Trastuzumab and Pertuzumab produce changes in morphology and estrogen receptor signaling in ovarian cancer xenografts revealing new treatment strategies

Dana Faratian; Annelien J. M. Zweemer; Yoko Nagumo; Andrew H. Sims; Morwenna Muir; Michael Dodds; Peter Mullen; Inhwa Um; Charlene Kay; Max Hasmann; David J. Harrison; Simon P. Langdon

doi:10.1158/1078-0432.CCR-10-2461

Trastuzumab and Pertuzumab produce changes in morphology and estrogen receptor signaling in ovarian cancer xenografts revealing new treatment strategies

Dana Faratian, Annelien J. M. Zweemer, Yoko Nagumo, Andrew H. Sims, Morwenna Muir, Michael Dodds, Peter Mullen, Inhwa Um, Charlene Kay, Max Hasmann, David J. Harrison, Simon P. Langdon

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

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 (ER alpha)-negative clear cell areas. Trastuzumab, but not pertuzumab, increased expression of ER alpha in SKOV3 xenografts when analyzed by quantitative immunofluorescence. ER alpha 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 ER alpha-positive ovarian cancer. Clin Cancer Res; 17(13); 4451-61. (C) 2011 AACR.

Original language	English
Pages (from-to)	4451-4461
Number of pages	11
Journal	Clinical Cancer Research
Volume	17
Issue number	13
DOIs	https://doi.org/10.1158/1078-0432.CCR-10-2461
Publication status	Published - 1 Jul 2011

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10.1158/1078-0432.CCR-10-2461

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Faratian, D., Zweemer, A. J. M., Nagumo, Y., Sims, A. H., Muir, M., Dodds, M., Mullen, P., Um, I., Kay, C., Hasmann, M., Harrison, D. J., & Langdon, S. P. (2011). Trastuzumab and Pertuzumab produce changes in morphology and estrogen receptor signaling in ovarian cancer xenografts revealing new treatment strategies. Clinical Cancer Research, 17(13), 4451-4461. https://doi.org/10.1158/1078-0432.CCR-10-2461

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title = "Trastuzumab and Pertuzumab produce changes in morphology and estrogen receptor signaling in ovarian cancer xenografts revealing new treatment strategies",

abstract = "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 (ER alpha)-negative clear cell areas. Trastuzumab, but not pertuzumab, increased expression of ER alpha in SKOV3 xenografts when analyzed by quantitative immunofluorescence. ER alpha 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 ER alpha-positive ovarian cancer. Clin Cancer Res; 17(13); 4451-61. (C) 2011 AACR.",

author = "Dana Faratian and Zweemer, {Annelien J. M.} and Yoko Nagumo and Sims, {Andrew H.} and Morwenna Muir and Michael Dodds and Peter Mullen and Inhwa Um and Charlene Kay and Max Hasmann and Harrison, {David J.} and Langdon, {Simon P.}",

year = "2011",

month = jul,

day = "1",

doi = "10.1158/1078-0432.CCR-10-2461",

language = "English",

volume = "17",

pages = "4451--4461",

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Faratian, D, Zweemer, AJM, Nagumo, Y, Sims, AH, Muir, M, Dodds, M, Mullen, P, Um, I, Kay, C, Hasmann, M, Harrison, DJ & Langdon, SP 2011, 'Trastuzumab and Pertuzumab produce changes in morphology and estrogen receptor signaling in ovarian cancer xenografts revealing new treatment strategies', Clinical Cancer Research, vol. 17, no. 13, pp. 4451-4461. https://doi.org/10.1158/1078-0432.CCR-10-2461

TY - JOUR

T1 - Trastuzumab and Pertuzumab produce changes in morphology and estrogen receptor signaling in ovarian cancer xenografts revealing new treatment strategies

AU - Faratian, Dana

AU - Zweemer, Annelien J. M.

AU - Nagumo, Yoko

AU - Sims, Andrew H.

AU - Muir, Morwenna

AU - Dodds, Michael

AU - Mullen, Peter

AU - Um, Inhwa

AU - Kay, Charlene

AU - Hasmann, Max

AU - Harrison, David J.

AU - Langdon, Simon P.

PY - 2011/7/1

Y1 - 2011/7/1

N2 - 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 (ER alpha)-negative clear cell areas. Trastuzumab, but not pertuzumab, increased expression of ER alpha in SKOV3 xenografts when analyzed by quantitative immunofluorescence. ER alpha 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 ER alpha-positive ovarian cancer. Clin Cancer Res; 17(13); 4451-61. (C) 2011 AACR.

AB - 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 (ER alpha)-negative clear cell areas. Trastuzumab, but not pertuzumab, increased expression of ER alpha in SKOV3 xenografts when analyzed by quantitative immunofluorescence. ER alpha 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 ER alpha-positive ovarian cancer. Clin Cancer Res; 17(13); 4451-61. (C) 2011 AACR.

U2 - 10.1158/1078-0432.CCR-10-2461

DO - 10.1158/1078-0432.CCR-10-2461

M3 - Article

SN - 1078-0432

VL - 17

SP - 4451

EP - 4461

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 13

ER -

Trastuzumab and Pertuzumab produce changes in morphology and estrogen receptor signaling in ovarian cancer xenografts revealing new treatment strategies

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