Screening for Epidermal Growth Factor Receptor Mutations in Lung Cancer

https://digital.library.unt.edu/ark:/67531/metadc284540/m2/1/high_res_d/1-s2.0-S0304419X13000644-main.pdf

Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors.

Exosomes are small (∼30–140 nm) lipid bilayer-enclosed particles of endosomal origin. They are a subset of extracellular vesicles (EVs) that are secreted by most cell types. There has been growing interest in exosome research in the last decade due to their emerging role as intercellular messengers and their potential in disease diagnosis. Indeed, exosomes contain proteins, lipids, and RNAs that are specific to their cell origin and could deliver cargo to both nearby and distant cells. As a result, investigation of exosome cargo contents could offer opportunities for disease detection and treatment. Moreover, exosomes have been explored as natural drug delivery vehicles since they can travel safely in extracellular fluids and deliver cargo to destined cells with high specificity and efficiency. Despite significant efforts made in this relatively new field of research, progress has been held back by challenges such as inefficient separation methods, difficulties in characterization, and lack of specific biomarkers. In this review, we summarize the current knowledge in exosome biogenesis, their roles in disease progression, and therapeutic applications and opportunities in bioengineering. Furthermore, we highlight the established and emerging technological developments in exosome isolation and characterization. We aim to consider critical challenges in exosome research and provide directions for future studies.

Challenges and opportunities in exosome research—Perspectives from biology, engineering, and cancer therapy

Importance The EURTAC trial demonstrated the greater efficacy of erlotinib compared with chemotherapy for the first-line treatment of European patients with advanced non–small-cell lung cancer (NSCLC) harboring oncogenic epidermal growth factor receptor ( EGFR ) mutations (exon 19 deletion or L858R mutation in exon 21) in tumor tissue. Objective To assess the feasibility of using circulating free DNA (cfDNA) from blood samples as a surrogate for tumor biopsy for determining EGFR mutation status and to correlate EGFR mutations in cfDNA with outcome. Design, Setting, and Participants This prespecified analysis was a secondary objective of the EURTAC trial using patients included in the EURTAC trial from 2007 to 2011 with available baseline serum or plasma samples. Patients had advanced NSCLC, oncogenic EGFR mutations in the tumor, and no prior chemotherapy for metastatic disease and were treated with erlotinib or chemotherapy. EGFR mutations were examined in cfDNA isolated from 97 baseline blood samples by our novel peptide nucleic acid–mediated 5´ nuclease real-time polymerase chain reaction (TaqMan) assay. Main Outcomes and Measures Overall survival (OS), progression-free survival (PFS), and response to therapy were correlated with type of EGFR mutations in cfDNA. Results In samples from 76 of 97 (78%) patients with usable blood samples, EGFR mutations in cfDNA were detected. Median OS was shorter in patients with the L858R mutation in cfDNA than in those with the exon 19 deletion (13.7 [95% CI, 7.1-17.7] vs 30.0 [95% CI, 19.3-37.7] months; P EGFR mutations in cfDNA identified the L858R mutation in tumor tissue or in cfDNA as a marker of shorter OS (hazard ratio [HR], 2.70 [95% CI, 1.60-4.56]; P P  = .008). For patients with the L858R mutation in tissue, median OS was 13.7 (95% CI, 7.1-17.7) months for patients with the L858R mutation in cfDNA and 27.7 (95% CI, 16.1-46.2) months for those in whom the mutation was not detected in cfDNA (HR, 2.22 [95% CI, 1.09-4.52]; P  = .03). In the multivariate analysis of the 76 patients with EGFR mutations in cfDNA, only erlotinib treatment remained an independent predictor of longer PFS (HR, 0.41 [95% CI, 0.23-0.74]; P  = .003). Conclusions and Relevance The peptide nucleic acid–mediated 5´ nuclease real-time polymerase chain reaction (TaqMan) assay used in this study can be used to efficiently assess EGFR mutations in cfDNA. The L858R mutation in cfDNA may be a novel surrogate prognostic marker. Trial Registration clinicaltrials.gov Identifier:NCT00446225

https://jamanetwork.com/journals/jamaoncology/articlepdf/2120916/coi140019.pdf

Association of EGFR L858R Mutation in Circulating Free DNA With Survival in the EURTAC Trial.

