Development of anti-tumor therapy by novel compounds targeting pyruvate dehydrogenase kinase
| Project/Area Number |
16K08711
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | Shiga University of Medical Science |
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Principal Investigator |
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| Research Collaborator |
Kim Chul Jang
Mukaisho Ken-ichi
Tambe Yukihiro
Ushio Akiyo
Nakano Hirofumi
Omura Satoshi
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | KRAS / ピルビン酸代謝 / 膵臓癌 / PDK4 / cryptotanshinone / Cryptotanshinone / PDK４ / エネルギー代謝 / PDK4阻害剤 / ワールブルグ効果 / K-Ras / mTOR / 癌幹細胞 / 新規抗癌剤 |
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| Outline of Final Research Achievements |
Most proliferating tumor cells preferentially metabolize glucose via glycolysis even under aerobic conditions. This metabolic shift, the Warburg effect, is a hallmark of malignant cancer cells. We found that the novel specific inhibitors of PDK4 (KIS) significantly suppressed the malignant phenotypes of human colon and pancreatic cancer cells in vitro. A novel PDK4 inhibitor, KIS37 (cryptotanshinone), reduced the phosphorylation of pyruvate dehydrogenase and the expression of mutant K-Ras protein in human pancreatic and colon cancer cell lines. KIS37 also suppressed the phosphorylation of PI3K-Akt-mTOR pathway and expression of cyclin D1 protein. Furthermore, KIS37 suppressed pancreatic tumor formation in orthotopic model of nude mouse without detectable adverse effects. These results indicate that this novel PDK4 inhibitor can be a potential therapeutic drug for mutant KRAS-containing intractable pancreatic and colorectal cancers.
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| Academic Significance and Societal Importance of the Research Achievements |
K-ras遺伝子変異が90%を占める膵臓癌は癌の中でも最も10年生存率が低い難治性癌であり、有効で副作用の少ない新規分子標的治療薬の開発は大きな課題である。また、大腸癌は最も罹患率が高い癌で、特にK-ras遺伝子変異は44%を占めこれらは予後が悪く難治性が高い。米国でも癌治療の最重要課題として”The RAS project”を立ち上げているが、これまでのRas阻害剤では未だ有効な臨床的成果を上げていない。これらの難治癌に対する新しい作用機作の抗癌剤の開発は重要であり、我々が見出したピルビン酸代謝を標的としたKIS化合物の抗腫瘍活性を示した今回の成果は臨床での治験にも直接つながると考えられる。
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Report
(4 results)
Research Products
(12 results)
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[Journal Article] Antitumor activity of potent pyruvate dehydrogenase kinase 4 inhibitors from plants in pancreatic cancer.2019
Author(s)
Tambe, Y., Terado, T., Kim, C. J., Mukaisho, K., Yoshida, S., Sugihara, H., Tanaka, H., Chida, J., Kido, H., Yamaji, K., Yamamoto, T., Nakano, H., Omura, S. and Inoue, H
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Journal Title
Mol. Carcinog.
Volume: 印刷中
Related Report
Peer Reviewed
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[Journal Article] Transplantation of iPS-derived tumor cells with a homozygous MHC haplotype induces GRP94 antibody production in MHC-matched macaques.2018
Author(s)
Ishigaki, H., Maeda, T., Inoue, H., Akagi, T., Sasamura, T., Ishida, H., Inubushi, T., Okahara, J., Shiina, T., Nakamura, M., Otoh, Y., Ogasawara, K.
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Journal Title
Cancer Res.
Volume: 印刷中
Issue: 21
Pages: 6001-6010
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Periostin suppresses in vitro invasiveness via PDK1/Akt/mTOR signaling pathway in a orthotopic model of bladder cancer.2017
Author(s)
Kim, C. J., Tambe, Y., Mukaisho, K., Sugihara, H., Kageyama, S., Kawauchi, A., Inoue, H.
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Journal Title
Oncology Letters
Volume: 13
Issue: 6
Pages: 4276-4284
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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