EGFR and VEGFR as potential target for biological therapies in HCC cells

Giannelli, Gianluigi; Sgarra, Concetta; Porcelli, Letizia; Azzariti, Amalia; Antonaci, Salvatore; Paradiso, Angelo

doi:10.1016/j.canlet.2007.12.001

Cited by 46 publications

(36 citation statements)

References 21 publications

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“…This finding is in agreement with previous studies. 31 Expression of phosphorylated Akt at Ser-473 in breast tumors is significantly associated with HER-2, ER and proliferating index Ki-67, 32 and in patients prone to relapse with distant metastases. 33 Inhibition of Akt phosphorylation by a novel Akt inhibitor KP-372-1 successfully suppressed cellular growth and induced apoptosis in thyroid cancer cells.…”

Section: Discussionmentioning

confidence: 99%

ZD6474, a dual tyrosine kinase inhibitor of EGFR and VEGFR-2, inhibits MAPK/ERK and AKT/PI3-K and induces apoptosis in breast cancer cells

Sarkar

Mazumdar²,

Dash

et al. 2010

Cancer Biology & Therapy

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Abnormalities in gene expression and signaling pathways downstream of the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) contribute to the progression, invasion, and maintenance of the malignant phenotype in human cancers, including breast. Consequently, the dual kinase inhibitor of EGFR and VEGFR ZD6474 represents a promising biologically-based treatment that is currently undergoing clinical trials for non-small cell lung cancer. Patients suffering from breast cancers have a poor prognosis because of the lack of effective agents and treatment strategies. We hypothesized that inhibition of phosphorylation of the EGFR and VEGFR by ZD6474 would inhibit breast cancer cell proliferation and induce apoptosis. This hypothesis was tested using human breast cancer cell lines. ZD6474 inhibited cell proliferation in a dose-dependent manner, by blocking cell progression at the G(0)-G(1) stage, through downregulation of expression of cyclin D1 and cyclin E. In vitro, ZD6474 inhibited growth factor-induced phosphorylation of EGFR, VEGFR-2, MAPK and Akt. ZD6474 also downregulated anti-apoptotic markers including Bcl-2, upregulated pro-apoptotic signaling events involving expression of bax, activation of caspase-3, and induction of poly (ADP-ribose) polymerase during apoptosis. ZD6474 inhibited anchorage independent colony formation using soft agar assays, and invasion of breast cancer cells in vitro using Boyden chamber assays. In a xenograft model using human MDA-MB-231 breast cancer cells, ZD6474 inhibited tumor growth and induced cancer-specific apoptosis. Collectively, these data imply that ZD6474 a dual kinase inhibitor has potential for the targeted therapy of breast cancer.

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Section: Discussionmentioning

confidence: 99%

ZD6474, a dual tyrosine kinase inhibitor of EGFR and VEGFR-2, inhibits MAPK/ERK and AKT/PI3-K and induces apoptosis in breast cancer cells

Sarkar

Mazumdar²,

Dash

et al. 2010

Cancer Biology & Therapy

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“…PARP inhibition was found to produce a considerable reduction in mRNA levels of EGFR, MDM2, ANGPT2 (ANG‐2), HGF, and MYC . These genes have been reported to contribute to hepatocarcinogenesis by stimulating mitogenesis, survival, the invasiveness of HCC, etc., and have been proposed as a potential target for biological therapies aimed at HCC cells 21–23. Of particular interest is the reduction in the induction of EPAS1 (HIF2A), FLT1 (VEGFR1), SPP1 (OPN) , and ENG (END) as well as of genes that are regulated by HIF‐1α; for example, EGLN1/PHD2, ANXA3, and ADORA3 after treatment with DPQ.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of poly adenosine diphosphate-ribose polymerase decreases hepatocellular carcinoma growth by modulation of tumor-related gene expression

et al. 2009

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H epatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third most common cause of death from cancer in the world, accounting for an estimated 500,000 deaths annually. 1 The prognosis of HCC patients is generally very poor. Most studies have shown a 5-year survival rate of less than 5% in symptomatic patients. Because current therapies are rarely able to achieve complete tumor abla-

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“…Notably, VEGF and EGF pathways share common downstream signals, and several preclinical studies have shown indications of either direct or indirect pro-angiogenic effects of EGF receptor (EGFR) signaling [8,9,10]. Furthermore, upregulation of VEGF has been implicated in poor prognosis, high recurrence rate, and resistance to EGFR inhibition [10]. …”

Section: Introductionmentioning

confidence: 99%

“…Recently, a growing number of novel agents with activity against different growth factors, such as VEGF, platelet-derived growth factor (PDGF), and epidermal growth factor (EGF), have shown clinical activity in HCC [4,5,6,7]. Notably, VEGF and EGF pathways share common downstream signals, and several preclinical studies have shown indications of either direct or indirect pro-angiogenic effects of EGF receptor (EGFR) signaling [8,9,10]. Furthermore, upregulation of VEGF has been implicated in poor prognosis, high recurrence rate, and resistance to EGFR inhibition [10].…”

Section: Introductionmentioning

confidence: 99%

Efficacy of Bevacizumab plus Erlotinib for Advanced Hepatocellular Carcinoma and Predictors of Outcome: Final Results of a Phase II Trial

et al. 2012

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Objective: A phase II study was performed to evaluate the efficacy and tolerability of bevacizumab and erlotinib in advanced hepatocellular carcinoma (HCC) patients, and to investigate clinical and molecular predictors of outcome. Methods: 59 patients with advanced HCC received 10 mg/kg i.v. of bevacizumab every 14 days and 150 mg p.o. of erlotinib daily. The primary endpoint was progression-free survival (PFS) at 16 weeks. Clinical characteristics and plasma biomarkers expression levels were analyzed. Results: PFS at 16 weeks was 64% (95% CI 51–76): 14 patients achieved partial response (24%), 33 had stable disease (56%), 6 progressed (10%), and 6 were not evaluable (10%). Median overall survival was 13.7 months (95% CI 9.6–19.7), and median PFS was 7.2 months (95% CI 5.6–8.3). Grade 3–4 adverse events included fatigue (30%), diarrhea (17%), hypertension (14%), elevated transaminases (12%), and gastrointestinal hemorrhage (10%). High plasma angiopoietin-2, epidermal growth factor receptor, and endothelin-1, and lack of acneiform rash were associated with poor outcome. Conclusions: The combination of bevacizumab with erlotinib achieved encouraging results in patients with advanced HCC. Current correlatives may help to guide future HCC studies.

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EGFR and VEGFR as potential target for biological therapies in HCC cells

Cited by 46 publications

References 21 publications

ZD6474, a dual tyrosine kinase inhibitor of EGFR and VEGFR-2, inhibits MAPK/ERK and AKT/PI3-K and induces apoptosis in breast cancer cells

ZD6474, a dual tyrosine kinase inhibitor of EGFR and VEGFR-2, inhibits MAPK/ERK and AKT/PI3-K and induces apoptosis in breast cancer cells

Inhibition of poly adenosine diphosphate-ribose polymerase decreases hepatocellular carcinoma growth by modulation of tumor-related gene expression

Efficacy of Bevacizumab plus Erlotinib for Advanced Hepatocellular Carcinoma and Predictors of Outcome: Final Results of a Phase II Trial

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