2019 Fiscal Year Final Research Report
Molecular therapy for esophageal cancer targeting the p53 and the Hippo pathways
| Project/Area Number |
17K10617
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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 |
Digestive surgery
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| Research Institution | Chiba Cancer Center (Research Institute) |
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Principal Investigator |
TAGAWA Masatoshi 千葉県がんセンター(研究所), がん治療開発グループ, 特任研究員 (20171572)
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| Co-Investigator(Kenkyū-buntansha) |
島田 英昭 東邦大学, 医学部, 教授 (20292691)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Keywords | 食道がん / 遺伝子変異 / p53経路 / Hippo経路 / FAK経路 / 細胞障害活性 |
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| Outline of Final Research Achievements |
Esophageal carcinoma has frequent mutations in genes encoding p53 and several molecules in the Hippo pathway. This suggests that restoration of the p53 pathway and suppression of the elevated Hippo pathway are therapeutic strategies for the malignancy. We used agents which augmented p53 expression or suppressed several Hippo-linked pathways and examined whether these agents induced apoptotic cell death. The present study showed that small molecules activating p53 expression killed the tumor cells but the apoptosis induced was not always relevant to p53-mediated cell death. Among agents inhibiting elevated Hippo-linked pathways, an inhibitor for focal adhesion kinase effectively suppressed the growth and augmented p53 expression. A combinatory use of p53-activating agent and the FAK inhibitor synergistically suppressed the growth through augmenting p53 and dephosphorylating FAK levels. These data indicated that agents targeting the pathways are potentially useful for the treatments.
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| Free Research Field |
分子腫瘍学
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| Academic Significance and Societal Importance of the Research Achievements |
高齢者に多い食道がんは、周辺組織への進展が早いことも多く、進行がんは難治であり根治的治療は困難であることが多い。そこで、同疾患の遺伝子変異に基づいて、それを標的とした薬剤の開発は、従来の放射線治療、抗がん剤治療に引き続いて新たな治療の方向性となる。このような遺伝子変異を狙う薬物は、正常組織では同変異がないことから、有害事象が少なく当該疾患に特異的に作用すると想定され、また従来の治療法との併用が可能である。高齢化社会でのがん治療に向けて、また今後臨床応用されるゲノム研究の成果を生かす方向として、遺伝子変異に立脚した当該疾患の治療法が開発できる可能性を本研究では示している。
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