Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatocellular carcinoma (HCC) is a highly malignant cancer with poor prognosis. Inhibitors of EGFR and VEGFR for HCC treatment are currently under investigation. Gefitinib and vandetanib inhibit migration of HCC cells on Laminin-5 and Fibronectin, and invasion through matrigel. Both drugs inhibit p-EGFR after short time, while their efficacy on p-Erk1/2 and p-Akt is progressive and stable over time. PI3K/Akt and MEK/Erk1/2 inhibitors, inhibit migration and invasion as well as inducing de-phosphorylation of downstream effectors. Finally, both inhibitors, vandetanib and gefitinib down-regulated the secretion of matrix metalloproteases MMP-2 and MMP-9. All these biological effects seem to depend on the activity of gefitinib and vandetanib blocking activity towards p-EGFR mediated pathways.
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PMID:EGFR and VEGFR as potential target for biological therapies in HCC cells. 1824 88

Sorafenib (BAY 43-9006) is a novel oral bis-aryl urea compound originally developed as an inhibitor to RAF kinase for its anti-proliferative property. It also inhibits receptor tyrosine kinases of multiple pro-angiogenic factors such as VEGFR-2/3, Flt-3/ and PDGFR-beta. The combination of both its anti-proliferative and anti-angiogenic properties makes sorafenib an attractive agent in cancer treatment. Phase I studies demonstrated that sorafenib was well tolerated, and the recommended phase II dose was 400 mg twice daily continuously. Common toxicities included skin toxicity (rash and hand-foot syndrome), gastrointestinal toxicities (nausea and diarrhea) and fatigue. Anti-tumor activities were observed in multiple tumors types including renal cell carcinoma and hepatocellular carcinoma. Randomized phase III studies in these tumor types are ongoing, and results are eagerly waited.
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PMID:Sorafenib (BAY 43-9006): review of clinical development. 1866 47

Hepatocellular carcinoma (HCC) is the fifth most frequent malignant tumour and the third leading cause of death due to cancer worldwide [1]. Surgical treatment is the only long-term curative therapy. But the resection rate remains low in cirrhotic patients due to contraindications imposed mainly by hepatic insufficiency and excessively advanced tumoral stages. In recent years, however, due to the extended use of screening programmes in high-risk patients, tumours are smaller at presentation, making treatments easier. In the current context of shortage of organs for transplantation, surgical resection remains the best available treatment option for most patients with HCC in cirrhotic livers. Despite the encouraging results reported by several groups in terms of overall survival, the high recurrence rate is still an unsolved problem. Recently, a large, randomised, placebo-controlled trial has shown that a multikinase inhibitor targeting Ras-kinase and VEGFR-2, sorafenib, improves survival of patients with advanced HCC. Sorafenib was approved by regulatory agencies during 2007 and is likely to become the new standard therapy for HCC patients with advanced disease.
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PMID:Surgical treatment for hepatocellular carcinoma in cirrhotic patients. Guide to the selection and decision-making process in a context of multimodal strategy. 1915

Sorafenib (Nexavar) is a targeted therapy acting as VEGFR and PDGFR tyrosine-kinase inhibitor that has been approved in France in the treatment of metastatic renal cell carcinoma and hepatocarcinoma. Hand-foot syndrome is one of the more frequent toxicity related to sorafenib. This paper up lights the main points concerning this toxicity in the view of specialists working together in the care of these patients: a pharmacologist, a dermatologist and a medical oncologist. The clinic and symptoms of hand-foot syndrome as the biological interpretation, the symptomatic treatment and the impact on the specific treatment of sorafenib are developed.
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PMID:[Hand-foot syndrome and sorafenib]. 1925 26

