We have previously reported that
breast cancer cells which overexpress HER2 produce higher levels of
VEGF than cells with low levels of HER2. This study tested the hypothesis that dual targeting of the
VEGF (with
VEGF-Trap) and HER2 (with
trastuzumab) pathways would result in greater growth inhibition of HER2-overexpressing
breast cancer xenografts than either agent alone. In this study we found that human and murine endothelial cells expressed high levels of
VEGF receptors (VEGFR1, VEGFR2, & VEGFR3).
VEGF-Trap decreased levels of secreted
VEGF derived from both human and murine cells and effectively blocked
VEGF-induced
tyrosine phosphorylation of VEGFR2.
VEGF-Trap as a single treatment inhibited
tumor microvessel density (MVD),
tumor vasculature, cell proliferation and
tumor growth of BT474 xenografts in a dose-dependent manner from 2.5 mg/kg to 25 mg/kg.
VEGF-Trap decreased levels of both human
VEGF and PlGF
protein in vivo.
Trastuzumab as a single agent effectively inhibited BT474
tumor growth in a dose-dependent manner, associated with a decrease in human
VEGF,
tumor MVD and
tumor cell proliferation. Treatment with a combination of
VEGF-Trap (2.5-10 mg/kg) and
trastuzumab (1 mg/kg) produced significantly greater inhibition of BT474
tumor growth than either individual agent, associated with greater inhibition of
tumor MVD and
tumor cell proliferation. Thus,
VEGF-Trap in combination with
trastuzumab produces superior growth inhibition of
tumor xenografts which overexpress HER2, which may result from inhibition of both
tumor angiogenesis and proliferation. Similar mechanisms may contribute to the clinical anti-
tumor activity of
trastuzumab in combination with inhibitors of
VEGF signaling pathway in women with breast
cancers which overexpress HER2.