Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri.
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
J Nucl Med. 2023 Oct;64(10):1638-1646. doi: 10.2967/jnumed.122.265172. Epub 2023 Jun 29.
The human epidermal growth factor receptor 2 (HER2)-targeting trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) are antibody-drug conjugates (ADC) clinically used to treat HER2-positive breast cancer, with the latter receiving clinical approval in 2021 for HER2-positive gastric cancer. Lovastatin, a cholesterol-lowering drug, temporally elevates cell-surface HER2 in ways that enhance HER2-ADC binding and internalization. In an NCIN87 gastric xenograft model and a gastric patient-derived xenograft model, we used the Zr-labeled or Cu-labeled anti-HER2 antibody trastuzumab to investigate the dosing regimen of ADC therapy with and without coadministration of lovastatin. We compared the ADC efficacy of a multiple-dose ADC regime, which replicates the clinical dose regimen standard, with a single-dose regime. T-DM1/lovastatin treatment inhibited tumor growth, regardless of multiple- or single-dose T-DM1 administration. Coadministration of lovastatin with T-DM1 or T-DXd as a single dose enhanced tumor growth inhibition, which was accompanied by a decrease in signal on HER2-targeted immuno-PET and a decrease in HER2-mediated signaling at the cellular level. DNA damage signaling was increased on ADC treatment in vitro. Our data from a gastric cancer xenograft show the utility of HER2-targeted immuno-PET to inform the tumor response to ADC therapies in combination with modulators of cell-surface target availability. Our studies also demonstrate that statins enhance ADC efficacy in both a cell-line and a patient-derived xenograft model in ways that enable a single-dose administration of the ADC.
人表皮生长因子受体 2（HER2）靶向曲妥珠单抗美坦新（T-DM1）和曲妥珠单抗德拉斯鲁（T-DXd）是临床用于治疗 HER2 阳性乳腺癌的抗体药物偶联物（ADC），后者于 2021 年获得 HER2 阳性胃癌的临床批准。洛伐他汀是一种降胆固醇药物，它以暂时提高细胞表面 HER2 的方式增强 HER2-ADC 结合和内化。在 NCIN87 胃异种移植模型和胃患者来源的异种移植模型中，我们使用标记的 Zr 或 Cu 的抗 HER2 抗体曲妥珠单抗来研究 ADC 治疗与洛伐他汀联合给药的剂量方案。我们比较了多剂量 ADC 方案和单剂量方案的 ADC 疗效，多剂量 ADC 方案复制了临床剂量方案标准。T-DM1/洛伐他汀治疗抑制肿瘤生长，无论多剂量还是单剂量 T-DM1 给药。T-DM1 或 T-DXd 与洛伐他汀联合单剂量给药可增强肿瘤生长抑制作用，同时伴随 HER2 靶向免疫 PET 信号降低和细胞水平 HER2 介导的信号降低。体外 ADC 治疗增加了 DNA 损伤信号。我们从胃腺癌异种移植模型获得的数据表明，HER2 靶向免疫 PET 可用于告知 ADC 联合细胞表面靶标可用性调节剂治疗的肿瘤反应。我们的研究还表明，他汀类药物以能够单次给予 ADC 的方式增强了细胞系和患者来源的异种移植模型中 ADC 的疗效。
