Editors' ChoiceCancer

Triple Therapy Targets Tumors

Science Signaling  13 Nov 2012:
Vol. 5, Issue 250, pp. ec291
DOI: 10.1126/scisignal.2003770

About 50% of patients with breast cancer characterized as human epidermal growth factor receptor 2 (HER2)–positive develop brain metastases. Although patients with extracranial disease generally respond to treatment with HER2 inhibitors, such as the antibody trastuzumab, brain metastases often fail to respond; thus, alternative therapies are required. Given the importance of angiogenesis to breast cancer development and metastasis, Kodack et al. developed a xenograft-based mouse model of HER2-dependent breast cancer and investigated a role for signaling by vascular endothelial growth factor receptor (VEGFR), which promotes angiogenesis, in brain metastases. Brain imaging of tumor cells, which expressed a fluorescent protein and luciferase to enable their identification, showed that, whereas tumor cells in the mammary fat pad responded to anti-HER2 therapy, those in the brain did not, demonstrating that the mouse model recapitulated critical aspects of the human disease. Combined antibody-mediated inhibition of both HER2 and VEGFR delayed brain metastatic growth and increased survival compared to that in mice treated with anti-HER2 therapy alone. Western blotting analysis of Akt and mitogen-activated protein kinase signaling showed that the addition of VEGFR-targeted antibody did not enhance the effects of the HER2 inhibitor on HER2 signaling. Instead, combined therapy led to necrotic death of tumor cells, which was accompanied by a reduction in the microvascular density in the tumors, as assessed by staining for endothelial cell markers. Triple therapy, in which two HER2 inhibitors were combined with the VEGFR-targeted antibody, resulted in the greatest reduction in brain tumor growth and increase in mouse survival, which was more than twofold longer than those that received anti-VEGFR therapy with a single HER2 inhibitor. Thus, targeting both HER2 and VEGFR should be investigated in clinical trials.

D. P. Kodack, E. Chung, H. Yamashita, J. Incio, A. M. M. J. Duyverman, Y. Song, C. T. Farrar, Y. Huang, E. Ager, W. Kamoun, S. Goel, M. Snuderl, A. Lussiez, L. Hiddingh, S. Mahmood, B. A. Tannous, A. F. Eichler, D. Fukumura, J. A. Engelman, R. K. Jain, Combined targeting of HER2 and VEGFR2 for effective treatment of HER2-amplified breast cancer brain metastases. Proc. Natl. Acad. Sci. U.S.A. 109, E3119–E3127 (2012). [Abstract] [Full Text]