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At least 271 records · Page 15Linked to original sources
PubMed1996

Options of flow cytometric three-colour DNA measurements to quantitate EGFR in subpopulations of human bladder cancer.

Flow cytometric multi-parameter analysis has proven to be a powerful tool to characterize subpopulations of cell suspensions, and is applied routinely in hematology. However, in studies of cancer where there is interest in defining phenotypic markers in conjunction with DNA content, this method has hardly been applied [6]. Our objective was to develop a methodology that extends previous investigations on relative and absolute quantitation of the epidermal growth factor receptor (EGFR) in dual parameter analysis in vitro on human bladder cancer cell lines [3]. In order to quantitate EGFR content in tumours and to relate it to DNA content, tumour selection, DNA-content, and EGFR-content measurements should be carried out simultaneously. Different fluorescent dyes were used to optimize DNA assessment and antibody staining, using a single laser instrument as a practical approach for clinical routine. In vitro cultures were used to validate the quality of tumour cell selection and antigen quantitation. Therefore, two urothelial tumour cell lines-lowly and highly differentiated-were incubated under different conditions: monolayer (ML), three-dimensional multi-cellular spheroids (MCS) and cocultures (COCU) with the fibroblast cell line NI were investigated and EGFR quantitation was related to S-phase fraction (SPF). Accurate determination of instrument settings allows simultaneous three-colour analysis with DNA assessment. Tumor cell selection based on staining with phycoerythrine (R-PE) against a highly expressed urothelial glycoprotein, detected with the antibody Uro5 or against cytokeratin appeared to be possible in FL2, using the fluorochrome combination fluorescein-isothiocyanate (FITC), R-PE and propidiumiodide (PI). Using this staining protocol, relative and absolute EGFR quantitation (quantum simply cellular beads) is shown to be accurate, when FITC is used for EGFR staining and measured in the green fluorescence channel (FL1). Using this colour combination EGFR content and SPF of tumour cells were compared in different growth states, and could be monitored reliably. In spite of a higher emission spectrum of 7-aminoactinomycin-D (7-AAD), this DNA stain provided no advantage over PI. Broad coefficients of variation (CV) were found when intact cells were stained, thus hindering accurate assessment of ploidy and S-phase fraction. Similarly, Syto-13, a DNA dye detected in FL1, could not be optimized for multi-parameter measurements. Although the emission maximum is at 520 nm, the spectrum is too wide to compensate fluorescence overlap in FL2 or FL3. Quantum Red (QR), used as a streptavidin conjugate in FL3, could not be combined with two other colours for DNA staining, since sufficient compensation was not obtainable when an argon ion laser is used. The coculture model allows verification of tumour cell selection and discrimination. The high differentiated tumour cell line RT4 shows an unambiguous correlation between EGFR content and S-phase fraction. The low differentiated tumour cell line J82 presents a similar pattern of post-transcriptional EGFR regulation with respect to culture condition, however, the S-phase fraction is basically unaffected.

Carcinoma↗
PubMedDate not supplied

The prognostic significance of epidermal growth factor receptor (EGFR), C-erbB-2, Ki-67 and PCNA expression in breast cancer.

The evaluation of the immunohistochemical expression of epidermal growth factor receptor (EGFR), c-erbB-2 oncoprotein, proliferating indices Ki-67, and PCNA were determined on 68 primary breast carcinomas. These markers were correlated with each other and with other clinicopathological variables such as: age, tumor size? histotype, tumor grade and steroid receptors' content as well as nodal status. The monoclonal antibodies anti-human Epidermal Growth Factor Receptor (EGFR1), anti-human Ki67 (DAKO) and N13259 (Oncogene Science) were applied to paraffin and frozen tissue sections. All markers showed an heterogeneous pattern of staining. There was almost equally high staining intensity at the membranus for EGFR and c-erbB-2 in about 32% of the cases. The EGFR and c-erbB-2 positive cases were much less common in infiltrating lobular (2,2/13) rather than in ductal adenocarcinomas (21,20/55). The low grade carcinomas showed low expression of EGFR and c-erbB-2 oncoprotehl comparing with high grade ductal adenocarcinomas. A high index of Ki-67 was correlated with EGFR and c-erbB-2 membrane positivity. There was an inverse relationship between the expression of c-erbB-2 and EGFR, when compared with oestrogen receptors' content. A significant correlation was also demonstrated between EGFR and c-erbB-2 immunoreactivity with lymph node status. Our results provide evidence that the synchronous immunohistochemical detection of EGFR, c-erbB-2 and Ki-67 may be of useful significance in breast cancer patients, especially when combined with other clinicopathological variables. Furthermore the expression of EGFR and c-erbB-2 oncoprotein may affect the cell proliferation and differentiation.

