthetic lethality / 微少環境改変による増感 / アルクチゲニン / がん / 腫瘍血管 / Normalization / 抗がん剤 / X線 / イメージング

Outline of Final Research Achievements

An active principle in fruit of Actinum Lappa, a traditional medicine was found to normalize tumor vasculature, leading to significant improvement of tumor hypoxia. By utilizing this activity of arctigenin, we intended to develop a combination therapy of tumor with both X-ray and chemotherapeutics. Taking several xenograft models and X-ray and anticancer drugs, we could clearly show tissue level synthetic lethality (synergistic antitumor effect by modulating tissue structure). Previously, we have shown the bioavailability and clinical safety of Arctigenin in a phase I trial in patients with pancreatic cancer, we plan to conduct clinical trial of arctigenin to enhance X-ray and chemotherapy of cancer.

Research Products

• [Journal Article] Oncogenic Kit signalling on the Golgi is suppressed by blocking secretory trafficking with M-COPA in gastrointestinal stromal tumours. (2018)
  • Author(s): Obata Y, Horikawa K, Shiina I, Takahashi T, Murata T, Tasaki Y, Suzuki K, Yonekura K, Esumi H, Nishida T, Abe R
  • Journal Title: Cancer Lett. Volume: 415 Pages: 1-10
  • DOI: 10.1016/j.canlet.2017.11.032
  • Peer Reviewed / Open Access
• [Journal Article] Metabolic determinants of sensitivity to phosphatidylinositol 3-kinase pathway inhibitor in small-cell lung carcinoma (2018)
  • Author(s): Makinoshima H et al.
  • Journal Title: Cancer Research Volume: - Issue: 9 Pages: 2179-2190
  • DOI: 10.1158/0008-5472.can-17-2109
  • Peer Reviewed / Open Access
• [Journal Article] Colorectal tumors require NUAK1 for protection from oxidative stress. (2018)
  • Author(s): Port JLF, Muthalagu N, Raja M, Ceteci F, Monteverde T, Kruspig B, Hedley A, Kalna G, Lilla S, Neilson L, Brucoli M, Gyuraszova K, Tait-Mulder J, Mezna M, Svambaryte S, Bryson A, Sumpton D, McVie A, Nixon C, Drysdale M, Esumi H, Murray GI, Sansom OJ, Zanivan S, Murphy DJ.
  • Journal Title: Cancer Discov. Volume: - Issue: 5 Pages: 632-647
  • DOI: 10.1158/2159-8290.cd-17-0533
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Highly oxygenated antiausterity agents from the leaves of Uvaria dac. (2017)
  • Author(s): Awale S, Tawila AM, Dibwe DF, Ueda JY, Sun S, Athikomkulchai S, Balachandran C, Saiki I, Matsumoto K, Esumi H.
  • Journal Title: Bioorg Med Chem Lett. Volume: 27 Issue: 9 Pages: 1967-1967
  • DOI: 10.1016/j.bmcl.2017.03.021
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Thymidine Catabolism as a Metabolic Strategy for Cancer Survival (2017)
  • Author(s): Tabata S, Yamamoto M, Goto H, Hirayama A, Ohishi M, Kuramoto T, Mitsuhashi A, Ikeda R, Haraguchi M, Kawahara K, Shinsato Y, Minami K, Saijo A, Hanibuchi M, Nishioka Y, Sone S, Esumi H, Tomita M, Soga T, Furukawa T, Akiyama SI
  • Journal Title: Cell Rep Volume: 19 Issue: 7 Pages: 1313-1321
  • DOI: 10.1016/j.celrep.2017.04.061
  • NAID: 120007001420
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Significance of BRAF Non-V600E Mutations on the Therapeutic Effects of Anti-EGFR Monoclonal Antibody Treatment in Patients with Pretreated Metastatic Colorectal Cancer: the Biomarker Research for Anti-EGFR Monoclonal Antibodies by Comprehensive Cancer Genomics (BREAC) study. (2017)
  • Author(s): Shinozaki E
  • Journal Title: Br J Cancer Volume: 117 Issue: 10 Pages: 1450-1458
  • DOI: 10.1038/bjc.2017.308
  • Peer Reviewed / Open Access
• [Journal Article] がん微小環境におけるエネルギー代謝と創薬 (2017)
  • Author(s): 江角 浩安
  • Journal Title: 実験医学増刊 Volume: 35 Pages: 159-164
• [Journal Article] フマル酸呼吸 (2017)
  • Author(s): 冨塚江利子，北 潔，江角浩安
  • Journal Title: 実験医学増刊 Volume: 35 Pages: 71-78
• [Journal Article] Constituents of the Rhizomes of Boesenbergia pandurata and Their Antiausterity Activities against the PANC-1 Human Pancreatic Cancer Line (2017)
  • Author(s): Nhan Trung Nguyen, Mai Thanh Thi Nguyen, Hai Xuan Nguyen, Phu Hoang Dang, Dya Fita Dibwe, Hiroyasu Esumi, Suresh Awale
  • Journal Title: Journal of Natural Products Volume: 80 Issue: 8 Pages: 141-148
  • DOI: 10.1021/acs.jnatprod.6b00381
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Development of Highly Selective Fluorescent Probe Enabling Flow-Cytometric Isolation of ALDH3A1-Positive Viable Cells. (2017)
  • Author(s): Yagishita A, Ueno T, Esumi H, Saya H, Kaneko K, Tsuchihara K, Urano Y.
