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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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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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 / DNA障害 / CP-31398 / FAK活性 / 細胞傷害活性 / MDM2分子 / p21分子誘導 / 細胞死 / MDM2 / MDM4 / DNA傷害 / 遺伝子 / 癌 / シグナル伝達 / バイオテクノロジー / 薬理学 |
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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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| 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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Report
(4 results)
Research Products
(10 results)
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[Journal Article] Combination of a p53-activating CP-31398 and an MDM2 or a FAK inhibitor produces growth suppressive effects in mesothelioma with wild-type p53 genotype.2020
Author(s)
Zhong, B., Shingyoji, M., Hanazono, M., Nguye;n, T.T.T., Morinaga, T., Tada, Y., Hiroshima, K., Shimada, H. and Tagawa, M
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Journal Title
Related Report
Peer Reviewed
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[Journal Article] A p53-stabilizing agent, CP-31398, induces p21 expression with increased G2/M phase through the YY1 transcription factor in esophageal carcinoma defective of the p53 pathway.2019
Author(s)
Zhong, B., Shingyoji, M., Hanazono, M., Nguyen, T.T.T., Morinaga, T., Tada, Y., Hiroshima, K., Shimada, H. and Tagawa, M.
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Journal Title
Am. J. Cancer Res.
Volume: ９
Pages: 79-93
Related Report
Peer Reviewed / Open Access
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