FOXM1 (forkhead box protein M1) is a critical proliferation-associated transcription factor that is widely spatiotemporally expressed during the cell cycle It is closely involved with the processes of cell proliferation, self-renewal, and tumorigenesis In most human cancers, FOXM1 is overexpressed, and this indicates a poor prognosis for cancer patients FOXM1 maintains cancer hallmarks by regulating the expression of target genes at the transcriptional level Due to its potential role as molecular target in cancer therapy, FOXM1 was named the Molecule of the Year in 2010 However, the mechanism of FOXM1 dysregulation remains indistinct A comprehensive understanding of FOXM1 regulation will provide novel insight for cancer and other diseases in which FOXM1 plays a major role Here, we summarize the transcriptional regulation, post-transcriptional regulation and post-translational modifications of FOXM1, which will provide extremely important implications for novel strategies targeting FOXM1

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Regulation of the master regulator FOXM1 in cancer

JAK2/STAT3 signaling pathway activation mediates tumor angiogenesis by upregulation of VEGF and bFGF in non-small-cell lung cancer

Vertical bearing capacity for ring footings

Forkhead box M1 (FOXM1), a member of the Fox family of transcriptional factors, is considered to be an independent predictor of poor survival in many solid cancers. However, the underlying mechanism is not yet clear. The aim of the present study was to investigate the clinical significance of the correlation between FOXM1 and epithelial-mesenchymal transition (EMT) in non-small cell lung carcinoma and the possible mechanism responsible for FOXM1-induced EMT and metastasis. In the present study, expression levels of FOXM1 and EMT indicator proteins were determined by tissue microarray (TMA) and immunohistochemical staining, western blotting and reverse transcription-PCR (RT-PCR). Other cellular and molecular approaches including gene transfection, small interfering RNA (siRNA), and migration and invasion assays were utilized. Our results demonstrated that FOXM1 overexpression was statistically significantly associated with a higher TNM stage (p=0.036), lymph node metastasis (p=0.009) and a positive smoking history of the patients (p=0.044). Additionally, high expression of FOXM1 correlated with loss of E-cadherin expression (p<0.001) and anomalous immunopositivity of Vimentin (p=0.002). Moreover, patient survival analysis demonstrated that high expression of FOXM1 (p=0.043) and the presence of lymph node metastasis (p=0.042) were independent prognostic factors for non-small cell lung cancer (NSCLC). Furthermore, various in vitro experiments indicated that overexpression or knockdown of FOXM1 expression altered EMT through activation or inhibition of the AKT/p70S6K signaling pathway. Collectively, the results suggest that FOXM1 may be used as a prognostic indicator for patients with NSCLC and promotes metastasis by inducing EMT of lung cancer cells through activation of the AKT/p70S6K pathway. Therefore, we suggest that FOXM1 may be a potential target for lung cancer therapy.

/pdf/overexpression-of-foxm1-is-associated-with-emt-and-is-a-4840259ont.pdf

Overexpression of FOXM1 is associated with EMT and is a predictor of poor prognosis in non-small cell lung cancer.

Probabilistic parameter estimation and predictive uncertainty based on field measurements for unsaturated soil slope

Epidermal growth factor receptor gene (EGFR) mutations are among the best predictive markers of the efficacy of EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment. Mutations in the EGFR gene confer sensitivity to EGFR-TKIs in patients with advanced non-small cell lung cancer (NSCLC). This study determined the concordance rate of EGFR mutations in serum samples and tumour tissue from Chinese patients with advanced NSCLC and compared two detection methods: mutant-enriched polymerase chain reaction-based DNA sequencing and non-enriched sequencing. The EGFR mutation status in serum was consistent with that in paired tumour samples, with a concordance rate of 93.1% for mutant-enriched sequencing. In serum samples, mutant-enriched sequencing demonstrated sensitivity and specificity of 77.8% and 100%, respectively, and was more sensitive than the non-enriched assay. Mutant-enriched sequencing in serum may provide a non-invasive and sensitive method for detecting EGFR mutation status in patients with unresectable NSCLC.

https://journals.sagepub.com/doi/pdf/10.1177/147323001103900425

Serum detection of epidermal growth factor receptor gene mutations using mutant-enriched sequencing in Chinese patients with advanced non-small cell lung cancer

Jiong-Yi Wang

Papers

JAK2/STAT3 signaling pathway activation mediates tumor angiogenesis by upregulation of VEGF and bFGF in non-small-cell lung cancer

Vertical bearing capacity for ring footings

Overexpression of FOXM1 is associated with EMT and is a predictor of poor prognosis in non-small cell lung cancer.

Probabilistic parameter estimation and predictive uncertainty based on field measurements for unsaturated soil slope

Serum detection of epidermal growth factor receptor gene mutations using mutant-enriched sequencing in Chinese patients with advanced non-small cell lung cancer