New construction of innovative drug discovery foundation technology for refractory gastrointestinal cancer targeting cancer metabolomics

• Project/Area Number: 26293303
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Osaka University
• Principal Investigator: ISHII Hideshi 大阪大学, 医学(系)研究科(研究院), 特任教授(常勤) (10280736)
• Co-Investigator(Kenkyū-buntansha): 土岐 祐一郎 大阪大学, 医学(系)研究科(研究院), 教授 (20291445) ; 三森 功士 九州大学, 大学病院, 教授 (50322748) ; 今野 雅允 大阪大学, 医学(系)研究科(研究院), 寄附講座助教 (80618207) ; 永野 浩昭 山口大学, 医学(系)研究科(研究院), 教授 (10294050)
• Co-Investigator(Renkei-kenkyūsha): Mori Masaki 大阪大学, 大学院医学系研究科, 教授 (70190999) ; Tozuka Zenzaburo 大阪大学, 大学院薬学系研究科, 教授 (50624748) ; Obika Satoshi 大阪大学, 大学院薬学系研究科, 教授 (80243252) ; Nishiyama Nobuhiro 東京工業大学, 化学生命科学研究所, 教授 (10372385) ; Kawamoto Koichi 大阪大学, 大学院医学系研究科, 特任助教(常勤) (30432470) ; Matsui Hidetoshi 滋賀大学, データサイエンス学部, 准教授 (90633305) ; Saito Toshiyuki 独立行政法人放射線医学総合研究所, 重粒子医科学センター, 主任研究員 (90205667)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000); Fiscal Year 2016: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2015: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2014: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
• Keywords: 癌 / シグナル伝達 / 核酸 / 生体分子

Outline of Final Research Achievements

A major goal is to elucidate the specific cancer metabolic pathway and establish a solid foundation for cancer-specific drug discovery of refractory gastrointestinal cancer. To achieve this drug discovery centered on cancer metabolism, we focus on the metabolic pathology of the specifically important oncogene K-RAS mutation downstream, from fresh materials of gastrointestinal cancer patients in compliance with ethical regulations. Creating an animal model that reproduces the cancer-host relationship and reconstructs the microenvironment, detects the dynamic behavior of cancer metabolites with high accuracy, which is comparable with omics information in other static state and mathematical statistical analysis using supercomputer.

Research Products

• [Journal Article] The importance of mitochondrial folate enzymes in human colorectal cancer. (2017)
  • Author(s): Miyo, M., Konno, M., Colvin, S. H., Nishida, N., Koseki, J., Kawamoto, K., Tsunekuni, K., Nishimura, J., Hata, T., Takemasa, I., Mizushima, T., Doki, Y., Mori, M., Ishii, H.
  • Journal Title: Oncol. Rep. Volume: 37 Issue: 1 Pages: 417-425
  • DOI: 10.3892/or.2016.5264
  • Peer Reviewed / Open Access
• [Journal Article] Clinical significance of histone demethylase NO66 in invasive colorectal cancer. (2017)
  • Author(s): Nishizawa, Y., Nishida, N., Konno, M., Kawamoto, K., Asai, A., Koseki, J., Takahashi, H., Haraguchi, N., Nishimura, J., Hata, T., Matsuda, C., Mizushima, T., Satoh, T., Doki, Y., Mori, M., Ishii, H.
  • Journal Title: Ann. Surg. Oncol. Volume: 24 Issue: 3 Pages: 841-849
  • DOI: 10.1245/s10434-016-5395-9
  • Peer Reviewed / Open Access
• [Journal Article] Genomic Landscape of Esophageal Squamous Cell Carcinoma in a Japanese Population. (2016)
  • Author(s): G. Sawada (他43名, 山本21番目)
  • Journal Title: Gastroenterology Volume: 150 Issue: 5 Pages: 1171-1182
  • DOI: 10.1053/j.gastro.2016.01.035
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fetal hepatocyte derived culture medium elicits adipocyte differentiation to bile duct cell lineages in mouse. (2016)
  • Author(s): Ogawa, H., Konno, M., Kawamoto, K., Nishida, N., Koseki, J., Mizushima, T., Satoh, T., Eguchi, H., Doki, Y., Mori, M., Ishii, H.
