Novel drug discovery and application of intractable cancer targeting RNA m6A modification

• Project/Area Number: 18K16356
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Osaka University
• Principal Investigator: Koseki Jun 大阪大学, 医学系研究科, 特任助教(常勤) (20616669)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: エピゲノム制御因子

Outline of Final Research Achievements

Subclass classification based on RNA methylation information was performed using surgically excised samples of intractable gastrointestinal cancer.
Then, we constructed a platform for companion drug discovery by linking the methylation information of microRNA of peripheral blood.
The effect of oncoprotein on the translation system was examined in 18 types of cancer cells. In addition, the effect of hit compounds on normal cells was examined by Run-On assay.

Academic Significance and Societal Importance of the Research Achievements

オンコプロテイン翻訳系を標的とした創薬において、特許情報プラットフォーム でMettl3、Ythdf1を記載した特許は３件のみで、化合物の特許はない。またModomics DatabaseやNCBI DatabaseやTCGA Databaseにおいても、がんの手術材料からm6A修飾RNAに特化したデータベースとして確立されたものも研究開始当時存在していなかった。そのため、開発リスクが伴う難治がんへの創薬では、アカデミア創薬の役割がとくに重要である。さらに体内の腫瘍と末梢血のリキッドバイオプシーを並列で解析することは、コンパニオン診断として意義がある。本研究でこの創薬基盤を構築した。

