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

Roshani R. Patel, Surojeet Sengupta, Helen R. Kim, Andres J. Klein-Szanto, Jennifer R. Pyle, Fang Zhu, Tianyu Li, Eric A. Ross, Salewa Oseni, Joseph Fargnoli, V. Craig Jordan

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29 Scopus citations

Abstract

Purpose: 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. Experimental design: 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 μg 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. Results: 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)1537-1553
Number of pages17
JournalEuropean Journal of Cancer
Volume46
Issue number9
DOIs
StatePublished - Jun 2010
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the following grants: Department of Defense Breast Program under award number BC050277 Center of Excellence (Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense) (VCJ), SPORE in Breast Cancer CA 89018 (VCJ), Genuardis Fund (VCJ), FCCC Core Grant NIH P30 CA006927, the Avon Foundation and the Weg Fund of Fox Chase Cancer Center (VCJ), Bristol Myers Squibb (VCJ), 5T32CA10365-03 (R.R.P.).

Funding Information:
A research grant was provided as partial funding of this project by Bristol Myers Squibb. Brivanib alaninate was also provided by Bristol Myers Squibb.

Funding Information:
Roshani Patel’s salary is supported by 5T32CA10365-03. Surojeet Sengupta, Helen Kim, and Jennifer Pyle’s salaries, as well as laboratory supplies supported by the following: the Department of Defense Breast Program under award number BC050277 Center of Excellence, SPORE in Breast Cancer CA 89018 (VCJ), Genuardis Fund (VCJ), FCCC Core Grant NIH P30 CA006927, the Avon Foundation and the Weg Fund of Fox Chase Cancer Center (VCJ). Bristol Myers Squibb provided funding for this research, as well as the drug, brivanib alaninate.

Keywords

  • Angiogenesis
  • Breast cancer
  • Brivanib alaninate
  • Hormone resistance
  • Tamoxifen
  • VEGFR-2

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