Biomarkers, Tumor↗
PubMedDate not supplied

EGFR and steroid receptors in ovarian carcinoma: comparison with prognostic parameters and outcome of patients.

Epidermal growth factor receptor (EGFR), progesterone receptor (PR) and estrogen receptor (ER) status were analyzed in 108 primary ovarian epithelial carcinoma specimens. Receptor concentration was determined with radioligand binding assays. 61% of the carcinomas investigated were positive for EGFR, 29% for PR and 57% for ER. EGFR status was not correlated with histological grading of tumors and no difference in EGFR positivity was found between subgroups of ovarian carcinomas. On the other hand, 50% of the tumors with FIGO stage III and IV and tumors which could not be operated to be free of residual tumor mass were EGFR positive, whereas only 30% were positive within the group of tumors with FIGO stage I and II and no residual tumor mass. The outcome of the carcinoma patients was followed up for a maximum of 100 months. A significant correlation between EGFR positivity and a shorter progressive-free period as well as shorter overall survival was found. For PR and ER status no relation to patient survival became evident. The response to chemotherapy was significantly correlated to EGFR status. After 5 years 63% of the patients with negative versus 25% with positive EGFR were still alive indicating the impaired response of EGFR positive carcinomas to chemotherapy containing platinum compounds.

Adenocarcinoma, Clear Cell↗
PubMed2026

Identification of STK35L1 as a potential prognostic biomarker in breast carcinoma, and its expression exhibits high correlation with EGFR activity.

Breast cancer (BC) is the second most prevalent malignancy after lung cancer, and the life expectancy is still very low due to therapeutic resistance and tumor relapse. It is crucial to identify novel biomarkers that can serve as potential therapeutic targets. In TNBC, aberrant activation of EGFR has also been implicated in the development of drug resistance. STK35L1 is a critical regulator of diverse cellular processes, including apoptosis and DNA damage. Notably, STK35L1 promotes drug resistance and regulates glycolysis and apoptosis through AKT signaling. The oncogenic role of STK35L1 is established in various cancers, including osteosarcoma, colorectal cancer, and acute myeloid leukemia. However, its association in BC has not yet been explored. In this study, we found that STK35L1 was significantly upregulated in multiple cancers, and its higher expression was associated with poor survival outcomes in BC patients. STK35L1 was differentially upregulated across all BC subtypes. An association between EGFR and STK35L1 expression was observed in normal breast tissues but not in BC. Interestingly, compared with normal breast tissue, EGFR mRNA expression is downregulated in BC tissues, with the greatest downregulation in the luminal B subtype and the least in TNBC. Furthermore, EGFR inhibition with gefitinib increased STAT3 phosphorylation at Tyr-705, and STK35L1 and EGFR gene expression were significantly upregulated. These data suggest that EGFR-STAT3 signaling may regulate STK35L1 and EGFR expression. In conclusion, we report an association of STK35L1 and EGFR in BC, highlighting STK35L1 as a potential prognostic biomarker and therapeutic target.

Humans↗
PubMed1995

Anti-tumor efficacy of an anti-epidermal-growth-factor-receptor monoclonal antibody and its F(ab')2 fragment against high- and low-EGFR-expressing carcinomas in nude mice.

