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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

From histological and biological perspectives, lung cancer is a complex neoplasm. Although the sequential preneoplastic changes have been defined for centrally arising squamous carcinomas of the lung, they have been poorly documented for the other major forms of lung cancers, including small cell lung carcinoma and adenocarcinomas. There are three main morphologic forms of preneoplastic lesions recognized in the lung: squamous dysplasias, atypical adenomatous hyperplasia, and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. However, these lesions account for the development of only a subset of lung cancers. Several studies have provided information regarding the molecular characterization of lung preneoplastic changes, especially for squamous cell carcinoma. These molecular changes have been detected in the histologically normal and abnormal respiratory epithelium of smokers. Two different molecular pathways have been detected in lung adenocarcinoma pathogenesis: smoking-associated activation of RAS signaling, and nonsmoking-associated activation of EGFR signaling; the latter is detected in histologically normal respiratory epithelium.
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PMID:Lung cancer preneoplasia. 1803 18

Advanced non-small cell lung carcinoma (NSCLC) remains a challenge to treat due to its high local and systemic recurrence. The overall survival remains poor despite the approval of several new chemotherapeutic agents in the management of advanced NSCLC. Overexpression or mutations in the EGFR have been shown to be associated with a significant percentage of NSCLC. The development of targeted agents, such as cetuximab, against the EGFR is therefore a rational objective. Several preclinical and clinical studies suggest that cetuximab is active against NSCLC. This paper reviews the application of cetuximab in NSCLC.
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PMID:Cetuximab in non-small cell lung cancer. 1808 40

To improve activity of a recombinant IL-13 cytotoxin (CT) comprised of IL-13 spliced to truncated diphtheria toxin (DT(390)), epidermal growth factor (EGF) was added to the same single chain protein. This new recombinant bispecific CT, called DTEGF13, enhanced the killing potency against the human glioblastoma lines, U87MG (0.015 nM) and U118MG (0.02 nM). A similar enhancement was observed against the lung carcinoma cell line, Calu-3 (0.0018 nM). Enhanced activity could not be explained by an increased number of cytokines available for binding since a combination of monospecific DTEGF and DTIL13 did not cause the same enhanced activity. Enhanced activity was dependent on the presence of both cytokines on the same single chain molecule and killing was receptor specific since target receptor negative leukemia cells were unaffected by the highly selective DTEGF13 and cytotoxicity could be blocked with anti-EGFR and anti-IL-13 antibodies. In a xenograft flank tumor model, intratumoral injection of DTEGF13, but not monospecific DTEGF or DTIL13, significantly inhibited the growth of established U87 tumors in nude mice (P < 0.04). In this model, the human EGF and IL-13 components of DTEGF13 are reactive with mouse EGFR and IL-13R, respectively. These studies show that a new co-targeting agent that simultaneously recognizes EGFR and IL-13R is more effective than its monospecific counterparts and that DTEGF13 has therapeutic advantages for glioblastoma.
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PMID:Anti-glioblastoma effect of a recombinant bispecific cytotoxin cotargeting human IL-13 and EGF receptors in a mouse xenograft model. 1808 21

Up to 10% of patients with non-small cell lung carcinoma (NSCLC) achieve an objective response to EGFR tyrosine kinase inhibitors (EGFR-TKI) such as erlotinib or gefitinib. This rate of response is related to non-smoker status, female gender, adenocarcinoma subtype, and Asian ethnicity. Molecular analysis showed that EGFR tyrosine kinase domain somatic mutations appear to be a strong predictor of response to EGFR-TKI. The L858R point mutation and the E746-A750 deletion represent 90% of the mutations encountered in responding patients. The amplification of EGFR gene also seems to be predictive of the response to EGFR-TKI, whereas T790M point mutation induces secondary resistance to EGFR-TKI. Nevertheless, objective responses or strong long-term stabilizations are observed in patients without any EGFR abnormality. Thus, the assessment of the EGFR status in patients with NSCLC remains controversial for clinical practice. The assessment of EGFR abnormalities should be targeted to identify reliable biomarkers of the NSCLC response to EGFR-TKI. This review presents the current knowledge on predictive biomarkers of NSCLC response to EGFR-TKI and the methods available for the assessment of EGFR status.
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PMID:[Clinical and molecular predictors of response to EGFR tyrosine kinase inhibitors in non-small cell lung cancer]. 1818 70