  • Journal Title: Biomedical. Reports. Volume: -
  • Peer Reviewed / Open Access
• [Journal Article] c-Met affects gemcitabine resistance over carcinogenesis in a mouse model of pancreatic cancer. (2016)
  • Author(s): Noguchi, K., Konno, M., Eguchi, H., Kawamoto, K., Mukai, R., Nishida, N., Koseki, J., Wada, H., Akita, H., Satoh, T., Marubashi, S., Nagano, H., Doki, Y., Mori, M., Ishii, H.
  • Journal Title: Oncol. Lett. Volume: -
  • Peer Reviewed / Open Access
• [Journal Article] MicroRNA miR-374, a potential radiosensitizer for carbon ion beam radiotherapy. (2016)
  • Author(s): Baek, SJ., Sato, K., Nishida, N., Koseki, J., Azuma, R., Kawamoto, K., Konno, M., Hayashi, K., Satoh, T., Doki, Y., Mori, M., Ishii, H., Ogawa, K.
  • Journal Title: Oncol. Rep. Volume: 36 Issue: 5 Pages: 2946-2950
  • DOI: 10.3892/or.2016.5122
  • Peer Reviewed / Open Access
• [Journal Article] Oncometabolite D-2-hydroxyglurate directly induces epithelial-mesenchymal transition and is associated with distant metastasis in colorectal cancer. (2016)
  • Author(s): Colvin, S. H., Nishida, N., Konno, M., Haraguchi, N., Takahashi, H., Nishimura, J., Hata, T., Kawamoto, K. Asai, A., Tsunekuni, K., Koseki, J., Mizushima, T., Satoh, T., Doki, Y., Mori, M., Ishii, H.
  • Journal Title: Sci. Rep Volume: 6 Issue: 1 Pages: 36289-36289
  • DOI: 10.1038/srep36289
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Metabolic adaptation to nutritional stress in human colorectal cancer. (2016)
  • Author(s): Miyo, M., Konno, M., Nishida, N. Sueda, T., Noguchi, K., Matsui, H., Colvin, H., Kawamoto, K., Koseki, J., Haraguchi, N., Nishimura, J., Hata, T., Gotoh, N., Mastuda, F., Saatoh, T., Mizushima, T., Shimizu, H., Doki, Y., Mori, M., Ishii, H.
  • Journal Title: Sci. Rep. Volume: 6 Issue: 1 Pages: 38415-38415
  • DOI: 10.1038/srep38415
  • Peer Reviewed / Open Access
• [Journal Article] Intestinal epithelial culture under an air-liquid interface: a tool for studying human and mouse esophagi. (2015)
  • Author(s): Yokobori T, Suzuki S, Miyazaki T, Sohda M, Sakai M, Tanaka N, Ozawa D, Hara K, Honjo H, Altan B, Fukuchi M, Ishii H, Iwatsuki M, Sugimachi K, Sudo T, Iwaya T, Nishida N, Mimori K, Kuwano H, Mori M.
  • Journal Title: Dis Esophagus. Volume: [Epub ahead of print] Issue: 7 Pages: 843-847
  • DOI: 10.1111/dote.12346
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Mathematical analysis predicts imbalanced IDH1/2 expression associates with 2-HG-inactivating β-oxygenation pathway in colorectal cancer (2015)
  • Author(s): Koseki, J., Colvin, H., Fukusumi, T., Nishida, N., Konno, M., Kawamoto, K., Tsunekuni, K., Matsui, H., Doki, Y., Mori, M. and Ishii, H.
  • Journal Title: International Journal of Oncology Volume: 46 Issue: 3 Pages: 1181-1191
  • DOI: 10.3892/ijo.2015.2833
  • Peer Reviewed
• [Journal Article] Pyruvate kinase M2, but not M1, allele maintains immature metabolic states of murine embryonic stem cells (2015)
  • Author(s): Konno, M., Ishii, H., Koseki, J., Tanuma, N., Nishida, N., Kawamoto, K., Nishimura, T., Nakata, A., Matsui, H., Noguchi, K., Ozaki, M., Noguchi, Y., Shima, H., Gotoh N., Nagano, H., Doki, Y. and Mori, M.