Hepatocellular carcinoma (HCC) is one of the 5th most common cancers around the world with a limited number of systemic therapeutic options. Cytotoxic agents, hormonotherapy and immunotherapy have failed to demonstrate benefit compared to best supportive care in patients with advanced HCC. The recent development of targeted therapies provided hope for the treatment of advanced HCC. We reviewed phases II-III trials presented in 2007 and 2008. Results are promising with a clinical benefit reported with molecular therapies targeting EGF/EGFR and VEGF/VEGFR pathways.
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PMID:[Targeted therapies in hepatocellular carcinomas: recent results and future development]. 1946 86

The receptor tyrosine kinase vascular endothelial growth factor (VEGF) receptor (VEGFR) plays an important role in tumor angiogenesis of hepatocellular carcinoma (HCC). (-)-Epigallocatechin gallate (EGCG), the major biologically active component of green tea, inhibits growth in a variety of human cancer cells by inhibiting the activation of several types of receptor tyrosine kinases. In this study, we examined the effects of EGCG on the activity of the VEGF-VEGFR axis in human HCC cells. The levels of total and phosphorylated (i.e. activated) form of VEGFR-2 protein (p-VEGFR-2) were observed to increase in a series of human HCC cell lines in comparison to the Hc normal human hepatocytes. EGCG preferentially inhibited the growth of HuH7 HCC cells, which express constitutive activation of the VEGF-VEGFR axis, in comparison to Hc cells. Treatment of HuH7 cells with EGCG caused a time- and dose-dependent decrease in the expression of VEGFR-2 and p-VEGFR-2 proteins. The production of VEGF from HuH7 cells was reduced by treatment with EGCG. Drinking of EGCG significantly inhibited the growth of HuH7 xenografts in nude mice and this was associated with inhibition of the activation of VEGFR-2 and its related downstream signaling molecules, including ERK and Akt. EGCG drinking also decreased the expression of Bcl-x(L) protein and VEGF mRNA in the xenografts. These findings suggest that EGCG can exert, at least in part, its growth-inhibitive effect on HCC cells by inhibiting the VEGF-VEGFR axis. EGCG might therefore be useful in the treatment of HCC.
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PMID:(-)-Epigallocatechin gallate suppresses the growth of human hepatocellular carcinoma cells by inhibiting activation of the vascular endothelial growth factor-vascular endothelial growth factor receptor axis. 1955 47

Raf kinases and vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) tyrosine kinases are potential molecular targets for obtaining both anti-tumor cell progression and anti-angiogenesis effects in cancers, including hepatocellular carcinoma (HCC). Sorafenib is an oral multi-kinase inhibitor that mainly targets Raf kinases and receptor tyrosine kinases associated with angiogenesis (VEGFR-2/-3, PDGFR-beta). A global randomized controlled trial (RCT) of sorafenib versus placebo conducted in patients with advanced HCC demonstrated the beneficial effects of the drug on the time-to-progression and overall survival. Furthermore, a RCT with a similar design to that of the global trial conducted in the Asia-Pacific region also demonstrated the efficacy of the drug. The most common treatment-related adverse events of sorafenib were found to be diarrhea, fatigue, and skin toxicity, namely, hand-foot syndromes and rash. Based on the results of the RCTs, sorafenib has been established as a standard agent for systemic chemotherapy in HCC patients with metastatic disease or transcatheter arterial chemoembolization (TACE)-refractory disease who are not suitable candidates for local treatments. The efficacy and safety of sorafenib in patients with moderate liver dysfunction have not been confirmed to date and more data are needed. Development of new therapeutic methods is needed for the treatment of advanced HCC in the future; clinical trials of sorafenib-based combination therapy, second-line therapy after sorafenib failure, and adjuvant therapy after local treatments are warranted in HCC patients.
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PMID:Sorafenib for the treatment of unresectable hepatocellular carcinoma. 1970 58