Research Products

• [Journal Article] Theoretical analyses and experimental validation of the effects caused by the fluorinated substituent modification of DNA (2020)
  • Author(s): Koseki Jun、Konno Masamitsu、Asai Ayumu、Horie Naohiro、Tsunekuni Kenta、Kawamoto Koichi、Obika Satoshi、Doki Yuichiro、Mori Masaki、Ishii Hideshi
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 1138-1138
  • DOI: 10.1038/s41598-020-57899-7
  • Peer Reviewed / Open Access
• [Journal Article] One-carbon metabolism for cancer diagnostic and therapeutic approaches (2020)
  • Author(s): Asai Ayumu、Konno Masamitsu、Koseki Jun、Taniguchi Masateru、Vecchione Andrea、Ishii Hideshi
  • Journal Title: Cancer Letters Volume: 470 Pages: 141-148
  • DOI: 10.1016/j.canlet.2019.11.023
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Distinct methylation levels of mature microRNAs in gastrointestinal cancers (2019)
  • Author(s): Konno Masamitsu、Koseki Jun、Asai Ayumu、Yamagata Akira、Shimamura Teppei、Motooka Daisuke、Okuzaki Daisuke、Kawamoto Koichi、Mizushima Tsunekazu、Eguchi Hidetoshi、Takiguchi Shuji、Satoh Taroh、Mimori Koshi、Ochiya Takahiro、Doki Yuichiro、Ofusa Ken、Mori Masaki、Ishii Hideshi
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 3888-3888
  • DOI: 10.1038/s41467-019-11826-1
  • Peer Reviewed / Open Access
• [Journal Article] A Hydrogen Peroxide Activatable Gemcitabine Prodrug for the Selective Treatment of Pancreatic Ductal Adenocarcinoma (2019)
  • Author(s): Matsushita Katsunori、Konno Masamitsu、Eguchi Hidetoshi、Koseki Jun、Satoh Taroh、Doki Yuichiro、Mori Masaki、Ishii Hideshi、Obika Satoshi
  • Journal Title: ChemMedChem Volume: 14 Issue: 15 Pages: 1384-1391
  • DOI: 10.1002/cmdc.201900324
  • Peer Reviewed / Open Access
• [Journal Article] Disruption of Endolysosomal RAB5/7 Efficiently Eliminates Colorectal Cancer Stem Cells (2019)
  • Author(s): Takeda Mitsunobu、Koseki Jun、Takahashi Hidekazu、Miyoshi Norikatsu、Nishida Naohiro、Nishimura Junichi、Hata Taishi、Matsuda Chu、Mizushima Tsunekazu、Yamamoto Hirofumi、Ishii Hideshi、Doki Yuichiro、Mori Masaki、Haraguchi Naotsugu
  • Journal Title: Cancer Research Volume: 79 Issue: 7 Pages: 1426-1437
  • DOI: 10.1158/0008-5472.can-18-2192
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Computational analyses for cancer biology based on exhaustive experimental backgrounds (2019)
  • Author(s): Koseki Jun、Konno Masamitsu、Ishii Hideshi
  • Journal Title: Cancer Drug Resistance Volume: 2 Pages: 419-427
  • DOI: 10.20517/cdr.2019.33
  • Peer Reviewed / Open Access
• [Journal Article] Mitochondrial pyruvate carrier 1 expression controls cancer epithelial‐mesenchymal transition and radioresistance (2019)
  • Author(s): Takaoka Yuji、Konno Masamitsu、Koseki Jun、Colvin Hugh、Asai Ayumu、Tamari Keisuke、Satoh Taroh、Mori Masaki、Doki Yuichiro、Ogawa Kazuhiko、Ishii Hideshi
  • Journal Title: Cancer Science Volume: 110 Issue: 4 Pages: 1331-1339
  • DOI: 10.1111/cas.13980
  • Peer Reviewed / Open Access
• [Journal Article] Direct Analysis of Incorporation of an Anticancer Drug into DNA at Single-Molecule Resolution (2019)
  • Author(s): Ohshiro Takahito、Komoto Yuuki、Konno Masamitsu、Koseki Jun、Asai Ayumu、Ishii Hideshi、Taniguchi Masateru
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 3886-3886
  • DOI: 10.1038/s41598-019-40504-x
  • Peer Reviewed / Open Access
• [Journal Article] Association of iron metabolic enzyme hepcidin expression levels with the prognosis of patients with pancreatic cancer (2018)
  • Author(s): Toshiyama Reishi、Konno Masamitsu、Eguchi Hidetoshi、Asai Ayumu、Noda Takehiro、Koseki Jun、Asukai Kei、Ohashi Tomofumi、Matsushita Katsunori、Iwagami Yoshifumi、Yamada Daisaku、Asaoka Tadafumi、Wada Hiroshi、Kawamoto Koichi、Gotoh Kunihito、Kudo Toshihiro、Satoh Taroh、Doki Yuichiro、Mori Masaki、Ishii Hideshi
