Simó Cristina, Shmuel Shayla, Vanover Alex, Pereira Patrícia M R
Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
Mol Pharm. 2024 Dec 2;21(12):6311-6322. doi: 10.1021/acs.molpharmaceut.4c00777. Epub 2024 Oct 29.
Positron emission tomography (PET) has potential as a complementary technique to biomarker analysis, especially for human epidermal growth factor receptor 2 (HER2)-expressing tumors characterized by high heterogeneity. In this study, zirconium-89 (Zr) and copper-64 (Cu) labeled trastuzumab were employed to monitor varying levels of tumoral HER2 expression. Additionally, we studied the use of the cholesterol-depleting lovastatin as a pharmacological approach to enhance cell-surface HER2 expression in tumors with moderate to low HER2 levels, aiming to increase antibody accumulation in these tumor types. Both Zr- and Cu-labeled trastuzumab effectively monitor HER2 expression levels in xenografts exhibiting varying HER2 expression. No significant difference in tumor uptake was observed between Zr- or Cu-labeled trastuzumab, and tumor uptake for both radioimmunoconjugates positively correlated with HER2 protein levels. These findings underscore the potential of PET to monitor HER2 protein levels across heterogeneous tumors. Furthermore, our results suggest that further optimization of statin dosing and timing could offer a promising strategy to enhance trastuzumab accumulation in HER2-high, HER2-moderate, and HER2-low tumors.
正电子发射断层扫描（PET）作为生物标志物分析的补充技术具有潜力，特别是对于以高度异质性为特征的人表皮生长因子受体2（HER2）表达肿瘤。在本研究中，使用锆-89（Zr）和铜-64（Cu）标记的曲妥珠单抗来监测肿瘤HER2表达的不同水平。此外，我们研究了使用胆固醇消耗药物洛伐他汀作为一种药理学方法，以增强HER2水平中度至低度肿瘤的细胞表面HER2表达，旨在增加这些肿瘤类型中抗体的积累。Zr和Cu标记的曲妥珠单抗均能有效监测异种移植瘤中不同HER2表达水平的HER2表达。Zr或Cu标记的曲妥珠单抗之间未观察到肿瘤摄取的显著差异，并且两种放射免疫缀合物的肿瘤摄取与HER2蛋白水平呈正相关。这些发现强调了PET在监测异质性肿瘤中HER2蛋白水平方面的潜力。此外，我们的结果表明，进一步优化他汀类药物的给药剂量和时间可能提供一种有前景的策略，以增强曲妥珠单抗在HER2高表达、HER2中度表达和HER2低表达肿瘤中的积累。
