AG-013736, a novel inhibitor of VEGF receptor tyrosine kinases, inhibits breast cancer growth and decreases vascular permeability as detected by dynamic contrast-enhanced magnetic resonance imaging Lisa J. Wilmes a, * , Maria G. Pallavicini b , Lisa M. Fleming a , Jessica Gibbs a , Donghui Wang c , Ka-Loh Li a , Savannah C. Partridge d , Roland G. Henry a , David R. Shalinsky e , Dana Hu-Lowe e , John W. Park b , Teresa M. McShane f , Ying Lu a , Robert C. Brasch a , Nola M. Hylton a a Department of Radiology, University of California San Francisco, San Francisco, CA 94143-1290, USA b School of Natural Sciences, University of California Merced, Merced, CA 95344, USA c Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143-1710, USA d Department of Radiology, University of Washington, Seattle, WA 98109-1023, USA e Research Pharmacology, Pfizer Global Research and Development, San Diego, CA 92121, USA f Pfizer Oncology, Pfizer Global Pharmaceuticals, Mystic, CT 06355, USA Received 28 February 2006; accepted 19 September 2006 Abstract Dynamic contrast-enhanced MRI (DCE-MRI) was used to noninvasively evaluate the effects of AG- 03736, a novel inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, on tumor microvasculature in a breast cancer model. First, a dose response study was undertaken to determine the responsiveness of the BT474 human breast cancer xenograft to AG-013736. Then, DCE-MRI was used to study the effects of a 7-day treatment regimen on tumor growth and microvasculature. Two DCE-MRI protocols were evaluated: (1) a high molecular weight (MW) contrast agent (albumin-(GdDTPA) 30 ) with pharmacokinetic analysis of the contrast uptake curve and (2) a low MW contrast agent (GdDTPA) with a clinically utilized empirical parametric analysis of the contrast uptake curve, the signal enhancement ratio (SER). AG-013736 significantly inhibited growth of breast tumors in vivo at all doses studied (10–100 mg/kg) and disrupted tumor microvasculature as assessed by DCE-MRI. Tumor endothelial transfer constant (K ps ) measured with albumin-(GdDTPA) 30 decreased from 0.034F0.005 to 0.003F0.001 ml min 1 100 ml 1 tissue ( P b.0022) posttreatment. No treatment-related change in tumor fractional plasma volume (fPV) was detected. Similarly, in the group of mice studied with GdDTPA DCE-MRI, AG-013736-induced decreases in tumor SER measures were observed. Additionally, our data suggest that 3D MRI-based volume measurements are more sensitive than caliper measurements for detecting small changes in tumor volume. Histological staining revealed decreases in tumor cellularity and microvessel density with treatment. These data demonstrate that both high and low MW DCE-MRI protocols can detect AG-013736-induced changes in tumor microvasculature. Furthermore, the correlative relationship between microvasculature changes and tumor growth inhibition supports DCE-MRI methods as a biomarker of VEGF receptor target inhibition with potential clinical utility. D 2007 Elsevier Inc. All rights reserved. Keywords: Dynamic contrast-enhanced MRI (DCE-MRI); Vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor; Anti-angiogenic; Breast cancer 1. Introduction Growth factor receptor tyrosine kinases are promising targets for cancer therapy [1,2]. Vascular endothelial growth factor (VEGF), a member of the VEGF-platelet-derived growth factor (PDGF) supergene family, and its signaling pathways have been implicated in vasculogenesis, angio- genesis and vascular permeability [3,4]. VEGF plays an important role in tumor blood vessel formation, which in turn supports tumor growth and metastases [5,6]. The VEGF signaling pathway is activated by ligand-induced phosphor- ylation of the VEGF receptors (VEGFRs). The blocking of VEGFR phosphorylation by a kinase inhibitor is expected to 0730-725X/$ – see front matter D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.mri.2006.09.041 4 Corresponding author. Tel.: +1 415 476 1950; fax: +1 415 476 8809. E-mail address: lisa@mrsc.ucsf.edu (L.J. Wilmes). Magnetic Resonance Imaging 25 (2007) 319 – 327