  • Journal Title: Oncology Letters Volume: 15 Pages: 8125-8133
  • DOI: 10.3892/ol.2018.8357
  • Peer Reviewed / Open Access
• [Journal Article] Poly(ethylene glycol)ーpoly(lysine) block copolymerーubenimex conjugate targets aminopeptidase N and exerts an antitumor effect in hepatocellular carcinoma stem cells (2018)
  • Author(s): Toshiyama, R., Konno, M., Eguchi, H., Takemoto, H., Noda, T., Asai, A., Koseki, J., Haraguchi, N., Ueda, Y. Matsushita, K., Asukai, K., Ohashi, T., Iwagami, Y., Yamada, D., Sakai, D., Asaoka, T., Kudo, T., Kawamoto, K., Gotoh, K., Kobayashi, S., Satoh, T., Doki, Y., Nishiyama, N., Mori, M., Ishii, H.
  • Journal Title: Oncogene Volume: 38 Issue: 2 Pages: 244-260
  • DOI: 10.1038/s41388-018-0406-x
  • Peer Reviewed / Open Access
• [Journal Article] Cell?free culture conditioned medium elicits pancreatic β cell lineage?specific epigenetic reprogramming in mice (2018)
  • Author(s): Kawamoto Koichi、Ohashi Tomofumi、Konno Masamitsu、Nishida Naohiro、Koseki Jun、Matsui Hidetoshi、Sakai Daisuke、Kudo Toshihiro、Eguchi Hidetoshi、Satoh Taroh、Doki Yuichiro、Mori Masaki、Ishii Hideshi
  • Journal Title: Oncology Letters Volume: 16 Pages: 3255-3259
  • DOI: 10.3892/ol.2018.9008
  • Peer Reviewed / Open Access
• [Journal Article] A Convolutional Neural Network Uses Microscopic Images to Differentiate between Mouse and Human Cell Lines and Their Radioresistant Clones (2018)
  • Author(s): Toratani Masayasu、Konno Masamitsu、Asai Ayumu、Koseki Jun、Kawamoto Koichi、Tamari Keisuke、Li Zhihao、Sakai Daisuke、Kudo Toshihiro、Satoh Taroh、Sato Katsutoshi、Motooka Daisuke、Okuzaki Daisuke、Doki Yuichiro、Mori Masaki、Ogawa Kazuhiko、Ishii Hideshi
  • Journal Title: Cancer Research Volume: 78 Issue: 23 Pages: 6703-6707
  • DOI: 10.1158/0008-5472.can-18-0653
  • Peer Reviewed / Open Access
• [Journal Article] Carbon ion beam radioresistant rodent cells are sensitized to trifluorothymidine exposure (2018)
  • Author(s): Baek Sung Jae、Sato Katsutoshi、Nishida Naohiro、Koseki Jun、Hayashi Kazuhiko、Kawamoto Koichi、Konno Masamitsu、Doki Yuichiro、Mori Masaki、Ogawa Kazuhiko、Ishii Hideshi
  • Journal Title: Oncology Letters Volume: 16 Pages: 3389-3393
  • DOI: 10.3892/ol.2018.9004
  • Peer Reviewed / Open Access
• [Journal Article] Drug discovery of anticancer drugs targeting methylenetetrahydrofolate dehydrogenase 2 (2018)
  • Author(s): Asai Ayumu、Koseki Jun、Konno Masamitsu、Nishimura Tatsunori、Gotoh Noriko、Satoh Taroh、Doki Yuichiro、Mori Masaki、Ishii Hideshi
  • Journal Title: Heliyon Volume: 4 Issue: 12 Pages: e01021-e01021
  • DOI: 10.1016/j.heliyon.2018.e01021
  • Peer Reviewed / Open Access
• [Journal Article] Polyamine flux suppresses histone lysine demethylases and enhances ID1 expression in cancer stem cells (2018)
  • Author(s): Tamari K, KonnoM , Asai A, Koseki J, Hayashi K, Kawamoto K, Murai N, Matsufuji S, Isohashi F, Satoh T, Gotoh N, Tanaka S, Doki Y, Mori M, Ogawa K, Ishii H.
  • Journal Title: Cell Death Discovery Volume: 4 Issue: 104 Pages: 104-104
  • DOI: 10.1038/s41420-018-0117-7
  • Peer Reviewed / Open Access
• [Presentation] 消化器がん治療のための理論科学手法と機械学習を駆使した創薬研究 (2019)
  • Author(s): 小関準、今野雅允、土岐祐一郎、石井秀 始
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] 早期膵がんマーカーとしてのマイクロRNAの機能変化 (2019)
  • Author(s): 小関準、今野雅允、浅井歩、土岐祐一郎、石井秀 始
  • Organizer: 第７回がんと代謝研究会
• [Presentation] 新規トランスオミックス法を用いたがん幹細胞のDNAメチル化量及び転写量変 化の相関解析 (2018)
  • Author(s): 小関準、今野雅允、浅井歩、佐藤太郎、土岐祐一郎、森正樹、石井秀始
  • Organizer: 第６回がんと代謝研究会
• [Presentation] 消化器がん幹細胞のエピゲノム異常の標的化と制御 (2018)
  • Author(s): 小関準、浅井歩、今野雅允、佐藤太郎、土岐祐一郎、辻川和丈、森正樹、石井秀始
  • Organizer: 第77回日本癌学会学術総会