VEGFR inhibitors are in broad use for the treatment of metastatic renal-cell carcinoma, gastrointestinal stromal tumors and hepatocellular carcinoma and in development in a number of other oncology indications, including colorectal cancer, non-small-cell lung cancer, pancreatic cancer, thyroid malignancies, ovarian cancer, breast cancer and sarcomas. This Review outlines the structure-activity relationships of the 44 VEGFR inhibitors currently in development. An overview of the pharmacokinetic profile of each molecule and its stage in development is provided. Phase III clinical trials being conducted for licensing of these agents for specific indications and phase III developmental efficacy trials are described in detailed tables that include the disease studied, trial design including combination therapy, study end points, and projected or final accrual. The relative frequency of on-target and off-target adverse events observed in 3,060 patients is described for a subset of agents in development in clinical trials sponsored by the National Cancer Institute. No interagent comparisons were undertaken and no data from pharmaceutical pharmacovigilance databases were used. The on-target effects seem to be mechanistically based and predicted by VEGFR inhibition. Small-molecule inhibitors of angiogenesis are active in a wide variety of malignancies and fill a unique niche for cancer therapeutics.
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PMID:An overview of small-molecule inhibitors of VEGFR signaling. 1973 52

Hepatocellular carcinoma (HCC) is the fifth most common and third deadliest primary neoplasm. Since HCC is a particularly vascular solid tumor, we determined the antitumor and antiangiogenic activities of sunitinib malate, a potent inhibitor of two receptors involved in angiogenesis - vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). In the present study, we reported that treatment of HepG2 and SK-Hep-1 cells with sunitinib led to growth inhibition and apoptosis in a dose-dependent fashion. Sunitinib inhibited phosphorylation of VEGFR-2 at Tyr951 and PDGFR-beta at Tyr1021 both in vitro and in vivo. Sunitinib also suppressed tumor growth of five patient-derived xenografts. Sunitinib-induced tumor growth inhibition was associated with increased apoptosis, reduced microvessel density and inhibition of cell proliferation. This study provides a strong rationale for further clinical investigation of sunitinib in patients with hepatocellular carcinoma.
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PMID:Sunitinib (SUTENT, SU11248) suppresses tumor growth and induces apoptosis in xenograft models of human hepatocellular carcinoma. 1975 58

The effect of vascular endothelial growth factor (VEGF) ligands and cediranib on tumor cell proliferation, migration, and invasion was determined. It has recently been suggested that autocrine signaling through the VEGF receptor (VEGFR) pathway may play a role in tumor cell survival, invasion, and migration. The purpose of the present study was to determine the expression of VEGFRs and VEGFR ligands in a panel of gastrointestinal carcinoma cells. Additionally, we evaluated the effects of VEGF autocrine signaling on tumor cell proliferation, migration, and invasion utilizing cediranib (AZD2171), a pan-VEGFR inhibitor. Five colorectal, three pancreatic, and two hepatocellular carcinoma cell lines were screened for VEGFR and VEGF expression by several methods. Expression of VEGFR-1 and VEGFR-3 was cell line-dependent, whereas VEGFR-2 was not detected. Secretion of VEGF-A was detected in the supernatants of all cell lines whereas VEGF-C secretion was detected in the Panc-1, MiaPaca2, and Hep1 cells only. Tumor cells showed increased migratory activity, but not proliferation, when stimulated with VEGFs. The pan-VEGFR inhibitor cediranib (100 nmol/L) inhibited tumor cell migration and invasion, with no effects on proliferation. Cediranib decreased VEGFR-1 and VEGFR-3 phosphorylation as well as activation of downstream effectors. VEGFR-1 and VEGFR-3 expression was detected in all the gastrointestinal carcinoma cells evaluated. Although activation of the VEGF pathway did not affect cell proliferation, our data indicate that this pathway seems to play a role in tumor cell migration and invasion in these cell lines. Therefore, inhibition of VEGFR by cediranib may represent a clinically relevant treatment option for gastrointestinal tumors.
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PMID:Targeting vascular endothelial growth factor receptor-1 and -3 with cediranib (AZD2171): effects on migration and invasion of gastrointestinal cancer cell lines. 1975 10


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