Monoclonal antibody (MAb) MINT5 specifically detects the epidermal-growth-factor receptor (EGFR). In vitro analyses of intact MINT5 (IgG1) and its F(ab')2 fragment indicated that both forms of the MAb inhibited binding of 125I-mEGF to EGFR, induced receptor internalization and blocked EGF-induced EGFR tyrosine-kinase activation in A431 cells. Both forms of the MAb also inhibited to the same extent the proliferation of the carcinoma cell lines A431 and IGROVI, despite the difference in EGFR levels on the cells. The detection of TGF alpha mRNA and the inhibition of cell growth in EGF-free conditions by anti-EGFR MAb indicated the involvement of an EGFR/TGF alpha autocrine/paracrine pathway in the in vitro growth of both cell lines. Analysis of mice xenotransplanted s.c. with A431 cells and treated with MINT5 revealed a block in A431 tumor take in 6 of 10 animals when intact MAb was administered from day 0 to day 11. On a molar basis, F(ab')2 at the same dose was ineffective, although at a 7-fold higher dose F(ab')2 reduced s.c. tumor growth by 80%. At the same dose, intact MINT5 MAb reduced s.c. growth of the EGFR-negative MeWo cell line by 5%. Survival of mice bearing IGROVI i.p. xenotransplants and treated locally with either form of MAb was significantly prolonged even when treatment was initiated on day 3. Corrected doses of intact and F(ab')2 fragment, which accounted for the difference in serum half-lives of the MAb forms, resulted in similar survival rates in the tumor-bearing mice. These pre-clinical results suggest that MINT5 MAb might be safely used for systemic therapy of EGFR-over-expressing tumors. Loco-regional therapy might be contemplated in the case of tumors with moderate/low EGFR expression.

Animals↗
PubMed2003

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs): simple drugs with a complex mechanism of action?

A range of target-based agents for the treatment of solid tumors are in development. The epidermal growth factor receptor (EGFR) has been identified as a relevant target as it is involved in regulating several cellular functions important in the proliferation and survival of cancer cells, is commonly expressed at high levels in a range of tumors, and high expression is often related to poor prognosis. EGFR is a member of the ErbB family of receptors which also includes ErbB-2, ErbB-3, and ErbB-4. These receptors form dimers of the same type (homodimers) or with other family members (heterodimers), each combination resulting in different downstream effects. Some of the most advanced targeted agents in development are the EGFR tyrosine kinase inhibitors (EGFR-TKIs), of which ZD1839 ('Iressa') is an example. In Phase II monotherapy trials, oral ZD1839 was well tolerated and demonstrated clinically meaningful antitumor activity and symptom relief in pretreated patients with advanced NSCLC. Preclinical studies have suggested that the antitumor activity of ZD1839 does not depend on the level of EGFR expression. Furthermore, in addition to an effect on EGFR signaling, treatment with ZD1839 as well as with other quinazoline EGFR-TKIs, may also affect signaling of other ErbB family members. EGFR-TKIs have been shown in preclinical studies to increase the efficacy of cytotoxic drugs and Phase III trials of such combinations are ongoing. On the basis that different signal transduction pathways contribute to the control of tumor growth, future therapeutic approaches are likely to involve combination of different targeted agents.

Animals↗
PubMed2007

Association of the EGFR intron 1 CA repeat length with lung cancer risk.

Epidermal growth factor receptor (EGFR) plays an important role in the development and progression of lung cancer. A previous report noted that an increased number of polymorphic CA repeats in the first intron of the EGFR gene results in decreased transcriptional activity. To estimate the association of the length of polymorphic CA repeats in intron 1 of the EGFR gene with lung cancer, a case-control study of 176 lung cancer patients and 161 controls was conducted in Caucasians. This case-control study is based on two existing prospective cohorts: the Early Detection Research Network (EDRN) and the Lung Cancer Specialized Program of Research Excellence (SPORE) at the University of Pittsburgh. The frequencies of the SL (one allele>16 repeats), and SS (both allele 36) was 20.5% versus 36.7%, for lung cancer cases versus controls. The lower sum of EGFR-CA repeats associated with the risk of lung cancer; the estimated odds ratio was 2.25 with 95% confidence interval: 1.38-3.66 (P=0.001). Associations involving EGFR-CA repeat genotype and EGFR-CA repeat sum remained significant when adjusted for age, gender, and tobacco exposure. Our study, which is preliminary, demonstrates for the first time that shorter EGFR-CA repeats associate with lung cancer risk. The number of EGFR-CA repeats identifies a possible susceptible population to lung cancer.