  • Journal Title: Regenerative Therapy Volume: 1 Pages: 63-71
  • DOI: 10.1016/j.reth.2015.01.001
  • Peer Reviewed / Open Access
• [Journal Article] System-wide analysis of the transcriptional network of human myelomonocytic leukemia cells predicts attractor structure and phorbol-ester-induced differentiation and dedifferentiation transitions (2015)
  • Author(s): Katsumi Sakata, Hajime Ohyanagi, Toshiyuki Saito, et al.
  • Journal Title: Scientific Reports Volume: 5 Issue: 1 Pages: 8283-8283
  • DOI: 10.1038/srep08283
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] RFPL4A increases the G1 population and decreases sensitivity to chemotherapy in human colorectal cancer cells. (2015)
  • Author(s): Naito et al.
  • Journal Title: J Biol Chem Volume: 290 Issue: 10 Pages: 6326-6337
  • DOI: 10.1074/jbc.m114.614859
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] MicroRNAs induce epigenetic reprogramming and suppress malignant phenotypes of human colon cancer cells. (2015)
  • Author(s): Ogawa, H., Wu, X., Kawamoto, K., Nishida, N., Konno, M., Koseki, J., Matsui, H., Noguchi, K., Gotoh, N., Yamamoto, T., Miyata, K., Nishiyama, N., Nagano, H., Yamamoto, H., Obika, S., Kataoka, K., Doki, Y., Mori, M., Ishii, H.
  • Journal Title: PLoS One. Volume: 10 Issue: 5 Pages: 1-23
  • DOI: 10.1371/journal.pone.0127119
  • Peer Reviewed / Open Access
• [Journal Article] Tumour-suppressive function of SIRT4 in human colorectal cancer. (2015)
  • Author(s): Miyo, M., Yamamoto, H., Konno, M., Colvin, H., Nishida, N., Koseki, J., Kawamoto, K., Ogawa, H., Hamabe, A., Uemura, M., Nishimura, J., Hata, T., Takemasa, I., Mizushima, T., Doki, Y., Mori, M., Ishii, H.
  • Journal Title: Br. J. Cancer Volume: 113 Issue: 3 Pages: 492-499
  • DOI: 10.1038/bjc.2015.226
  • Peer Reviewed / Open Access
• [Journal Article] Embryonic microRNA-369 controls metabolic splicing factors and urges cellular reprograming. (2015)
  • Author(s): Masamitsu Konno, Jun Koseki, Koichi Kawamoto, Naohiro Nishida, Hidetoshi Matsui, Dyah Laksmi Dewi, Miyuki Ozaki, Yuko Noguchi, Koshi Mimori, Noriko Gotoh, Nobuhiro Tanuma, Hiroshi Shima, Yuichiro Doki, Masaki Mori , Hideshi Ishii
  • Journal Title: PLOS ONE Volume: 10(7) Issue: 7 Pages: 1-16
  • DOI: 10.1371/journal.pone.0132789
  • Peer Reviewed / Open Access
• [Journal Article] Susceptibility of pancreatic cancer stem cells to reprogramming. (2015)
  • Author(s): Noguchi, K., Eguchi, H., Konno, M., Kawamoto, K., Nishida, N., Koseki, J., Wada, H., Marubashi, S., Nagano, H., Doki, Y., Mori, M., Ishii, H.
  • Journal Title: Cancer Sci. Volume: 106 Issue: 9 Pages: 1182-1187
  • DOI: 10.1111/cas.12734
  • Peer Reviewed / Open Access
• [Journal Article] Ultra-sensitive liquid biopsy of circulating extracellular vesicles using ExoScreen. (2014)
  • Author(s): Yoshioka Y, Kosaka N, Konishi Y, Ohta H, Okamoto H, Sonoda H, Nonaka R, Yamamoto H, Ishii H, Mori M, Furuta K, Nakajima T, Hayashi H, Sugisaki H, Higashimoto H, Kato T, Takeshita F, Ochiya T.
