Development of chemopreventive agents using Connectivity Map analysis

• Project/Area Number: 17H04163
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: The University of Tokushima
• Principal Investigator: TAKAYAMA Tetsuji 徳島大学, 大学院医歯薬学研究部(医学域), 教授 (10284994)
• Co-Investigator(Kenkyū-buntansha): 武藤 倫弘 国立研究開発法人国立がん研究センター, 社会と健康研究センター, 室長 (30392335) ; 堀本 勝久 国立研究開発法人産業技術総合研究所, 生命工学領域, 招聘研究員 (40238803) ; 岡本 耕一 徳島大学, 病院, 講師 (60531374) ; 六車 直樹 徳島大学, 大学院医歯薬学研究部(医学域), 准教授 (90325283)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000); Fiscal Year 2019: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2017: ¥8,450,000 (Direct Cost: ¥6,500,000、Indirect Cost: ¥1,950,000)
• Keywords: 大腸癌予防薬 / 大腸腺腫 / オルガノイド / SSA/P / 予防薬 / 癌予防 / 腺腫 / Connectivity map解析 / マイクロアレイ / 癌 / 薬理学

Outline of Final Research Achievements

We performed microarray analysis of human adenoma and serrated sessile lesions (SSL) tissues as well as of normal colorectal mucosa, and determined gene expression signature in each lesion. Applying the gene signature data for connectivity map analysis which includes the data of all existing drugs, we chose candidate preventive drugs, which are expected to normalize gene expression profile of those lesions. We then established organoid from human adenoma and SSL tissues respectively, and screened candidate drugs to evaluate inhibitory effects of candidate preventive drugs. The most effective 5 drugs for adenoma and 3 drugs for SSL have been chosen. When some of the drug were administered to rat chemical carcinogenesis model, APC KO mice or SSL-xennograft model, numbers of polyps were significantly inhibited. Currently, we are planning a clinical trial for these drugs to evaluate inhibitory effect on adenoma or SSL in human.

Academic Significance and Societal Importance of the Research Achievements

これまでに、既存の薬剤を網羅的に解析して、大腸腺腫やSSLに対する予防薬を探索した研究は無く、本研究が初めてである。本研究では、大腸腺腫に対する予防候補薬とSSLに対する予防候補役を抽出し、in vitroの系で有効な薬剤を絞り込み、in vivoの系で有効性の高い薬剤を絞り込むことができた。既存の薬剤を対象にしているので、速やかに臨床試験に進むことができるという利点がある。また、本研究はドラッグ・リポジショニングという観点からも重要性が高い。

Research Products

• [Journal Article] Theracurmin inhibits intestinal polyp development in Apc-mutant mice by inhibiting inflammation-related factors. (2020)
  • Author(s): Adachi S, Hamoya T, Fujii G, Narita T, Komiya M, Miyamoto S, Kurokawa Y, Takahashi M, Takayama T, Ishikawa H, Tashiro K, Mutoh M.
  • Journal Title: Cancer Science Volume: 111 Issue: 4 Pages: 1367-1374
  • DOI: 10.1111/cas.14329
  • NAID: 120007053403
  • Peer Reviewed / Open Access
• [Journal Article] EGFR-targeted molecular imaging of colorectal tumors: detection and treatment evaluation of tumors in animal models (2019)
  • Author(s): Miyamoto Y, Muguruma N, Fujimoto S, Okada Y, Kida Y, Nakamura F, Tanaka K, Nakagawa T, Kitamura S, Okamoto K, Miyamoto H, Sato Y, Takayama T.
  • Journal Title: Cancer Science Volume: in press Issue: 6 Pages: 1921-1930
  • DOI: 10.1111/cas.14020
  • Peer Reviewed / Open Access
• [Journal Article] Detection of aberrant crypt foci with image-enhanced endoscopy (2018)
  • Author(s): Kagemoto K, Okamoto K, Takaoka T, Sato Y, Kitamura S, Kimura T, Sogabe M, Miyamoto H, Muguruma N, Tsuneyama K, Takayama T.
  • Journal Title: Endoscopy International Open Volume: 8 Issue: 08 Pages: E924-E933
  • DOI: 10.1055/a-0621-8794
  • Peer Reviewed
• [Journal Article] Molecular imaging of aberrant crypt foci in the human colon targeting glutathione S-transferase P1-1 (2017)
  • Author(s): Naoki Muguruma, Koichi Okamoto, Tadahiko Nakagawa, Katsutaka Sannomiya, Shota Fujimoto, Yasuhiro Mitsui, Tetsuo Kimura, Hiroshi Miyamoto, Jun Higashijima, Mitsuo Shimada, Yoko Horino, Shinya Matsumoto, Kenjiro Hanaoka, Tetsuo Nagano, Makoto Shibutani, Tetsuji Takayama
  • Journal Title: Sci. Rep. Volume: 7 Issue: 1 Pages: 6536
  • DOI: 10.1038/s41598-017-06857-x
  • NAID: 120006535003
  • URL: https://tokushima-u.repo.nii.ac.jp/records/2005524
  • Peer Reviewed / Open Access
• [Journal Article] Colon capsule endoscopy: toward the future. (2017)
  • Author(s): Muguruma N, Tanaka K, Teramae S, Takayama T.
  • Journal Title: Clinical Journal of Gastroenterology Volume: 10 Issue: 1 Pages: 1-6
  • DOI: 10.1007/s12328-016-0710-3
  • Peer Reviewed
• [Journal Article] 大腸癌の疫学と基礎 大腸鋸歯状病変のメカニズム (2017)
  • Author(s): 岡本耕一，川口智之，影本開三，藤本大策，六車直樹，高山哲治
  • Journal Title: 臨床消化器病 Volume: 32 Pages: 818-824
• [Presentation] 大腸腫瘍に発現する EGFR を標的とした内視鏡分子イメージング の試み (2019)
  • Author(s): 宮本佳彦, 六車直樹, 高山哲治
  • Organizer: 第97回日本消化器内視鏡学会総会
• [Presentation] 新規蛍光プローブIndocyanine green (ICG) 標識Dasatinibを用いた消化管間質腫瘍 (GIST) の近赤外蛍光 イメージング (2019)
  • Author(s): 藤本将太, 六車直樹, 中尾允泰, 安藤英紀, 宮本佳彦, 岡本耕一, 佐藤康史, 石田竜 弘, 佐野茂樹, 高山哲治
  • Organizer: 第14回日本分子イメージング学会総会・学術集会
• [Presentation] 上皮増殖因子受容体(EGFR)をターゲットとした大腸腫瘍の分子イメージング (2018)
  • Author(s): 宮本佳彦、高山哲治
  • Organizer: 第77回日本癌学会総会
• [Presentation] microRNA arrayを用いた大腸粘膜下層浸潤癌リンパ節転移に関わるバイオマーカーの同定及び機能解析 (2018)
  • Author(s): 3）藤野泰輝, 岡本耕一, 六車直樹, 三井康裕, 北村晋志, 藤本大策, 曽我部正弘, 宮本弘志, 佐藤康史, 高山哲治
  • Organizer: 第14回日本消化管学会総会学術集会
• [Presentation] Detection of Aberrant Crypt Foci Using Image-Enhanced Endoscopy. (2017)
  • Author(s): 7）Kagemoto K, Okamoto K, Takaoka T, Okada Y, Tanaka K, Hirao A, Kitamura S, Kimura T, Miyamoto H, Muguruma N, Okahisa T, Tsuneyama K, Takayama T.
  • Organizer: Digestive Disease Week 2017
  • Int'l Joint Research