Adult↗
PubMed1996

Localization of Epidermal Growth Factor (EGF) and Epidermal Growth Factor Receptor (EGFr) in Human Pituitary Adenomas and Nontumorous Pituitaries: An Immunocytochemical Study.

Epidermal growth factor (EGF) and epidermal growth factor receptor (EGFr) were investigated by immunocytochemistry (ICH) in 57 human pituitary adenomas and 10 nontumorous autopsy pituitaries. EGF immunoreactivity was demonstrated in 24 adenomas (42%), representing 23 functioning tumors and 1 nonfunctioning tumor of oncocytic type, and in all nontumorous pituitaries. Among 40 tumors, EGFr was found positive in 15 functioning adenomas (37.5%), representing 50% of them. The presence of both EGF and EGFr was found mainly in corticotroph adenomas (60%) and less frequently in somatotroph and lactotroph adenomas (20%). ICH on serial sections with EGF or EGFr and adrenocorticotrophic hormone (ACTH) or S-100 protein revealed that EGF and EGFr are localized specifically in corticotrophs and EGFr in stellate cells of nontumorous adenohypophysis. These results confirm the presence of EGF and EGFr in human pituitary adenomas and nontumorous pituitaries and highlight their frequent occurrence in hormone-producing adenomas. Further work is required to explore the possiblity that EGF and EGFr play a role in hormone production, release, and tumor progression.

Journal Article↗
PubMed2005

The enlargement of the hormone immune deprivation concept to the blocking of TGFalpha-autocrine loop: EGFR signaling inhibition.

Transforming growth factor alpha (TGFalpha) is a potent ligand of the epidermal growth factor receptor (EGFR). EGFR is frequently over-expressed in epithelial tumors and endogenous ligands, mostly TGFalpha, are frequently co-expressed with EGFR, potentially resulting in autocrine stimulation of tumor cell growth. Therefore, different therapeutic approaches aim for the inactivation of TGFalpha/EGF/EGFR signaling system, but no approach is based on TGFalpha as a target. The principal goal of this work was to assess the potential of an active specific immunotherapy approach to block the TGFalpha/EGFR autocrine loop. For the proof of the concept, a fusion protein between human TGFalpha (hTGFalpha) and P64k protein from Neisseria meningitidis was generated, and its immunogenicity characterized in a mouse model using different adjuvants. All immunogens were effective for the generation of specific humoral responses against hTGFalpha. The inmunodominant epitope of hTGFalpha when immunizing mice with the fusion protein involved the C-loop/C-terminal region. This region includes key residues for hTGFalpha binding to EGFR. The anti-hTGFalpha immune mice sera recognized the natural hTGFalpha precursor in A431 cells and hTGFalpha-transfected 3T3 fibroblasts as revealed by flow cytometry analysis and immunoblotting. They inhibited the binding of (125)I-TGFalpha to the EGFR, EGFR-autophosphorylation, and downstream activation of MAP kinases as well as proliferation of two EGFR-expressing human carcinoma cell lines. These data suggest that EGFR signaling activation by the hTGFalpha autocrine loop may be inhibited in vivo by induction of specifically blocking antibodies. The fusion protein reported in this paper could be a potential immunogen for the development of a new cancer vaccine.

Animals↗
PubMed2002

The combi-targeting concept: a novel 3,3-disubstituted nitrosourea with EGFR tyrosine kinase inhibitory properties.

