Antiangiogenic Therapies for Advanced Hepatocellular Carcinoma

Sampat, Keeran; O’Neil, Bert H.

doi:10.1634/theoncologist.2012-0388

Cited by 48 publications

(33 citation statements)

References 56 publications

(58 reference statements)

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“…Despite improvements in diagnostic and therapeutic strategies, the prognosis of HCC still remains poor (2)(3)(4). Inhibiting angiogenesis has been used as a strategy in the treatment of HCC (5,6). For example, sorafenib, a VEGF receptor (VEGFR) inhibitor with activity against platelet-derived growth factor receptor (PDGFR), c-Kit receptor, RAF and p38 signal transduction pathways, has become a standard treatment in patients with advanced HCC (7).…”

Section: Introductionmentioning

confidence: 99%

Cabozantinib Suppresses Tumor Growth and Metastasis in Hepatocellular Carcinoma by a Dual Blockade of VEGFR2 and MET

Xiang

Chen

Ren

et al. 2014

Clinical Cancer Research

199

159

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Purpose: MET signaling has been suggested a potential role in hepatocellular carcinoma (HCC) and associated with prometastasis during antiangiogenesis therapy. We investigated the potential association between MET expression and therapeutic response to sorafenib in patients with HCC. Antitumor effects of cabozantinib, a dual inhibitor of MET and VEGFR2, were examined in cultured HCC cells as well as in vivo models.Experimental Design: Total MET and phosphorylated MET (p-MET) were measured in 29 resected HCC specimens, and correlated with response to sorafenib as postoperative adjuvant therapy. In the second set of experiments using cultured HCC cells, and mouse xenograft and metastatic models, effects of cabozantinib were examined.Results: High level of p-MET in resected HCC specimens was associated with resistance to adjuvant sorafenib therapy. In cultured HCC cells that expressed p-MET, cabozantinib inhibited the activity of MET and its downstream effectors, leading to G 1 -phase arrest. Cabozantinib inhibited tumor growth in p-METpositive and p-MET-negative HCC by decreasing angiogenesis, inhibiting proliferation, and promoting apoptosis, but it exhibited more profound efficacy in p-MET-positive HCC xenografts. Cabozantinib blocked the hepatocyte growth factor (HGF)-stimulated MET pathway and inhibited the migration and invasion of the HCC cells. Notably, cabozantinib reduced the number of metastatic lesions in the lung and liver in the experimental metastatic mouse model.Conclusions: Patients with HCC with high level of p-MET are associated with resistance to adjuvant sorafenib treatment. The dual blockade of VEGFR2 and MET by cabozantinib has significant antitumor activities in HCC, and the activation of MET in HCC may be a promising efficacy-predicting biomarker.

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Section: Introductionmentioning

confidence: 99%

Cabozantinib Suppresses Tumor Growth and Metastasis in Hepatocellular Carcinoma by a Dual Blockade of VEGFR2 and MET

Xiang

Chen

Ren

et al. 2014

Clinical Cancer Research

199

159

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show abstract

“…Drugs inhibiting VEGF biological actions are being used to treat different types of cancer, including hepatocellular carcinoma. 12 This approach has also been proposed to treat portal hypertension and attenuate liver fibrosis. 13 There are no available drugs to stimulate VEGF actions in humans, which could theoretically be beneficial in promoting hepatic fibrosis resolution.…”

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confidence: 99%

Identifying Molecular Factors That Contribute to Resolution of Liver Fibrosis

Iredale

Bataller

2014

Gastroenterology

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“…ZNF281 has been identified to be involved in epithelial-mesenchymal transition and cancer (33). Previous studies have demonstrated that VEGF has various effects on several types of cancer, including the promotion angiogenesis, invasion and migration (34,35). Presently, to the best of our knowledge, there are no data that associate cancer with BIVM, NPAS4 or MKLN1.…”

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confidence: 99%

Dysregulation of miR-638 in hepatocellular carcinoma and its clinical significance

et al. 2017

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Abstract. MicroRNAs (miRNAs/miRs) have been identified as important post-transcriptional regulators in healthy liver physiology and liver diseases. However, the clinical significance of miR-638 in hepatocellular carcinoma (HCC) remains unclear. The aim of the present study was to investigate the status of miR-638 expression in HCC and to determine its clinical significance. The expression of miR-638 was evaluated in 60 HCC tissues samples and HCC SMMC-7721, HepG2 and Hep3B cell lines using reverse transcription-quantitative polymerase chain reaction. The association between the expression of miR-638 and the clinicopathological characteristics of patients with HCC was analyzed. The proportion of HCC patients with low miR-638 expression was identified as 68.3% (41/60). Furthermore, significantly lower miR-638 expression was identified in HCC tissue samples compared with the healthy control group (P=0.031). miR-638 expression was significantly lower in SMMC-7721 (P=0.021), HepG2 (P=0.005) and Hep3B (P=0.003) cells compared with the healthy human hepatic HL-7702 cell line. In addition, miR-638 expression was correlated with α-fetoprotein levels (P=0.042) and portal vein invasion (P=0.025). The area under curve was identified as 0.71 (95% confidence interval= 0.63-0.79; P=0.001). The cut-off value for miR-638 was the median 2 -Δ∆Cq =0.125. In conclusion, miR-638 may be involved in the progression of HCC and act as a potential biomarker for the prediction of HCC.

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Antiangiogenic Therapies for Advanced Hepatocellular Carcinoma

Cited by 48 publications

References 56 publications

Cabozantinib Suppresses Tumor Growth and Metastasis in Hepatocellular Carcinoma by a Dual Blockade of VEGFR2 and MET

Cabozantinib Suppresses Tumor Growth and Metastasis in Hepatocellular Carcinoma by a Dual Blockade of VEGFR2 and MET

Identifying Molecular Factors That Contribute to Resolution of Liver Fibrosis

Dysregulation of miR-638 in hepatocellular carcinoma and its clinical significance

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