  • Journal Title: Nature Communications Volume: 5 Issue: 1 Pages: 3591-3591
  • DOI: 10.1038/ncomms4591
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] LZTS1 downregulation confers paclitaxel resistance and is associated with worse prognosis in breast cancer. (2014)
  • Author(s): Lovat, F., Ishii, H., Schiappacassi, M., Fassan, M., Barbareschi, M., Galligioni, E., Gasparini, P., Baldassarre, G., Croce, CM., Vecchione, A.
  • Journal Title: Oncotarget Volume: 5 Pages: 970-977
  • Peer Reviewed
• [Journal Article] CD10 as a novel marker of therapeutic resistance and cancer stem cells in head and neck squamous cell carcinoma. (2014)
  • Author(s): Fukusumi T, Ishii H, Konno M, Yasui T, Nakahara S, Takenaka Y, Yamamoto Y, Nishikawa S, Kano Y, Ogawa H, Hasegawa S, Hamabe A, Haraguchi N, Doki Y, Mori M, Inohara H.
  • Journal Title: Br J Cancer Volume: 111(3) Issue: 3 Pages: 506-514
  • DOI: 10.1038/bjc.2014.289
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] MicroRNA-1246 expression associated with CCNG2-mediated chemoresistance and stemness in pancreatic cancer. (2014)
  • Author(s): Hasegawa S, Eguchi H, Nagano H, Konno M, Tomimaru Y, Wada H, Hama N, Kawamoto K, Kobayashi S, Nishida N, Koseki J, Nishimura T, Gotoh N, Ohno S, Yabuta N, Nojima H, Mori M, Doki Y, Ishii H.
  • Journal Title: Br. J. Cancer Volume: 111 Issue: 8 Pages: 1572-80
  • DOI: 10.1038/bjc.2014.454
  • Peer Reviewed
• [Journal Article] Combined evaluation of hexokinase 2 and phosphorylated pyruvate dehydrogenase-E1alpha in invasive front lesions of colorectal tumors predicts cancer metabolism and patient prognosis (2014)
  • Author(s): Hamabe, A. Yamamoto, H. Konno, M. Uemura, M. Nishimura, J. Hata, T. Takemasa, I. Mizushima, T. Nishida, N. Kawamoto, K. Koseki, J. Doki, Y. Mori, M. Ishii, H.
  • Journal Title: Cancer Science Volume: 105 Issue: 9 Pages: 1100-8
  • DOI: 10.1111/cas.12487
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Role of pyruvate kinase M2 in transcriptional regulation leading to epithelial-mesenchymal transition (2014)
  • Author(s): Hamabe, A. Konno, M. Tanuma, N. Shima, H. Tsunekuni, K. Kawamoto, K. Nishida, N. Koseki, J. Mimori, K. Gotoh, N. Yamamoto, H. Doki, Y. Mori, M. Ishii, H.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 111 Issue: 43 Pages: 15526-31
  • DOI: 10.1073/pnas.1407717111
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Cancer Stem Cells of the Digestive System. (2014)
  • Author(s): Colvin, S. H., Nishida, N., Koseki, J., Konno, M., Kawamoto, K., Tsunekuni, K., Doki, Y., Mori, M., Ishii, H.
