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ABSTRACT: The epidermal growth factor receptor (EGFR) autocrine pathway plays a crucial role in human cancer since it contributes to
relevant processes in tumor development and progression, including cell proliferation, regulation of apoptotic cell death,
angiogenesis and metastatic spread. EGFR-blocking monoclonal antibodies and small-molecule EGFR tyrosine kinase inhibitors
have been developed as anticancer drugs. Although anti-EGFR agents are active in a subset of cancer patients, constitutive
resistance in a large number of patients and the development of acquired resistance in initially responding patients are a
relevant clinical issue. A major problem is that intrinsic and/or acquired resistance can occur, and it could be due to the
activation of alternative cancer cell growth controlling pathways. One mechanism linked to acquired resistance to EGFR-inhibitor
treatment, in particular, is the activation of uncontrolled, tumor-induced angiogenesis through an increase in vascular endothelial
growth factor (VEGF) secretion by cancer cells. Significant and sustained antitumor activity in this context can be obtained
by combining selective anti-EGFR drugs with antiangiogenic agents. In this review, we focus on the preclinical and clinical
evidence showing that an approach combining anti-EGFR and antiangiogenic drugs is feasible and could represent a paradigm
for a rational combined multi-targeted treatment of cancer.
Targeted Oncology 04/2012; 1(3):123-129. · 0.46 Impact Factor
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Erika Martinelli,
Teresa Troiani,
Floriana Morgillo,
Gabriella Rodolico,
Donata Vitagliano, Maria Pia Morelli,
Concetta Tuccillo,
Loredana Vecchione,
Anna Capasso,
Michele Orditura,
Ferdinando De Vita,
S Gail Eckhardt,
Massimo Santoro,
Liberato Berrino,
Fortunato Ciardiello
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ABSTRACT: Cancer cell survival, invasion, and metastasis depend on cancer cell proliferation and on tumor-induced angiogenesis. We evaluated the efficacy of the combination of sorafenib and erlotinib or cetuximab.
Sorafenib, erlotinib, and cetuximab, alone or in combination, were tested in vitro in a panel of non-small cell lung cancer (NSCLC) and colorectal cancer cell lines and in vivo in H1299 tumor xenografts.
Epidermal growth factor receptor (EGFR) ligand mRNAs were expressed in all NSCLC and colorectal cancer cell lines with variable levels ranging from 0.4- to 8.1-fold as compared with GEO colorectal cancer cells. Lung cancer cells had the highest levels of vascular endothelial growth factors (VEGF) A, B, and C, and of VEGF receptors as compared with colorectal cancer cells. Combined treatments of sorafenib with erlotinib or cetuximab produced combination index values between 0.02 and 0.5, suggesting a significant synergistic activity to inhibit soft agar colony formation in all cancer cell lines, which was accompanied by a marked blockade in mitogen-activated protein kinase and AKT signals. The in vitro migration of H1299 cells, which expressed high levels of both VEGF ligands and receptors, was inhibited by treatment with sorafenib, and this effect was significantly increased by the combination with anti-EGFR drugs. In nude mice bearing established human H1299 xenografts, treatment with the combination of sorafenib and erlotinib or cetuximab caused a significant tumor growth delay resulting in 70 to 90 days increase in mice median overall survival as compared with single-agent sorafenib treatment.
Combination treatment with sorafenib and erlotinib or cetuximab has synergistic antitumor effects in human colorectal and lung cancer cells.
Clinical Cancer Research 10/2010; 16(20):4990-5001. · 7.74 Impact Factor
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Tina Cascone, Maria Pia Morelli,
Floriana Morgillo,
Woo-Young Kim,
Gabriella Rodolico,
Stefano Pepe,
Giampaolo Tortora,
Liberato Berrino,
Ho-Young Lee,
John V Heymach,
Fortunato Ciardiello
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ABSTRACT: The proteasome plays a pivotal role in the turnover of regulatory transduction proteins induced by activated cell membrane growth factor receptors. The epidermal growth factor receptor (EGFR) pathway is crucial in the development and progression of human epithelial cancers. Proteasome inhibition may sensitize human cancer cell lines to EGFR inhibitors. We investigated the growth inhibitory and pro-apoptotic effects of the proteasome inhibitor bortezomib in combination with anti-EGFR drugs, such as gefitinib, vandetanib, and cetuximab in EGFR-expressing human cancer cell lines. Bortezomib determined dose-dependent growth inhibition in a nine cancer cell line panel (IC(50) values, range 6-42 nM). A significant synergistic growth inhibitory effect was observed with the combination of bortezomib and each EGFR inhibitor in all cell lines (combination index, CI, range 0.10-0.55), which was accompanied by a significant induction in apoptosis by the combined treatment with bortezomib, cetuximab and vandetanib. In HCT-116 colon cancer and A549 lung adenocarcinoma cells, bortezomib plus EGFR inhibitor treatment induced a more effective inhibition of EGFR-activated down-stream signals, including a marked suppression in activated, phosphorylated Akt (P-Akt). In contrast, overexpression of a constitutively active P-Akt protected A549 cells by cell growth inhibition and apoptosis following treatment with bortezomib and EGFR inhibitors. The combined treatment with bortezomib and EGFR inhibitors has a synergistic growth inhibitory and pro-apoptotic activity in different human cancer cells which possess a functional EGFR-dependent autocrine growth pathway through to a more efficient and sustained inhibition of Akt.
