Division of Pathology and Edinburgh Breakthrough Research Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
Clin Cancer Res. 2011 Jul 1;17(13):4451-61. doi: 10.1158/1078-0432.CCR-10-2461. Epub 2011 May 13.
The aim of this study was to investigate the antitumor effects of HER2-directed combination therapy in ovarian cancer xenograft models to evaluate their potential. The combinations of trastuzumab and pertuzumab, and trastuzumab and aromatase inhibitor therapy were investigated.
The effects of trastuzumab, pertuzumab, and letrozole on growth response, apoptosis, morphology, and gene and protein expression were evaluated in the SKOV3 ovarian cancer cell line xenograft and a panel of five human ovarian xenografts derived directly from clinical specimens.
The combination of HER2-directed antibodies showed enhanced antitumor activity compared with single antibody therapy in the SKOV3 xenograft model. Apoptosis, morphology, and estrogen-regulated gene expression were modulated by these antibodies in both spatial and temporal manners. A panel of ovarian cancer xenografts showed differential growth responses to the combination of trastuzumab and pertuzumab. High HER2 expression and increasing HER3 protein expression on treatment were associated with growth response. In trastuzumab-treated SKOV3 tumors, there was a change in tumor morphology, with a reduction in frequency of estrogen receptor alpha (ERα)-negative clear cell areas. Trastuzumab, but not pertuzumab, increased expression of ERα in SKOV3 xenografts when analyzed by quantitative immunofluorescence. ERα and downstream signaling targets were modulated by trastuzumab alone and in combination. Trastuzumab enhanced the responsiveness of SKOV3 xenografts to letrozole when given in combination.
These data suggest that trastuzumab in combination with pertuzumab could be an effective approach in high HER2-expressing ovarian cancers and could also enhance sensitivity to endocrine therapy in ERα-positive ovarian cancer.
本研究旨在探讨曲妥珠单抗联合帕妥珠单抗和曲妥珠单抗联合芳香化酶抑制剂治疗在卵巢癌异种移植模型中的抗肿瘤作用，评估其潜力。
在 SKOV3 卵巢癌细胞系异种移植模型和一组源自临床标本的五个人类卵巢异种移植模型中，评估曲妥珠单抗、帕妥珠单抗和来曲唑对生长反应、凋亡、形态以及基因和蛋白表达的影响。
与单药治疗相比，HER2 靶向抗体联合治疗在 SKOV3 异种移植模型中显示出更强的抗肿瘤活性。这些抗体在时空上调节了凋亡、形态和雌激素调节基因的表达。一组卵巢癌异种移植模型显示出对曲妥珠单抗联合帕妥珠单抗联合治疗的不同生长反应。高 HER2 表达和治疗后 HER3 蛋白表达增加与生长反应相关。在曲妥珠单抗治疗的 SKOV3 肿瘤中，肿瘤形态发生变化，雌激素受体 α（ERα）阴性透明细胞区的频率降低。通过定量免疫荧光分析，曲妥珠单抗而非帕妥珠单抗增加了 SKOV3 异种移植中的 ERα 表达。ERα 和下游信号靶标被曲妥珠单抗单独和联合调节。曲妥珠单抗联合治疗增强了 SKOV3 异种移植对来曲唑的反应性。
这些数据表明，曲妥珠单抗联合帕妥珠单抗可能是高 HER2 表达卵巢癌的有效治疗方法，并且还可以增强 ERα 阳性卵巢癌对内分泌治疗的敏感性。
