Article

Experimental treatment of oestrogen receptor (ER) positive breast cancer with tamoxifen and brivanib alaninate, a VEGFR-2/FGFR-1 kinase inhibitor: A potential clinical application of angiogenesis inhibitors

Dartmouth Hitchcock Medical Center, Dept. of Surgery, Manchester, NH 03104, USA.
European journal of cancer (Oxford, England: 1990) (Impact Factor: 5.42). 03/2010; 46(9):1537-53. DOI: 10.1016/j.ejca.2010.02.018
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ABSTRACT

Tamoxifen, a selective oestrogen receptor modulator (SERM), and brivanib alaninate, a vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor, are two target specific agents that result in a substantial decrease in tumour growth when given alone. Tamoxifen activates SERM stimulated breast and endometrial tumour growth. Tamoxifen and brivanib alaninate have side-effects that can affect therapeutic outcomes. The primary goal of the current study was to evaluate the therapeutic effects of lower doses of both agents when given in combination to mice with SERM sensitive, oestrogen stimulated tumour xenografts (MCF-7 E2 tumours). Experiments were conducted to evaluate the response of SERM stimulated breast (MCF-7 Tam, MCF-7 Ral) and endometrial tumours (EnCa 101) to demonstrate the activity of brivanib alaninate in SERM resistant models.
In the current study, tumour xenografts were minced and bi-transplanted into the mammary fat pads of athymic, ovariectomised mice. Preliminary experiments were conducted to determine an effective oral dose of tamoxifen and brivanib alaninate that had minimal effect on tumour growth. Doses of 125 microg of tamoxifen and 0.05 mg/g of brivanib alaninate were evaluated. An experiment was designed to evaluate the effect of the two agents together when started at the time of tumour implantation. An additional experiment was done in which tumours were already established and then treated, to obtain enough tumour tissue for molecular analysis.
Brivanib alaninate was effective at inhibiting tumour growth in SERM sensitive (MCF-7 E2) and SERM stimulated (EnCa 101, MCF-7 Ral, MCF-7 Tam) models. The effect of the low dose drug combination as an anti-tumour strategy for SERM sensitive (MCF-7 E2) in early treatment was as effective as higher doses of either drug used alone. In established tumours, the combination is successful at decreasing tumour growth, while neither agent alone is effective. Molecular analysis revealed a decreased phosphorylation of VEGFR-2 in tumours that were treated with brivanib alaninate and an increase in VEGFA transcription to compensate for the blockade of VEGFR-2 by increasing the transcription of VEGFA. Tamoxifen increases the phosphorylation of VEGFR-2 and this effect is abrogated by brivanib alaninate. There was also increased necrosis in tumours treated with brivanib alaninate.
Historically, tamoxifen has a role in blocking angiogenesis as well as the blockade of the ER. Tamoxifen and a low dose of an angiogenesis inhibitor, brivanib alaninate, can potentially be combined not only to maximise therapeutic efficacy but also to retard SERM resistant tumour growth.

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    • "Comparative cytogenetic analysis found that, given the evident heterogeneity and differential capabilities of the techniques used (FISH or SKY) to detect abnormalities in small chromosomal segments, the karyotypic similarity was likely underestimated, and is consistent with the two lines sharing a common origin. Thus, we conclude that the original ECC-1 cell line has been lost, although the persistence of the EnCa-101 tumor [56] provides an opportunity for its re-derivation. ECC-1 cells have been extensively used as models of ER positive, type 1, endometrial cancers. "
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    ABSTRACT: By way of clarification, this is not my publication but I am posting it to inform other scientists and as we have previously published using this cell line, under the impression it was an endometrial epithelial cell line. The manuscript by Korch et al was subsequently published. As a ER-positive breast cancer cell line, in which we confirmed findings obtained using Ishikawa endometrial epithelial cells, this does not change the final result, indeed it confirms that LXA4 is an ER agonist.
    Full-text · Dataset · May 2013
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    • "Comparative cytogenetic analysis found that, given the evident heterogeneity and differential capabilities of the techniques used (FISH or SKY) to detect abnormalities in small chromosomal segments, the karyotypic similarity was likely underestimated, and is consistent with the two lines sharing a common origin. Thus, we conclude that the original ECC-1 cell line has been lost, although the persistence of the EnCa-101 tumor [56] provides an opportunity for its re-derivation. ECC-1 cells have been extensively used as models of ER positive, type 1, endometrial cancers. "

    Full-text · Dataset · May 2013
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    • "In fact, the Her-2/neu gene is rarely amplified in lobular carcinoma, avoiding trastuzumab therapeutic chances for most the patients, and even worse, the topoisomerase-IIa is constantly not-amplified [2], thus predicting high chances of chemo-resistance to anthracyclines. In this poor context of medical therapies, new promising predictive biomarkers, giving chances in selecting appropriate patients suitable for receiving new effective regimens, are needed [5,6]. "
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    ABSTRACT: Background: Lobular breast carcinoma usually shows poor responsiveness to chemotherapies and often lacks targeted therapies. Since FGFR1 expression has been shown to play pivotal roles in primary breast cancer tumorigenesis, we sought to analyze the status of FGFR1 gene in a metastatic setting of lobular breast carcinoma, since promising FGFR1 inhibitors has been recently developed. Methods: Fifteen tissue metastases from lobular breast carcinomas with matched primary infiltrative lobular breast carcinoma were recruited. Eleven cases showed loco-regional lymph-nodal and four haematogenous metastases.FGFR-1 gene (8p12) amplification was evaluated by chromogenic in situ hybridization (CISH) analysis. Her-2/neu and topoisomerase-IIα gene status was assessed. E-cadherin and Hercept Test were also performed. We distinguished amplification (>6 or cluster of signals) versus gains (3-6 signals) of the locus specific FGFR-1 gene. Results: Three (20%) primary lobular breast carcinomas showed >6 or cluster of FGFR1 signals (amplification), six cases (40%) had a mean of three (range 3-6) chromogenic signals (gains) whereas in 6 (40%) was not observed any abnormality. Three of 15 metastasis (20%) were amplified, 2/15 (13,4%) did not. The ten remaining cases (66,6%) showed three chromogenic signals.The three cases with FGFR-1 amplification matched with those primary breast carcinomas showing FGFR-1 amplification. The six cases showing FGFR-1 gains in the primary tumour again showed FGFR-1 gains in the metastases. Four cases showed gains of FGFR-1 gene signals in the metastases and not in the primary tumours. Her-2/neu gene amplification was not observed in all cases but one (6%) case. Topoisomerase-IIα was not amplified in all cases. Conclusions: 1) a subset of metastatic lobular breast carcinoma harbors FGFR-1 gene amplification or gains of chromogenic signals; 2) a minor heterogeneity has been observed after matching primary and metastatic carcinomas; 3) in the era of tailored therapies, patients affected by the lobular subtype of breast carcinoma with FGFR1 amplification could be approached to the new target biological therapy such as emerging FGFR-1 inhibitors.
    Full-text · Article · Dec 2012 · Journal of Experimental & Clinical Cancer Research
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