PURPOSE: To study the dual mechanism of action of FD137, a 3,3-disubstituted nitrosourea designed to block signaling mediated by the epidermal growth factor receptor (EGFR) on its own and to be hydrolyzed to an inhibitor of EGFR plus a DNA-damaging species. MATERIALS AND METHODS: HPLC was used to determine the half-life (t(1/2)) of FD137 and to characterize its derived metabolite FD110. The dual mechanisms of DNA damaging and EGFR tyrosine kinase (TK) targeting were ascertained by the comet assay for DNA damage and by inmunodetection of phosphotyrosine in an ELISA and a whole-cell assay for EGFR-mediated signaling. The antiproliferative effects of the different drugs and their combinations were determined by the sulforhodamine B (SRB) assay. RESULTS: In contrast to BCNU, FD137 significantly blocked EGF-induced EGFR autophosphorylation (IC(50) 4 micro M) in the human solid tumor cell line A431. DNA damage induced by FD137 could only be observed after 24 h exposure, but the level of DNA damage remained 3.6-fold lower than that induced by BCNU. This difference was rationalized by the 160-fold greater stability of FD137 when compared with BCNU in serum-containing medium. Further, degradation of FD137 was accompanied by the slow release of FD110, an extremely potent inhibitor of EGFR TK [IC(50) (EGFR autophosphorylation) <0.3 micro M]. The complex properties of FD137 translated into a 55-fold greater antiproliferative activity than BCNU against the EGFR-overexpressing A431 cells that coexpresses the O(6)-alkylguanine transferase (AGT). Depletion of AGT in these cells by the use of O(6)-benzylguanine (O(6)-BG) enhanced their sensitivity to BCNU by 8-fold, but only by 3-fold to FD137. CONCLUSIONS: The results overall suggest that the superior antiproliferative activity of FD137 when compared with BCNU may be associated with its ability to behave as a combination of many species with different mechanisms of action. However, the enhancement of its potency by O(6)-BG suggests that its antiproliferative effect was at least partially mitigated by AGT and perhaps it may be largely dominated by its signal transduction inhibitory component.

Antineoplastic Agents, Alkylating↗
PubMed2004

Increased expression of EGFR and TGF-alpha in segmental renal dysplasia in duplex kidney.

Renal dysplasia (RD) is a disorganised development of renal parenchyma that results in a deficit of functional renal tissue. It is known that the epidermal growth factor (EGF) and the transforming growth factor-alpha (TGF-alpha) enhance renal cell proliferation, migration and differentiation during kidney development through binding to the same EGF receptor (EGFR). The aim of the study was to analyse the expression of TGF-alpha and EGFR in the dysplastic kidney. The specimens of dysplastic upper poles duplex kidneys were surgically resected from 19 patients. Indirect immunohistochemistry was performed using the ABC method employing antibodies against EGFR and TGF-alpha, and gene expression using primers specific to the human genes. There was absent or weak EGFR and TGF-alpha immunoreactivity in normal kidney tissue. In dysplastic kidneys, there was strong TGF-alpha and EGFR immunoreactivity in the epithelium of primitive tubules and strong EGFR immunoreactivity in the connective tissue around the primitive tubules. Our findings of markedly increased local expression of EGFR and TGF-alpha in primitive tubules suggest that EGFR and TGF-alpha may play an important role in altering renal morphogenesis resulting in renal dysplasia.

Child↗
PubMed2004

Epidermal growth factor receptor family (EGFR, ErbB2-4) in gliomas and meningiomas.

Overexpression of epidermal growth factor receptor (EGFR, ErbB1) correlates with enhanced malignant potential of many human tumor types including glioblastoma multiforme. The significance of EGFR expression in meningiomas is, however, unclear. Reports regarding the other EGFR family members, ErbB2-4, in brain tumors are sparse. In this study, the expression of the EGFR family members was analyzed in relation to various parameters for the clinical importance of these receptors in 44 gliomas and 26 meningiomas. In gliomas, quantitative real-time reverse transcription (RT)-PCR revealed the highest EGFR mRNA expression in high-grade gliomas, while ErbB2 and ErbB3 mRNA were detected only in a few high-grade gliomas. In contrast, ErbB4 expression was most pronounced in low-grade gliomas. Immunohistochemistry showed significantly higher EGFR protein expression in high-grade gliomas compared to low-grade gliomas (P= 0.004). ErbB2 protein expression was mainly seen in high-grade gliomas. ErbB3 protein expression was low in all gliomas analyzed. ErbB4 protein expression was significantly higher in low-grade gliomas than in high-grade gliomas (P= 0.007). In meningiomas, quantitative real-time RT-PCR revealed expression of EGFR, ErbB2, and ErbB4 mRNA in the majority of the tumors. ErbB3 was detected in only one of the meningiomas analyzed. Immunohistochemistry demonstrated high ErbB2 protein expression in meningiomas. An intriguing observation in astrocytomas and oligodendrogliomas grade II, was a significantly decreased overall survival for patients with high EGFR protein expression (P= 0.04). The high ErbB4 expression in low-grade compared to high-grade gliomas might suggest that ErbB4 acts as a suppressor of malignant transformation in brain tumors, which is in line with previous studies in other tumor types.