Mucoepidermoid carcinoma (MEC) of lung is a rare malignancy of lung which originates from minor salivary glands of tracheobronchial tree. EGFR targeted therapy by inhibition of EGFR activation with the specific tyrosine kinase inhibitors (TKIs) has shown meaningful anti-tumor activity in patients with EGFR TK mutation and/or amplification, or in patients with adenocarcinoma. In the present study, we find that MEC has EGFR mutation in 40% (2 out of 5) of cases, and all mutations are L858R mutation. In addition, we also observed that a MEC patient well-responded to EGFR TKI in the absence of EGFR mutation or amplification. These data indicate for the first time that MEC of lung is another potential target of EGFR inhibitor, and more extended clinical investigation is warranted.
Lung Cancer 2008 Jul
PMID:Mucoepidermoid carcinoma of lung: potential target of EGFR-directed treatment. 1899 60

The goal of this study was to characterize the effects of non-small cell lung carcinoma (NSCLC)-associated mutations in epidermal growth factor receptor (EGFR/ErbB1) and HER2 (ErbB2) on interactions with the dual tyrosine kinase inhibitor lapatinib. Biochemical studies show that commonly observed variants of EGFR [G719C, G719S, L858R, L861Q, and Delta746-750 (del15)] are enzyme activating, increasing the tyrosine kinase V(max) and increasing the K(m)((app)) for ATP. The point mutations G719C and L861Q had minor effects on lapatinib K(i)s, whereas EGFR mutations L858R and del15 had a higher K(i) for lapatinib than wild-type EGFR. Structural analysis of wild-type EGFR-lapatinib complexes and modeling of the EGFR mutants were consistent with these data, suggesting that loss of structural flexibility and possible stabilization of the active-like conformation could interfere with lapatinib binding, particularly to the EGFR deletion mutants. Furthermore, EGFR deletion mutants were relatively resistant to lapatinib-mediated inhibition of receptor autophosphorylation in recombinant cells expressing the variants, whereas EGFR point mutations had a modest or no effect. Of note, EGFR T790M, a receptor variant found in patients with gefitinib-resistant NSCLC, was also resistant to lapatinib-mediated inhibition of receptor autophosphorylation. Two HER2 insertional variants found in NSCLC were less sensitive to lapatinib inhibition than two HER2 point mutants. The effects of lapatinib on the proliferation of human NSCLC tumor cell lines expressing wild-type or variant EGFR and HER2 cannot be explained solely on the basis of the biochemical activity or receptor autophosphorylation in recombinant cells. These data suggest that cell line genetic heterogeneity and/or multiple determinants modulate the role played by EGFR/HER2 in regulating cell proliferation.
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PMID:Impact of common epidermal growth factor receptor and HER2 variants on receptor activity and inhibition by lapatinib. 1819 54

EML4-ALK gene fusions have recently been discovered in a subset of human lung carcinomas, and fusions of the ALK tyrosine kinase gene with the NPM, TPM3, CLTC, ATIC, and TFG genes have been found in hematological malignancies. To elucidate the role of fusions between ALK and other genes in pulmonary carcinogenesis, we examined 77 non-small cell lung carcinomas (NSCLCs) for EML4-, NPM-, TPM3-, CLTC-, ATIC-, and TFG-ALK fusion transcripts by RT-PCR and subsequent sequencing analysis. Although no expression of NPM-, TPM3-, CLTC-, ATIC-, or TFG-ALK fusion transcripts were detected in any of the cases, expression of EML4-ALK fusion transcripts was detected in two (2.6%) of the 77 NSCLCs. In one of the two NSCLCs there was fusion between exon 13 of EML4 and exon 20 of ALK, i.e., variant 1, and in the other there was fusion between exon 20 of EML4 and exon 20 of ALK, i.e., variant 2. Both patients had a history of smoking, and histologically the carcinomas were adenocarcinoma. No somatic mutations were detected in the mutation cluster regions of the EGFR, K-RAS, and PIK3CA genes in these two carcinomas, however, a Pro177Ser mutation of the p53 gene was detected in the carcinoma that contained the variant 1 EML4-ALK fusion transcripts. In situ PCR of a paraffin block section showed that the carcinoma with expression of the variant 1 actually contained an EML4-ALK fusion gene. These results suggested that the EML4-ALK fusion gene product is involved in the carcinogenesis of a subset of NSCLCs.
Lung Cancer 2008 Aug
PMID:EML4-ALK fusion transcripts, but no NPM-, TPM3-, CLTC-, ATIC-, or TFG-ALK fusion transcripts, in non-small cell lung carcinomas. 1824 62

