2019 Fiscal Year Final Research Report

Development of chemopreventive agents using Connectivity Map analysis

Research Project

PDF

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
Keywords	大腸癌予防薬 / 大腸腺腫 / オルガノイド / SSA/P
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.
Free Research Field	消化器病学
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。