Both the
epidermal growth factor (
EGF) and the
vascular endothelial growth factor (
VEGF) pathways are associated with
intestinal cancer, and therapeutic approaches targeting either
EGF receptor (EGFR) or
VEGF receptor (VEGFR) signaling have recently been approved for patients with advanced
colorectal cancer. The Apc(Min/+) mouse is a well-characterized in vivo model of intestinal
tumorigenesis, and animals with this genetic mutation develop macroscopically detectable
adenomas from approximately 6 weeks of age. Previous work in the Apc(Min/+) mouse has shown that therapeutic approaches targeting either VEGFR or EGFR signaling affect predominantly the size or number of
adenomas, respectively. In this study, we have assessed the effect of inhibiting both these key pathways simultaneously using
ZD6474 (
Vandetanib,
ZACTIMA), a selective inhibitor of VEGFR and EGFR
tyrosine kinases. To assess the effects of
ZD6474 on early- and later-stage disease, treatment was initiated in 6- and 10-week-old Apc(Min/+) mice for 28 days.
ZD6474 markedly reduced both the number and the size of
polyps when administered at either an early or a later stage of
polyp development. This reduction in both
adenoma number and size resulted in a total reduction in
tumor burden in the small intestine of nearly 75% in both studies (P < 0.01). The current data build on the concept that EGFR-dependent
tumor cell proliferation and
VEGF/VEGFR2-dependent angiogenesis and survival are distinct key mechanisms in
polyp development. Pharmacologic inhibition of both signaling pathways has significant antitumor effects at both early and late stages of
polyp development. Therefore, targeting both VEGFR- and EGFR-dependent signaling may be a beneficial strategy in early
intestinal cancer.