Expression and prognostic value of VEGFR-2, PDGFR-β, and c-Met in advanced hepatocellular carcinoma

Chu, Jie Sheng; Ge, Fei; Zhang, Bo; Wang, Yan; Silvestris, Nicola; Liu, Lie Jun; Zhao, Chuanqi; Li, Lin; Brunetti, Anna Elisabetta; Fu, Ya Li; Wang, Jun; Paradiso, Angelo; Xu, Jian

doi:10.1186/1756-9966-32-16

Cited by 88 publications

(68 citation statements)

References 21 publications

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“…The HGF-MET cascade is associated with hepatocarcinogenesis (19). Elevated HGF levels have been associated with poor prognosis in patients with hepatocellular carcinoma (15), and high expression of c-MET has been associated with poor outcomes in patients with hepatocellular carcinoma treated with sorafenib (20). The current clinical results, showing that elevated HGF levels at baseline were associated with significantly shorter OS in patients with advanced hepatocellular carcinoma, are consistent with these earlier findings.…”

Section: Discussionsupporting

confidence: 81%

Biomarker Analyses of Clinical Outcomes in Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib with or without Erlotinib in the SEARCH Trial

Zhu

Kang

Rosmorduc

et al. 2016

Clinical Cancer Research

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Purpose: Sorafenib is the current standard therapy for advanced hepatocellular carcinoma, but validated biomarkers predicting clinical outcomes are lacking. This study aimed to identify biomarkers predicting prognosis and/or response to sorafenib, with or without erlotinib, in hepatocellular carcinoma patients from the phase III SEARCH trial.Experimental Design: A total of 720 patients were randomized to receive oral sorafenib 400 mg twice daily plus erlotinib 150 mg once daily or placebo. Fifteen growth factors relevant to the treatment regimen and/or to hepatocellular carcinoma were measured in baseline plasma samples.Results: Baseline plasma biomarkers were measured in 494 (69%) patients (sorafenib plus erlotinib, n ¼ 243; sorafenib plus placebo, n ¼ 251). Treatment arm-independent analyses showed that elevated hepatocyte growth factor [HGF; HR, 1.687 (high vs. low expression); endpoint multiplicity adjusted (e-adj) P ¼ 0.0001] and elevated plasma VEGFA (HR, 1.386; e-adj P ¼ 0.0377) were significantly associated with poor overall survival (OS) in multivariate analyses, and low plasma KIT [HR, 0.75 (high vs. low); P ¼ 0.0233; e-adj P ¼ 0.2793] tended to correlate with poorer OS. High plasma VEGFC independently correlated with longer TTP (HR, 0.633; e-adj P ¼ 0.0010) and trended toward associating with improved disease control rate (univariate: OR, 2.047; P ¼ 0.030; e-adj P ¼ 0.420). In 67% of evaluable patients (339/494), a multimarker signature of HGF, VEGFA, KIT, EPGN, and VEGFC correlated with improved median OS in multivariate analysis (HR, 0.150; P < 0.00001). No biomarker predicted efficacy from erlotinib.Conclusions: Baseline plasma HGF, VEGFA, KIT, and VEGFC correlated with clinical outcomes in hepatocellular carcinoma patients treated with sorafenib with or without erlotinib. These biomarkers plus EPGN constituted a multimarker signature for improved OS.

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Section: Discussionsupporting

confidence: 81%

Biomarker Analyses of Clinical Outcomes in Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib with or without Erlotinib in the SEARCH Trial

Zhu

Kang

Rosmorduc

et al. 2016

Clinical Cancer Research

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“…Many studies have reported on the association between alterations in MET and poor prognosis and/or disease severity in human cancers (25)(26)(27)(28). These findings support the hypothesis that specific alterations in MET may provide predictive capacity for identifying patients most likely to benefit from MET inhibitor therapy.…”

Section: Discussionsupporting

confidence: 76%

“…In addition, the HGF/MET signaling pathway has been shown to be activated during the genesis and progression of hepatocellular carcinoma. Many reports have highlighted the prevalence of MET gene and protein expression in hepatocellular carcinoma, and have investigated the role of MET signaling in hepatocellular carcinoma progression and maintenance (24)(25)(26)(27)(28). The importance of MET signaling in these processes suggests that the status of MET gene amplification and/or protein expression in patients with hepatocellular carcinoma may serve as potential biomarkers for prognosis or response to anti-HGF/MET therapy.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Evaluation of AMG 337, a Highly Selective Small Molecule MET Inhibitor, in Hepatocellular Carcinoma

