Blockade of Epidermal Growth Factor Receptor Signaling on Tumor Cells and Tumor-Associated Endothelial Cells for Therapy of Human Carcinomas

Baker, Cheryl H.; Kedar, Daniel; McCarty, Marya F.; Tsan, Rachel; Weber, Kristen L.; Bucana, Corazon D.; Fidler, Isaiah J.

doi:10.1016/s0002-9440(10)64253-8

Cited by 140 publications

(101 citation statements)

References 31 publications

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“…Evidence also suggests that EGFR gene copy number may contribute to resistance to EGFR antagonism (45). In preclinical models of renal cancer, tumor response to treatment with an EGFR inhibitor was dependent upon and correlated with tumor cell expression of EGF and/or TGF-a (11). Expression of the ligands EGF and/or TGF-a induced expression of EGFR on tumor-associated endothelial cells, thereby enhancing tumor sensitivity to the treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Western Blotting Western blotting was done as previously described (11). Cultured cells treated with recombinant human EGF (Invitrogen, Carlsbad, CA), VEGF (R&D Systems, Minneapolis, MN), and/or ZD6474 (AstraZeneca Pharmaceuticals, Macclesfield, United Kingdom) or vehicle control were harvested and lysed.…”

Section: Methodsmentioning

confidence: 99%

“…Immunostaining for proliferating cell nuclear antigen (DAKO, Copenhagen, Denmark); basic fibroblast growth factor, interleukin-8, EGF, transforming growth factor-a (TGF-a), and VEGF (all from Santa Cruz Biotechnology); EGFR (Zymed); activated-EGFR (Biosource International); VEGFR2 (Santa Cruz Biotechnology); activated VEGFR2 (Oncogene, Cambridge, MA); activated Akt and activated MAPK (Cell Signaling); and bromodeoxyuridine, caspase-3, and/or CD31/platelet/endothelial cell adhesion molecule 1 (PharMingen, San Diego, CA) were done using the methods indicated as described previously (11,32). TUNEL was done using a commercial apoptosis detection kit (Promega) with modifications (32).…”

Section: Targeted Therapy Of Orthotopic Human Lung Cancermentioning

confidence: 99%

“…EGFR overexpression is associated with poor outcome for several malignancies; yet, the relationship between EGFR overexpression and NSCLC prognosis is controversial (10). Although the primary direct target of anti-EGFR agents is the tumor cell, they can also exert direct (11) or indirect (12) antiangiogenic and antivascular effects. Currently, several different strategies, including antibodies or small-molecule inhibitors, to target EGFR are in late-stage clinical development for the treatment of lung and other cancers.…”

Section: Introductionmentioning

confidence: 99%

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Targeted therapy of orthotopic human lung cancer by combined vascular endothelial growth factor and epidermal growth factor receptor signaling blockade

Wu¹,

Onn²,

Isobe³

et al. 2007

Molecular Cancer Therapeutics

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The outcome for patients with lung cancer has not changed significantly for more than two decades. Several studies show that the overexpression of vascular endothelial growth factor (VEGF)/vascular permeability factor and epidermal growth factor (EGF) and their receptors correlates with the clinical outcome for lung cancer patients. However, clinical trials of agents that target either of these pathways alone have been disappointing. We hypothesize that targeting both the tumor and its vasculature by simultaneously blocking the VEGFR and EGFR pathways will improve the treatment of locoregional lung cancer. Human lung cancer specimens were first examined for the activation of VEGF receptor 2 (VEGFR2) and EGF receptor (EGFR) for tumor and tumor-associated endothelial cells, and both were found to be activated. The effects of ZD6474 (ZACTIMA), a small-molecule inhibitor of VEGFR2 and EGFR tyrosine kinases, were then studied in vitro using human lung cancer and microvascular endothelial cells. In vitro, ZD6474 inhibited EGFR, VEGFR2, mitogenactivated protein kinase and Akt phosphorylation, EGF-and VEGF-induced proliferation, and endothelial cell tube formation and also induced apoptosis. ZD6474 was further studied in vivo using an orthotopic mouse model of nonsmall cell lung cancer using NCI-H441 human lung adenocarcinoma cells. The inhibition of both VEGFR2 and EGFR signaling pathways by ZD6474 resulted in profound antiangiogenic, antivascular, and antitumor effects. These results provide a basis for the development of clinical strategies for the combination of selective protein tyrosine kinase inhibitors that block both EGFR and VEGFR signaling as part of the management of locally advanced lung cancer. [Mol Cancer Ther 2007;6(2):471 -83]

