Menderes Gulden, Bonazzoli Elena, Bellone Stefania, Altwerger Gary, Black Jonathan D, Dugan Katherine, Pettinella Francesca, Masserdotti Alice, Riccio Francesco, Bianchi Anna, Zammataro Luca, de Haydu Christopher, Buza Natalia, Hui Pei, Wong Serena, Huang Gloria S, Litkouhi Babak, Ratner Elena, Silasi Dan-Arin, Azodi Masoud, Schwartz Peter E, Santin Alessandro D
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Department of Pathology, Yale University School of Medicine, CT 06520, USA.
Gynecol Oncol. 2017 Oct;147(1):145-152. doi: 10.1016/j.ygyno.2017.07.009. Epub 2017 Jul 10.
Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy. The objective of this study was to compare the anti-tumor activity of HER2/neu-targeting monoclonal antibodies, trastuzumab (T), pertuzumab (P), combination of trastuzumab and pertuzumab (T+P) and trastuzumab-emtansine (T-DM1) in EOC with high HER2/neu expression.
Primary EOC cell lines were established and cell blocks were analyzed for HER2/neu expression. Cytostatic, apoptotic and antibody-dependent cell-mediated cytotoxicity (ADCC) activities of T, P, T+P and T-DM1 were evaluated in vitro. The in vivo antitumor activity was tested in xenograft models with 3+ HER2/neu expression.
High (3+) HER2/neu expression was detected in 40% of the primary EOC cell lines. T, P, T+P, and T-DM1 were similarly effective in inducing strong ADCC against primary EOC cell lines expressing 3+ HER2/neu. The combination of T and P was more cytostatic when compared with that of T or P used alone (p<0.0001 and p<0.0001, respectively). T-DM1 induced significantly more apoptosis when compared with T+P (p<0.0001). Finally, T-DM1 was significantly more effective in tumor growth inhibition in vivo in EOC xenografts overexpressing HER2/neu when compared to T alone, P alone and T+P (p=0.04).
In vitro and in vivo experiments with 3+ HER2/neu expressing EOC revealed limited anti-tumor activity of T or P. T-DM1 showed superior anti-tumor activity to T and P as single agents and as a combination. Our preclinical data support the design of clinical studies with T-DM1 for the treatment of chemotherapy-resistant EOC overexpressing HER2/neu.
上皮性卵巢癌（EOC）仍然是最致命的妇科恶性肿瘤。本研究的目的是比较HER2/neu靶向单克隆抗体曲妥珠单抗（T）、帕妥珠单抗（P）、曲妥珠单抗与帕妥珠单抗联合使用（T+P）以及曲妥珠单抗-恩美曲妥珠单抗（T-DM1）在HER2/neu高表达的EOC中的抗肿瘤活性。
建立原发性EOC细胞系，并分析细胞块的HER2/neu表达。在体外评估T、P、T+P和T-DM1的细胞生长抑制、凋亡及抗体依赖性细胞介导的细胞毒性（ADCC）活性。在HER2/neu表达为3+的异种移植模型中测试体内抗肿瘤活性。
在40%的原发性EOC细胞系中检测到HER2/neu高表达（3+）。T、P、T+P和T-DM1在诱导针对表达3+HER2/neu的原发性EOC细胞系的强烈ADCC方面同样有效。与单独使用T或P相比，T和P联合使用时细胞生长抑制作用更强（分别为p<0.0001和p<0.0001）。与T+P相比，T-DM1诱导的凋亡明显更多（p<0.0001）。最后，与单独使用T、P以及T+P相比，T-DM1在体内对HER2/neu过表达的EOC异种移植瘤的生长抑制作用明显更强（p=0.04）。
对HER2/neu表达为3+的EOC进行的体外和体内实验显示，T或P的抗肿瘤活性有限。T-DM1作为单一药物或联合用药时，显示出优于T和P的抗肿瘤活性。我们的临床前数据支持设计使用T-DM1治疗HER2/neu过表达的化疗耐药EOC 的临床研究。
