Antitumour efficacy of VEGFR2 tyrosine kinase inhibitor correlates with expression of VEGF and its receptor VEGFR2 in tumour models

Abstract

During the development of indazolylpyrimidines as novel and potent inhibitors of vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2) tyrosine kinase, we observed that some human tumour xenografts are more sensitive to VEGFR2 kinase inhibitors than others. A better understanding of the basis for this differential response may help to identify a predictive marker that would greatly aid in the identification of a suitable patient population for treatment. One representative compound from the indazolylpyrimidine series is GW654652 that inhibited all three VEGFRs with similar potency. The inhibition of VEGFR2 kinase by GW654652 was about 150 to 48800 more potent than the inhibition of eight other kinases tested. GW654652 inhibited VEGFand bFGF-induced proliferation in endothelial cells with an IC 50 of 110 and 1980 nM, respectively, and has good pharmacokinetic profile in mouse and dog. We investigated the association between VEGF and VEGFR2 expression and the antitumour efficacy of GW654652, in various xenograft models. Statistically significant associations were observed between the antitumour efficacy of GW654652 in xenografts and VEGF protein (P ¼ 0.005) and VEGFR2 expression (P ¼ 0.041). The oral dose of GW654652 producing 50% inhibition of tumour growth (ED 50 ) decreased with increasing levels of VEGF (r ¼ À0.94); and, in contrast, the ED 50 increased with the increased expression of VEGFR2 (r ¼ 0.82). These results are consistent with the observed inverse correlation between VEGF and VEGFR2 expression in tumours. These findings support the hypothesis that VEGF and VEGFR2 expression by tumours may predict the therapeutic outcome of VEGFR kinase inhibitors.

Immunohistochemical analysis of tumor angiogenic factors in human pituitary adenomas

“…Currently, multiple strategies to inhibit the VEGF pathway, and specifically those directed to the receptors of VEGF Flk1/ KDR, are under clinical development. In in vitro and in vivo models, they show antitumoral and anti-angiogenic activity [34,35]. These novel therapies would benefit especially those patients whose adenomas were incompletely resected and may progress.…”

Vascular Endothelial Growth Factor–Mediated Decrease in Plasma Soluble Vascular Endothelial Growth Factor Receptor-2 Levels as a Surrogate Biomarker for Tumor Growth

“…This had the advantage of allowing for the distinction between human (tumorderived) plasma VEGF and mouse (host-derived) sVEGFR-2 using ELISAs specific for the human and mouse proteins. Cells from human prostate line PC3, previously shown to have a low level of VEGF expression compared with other tumor cell types (39), were transfected to overexpress human VEGF 165 and clones expressing various levels of human VEGF 165 were isolated. Two distinct cell lines were derived, one with elevated VEGF expression, named ''PC3 VEGF-high '', and one with low levels of VEGF, named ''PC3 VEGF-low '', Parental and transfected variants were incubated for 24 h in vitro in serum-free medium and conditioned medium and then tested for VEGF; PC3 VEGF-high cells expressed >1,500-fold VEGF-low variants expressed levels of VEGF below the detectable range of the ELISA kit (Fig.…”

The therapeutic potential of a series of orally bioavailable anti-angiogenic microtubule disruptors as therapy for hormone-independent prostate and breast cancers

“…In this study, bevacizumab had no significant effect on tumour growth. The role of VEGF in sustaining the growth of PC-3 xenografts is difficult to ascertain as Takei et al (2004) showed siRNA against VEGF could reduce xenograft growth, but Dev et al (2004) showed that PC-3 cells expressed little VEGF and were not sensitive to a VEGFR2 inhibitor. The poor efficacy of 2-MeOE2 in vivo was further highlighted by its lack of activity in the PC-3 model, despite daily dosing at 100 mg kg À1 p.o.…”