New biological factors have not been extensively studied in stage III NSCLC as yet. The aim of this retrospective study was to assess the association between the expression and the prognostic role on survival of four biological markers in stage III NSCLC. Clinical characteristics were retrieved from the patients charts. EGF-R, Mdm2, p53 and TTF-1 expressions were evaluated by immunohistochemistry by three independent observers. Cox multivariate model was used to assess the impact of clinical and biological factors on patients' survival. A total of 84 stage III NSCLC patients, treated between 03/1987 and 08/2003, were included in the study. There was a statistically significant association between the expression of TTF-1 and EGFR (p=0.01) or TTF-1 and Mdm2 (p=0.04). Positive expressions for EGFR or TTF-1 were almost mutually exclusive. The status EGFR+/TTF-1--was mainly found in squamous cell carcinoma (18 among 19tumours). In multivariate analysis, only treatment with curative intent was independently associated with better survival (p=0.0004). In stage III NSCLC, there was a significant association between TTF-1 and EGFR or TTF-1 and Mdm2. The status EGFR+/TTF-1--was associated with squamous cell carcinoma.
Lung Cancer 2008 Oct
PMID:EGFR, TTF-1 and Mdm2 expression in stage III non-small cell lung cancer: a positive association. 1835 39

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) demonstrated to significantly improve survival of non-small cell lung cancer patients (NSCLC) previously exposed to chemotherapy. Although clinical features, particularly smoking history, help physicians for identifying the sensitive population, a proper patient selection should not preclude to drug target assessment. EGFR mutations or increased EGFR gene copy number assessed by fluorescence in situ hybridization (FISH) identify NSCLC with the highest chance to respond to the therapy. Although indirect comparisons suggest that mutation analysis is the best available technique for identification of responders, survival improvement is not confined to individuals with tumor shrinkage. For patients with metastatic NSCLC, where definitive cure in not achievable, response is probably not the best end-point, since survival improvement observed with TKI included also patients with stable or progressive disease. Data from large randomized studies indicated that FISH technology is probably the best method for patient selection when the main end-point is survival. FISH was the only EGFR test significantly associated with prolonged survival in large randomized trials with a control arm of placebo, the only studies able to discriminate between predictive and prognostic value of such biomarkers. Moreover, in absence of any convincing data on the prognostic role of EGFR FISH or EGFR mutations, results from large phase III trials suggest that patients with clinical or biological predictors for TKI sensitivity survive longer when exposed to standard chemotherapy, a relevant aspect that should be considered in designing clinical trials.
Lung Cancer 2008 May
PMID:EGFR FISH versus mutation: different tests, different end-points. 1836 87

FUS1 is a novel tumor suppressor gene identified in the human chromosome 3p21.3 region where allele losses and genetic alterations occur early and frequently for many human cancers. Expression of FUS1 protein is absent or reduced in the majority of lung cancers and premalignant lung lesions. Restoration of wt-FUS1 function in 3p21.3-deficient non-small cell lung carcinoma cells significantly inhibits tumor cell growth by induction of apoptosis and alteration of cell cycle kinetics. Here we present recent findings indicating that FUS1 induces apoptosis through the activation of the intrinsic mitochondrial-dependent and Apaf-1-associated pathways and inhibits the function of protein tyrosine kinases including EGFR, PDGFR, AKT, c-Abl, and c-Kit. Intravenous administration of a nanoparticle encapsulated FUS1 expression plasmid effectively delivers FUS1 to distant tumor sites and mediates an antitumor effect in orthotopic human lung cancer xenograft models. This approach is the rationale for an ongoing FUS1-nanoparticle-mediated gene delivery clinical trial for the treatment of lung cancer.
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PMID:Tumor suppressor FUS1 signaling pathway. 1837 48


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