| Project/Area Number |
18K09249
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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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| Review Section |
Basic Section 56040:Obstetrics and gynecology-related
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Oda Katsutoshi 東京大学, 医学部附属病院, 教授 (30359608)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 卵巣癌 / 分子標的薬 / ゲノム解析 / 相同組換修復欠損 / ネオアンチゲン / 卵巣高異型度漿液性癌 / 免疫チェックポイント阻害剤 / TP53 / MDM2 / PI3K / DNA修復 / 分子標的治療 / PARP / 相同組換え修復不全 / BRCA1/2 / 変異シグネチャー / 相同組換修復 / PARP阻害剤 / バイオマーカー |
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| Outline of Final Research Achievements |
The expression profiles of SMYD2 showed significant overexpression of SMYD2 in high-grade serous ovarian carcinomas (HGSOC). Inhibition of SMYD2 by a SMYD2 inhibitor, LLY-507, increased the number of apoptotic cells and showed additive effect with olaparib inHGSOC cells.
The numbers of predicted neoantigens (neoAgs) were lower in HR-proficient than HR-deficient tumors. However, 40% of the patients with HR-proficient tumors still had higher than median numbers of neoAgs. Patients with both high neoAg numbers and high HLA-class I expression had the best progression-free survival in HR-proficient HGSOC.
In mouse models, MDM2 inhibitor, DS-5272, significantly inhibited ascites production, and significantly improved overall survival. Furthermore, DS-5272 significantly decreased vascular endothelial growth factor concentrations in both sera and ascites. Combined DS-5272 and an mTOR inhibitor, everolimus, showed synergistic anti-tumor effect in clear cell carcinomas.
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| Academic Significance and Societal Importance of the Research Achievements |
卵巣癌におけるゲノム・エピゲノム異常に基づき、治療標的分子を同定し、新たな個別化医療につながる可能性のある知見を報告した。
相同組換修復と関連するような分子標的治療法は他がん種でも注目されており、卵巣高異型度漿液性癌における本研究成果に基づくサブタイプの同定や分子標的治療法の探索が、将来的な卵巣癌のPrecision Medicineの発展に寄与すると期待される。相同組換修復異常と関連する変異シグネチャーとの相関についての知見は、知財申請につなげており、新規の検査法につながることも期待される。
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