Antitumor Activity of BIBF 1120, a Triple Angiokinase Inhibitor, and Use of VEGFR2(+)pTyr(+) Peripheral Blood Leukocytes as a Pharmacodynamic Biomarker In Vivo

作者：Kudo Kanae; Arao Tokuzo; Tanaka Kaoru; Nagai Tomoyuki; Furuta Kazuyuki; Sakai Kazuko; Kaneda Hiroyasu; Matsumoto Kazuko; Tamura Daisuke; Aomatsu Keiichi; De Velasco Marco A; Fujita Yoshihiko; Saijo Nagahiro; Kudo Masatoshi; Nishio Kazuto^*

来源：Clinical Cancer Research, 2011, 17(6): 1373-1381.

DOI：10.1158/1078-0432.CCR-09-2755

Purpose: BIBF 1120 is a potent, orally available triple angiokinase inhibitor that inhibits VEGF receptors (VEGFR) 1, 2, and 3, fibroblast growth factor receptors, and platelet-derived growth factor receptors. This study examined the antitumor effects of BIBF 1120 on hepatocellular carcinoma (HCC) and attempted to identify a pharmacodynamic biomarker for use in early clinical trials.
Experimental Design: We evaluated the antitumor and antiangiogenic effects of BIBF 1120 against HCC cell line both in vitro and in vivo. For the pharmacodynamic study, the phosphorylation levels of VEGFR2 in VEGF-stimulated peripheral blood leukocytes (PBL) were evaluated in mice inoculated with HCC cells and treated with BIBF 1120.
Results: BIBF 1120 (0.01 mu mol/L) clearly inhibited the VEGFR2 signaling in vitro. The direct growth inhibitory effects of BIBF 1120 on four HCC cell lines were relatively mild in vitro (IC50 values: 2-5 mu mol/L); however, the oral administration of BIBF 1120 (50 or 100 mg/kg/d) significantly inhibited the tumor growth and angiogenesis in a HepG2 xenograft model. A flow cytometric analysis revealed that BIBF 1120 significantly decreased the phosphotyrosine (pTyr) levels of VEGFR2(+)CD45(dim) PBLs and the percentage of VEGFR2(+)pTyr(+) PBLs in vivo; the latter parameter seemed to be a more feasible pharmacodynamic biomarker.
Conclusions: We found that BIBF 1120 exhibited potent antitumor and antiangiogenic activity against HCC and identified VEGFR2(+)pTyr(+) PBLs as a feasible and noninvasive pharmacodynamic biomarker in vivo. Clin Cancer Res; 17(6); 1373-81.

• 出版日期2011-3-15