PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.
PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.
Authors: Dawei Jiang; Hyung-Jun Im; Haiyan Sun; Hector F Valdovinos; Christopher G England; Emily B Ehlerding; Robert J Nickles; Dong Soo Lee; Steve Y Cho; Peng Huang; Weibo Cai Journal: Eur J Nucl Med Mol Imaging Date: 2017-03-06 Impact factor: 9.236
Authors: S John Weroha; Marc A Becker; Sergio Enderica-Gonzalez; Sean C Harrington; Ann L Oberg; Matthew J Maurer; Sarah E Perkins; Mariam AlHilli; Kristina A Butler; Sarah McKinstry; Stephanie Fink; Robert B Jenkins; Xiaonan Hou; Kimberly R Kalli; Karin M Goodman; Jann N Sarkaria; Beth Y Karlan; Amanika Kumar; Scott H Kaufmann; Lynn C Hartmann; Paul Haluska Journal: Clin Cancer Res Date: 2014-01-07 Impact factor: 12.531
Authors: Monique D Topp; Lynne Hartley; Michele Cook; Valerie Heong; Emma Boehm; Lauren McShane; Jan Pyman; Orla McNally; Sumitra Ananda; Marisol Harrell; Dariush Etemadmoghadam; Laura Galletta; Kathryn Alsop; Gillian Mitchell; Stephen B Fox; Jeffrey B Kerr; Karla J Hutt; Scott H Kaufmann; Elizabeth M Swisher; David D Bowtell; Matthew J Wakefield; Clare L Scott Journal: Mol Oncol Date: 2014-01-24 Impact factor: 6.603