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

Abstract

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 mmol/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 (IC 50 values: 2-5 mmol/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

Chemotherapy and target therapy for hepatocellular carcinoma: New advances and challenges

“…BIBF 1120 clearly inhibited tumor growth and angiogenesis in a xenograft model and exhibited relatively mild effects on HCC cell lines in vivo [73][74][75] . Results from a phase Ⅲ study in patients with advanced recurrent non-small cell lung cancer who had failed with first-line chemotherapy showed that nintedanib notably benefited patients with adenocarcinoma in median PFS and OS, including those with a poor prognosis (NCT00805194) [76] .…”

Targeting Fibroblast Growth Factor Receptor Signaling in Hepatocellular Carcinoma

“…Treatment of HCC cell lines with intedanib reduced cell growth in vitro and dramatically decreased VEGFR signaling, tumor growth and angiogenesis in a xenograft mouse model of HCC [41]. Intedanib is currently being evaluated in preclinical studies with samples from patients with HCC.…”

Evaluating the role of treatment-related toxicities in the challenges facing targeted therapies for advanced hepatocellular carcinoma

“…This monitoring could enable reduction in the planned doses of targeted drugs, resulting in fewer AEs, less dose modifications and discontinuations, and, thus, more of a chance for the drug to exert a positive effect against the tumors. For example, VEGFR phosphorylation has been identified as a pharmacodynamic biomarker for nintedanib in preclinical studies [84].…”