  • Journal Title: Jpn. J. Clin. Oncol. Volume: 44 Issue: 12 Pages: 1141-1149
  • DOI: 10.1093/jjco/hyu146
  • Peer Reviewed
• [Presentation] 多能性幹細胞の種差に関わる内在性因子 (2017)
  • Author(s): 石井秀始、今野雅允
  • Organizer: 第16回日本再生医療学会総会
  • Place of Presentation: 仙台国際センター(宮城）
  • Year and Date: 2017-03-07
• [Presentation] Overcoming therapy-resistant cancer stem cells (2016)
  • Author(s): 石井秀始
  • Organizer: 15th World Congress on CANCER THERAPY, BIOMARKER ＆CLINCAL RESEARCH
  • Place of Presentation: DoubleTree by Hilton Hotel Philadelphia Airport（アメリカ）
  • Year and Date: 2016-12-05
  • Int'l Joint Research
• [Presentation] NEW STRATEGY FOR OVERCOMING MULTIFACETED THERAPY-RESISTANT CANCER STEM CELLS (2016)
  • Author(s): 石井秀始
  • Organizer: 第47回高松宮妃癌研究基金国際シンポジウム
  • Place of Presentation: パレスホテル東京(東京）
  • Year and Date: 2016-11-08
• [Presentation] 大腸癌の飢餓ストレスに適応した代謝変化 (2016)
  • Author(s): 今野雅允、三代雅明、西田尚弘、川本弘一、小関準、土岐祐一郎、森正樹、石井秀始
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜(神奈川）
  • Year and Date: 2016-10-06
• [Presentation] Innovative Medicine for Metabolic Reprogramming of Intractable Cancer Stem Cells (2015)
  • Author(s): 石井秀始
  • Organizer: 第46回高松宮妃癌研究基金国際シンポジウム
  • Place of Presentation: パレスホテル東京（東京）
  • Year and Date: 2015-11-17
• [Presentation] 難治性消化器癌幹細胞の可視化とシステム的理解 (2015)
  • Author(s): 石井秀始、土岐祐一郎、森正樹
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知）
  • Year and Date: 2015-10-08
• [Presentation] 癌医療における機能性核酸の応用 (2015)
  • Author(s): 石井秀始
  • Organizer: 第7回日本RNAi研究会 (第2回日本細胞外小胞学会)
  • Place of Presentation: グランドプリンスホテル広島（広島）
  • Year and Date: 2015-08-26
• [Presentation] 難治性消化器がんの克服を目指したがん代謝応答機能の解明 (2015)
  • Author(s): 石井秀始
  • Organizer: 第3回がんと代謝研究会
  • Place of Presentation: 石川県立音楽堂交流ホール（石川）
  • Year and Date: 2015-07-16
• [Presentation] Innovative drug discovery for intractable cancer stem cells (2014)
  • Author(s): 石井秀始
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場(大阪）
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] 難治性消化器癌に対する革新的治療法 (2014)
  • Author(s): 石井秀始、土岐祐一郎、森正樹
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜(神奈川）
  • Year and Date: 2014-09-25 – 2014-10-31
• [Presentation] 創薬標的としての癌幹細胞エピゲノム代謝 (2014)
  • Author(s): 石井秀始
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜(神奈川）
  • Year and Date: 2014-09-25 – 2014-10-31
• [Presentation] Innvovative Medicine for Gastrointestinal Cancer Stem Cells (2014)
  • Author(s): 石井秀始
  • Organizer: 第52回日本癌治療学会学術集会
  • Place of Presentation: パシフィコ横浜(神奈川）
  • Year and Date: 2014-08-28 – 2014-08-30
• [Patent(Industrial Property Rights)] がんを検出、又はがんの進行期を判定する方法 (2016)
  • Inventor(s): 石井秀始、西田尚弘、森正樹、土岐祐一郎 他7名
  • Industrial Property Rights Holder: 石井秀始、西田尚弘、森正樹、土岐祐一郎 他7名
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-162203
  • Filing Date: 2016-08-22
• [Patent(Industrial Property Rights)] タンパク質の部分立体構造を予測する方法 (2016)
  • Inventor(s): 石井秀始、土岐祐一郎、今野雅允 4名
  • Industrial Property Rights Holder: 石井秀始、土岐祐一郎、今野雅允 4名
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-058220
  • Filing Date: 2016-03-23
• [Patent(Industrial Property Rights)] 炭素線感受性バイオマーカー、炭素線感受性の評価方法およびキット、ならびに炭素線増感剤 (2016)
  • Inventor(s): 小川和彦、石井秀始、今野雅允 他7名
  • Industrial Property Rights Holder: 小川和彦、石井秀始、今野雅允 他7名
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-069684
  • Filing Date: 2016-03-31