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2021 Fiscal Year Final Research Report

Combination therapy with bevacizumab and CCR2 inhibitor for women with ovarian cancer

Research Project

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Project/Area Number 19K09818
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 56040:Obstetrics and gynecology-related
Research InstitutionHokkaido University

Principal Investigator

Mitamura Takashi  北海道大学, 大学病院, 助教 (90625641)

Co-Investigator(Kenkyū-buntansha) 渡利 英道  北海道大学, 医学研究院, 教授 (10344508)
畑中 佳奈子  北海道大学, 大学病院, 特任講師 (10399834)
天野 虎次  北海道大学, 大学病院, 特任助教 (20374514)
畑中 豊  北海道大学, 大学病院, 特任准教授 (30589924)
Project Period (FY) 2019-04-01 – 2022-03-31
Keywords卵巣がん / 血管新生阻害薬 / ベバシズマブ / CCR2 / 併用療法 / CCR2阻害薬 / 前臨床試験
Outline of Final Research Achievements

Experimental Design: We established three consecutive PDXs (first high-grade serous, second clear cell, and third high-grade serous carcinoma) using immunodeficient mice. We randomly assigned mice to receive bevacizumab(BEV) or a combination of BEV and the CCR2 inhibitor BMS CCR2 22 (BEV/CCR2i).
Results: BEV/CCR2i demonstrated significant growth suppression in the first BEV-resistant PDX and third BEV-sensitive PDX compared with BEV, and treatment cessation did not attenuate this effect. Angiogenesis on the tumor surface was suppressed in BEV/CCR2i compared with BEV. Although the second PDX did not respond to BEV/CCR2i after the fifth cycle, two additional cycles of high-dose BEV/CCR2i demonstrated significant growth suppression compared with BEV by inhibiting the CCR2B-MAPK pathway.
Conclusions: BEV/CCR2i showed a sustained and antitumor immunity-independent synergistic effect in human ovarian cancer. This benefit is more significant in serous carcinoma than in clear cell carcinoma.

Free Research Field

産婦人科学

Academic Significance and Societal Importance of the Research Achievements

血管新生阻害薬であるベバシズマブは進行再発卵巣がんに対する標準治療として用いられるが、薬剤耐性が発生するために一時的な治療効果しか得られない場合が多い。我々は、患者から摘出した腫瘍をマウスに移植してベバシズマブ/CCR2阻害薬併用療法の治療効果を検討し、併用療法が有意に優れていることを発見した。また機序が、ベバシズマブによる血管新生阻害作用の上乗せ効果のみならず、腫瘍細胞に対する直接的な増殖抑制効果もあることを発見した。本研究の成果は、臨床第2相試験を実施する上での科学的根拠なると思われる。

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Published: 2023-01-30  

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