In:
Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 8, No. 12_Supplement ( 2009-12-10), p. B4-B4
Abstract:
Angiogenesis is a critical driver of tumor growth and progression, and is controlled by a number of interconnected signaling pathways. In these pathways, the two tyrosine kinase receptors, vascular endothelial growth factor receptor (VEGFR) 2 and tyrosine kinase with immunoglobulin and EGF homology domain 2 (TIE2) play crucial roles in the neovascularization, stabilization, and maintenance of normal and tumor vasculature. Regorafenib, a novel oral multikinase inhibitor, potently inhibits both VEGFR2 and TIE2 in biochemical and cellular kinase phosphorylation assays. It inhibits additional angiogenic kinases ie VEGFR1, VEGFR3, platelet-derived growth factor receptor- , and fibroblast growth factor receptor-1 and the mutant oncogenic kinases KIT and RET, which play a role in human gastrointestinal stromal and thyroid cancers, respectively, and B-RAF. The mechanism of action of regorafenib on the tumor vasculature was demonstrated in vivo by dynamic contrast-enhanced magnetic resonance imaging using Gadomer as contrast agent. Regorafenib significantly decreased tumor perfusion and extravasation of the contrast agent in a rat GS9L glioblastoma tumor xenograft model grown i.m. in the rat leg compared to rat muscle tissue after a single oral administration of 10 mg/kg. The pharmacodynamic effects persisted for 48 hours after the last drug administration and correlated with the tumor growth inhibition in a QDx4 once daily oral dosing study. A significant reduction in tumor microvessel area was observed in a human colorectal xenograft after QDx5 daily oral dosing at 10 and 30 mg/kg of regorafenib in tumor-bearing mice. Regorafenib exhibited potent dose-dependent tumor growth inhibition in various preclinical murine xenograft models including breast (MDA-MB-231), NSCLC (NCI-H460), renal (786-O), and several colorectal (Colo-205, HCT-15, HT-29) carcinoma, some of which carry mutant K-RAS and/or B-RAF. Tumor shrinkage was observed in the breast MDA-MB-231 and the renal 786-O carcinoma models. The compound was well tolerated and no significant weight loss or lethality was observed. Immunohistochemical analyses of the breast xenograft tumor revealed a strong reduction in staining of the proliferation marker Ki-67 and of the phosphorylated extracellular regulated kinases 1 and 2. Non-clinical metabolism studies have detected two pharmacokinetically stable regorafenib metabolites, with similar but distinct kinase profiles. These data demonstrate that regorafenib is a well-tolerated, orally active multikinase inhibitor with a unique target profile that may have therapeutic benefit in human malignancies. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B4.
Type of Medium:
Online Resource
ISSN:
1535-7163
,
1538-8514
DOI:
10.1158/1535-7163.TARG-09-B4
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2009
detail.hit.zdb_id:
2062135-8
SSG:
12
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