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Targeted Therapy Of Orthotopic Human Lung Cancermentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Targeted therapy of orthotopic human lung cancer by combined vascular endothelial growth factor and epidermal growth factor receptor signaling blockade

Wu¹,

Onn²,

Isobe³

et al. 2007

Molecular Cancer Therapeutics

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“…Administration of PKI166 has been shown to be effective in controlling tumour growth and metastasis when used in combination with chemotherapy agents in preclinical models, including pancreatic cancer (Bruns et al, 2000), bladder and renal cell cancer (Baker et al, 2002). While used to target EGFR phosphorylation, PKI166 also inhibits phosphorylation of HER2 (Traxler et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Dual blockade of EGFR and ERK1/2 phosphorylation potentiates growth inhibition of breast cancer cells

et al. 2004

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One of the major targets for breast cancer therapy is the epidermal growth factor receptor (EGFR) and related receptors, which signal via different signal transduction pathways including the mitogen-activated protein kinase (MAPK) pathway. This study determined whether there is a correlation between EGFR/HER2 status and MAPK (ERK1/2) phosphorylation in breast cancer cells, and how this affects the response to an inhibitor of the receptors. Expression of EGFR, HER2 and phosphorylated ERK1/2 were measured by immunoblotting in a panel of breast cancer cell lines. Several lines expressed high levels of pERK1/2, with no obvious correlation with the level of EGFR/HER2. The EGFR tyrosine kinase inhibitor PKI166 inhibited growth and induced apoptosis in some cells with high levels of growth factor receptors (MDA-MB-468, SUM149, SKBR3), but was less effective in cells that also had high basal ERK1/2 activity (MDA-MB-231). The combination of an inhibitor of MAPK signalling (U0126) and PKI166 produced significantly more inhibition and apoptosis than either agent alone. This suggests that constitutive activation of the MAPK pathway may bypass inhibition of EGFR/HER2 tyrosine kinases, and lead to insensitivity to agents targeting the receptors. However, inhibiting both EGFR/ HER2 and MAPK signalling can result in significant growth inhibition and apoptosis of EGFR-expressing breast cancer cells.

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New transcatheter techniques for creation or enlargement of atrial septal defects in infants with complex congenital heart disease

Pedra

Neves

Pedra

et al. 2007

Cathet Cardio Intervent

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Creation or enlargement of ASDs in infants using new nonconventional transcatheter techniques is feasible, safe, and effective, at least in the short-to-mid-term follow-up. Infants with TGA seem to benefit the most because the procedure results in satisfactory clinical stability for subsequent early surgical intervention. In infants with HLHS palliated by a hybrid approach, stent implantation to the atrial septum seems to buy enough time to bring them to the phase II safely despite progressive in-stent obstruction.

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Blockade of Epidermal Growth Factor Receptor Signaling on Tumor Cells and Tumor-Associated Endothelial Cells for Therapy of Human Carcinomas

Cited by 140 publications

References 31 publications

Targeted therapy of orthotopic human lung cancer by combined vascular endothelial growth factor and epidermal growth factor receptor signaling blockade

Targeted therapy of orthotopic human lung cancer by combined vascular endothelial growth factor and epidermal growth factor receptor signaling blockade

Dual blockade of EGFR and ERK1/2 phosphorylation potentiates growth inhibition of breast cancer cells

New transcatheter techniques for creation or enlargement of atrial septal defects in infants with complex congenital heart disease

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