Adolescent↗
PubMed2005

EGF receptor-ligand interaction generates extracellular hydrogen peroxide that inhibits EGFR-associated protein tyrosine phosphatases.

Hydrogen peroxide (H(2)O(2)) has been shown to be an important modulator of intracellular phosphatase activity involved in cell signaling pathways, including signaling by members of the receptor tyrosine kinase family of receptors such as the epidermal growth factor receptor (EGFR). Intracellular H(2)O(2) can be generated by mitochondria-dependent pathways, whereas we recently showed that H(2)O(2) could be generated extracellularly by receptor-ligand interaction. Here, we show that H(2)O(2) produced by EGF-EGFR interaction can modulate the activity of intracellular protein tyrosine phosphatases (PTPs). Using purified proteins, we found that EGFR-ligand interaction generates H(2)O(2) that is capable of inhibiting the activity of PTP1B in vitro. Furthermore, the addition of catalase rescued phosphatase inhibition consequent to EGF-EGFR interaction. Using cells that overexpress EGFR, we found that the addition of extracellular catalase prevented EGF-induced inhibition of EGFR-associated phosphatase activity. Our findings suggest that extracellular H(2)O(2) generated by EGFR-ligand interaction permeates the plasma membrane and inhibits EGFR-associated tyrosine phosphatase activity, thereby modulating downstream signal transduction pathways.

Carcinoma, Squamous Cell↗
PubMed2007

EGFR mutations and human papillomavirus in squamous cell carcinoma of tongue and tonsil.

This study was performed to determine the clinical significance of mutations in the EGFR (epidermal growth factor receptor) along with their association with human papillomavirus (HPV) infections in patients with squamous cell carcinoma of the head and neck (HNSCC). Exons 18-21 of the EGFR tyrosine kinase domain were sequenced and HPV typing was carried out using the HPV DNA chip in tissues obtained from patients with tongue and tonsil cancer. Univariate and multivariate analyses were used to identify the significant factors. One hundred and eight patients were enrolled. Ten patients (9%) were HPV positive and 17 (16%) had EGFR mutations. None of the patients with EGFR mutations were HPV positive. Gender, age (<60 years versus 60 years), and smoking history were not associated with EGFR mutations. A higher percentage of patients with tonsillar cancer were HPV positive than those with tongue cancer (26% and 0%, respectively; P<0.001). EGFR mutations were not a significant prognostic factor (P=0.746). HPV-positive patients had prolonged survival (P=0.025). Multivariate analysis revealed a longer overall survival in HPV-positive patients (P=0.007). EGFR mutations are not associated with the HPV-positive status, which may confer a better survival outcome. Clinical features of lung cancer patients with EGFR mutations were not observed in HNSCC. A further study will be needed to confirm these results.

Adult↗
PubMed2005

Epidermal growth factor receptor (EGFR) signaling in cancer.

The epidermal growth factor receptor (EGFR) belongs to the ErbB family of receptor tyrosine kinases (RTK). These trans-membrane proteins are activated following binding with peptide growth factors of the EGF-family of proteins. Evidence suggests that the EGFR is involved in the pathogenesis and progression of different carcinoma types. The EGFR and EGF-like peptides are often over-expressed in human carcinomas, and in vivo and in vitro studies have shown that these proteins are able to induce cell transformation. Amplification of the EGFR gene and mutations of the EGFR tyrosine kinase domain have been recently demonstrated to occur in carcinoma patients. Interestingly, both these genetic alterations of the EGFR are correlated with high probability to respond to anti-EGFR agents. However, ErbB proteins and their ligands form a complex system in which the interactions occurring between receptors and ligands affect the type and the duration of the intracellular signals that derive from receptor activation. In fact, proteins of the ErbB family form either homo- or hetero-dimers following ligand binding, each dimer showing different affinity for ligands and different signaling properties. In this regard, evidence suggests that cooperation of multiple ErbB receptors and cognate ligands is necessary to induce cell transformation. In particular, the growth and the survival of carcinoma cells appear to be sustained by a network of receptors/ligands of the ErbB family. This phenomenon is also important for therapeutic approaches, since the response to anti-EGFR agents might depend on the total level of expression of ErbB receptors and ligands in tumor cells.

