| Project/Area Number |
18K08720
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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 55020:Digestive surgery-related
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| Research Institution | Japanese Foundation for Cancer Research |
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Principal Investigator |
WAKATSUKI Takeru 公益財団法人がん研究会, 有明病院 消化器化学療法科, 医長 (60443876)
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| Project Period (FY) |
2018-04-01 – 2024-03-31
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| Project Status |
Completed (Fiscal Year 2023)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2019: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
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| Keywords | 胃癌 / ラムシルマブ / 血管新生阻害剤 / SNPs / バイオマーカー / VEGF-A/VEGFR2経路の二重阻害療法 / 切除不能進行・再発胃癌 / VEGF-A / 血管新生因子 / 切除不能進行再発胃癌 / 二重阻害 / 抗VEGFR2抗体 |
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| Outline of Final Research Achievements |
The aim of this study was to identify the SNPs which predict the patients whose plasma VEGF-A levels are high after ramucirumab administration. Forty-two patients were enrolled in this study with the median PFS and OS was 4.1 and 11.0 months, respectively. The SNPs, VEGFR2 rs10013228 A>G (p=0.055), rs11133360 T>C (p=0.017), and rs2071559 A>G (p=0.072), were associated with higher plasma VEGF-A levels early after ramucirumab administration, but none of them were associated with survival. Instead, the SNPs potentially associated with worse prognosis were VEGFR1 XX with HR 2.23, p=0.070 for PFS and HR 3.10, p=0.030 for OS, and VEGFR2 YY with HR 2.11, p=0.093 for PFS. In preclinical mouse model, the combination therapy of anti-VEGF-A antibody and anti-VEGFR2 antibody showed higher antitumor efficacy compared to each monotherapy. The ligand and receptor dual blockade using antibodies in angiogenesis may be a promising therapy, and clinical trials are currently being prepared.
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| Academic Significance and Societal Importance of the Research Achievements |
VEGF-Aは血管新生の亢進だけでなく、腫瘍免疫の抑制にも関与することが明らかとなり、血管新生阻害剤は腫瘍免疫の改善にも貢献する。本研究で導かれた抗VEGF-A抗体/抗VEGFR2抗体併用によるVEGF-A/VEGFR2経路の二重阻害療法は、より高い血管新生阻害作用のみならず腫瘍免疫の改善も期待され、新たな治療選択肢として有望である。現在、新規医師主導治験実施の準備を行っている。
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