Reference Detail

Ref Type

Journal Article

PMID

(21170960)

Authors

Wilhelm SM, Dumas J, Adnane L, Lynch M, Carter CA, Schütz G, Thierauch KH, Zopf D

Title

Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity.

Journal	Vol	Issue	Date	Pages	Journal Short Title
International journal of cancer	129	1	2011 Jul 01	245-55	Int J Cancer

URL

Abstract Text

Angiogenesis, a critical driver of tumor development, is controlled by interconnected signaling pathways. Vascular endothelial growth factor receptor (VEGFR) 2 and tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 play crucial roles in the biology of normal and tumor vasculature. Regorafenib (BAY 73-4506), a novel oral multikinase inhibitor, potently inhibits these endothelial cell kinases in biochemical and cellular kinase phosphorylation assays. Furthermore, regorafenib inhibits additional angiogenic kinases (VEGFR1/3, platelet-derived growth factor receptor-β and fibroblast growth factor receptor 1) and the mutant oncogenic kinases KIT, RET and B-RAF. The antiangiogenic effect of regorafenib was demonstrated in vivo by dynamic contrast-enhanced magnetic resonance imaging. Regorafenib administered once orally at 10 mg/kg significantly decreased the extravasation of Gadomer in the vasculature of rat GS9L glioblastoma tumor xenografts. In a daily (qd)×4 dosing study, the pharmacodynamic effects persisted for 48 hr after the last dosing and correlated with tumor growth inhibition (TGI). A significant reduction in tumor microvessel area was observed in a human colorectal xenograft after qd×5 dosing at 10 and 30 mg/kg. Regorafenib exhibited potent dose-dependent TGI in various preclinical human xenograft models in mice, with tumor shrinkages observed in breast MDA-MB-231 and renal 786-O carcinoma models. Pharmacodynamic analyses of the breast model revealed strong reduction in staining of proliferation marker Ki-67 and phosphorylated extracellular regulated kinases 1/2. These data demonstrate that regorafenib is a well-tolerated, orally active multikinase inhibitor with a distinct target profile that may have therapeutic benefit in human malignancies.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
KIT K642E	gastrointestinal stromal tumor	sensitive	Regorafenib	Preclinical - Cell culture	Actionable	In a preclinical study, Stivarga (regorafenib) inhibited proliferation of gastrointestinal stromal tumor cells harboring KIT K642E in culture (PMID: 21170960).	21170960
VHL del	renal cell carcinoma	predicted - sensitive	Regorafenib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Stivarga (regorafenib) inhibited angiogenesis and tumor growth in cell line xenograft models of renal cell carcinoma harboring VHL gene deletion (PMID: 21170960).	21170960
RET C634W	thyroid cancer	sensitive	Regorafenib	Preclinical - Cell culture	Actionable	In a preclinical study, Stivarga (regorafenib) inhibited proliferation of thyroid cancer cells harboring RET C634W in culture (PMID: 21170960).	21170960
BRAF V600E	colorectal cancer	sensitive	Regorafenib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Stivarga (regorafenib) inhibited proliferation of colorectal cancer cells harboring BRAF V600E in culture and suppressed angiogenesis and tumor growth in cell line xenograft models (PMID: 21170960).	21170960