Journal of Cellular Physiology 10/2008; 216(3):698-707. · 3.87 Impact Factor
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ABSTRACT: The epidermal growth factor receptor (EGFR) is a cell membrane receptor that plays a key role in cancer development and in the progression of many human malignancies, including non-small-cell lung cancer (NSCLC). EGFR-dependent signaling is involved in cancer cell proliferation, apoptosis, angiogenesis, invasion and metastasis. Targeting the EGFR is a valuable molecular approach in cancer therapy. This receptor is overexpressed in up to 80% of NSCLC cases. Thus, several molecules inhibiting this critical biologic pathway have been synthesized and tested as a single agent or in combination with other anticancer modalities in a wide of clinical trials, including reversible and irreversible small tyrosine kinase inhibitors, such as gefitinib and erlotinib, dual vascular endothelial growth factor receptor EGFR tyrosine kinase inhibitors, such as vandetanib (ZD-6474), and monoclonal antibodies, such as cetuximab, which have shown promising activity in patients with NSCLC. This review focuses on the preclinical and clinical results available with EGFR inhibitors in the treatment of NSCLC patients.
Expert Opinion on Drug Discovery 03/2007; 2(3):335-48. · 2.12 Impact Factor
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Maria Pia Morelli,
Tina Cascone,
Teresa Troiani,
Concetta Tuccillo,
Roberto Bianco,
Nicola Normanno,
Marco Romano,
Bianca Maria Veneziani,
Gabriella Fontanini,
S Gail Eckhardt,
Sabino De Pacido,
Giampaolo Tortora,
Fortunato Ciardiello
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ABSTRACT: The epidermal growth factor receptor (EGFR) autocrine pathway plays an important role in cancer cell growth. Vascular endothelial growth factor A (VEGF-A) is a key regulator of tumor-induced endothelial cell proliferation and vascular permeability. ZD6474 is an orally available, small molecule inhibitor of VEGF receptor-2 (VEGFR-2), EGFR and RET tyrosine kinase activity. We investigated the activity of ZD6474 in combination with cetuximab, an anti-EGFR blocking monoclonal antibody, to determine the anti-tumor activity of EGFR blockade through the combined use of two agents targeting the receptor at different molecular sites in cancer cells and of VEGFR-2 blockade in endothelial cells.
The anti-tumor activity in vitro and in vivo of ZD6474 and/or cetuximab was tested in human cancer cell lines with a functional EGFR autocrine pathway.
The combination of ZD6474 and cetuximab determined synergistic growth inhibition in all cancer cell lines tested as assessed by the Chou and Talalay method. In nude mice bearing established human colon carcinoma (GEO) or lung adenocarcinoma (A549) xenografts and treated with ZD6474 and/or cetuximab for 4 weeks, a reversible tumor growth inhibition was caused by each drug. In contrast, a more significant tumor growth delay resulted from the combination of the two agents with an approximately 100-110 days increase in mice median overall survival as compared to single agent treatment.
This study provides a rationale for evaluating in a clinical setting the double blockade of EGFR in combination with inhibition of VEGFR-2 signaling as cancer therapy.
Journal of Cellular Physiology 09/2006; 208(2):344-53. · 3.87 Impact Factor
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ABSTRACT: A promising therapeutic target is the vascular endothelial growth factor pathway - a key mediator of tumor angiogenesis - which is important in tumor growth, invasion, and metastasis. This review focuses on the available clinical data on drugs targeting the vascular endothelial growth factor - vascular endothelial growth factor receptor pathway in the treatment of non-small cell lung cancer.
The therapeutic value of inhibiting the vascular endothelial growth factor pathway has been demonstrated by using drugs that prevent vascular endothelial growth factor receptor binding and by using drugs that inhibit receptor activation. Two antiangiogenic drugs exemplify these mechanisms: bevacizumab (Avastin; Genentech, South San Francisco, California, USA), a humanized monoclonal antibody that acts by binding and neutralizing vascular endothelial growth factor; and ZD6474 (Zactima; AstraZeneca, Macclesfield, UK), a small-molecule inhibitor of vascular growth factor receptor and epidermal growth factor receptor tyrosine kinase activity. Recently, the first results of a large, phase III randomized clinical trial of bevacizumab in combination with platinum-based doublet chemotherapy have been reported in patients with nonsquamous non-small cell lung cancer.
The inhibition of tumor angiogenesis is a key therapeutic strategy that holds great promise for the advancement of metastatic lung cancer therapy. The combination of bevacizumab and conventional chemotherapy could offer a new therapeutic option in selected non-small cell lung cancer histotypes.
Current Opinion in Oncology 04/2006; 18(2):151-5. · 4.10 Impact Factor
