Possibility of antibody drug conjugate targeting EGFR in triple negative breast cancer

• Project/Area Number: 19K16780
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Juntendo University
• Principal Investigator: nakai katsuya 順天堂大学, 医学部, 准教授 (10384108)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥130,000 (Direct Cost: ¥100,000、Indirect Cost: ¥30,000); Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 乳癌 / Triple Negative乳癌 / 上皮増殖因子受容体 / 抗体薬物複合体 / 効果予測因子 / アルギニン・メチルトランスフェラーゼ / メチル化 / 代抗体薬物複合体 / EGFR

Outline of Research at the Start

Triple Negative乳癌（TNBC）は最も予後不良のサブタイプの乳癌で、BRCAに関連した遺伝性乳癌との関係も深いことから効果的な治療法が期待されている．基礎研究では抗EGFR療法の有効性が指摘され，いくつかの第Ⅱ相臨床試験が行われたが臨床応用にいたっていない．本研究ではTNBC患者に対するEGFRをターゲットにした次世代抗体薬物複合体に注目し，TNBC細胞株における有効性を証明する．さらにADCのendocytosisに必要な抗体親和性を，翻訳後修飾として重要であるEFGRの細胞外ドメインのメチル化に注目し治療効果予測因子の確立を同時に目指す．

Outline of Final Research Achievements

The aim of this study was to analyze the methylation status of the extracellular domain of EGFR in triple negative breast cancer (TNBC) to identify the effect of antibody drug conjugate (ADC) and its predictive factors for the treatment of TNBC.　We analyzed the expression of EGFR and its methylation status in TNBC cell lines, and generated PRMT1-engineered cell lines (overexpression and knockdown models) to confirm the intracellular signaling changes. We used ADCs targeting EGFR in TNBC cell lines and confirmed the effect of the ADC. In addition, we confirmed the methylation status of EGFR in human TNBC samples, and confirmed the rate at which ADCs targeting EGFR are expected to be effective.

Academic Significance and Societal Importance of the Research Achievements

ADCの登場により，TNBCに対する抗EGFR治療に新たな可能性が出てきている．ADC治療薬に関する治療予測因子についての検討はいまだ明白なものはない． ADCの治療効果予測因子としてEGFRのメチル化に注目し機能変化と薬剤耐性に関する報告はなく新規性および将来性があると考えられる．

Research Products

• [Journal Article] Factors Affecting Decisions Regarding Terminal Care Locations of Patients With Metastatic Breast Cancer (2020)
  • Author(s): Noriko Nogami, Katsuya Nakai, Yoshiya Horimoto, Akio Mizushima, Mitsue Saito
  • Journal Title: American Journal of Hospice & Palliative Medicine Volume: 37 Issue: 10 Pages: 853-858
  • DOI: 10.1177/1049909119901154
• [Journal Article] Microsatellite instability and mismatch repair protein expressions in lymphocyte‐predominant breast cancer (2020)
  • Author(s): Yoshiya Horimoto, May Thinzar Hlaing, Harumi Saeki, Shigehisa Kitano, Katsuya Nakai, Ritsuko Sasaki, Aiko Kurisaki, Arakawa Atsushi, Naomi, Otsuji, Shuji Matsuoka, Emi Tokuda , Masami Arai, Mitsue Saito
  • Journal Title: Cancer Science Volume: 111 Issue: 7 Pages: 2647-2654
  • DOI: 10.1111/cas.14500
• [Journal Article] Neutrophil-to-lymphocyte ratio and histological type might predict clinical responses to eriburin-based treatment in patients with metastatic breast cancer (2020)
  • Author(s): Mayu Myojin , Yoshiya Horimoto , Mayuko Ito , Shigehisa Kitano , Yumiko Ishizuka , Ritsuko Sasaki , Toshitaka Uomori , Takanori Himuro , Fumi Murakami , Katsuya Nakai , Kotaro Iijima, Mitsue Saito
  • Journal Title: Breast Cancer Volume: 4 Issue: 4 Pages: 732-738
  • DOI: 10.1007/s12282-020-01069-0
• [Presentation] 当院における緩和ケアチームのとの連携 (2020)
  • Author(s): 中井克也，野上典子，堀本義哉，水嶋章郎，齊藤光江
  • Organizer: 日本乳癌学会総会