Development of novel region-selective epigenetic inhibitors against gastroenterological cancer
| Project/Area Number |
20K21625
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 55:Surgery of the organs maintaining homeostasis and related fields
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| Research Institution | Chiba University |
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Principal Investigator |
Kaneda Atsushi 千葉大学, 大学院医学研究院, 教授 (10313024)
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| Project Period (FY) |
2020-07-30 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2021: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Fiscal Year 2020: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
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| Keywords | エピゲノム / 消化器癌 / 化合物 / がん / 阻害剤 |
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| Outline of Research at the Start |
癌発生にはエピゲノム異常が大きく関わる。FDA承認を受けている癌エピゲノム薬は２種類６個に過ぎず、ゲノム全体に作用する阻害過多が問題となっている。この問題を解決するため、ピロール・イミダゾール（PI）ポリアミドが特定のDNA配列を認識することを利用し、エピゲノム阻害小分子とPIポリアミドを縮合し、特定DNA配列に阻害剤をリクルートする技術開発を進める。発癌に関与する重要領域へ効率よく作用させることで副作用を減弱し、局所的にエピゲノム状態をコントロールする治療戦略の創生に挑戦する。
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| Outline of Final Research Achievements |
Cell fate such as cellular development and differentiation is determined by epigenome such as DNA methylation and histone modification, and its abnormalities cause various diseases. In this study, important epigenomic aberrations observed in gastric cancer are analyzed using clinical gastric cancer specimens and cell culture models, to elucidate molecular mechanisms for gastric cancer development such as abnormal activation of enhancer regions via binding of transcription factors or foreign viral DNA. We identified important epigenomic aberrations, their causes, and sequence characteristics of the target regions. New condensate compounds using PI polyamide were synthesized so that an epigenomic enzyme inhibitor could be preferentially recruited to genomic regions with specific nucleotide sequence characteristics, to conduct region-selective intervention of epigenomic modification and lay the foundation for the development of anticancer compounds.
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| Academic Significance and Societal Importance of the Research Achievements |
癌は我が国において喫緊の対策が必要な疾患であるが、ゲノム変異を応用した標的薬剤開発が世界的に進められている中で、発癌のもう一つの重要な分子異常であるエピゲノム変異に対する治療開発は遅れている。本研究では胃癌に焦点を当て発癌に重要なエンハンサー領域のエピゲノム異常とその原因となる転写因子や外来ウイルスDNAの結合など、胃癌発生に重要なエピゲノム変化を同定した。それら特定の塩基配列的特徴を持ったゲノム領域に、エピゲノム酵素阻害薬を誘導できるようにPIポリアミドとの縮合化合物を合成し、選択的エピゲノム改変による新たな抗癌剤開発の基盤を築いた。
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Report
(3 results)
Research Products
(19 results)
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[Presentation] Molecular mechanism of carcinogenesis induced by HPV insertion in head and neck squamous cell carcinoma2021
Author(s)
Masato Mima, Atsushi Okabe, Takuya Nakagawa, Tomoya Kurokawa, Satoru Kondo, Harue Mizokami, Masaki Fukuyo, Bahityar Rahmutulla, Hoshii Takayuki, Kiyoshi Misawa, Hiroyuki Mineta, Atsushi Kaneda
Organizer
80th Annual Meeting of Japan Cancer Association
Related Report
Int'l Joint Research
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