Bachelier, Richard, Confavreux, Cyrille, Goehring, Delphine, van der Pluijm, Gabri, Clezardin, Philippe and Carmeli, Yael (2014) Combination of Antiangiogenic Therapies Reduces Osteolysis and Tumor Burden in Experimental Breast Cancer Bone Metastasis. International journal of cancer, 135 (6). pp. 1319-1329. ISSN 1097-0215

Abstract

Introduction:
The clinical efficacy of anti-angiogenic monotherapies in metastatic breast cancer is less than originally anticipated and it is not clear what the response of bone metastases to anti-angiogenic therapies is. Moreover, the evaluation of the combined use of antiangiogenic agents is still in its infancy. Therefore, we examined here the impact of neutralizing tumor-derived VEGF and/or VEGF receptor activity in a mouse model of breast cancer bone metastasis.
Methods:
VEGF expression in human MDA-MB-231/B02 breast cancer cells, which metastasize to bone, was invalidated using RNA interference strategy. The effects of VEGF silencing in B02 cells (Sh-VEGF) were compared with that of mock-transfected cells (Sc-VEGF) using in vitro cell migration and invasion assays and a model of tumor angiogenesis following subcutaneous implantation of Sh-VEGF and Sc-VEGF transfectants in nude mice. The effects of VEGF receptor tyrosine kinase inhibitor vatalanib were also investigated on bone metastasis formation caused by Sh-VEGF and Sc-VEGF transfectants. Additionally, the effects of vatalanib and VEGF-neutralizing antibody bevacizumab, used as single agents or in combination, were studied in the mouse model of bone metastasis caused by parental B02 breast cancer cells. Bone destruction was measured by radiography and histomorphometry. Skeletal tumor burden was measured by bioluminescence imaging and histomorphometry. All statistical tests were two-sided.
Results :
VEGF silencing severely impaired the motility and invasiveness of B02 breast cancer cells in vitro and decreased tumor angiogenesis in vivo, leading to growth inhibition of subcutaneous tumor xenografts in animals. VEGF silencing in B02 cells did not however inhibit the formation and progression of experimental bone metastases. Similarly, vatalanib did not inhibit bone metastasis formation caused by Sc-VEGF transfectants. By contrast, it did inhibit bone metastasis formation in animals bearing Sh-VEGF tumors. Moreover, B02 tumor-bearing mice treated with vatalanib + bevacizumab showed a decreased bone destruction and a reduced tumor burden compared with vehicle, whereas a single agent therapy had no effect.
Conclusion:
A combined therapy targeting both VEGF and its receptors efficiently reduces not only bone destruction but also skeletal tumor growth in a mouse model of breast cancer bone metastasis.

Keywords
Breast, cancer, bone, metastasis, tumor angiogenesis, VEGF, bevacizumab, PTK787, vatalanib

Item Type:	Article
Date Deposited:	04 May 2016 23:45
Last Modified:	04 May 2016 23:45
URI:	https://oak.novartis.com/id/eprint/7983