  • Journal Title: BIOCONJUGATE CHEMISTRY Volume: 28 Issue: 2 Pages: 302-306
  • DOI: 10.1021/acs.bioconjchem.6b00618
  • Peer Reviewed / Open Access
• [Journal Article] Oncogenic signaling by Kit tyrosine kinase occurs selectively on the Golgi apparatus in gastrointestinal stromal tumors (2017)
  • Author(s): Obata, Y., Horikawa, K., Takahashi, T., Akieda, Y., Tsujimoto, M., Fletcher, J.A., Esumi, H., Nishida, T. & Abe, R.
  • Journal Title: Oncogene Volume: - Issue: 26 Pages: 3661-3672
  • DOI: 10.1038/onc.2016.519
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Synthesis of new tricyclic thiolactams as potent antitumor agent for pancreatic cancer. (2016)
  • Author(s): Okada T, Minehira D, Takada M, Urata H, Kato A, Adachi I, Kurashima Y, Kaji S, Ogura T, Chiba S, Esumi H, Toyooka N.
  • Journal Title: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Volume: 26 Issue: 11 Pages: 2577-2579
  • DOI: 10.1016/j.bmcl.2016.04.035
  • Peer Reviewed / Open Access
• [Journal Article] Hypermutation and unique mutational signatures of occupational cholangiocarcinoma in printing workers exposed to haloalkanes. (2016)
  • Author(s): Mimaki S, Totsuka Y, Suzuki Y, Nakai C, Goto M, Kojima M, Arakawa H, Takemura S, Tanaka S, Marubashi S, Kinoshita M, Matsuda T, Shibata T, Nakagama H, Ochiai A, Kubo S, Nakamori S, Esumi H, Tsuchihara K.
  • Journal Title: Carcinogenesis Volume: 37 Issue: 8 Pages: 817-826
  • DOI: 10.1093/carcin/bgw066
  • Peer Reviewed / Open Access
• [Journal Article] Phase I trial of GBS-01 for advanced pancreatic cancer refractory to gemcitabine (2016)
  • Author(s): Ikeda M, Sato A, Mochizuki N, Toyosaki K, Miyoshi C, Fujioka R, Mitsunaga S, Ohno I, Hashimoto Y, Takahashi H, Hasegawa H, Nomura S, Takahashi R, Yomoda S, Tsuchihara K, Kishino S, Esumi H
  • Journal Title: Cancer Science Volume: 107(12) Issue: 12 Pages: 1818-1824
  • DOI: 10.1111/cas.13086
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Chemical Constituents of Mangifera indica and Their Antiausterity Activity against the PANC‐1 Human Pancreatic Cancer Cell Line (2016)
  • Author(s): Hai Xuan Nguyen, Truong Nhat Van Do, Tho Huu Le, Mai Thanh Thi Nguyen, Nhan Trung Nguyen, Hiroyasu Esumi, Suresh Awale
  • Journal Title: Journal of Natural Products Volume: 79 Issue: 1 Pages: 2053-2059
  • DOI: 10.1021/acs.jnatprod.6b00784
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] がん微小環境を標的とした栄養飢餓耐性制御薬の開発 (2016)
  • Author(s): 江角浩安 川島孝則 村田健太 山口雅之 土原一哉
  • Journal Title: 医学のあゆみ Volume: 258 Pages: 121-126
• [Presentation] がん代謝を切り口としたがん治療戦略の現状と課題 (2017)
  • Author(s): 江角 浩安
  • Organizer: 第17回日本抗加齢医学会総会
  • Invited
• [Presentation] Conjugation and de-conjugation of arctigenin in mice, relating to its safety and effectiveness (2017)
  • Author(s): Rumi Fujioka, Satoshi Kishino, Takanori Kawashima, Satoshi Yomoda, Katsuya Tsuchihara, Hiroyasu Esumi
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] アルクチゲニンの抱合、脱抱合とその安全性と有効性の関係の解明 (2017)
  • Author(s): 藤岡 ルミ、岸野 吏志、与茂田 敏、土原 一哉、江角 浩安