Du¹,

Caenepeel

Shen³

et al. 2016

Molecular Cancer Therapeutics

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Aberrant hepatocyte growth factor (HGF)/MET signaling has been implicated in hepatocarcinogenesis, suggesting that MET may serve as an attractive therapeutic target in hepatocellular carcinoma. We sought to investigate the in vitro and in vivo antitumor activity of AMG 337, a potent and highly selective small molecule MET kinase inhibitor, in preclinical models of hepatocellular carcinoma. The antiproliferative activity of AMG 337 was evaluated across a panel of hepatocellular carcinoma cell lines in a viability assay. Daily oral administration was used to evaluate the in vivo antitumor activity of AMG 337 in two patientderived xenograft (PDX) models of hepatocellular carcinoma (LI0612 and LI1078). AMG 337 exerted potent antiproliferative activity against 2 of 40 hepatocellular carcinoma cell lines, namely, MHCC97H (IC 50 , 0.015 mmol/L) and HCCLM3 (IC 50 , 0.025 mmol/L). Both sensitive cell lines showed MET amplification (MET/CEN-7 >2.0) assessed by FISH, and high MET expression (3þ IHC) assessed by IHC. AMG 337 potently inhibited p-MET in all cell lines with detectable levels of total MET. However, the dose-dependent inhibition of downstream effectors of HGF/MET signaling, including p-GAB1, p-AKT, and p-ERK, was limited to those cell lines sensitive to AMG 337 in a viability assay (MHCC97H and HCCLM3). AMG 337 significantly inhibited tumor growth at all doses tested in the MET-amplified and MET-high-expressing hepatocellular carcinoma PDX model LI0612 and had no effect on tumor growth in the non-METamplified and MET-low-expressing hepatocellular carcinoma PDX model LI1078. AMG 337 represents a promising and novel therapeutic strategy for targeting hepatocellular carcinomas with a dependence on HGF/MET signaling.

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“…The hepatocyte growth factor (HGF)-MET axis has been implicated as a key player in hepatocarcinogenesis based on preclinical work and as such is another logical target for HCC drug development [61][62][63][64][65][66][67]. MET overexpression occurs in 20 to 81 % of human HCC tumors, with variation based on the method of assessment [68][69][70][71][72][73]. High-level MET expression has been linked with more aggressive clinicopathologic parameters in several studies.…”

Section: Second-line Systemic Therapy-anti-angiogenesis and Beyondmentioning

confidence: 99%

Advanced Hepatocellular Cancer: the Current State of Future Research

Connell

Harding

Abou‐Alfa

2016

Curr. Treat. Options in Oncol.

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Hepatocellular carcinoma is a common malignancy worldwide, rapidly rising in incidence. While there have been some developments in advancing therapeutic options in this disease, these have admittedly been modest to date, and as a result, this is a patient population with an inherently poor prognosis. Currently, sorafenib remains the only established systemic therapy proven to increase the overall survival of patients with advanced disease. The approval of sorafenib in 2007 ushered in the era of targeted therapies. Several phase 2 and 3 clinical trials have failed however to improve on sorafenib in the first-line setting, and no single agent has been demonstrated to impact outcomes after sorafenib failure. Having reached somewhat of an impasse in terms of drug development in hepatocellular carcinoma, enthusiasm in the field has moved toward innovative approaches such as molecular characterization and immunotherapy in an attempt to impact survival. This review highlights the current endeavors in terms of experimental research for patients with advanced hepatocellular carcinoma.

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Expression and prognostic value of VEGFR-2, PDGFR-β, and c-Met in advanced hepatocellular carcinoma

Cited by 88 publications

References 21 publications

Biomarker Analyses of Clinical Outcomes in Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib with or without Erlotinib in the SEARCH Trial

Biomarker Analyses of Clinical Outcomes in Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib with or without Erlotinib in the SEARCH Trial

Preclinical Evaluation of AMG 337, a Highly Selective Small Molecule MET Inhibitor, in Hepatocellular Carcinoma

Advanced Hepatocellular Cancer: the Current State of Future Research

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