Animals↗
PubMed2006

ZD6474, an inhibitor of VEGFR and EGFR tyrosine kinase activity in combination with radiotherapy.

Radiation enhances both epithelial growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) expression, which are a part of key pathways for tumor progression. Some tumors may not respond well to EGFR inhibitors alone or may develop resistance to EGFR inhibitors. Therefore, drug therapy targeted to VEGF receptors and EGFRs, when combined with radiotherapy (RT), may improve tumor control and provide wider applicability. This article focuses on ZD6474, an inhibitor of EGFR and VEGF receptor signaling in combination with RT. We discuss preclinical and clinical studies with RT and inhibitors of VEGF or EGFR signaling first. We then address issues associated with ZD6474 pharmacokinetic dosing, and scheduling when combined with RT. We also discuss ZD6474 in the context of anti-EGFR therapy resistance. Dual inhibition of EGFR and VEGF receptor signaling pathways shows promise in enhancing RT efficacy.

Angiogenesis Inhibitors↗
PubMed2006

EGFR expression: associations with outcome and clinicopathological variables in malignant pleural mesothelioma.

Malignant mesothelioma (MM) is a fatal tumour of increasing incidence which is related to asbestos exposure. This work evaluated expression in MM of Epidermal Growth Factor Receptor (EGFR) by immunohistochemistry in 168 tumour sections and its correlations with clinicopathological and biological factors. The microvessel density (MVD) was derived from CD34 immunostained sections. Hematoxylin and eosin stained sections were examined for intratumoural necrosis. COX-2 protein expression was evaluated with semi-quantitative Western blotting of homogenised tumour supernatants (n=45). EGFR expression was correlated with survival by Kaplan-Meier and log rank analysis. Univariate and multivariate Cox proportional hazards models were used to compare the effects of EGFR with clinicopathological and biological prognostic factors and prognostic scoring systems. EGFR expression was identified in 74 cases (44%) and correlated with epithelioid cell type (p<0.0001), good performance status (p<0.0001), the absence of chest pain (p<0.0001) and the presence of TN (p=0.004), but not MVD or COX-2. EGFR expression was a good prognostic factor in univariate analysis (p=0.01). Independent indicators of poor prognosis in multivariate analysis were non-epithelioid cell type (p=0.0001), weight loss, performance status and WBC>8.3x10(9)L(-1). EGFR status was not an independent prognostic factor. EGFR expression in MM correlates with epithelioid histology and TN. EGFR may be a target for selective therapies in MM.

Biomarkers, Tumor↗
PubMed2006

Differential effects of Cbl isoforms on Egfr signaling in Drosophila.

The Cbl family of proteins downregulate epidermal growth factor receptor (Egfr) signaling via receptor internalization and destruction. These proteins contain two functional domains, a RING finger domain with E3 ligase activity, and a proline rich domain mediating the formation of protein complexes. The Drosophila cbl gene encodes two isoforms, D-CblS and D-CblL. While both contain a RING finger domain, the proline rich domain is absent from D-CblS. We demonstrate that expression of either isoform is sufficient to rescue both the lethality of a D-cbl null mutant and the adult phenotypes characteristic of Egfr hyperactivation, suggesting that both isoforms downregulate Egfr signaling. Interestingly, targeted overexpression of D-CblL, but not D-CblS, results in phenotypes characteristic of reduced Egfr signaling and suppresses the effect of constitutive Egfr activation. The level of D-CblL was significantly correlated with the phenotypic severity of reduced Egfr signaling, suggesting that D-CblL controls the efficiency of downregulation of Egfr signaling. Furthermore, reduced dynamin function suppresses the effects of D-CblL overexpression in follicle cells, suggesting that D-CblL promotes internalization of activated receptors. D-CblL is detected in a punctate cytoplasmic pattern, whereas D-CblS is mainly localized at the follicle cell cortex. Therefore, D-CblS and D-CblL may downregulate Egfr through distinct mechanisms.

Alternative Splicing↗