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Presentation] GIST and mast cell tumor require the PI3K-Akt pathway on intracellular compartments for their roliferation ~Oncogenic Kit signaling occurs selectively on the Golgi and endo/lysosomes~ (2016)
  • Author(s): Yuuki Obata, Keita Horikawa, Tsuyoshi Takahashi, Yuki Akieda, Masahiko ujimoto, Yasushi Hara, Hiroyasu Esumi, Toshirou Nishida, Ryo Abe
  • Organizer: 日本分子生物学会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市)
  • Year and Date: 2016-11-30
• [Presentation] 消化管間質細胞腫におけるKitチロシンキナーゼのがんシグナリングは細胞膜ではなくゴルジ体で起こる (2016)
  • Author(s): 堀川 啓太、小幡 裕希、高橋 剛、江角 浩安、西田 俊朗、安部 良
  • Organizer: 日本分子生物学会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市)
  • Year and Date: 2016-11-30
• [Presentation] Comparison of the mutation profiles of the multicentric tumors in an occupational cholangiocarcinoma case (2016)
  • Author(s): Sachiyo Mimaki, Shoji Nakamori, Shoji Kubo, Masahiko Kinoshita,Yukari Totsuka, Hitoshi Nakagama, Atsushi Ochiai, Hiroyasu Esumi,Katsuya Tsuchihara
  • Organizer: 日本癌学会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市)
  • Year and Date: 2016-10-06
• [Presentation] Thymidine異代謝による新規エネルギー産生機構 (2016)
  • Author(s): 田畑祥、山本雅達、後東久嗣、平山明由、西岡安彦、江角浩安、富田勝、曽我朋義、古川龍彦、秋山伸一
  • Organizer: がんと代謝研究会
  • Place of Presentation: かごしま県民交流センター(鹿児島県鹿児島市)
  • Year and Date: 2016-07-07
• [Presentation] 抗がん剤開発における小動物MRイメージング (2016)
  • Author(s): 山口雅之、江角浩安、町田雪乃、北林一生
  • Organizer: がんと代謝研究会
  • Place of Presentation: かごしま県民交流センター(鹿児島県鹿児島市)
  • Year and Date: 2016-07-07
• [Presentation] マウスにおけるアルクチゲニンの吸収・グルクロン酸包合と乳酸産生 (2016)
  • Author(s): 藤岡ルミ、岸野吏志、与茂田敏、土原一哉、江角浩安
  • Organizer: がんと代謝研究会
  • Place of Presentation: かごしま県民交流センター(鹿児島県鹿児島市)
  • Year and Date: 2016-07-07
• [Presentation] アルクチゲニンによるvascular normalization の組織学的および解剖学的解析 (2016)
  • Author(s): 村田健太、千葉殖幹、川島孝則、与茂田敏、高橋隆二、土原一哉、江角浩安
  • Organizer: 日本分子イメージング学会
  • Place of Presentation: 神戸国際会議場(兵庫県神戸市）
  • Year and Date: 2016-05-28
• [Presentation] アルクチゲニンのvascular re-modeling による腫瘍内血流量の改善 (2016)
  • Author(s): 川島孝則、山口雅之、村田健太、与茂田敏、高橋隆二、土原一哉、藤井博史、江角浩安
  • Organizer: 日本分子イメージング学会
  • Place of Presentation: 神戸国際会議場(兵庫県神戸市）
  • Year and Date: 2016-05-28
• [Remarks] 東京理科大学生命医科学研究所江角研究室
  • URL: http://www.ribs.tus.ac.jp/index.php/institute/labforres/esumilab/
• [Patent(Industrial Property Rights)] 抗癌剤、放射線増感剤および食品組成物 (2016)
  • Inventor(s): 江角 浩安,土原 一哉,川島 孝則
  • Industrial Property Rights Holder: クラシエ製薬,国立がん研究センター,東京理科大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016
  • Acquisition Date: 2017
• [Patent(Industrial Property Rights)] 抗癌剤、放射線増感剤および食品組成物 (2016)
  • Inventor(s): 江角浩安 他
  • Industrial Property Rights Holder: 江角浩安 他
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-139112
  • Filing Date: 2016-07-14
• [Patent(Industrial Property Rights)] 血管壁強化剤、血管壁を強化する方法および血管網形成抑制剤 (2016)
  • Inventor(s): 江角浩安 他
  • Industrial Property Rights Holder: 江角浩安 他
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-10-06
  • Overseas