Top PDF Bioinformatics Analyses of the Role of Vascular Endothelial Growth Factor in Patients with Non-Small Cell Lung Cancer.

Despite progresses achieved in the management of NSCLC, identification of specific molec- ular criteria is still a challenge to increase response rates [14]. In the present study, we analyzed the gene expression profiles (GSE39345) of peripheral blood mononuclear cells (PBMC) in patients with advanced stage NSCLC. The differentially expressed genes (DEGs) between healthy controls and patients before chemotherapy were analyzed. To the best of our knowl- edge, the dataset has not been analyzed before. Particularly, we evaluated VEGF genes expres- sion and analyzed the VEGF signaling pathway. The VEGFA sub-network was constructed and functional enrichment analysis were performed with its related DEGs. We aimed to identify the expression pattern of VEGF in NSCLC and to explore its potential correlation with the pro- gression of NSCLC. Unlike previous studies that explored the function of VEGF through exper- imental methods, the bioinformatics analyses performed in study provided a comprehensive evaluation of VEGF related protein-protein interactions and could be used to predict the inter- action relationships between VEGF and other genes.

Lung cancer leads cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC), the most prevalent subtype of this recalcitrant cancer, is usually diagnosed at advanced stages, and available systemic therapies are mostly palliative. The probing of the NSCLC kinome has identified numerous nonoverlapping driver genomic events, including epidermal growth factor receptor (EGFR) gene mutations. This review provides a synopsis of preclinical and clinical data on EGFR mutated NSCLC and EGFR tyrosine kinase inhibitors (TKIs). Classic somatic EGFR kinase domain mutations (such as L858R and exon 19 deletions) make tumors addicted to their signaling cascades and generate a therapeutic window for the use of ATP-mimetic EGFR TKIs. The latter inhibit these kinases and their downstream effectors, and induce apoptosis in preclinical models. The aforementioned EGFR mutations are stout predictors of response and augmentation of progression-free survival when gefitinib, erlotinib, and afatinib are used for patients with advanced NSCLC. The benefits associated with these EGFR TKIs are limited by the mechanisms of tumor resistance, such as the gatekeeper EGFR-T790M mutation, and bypass activation of signaling cascades. Ongoing preclinical efforts for treating resistance have started to translate into patient care (including clinical trials of the covalent EGFR-T790M TKIs AZD9291 and CO-1686) and hold promise to further boost the median survival of patients with EGFR mutated NSCLC.

Background. Although early-stage non-small-cell lung cancer (NSCLC) is considered a potentially curable disease following complete resection, patients have a wide spectrum of survival according to stage (IB, II, IIIA). Within each stage, gene expression profiles can identify patients with a higher risk of recurrence. We hypothesized that altered mRNA expression in nine genes could help to predict disease outcome: excision repair cross-complementing 1 (ERCC1), myeloid zinc finger 1 (MZF1) and Twist1 (which regulate N-cadherin expression), ribonucleotide reductase subunit M1 (RRM1), thioredoxin-1 (TRX1), tyrosyl- DNA phosphodiesterase (Tdp1), nuclear factor of activated T cells (NFAT), BRCA1, and the human homolog of yeast budding uninhibited by benzimidazole (BubR1). Methodology and Principal Findings. We performed real-time quantitative polymerase chain reaction (RT-QPCR) in frozen lung cancer tissue specimens from 126 chemonaive NSCLC patients who had undergone surgical resection and evaluated the association between gene expression levels and survival. For validation, we used paraffin-embedded specimens from 58 other NSCLC patients. A strong inter-gene correlation was observed between expression levels of all genes except NFAT. A Cox proportional hazards model indicated that along with disease stage, BRCA1 mRNA expression significantly correlated with overall survival (hazard ratio [HR], 1.98 [95% confidence interval (CI), 1.11-6]; P = 0.02). In the independent cohort of 58 patients, BRCA1 mRNA expression also significantly correlated with survival (HR, 2.4 [95%CI, 1.01-5.92]; P = 0.04). Conclusions. Overexpression of BRCA1 mRNA was strongly associated with poor survival in NSCLC patients, and the validation of this finding in an independent data set further strengthened this association. Since BRCA1 mRNA expression has previously been linked to differential sensitivity to cisplatin and antimicrotubule drugs, BRCA1 mRNA expression may provide additional information for customizing adjuvant antimicrotubule-based chemotherapy, especially in stage IB, where the role of adjuvant chemotherapy has not been clearly demonstrated.

When using clinical cut-off determination, pretreatment albumin lost its significance on predicting outcome for NSCLC, and ANPG was also disqualified for independent prognostic factor in multivariate analyses. This might be due to serious maldistribution of dichotomy and tiny sample size of low albumin level, high neutrophil level and grade3 (ANPG). Besides, for patients initially diagnosed as primary lung cancer, most haematoglgical parameters of them had not changed too much and were still in normal clinical reference range. Therefore, the clin- ical reference cut-off values may not be suitable for dichotomy of these patients. Even so, K-M curve and survival data indicated that there still existed worse prognostic trend for patients with low pretreatment level, high pretreatment level and high ANPG grade (Fig 3).

Despite the initial response, all patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) eventually develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). The EGFR- T790M secondary mutation is responsible for half of acquired resistance cases, while MET amplification has been associated with acquired resistance in about 5-15% of NSCLCs. Clinical findings indicate the retained addiction of resistant tumors on EGFR signaling. Therefore, we evaluated the molecular mechanisms supporting the therapeutic potential of gefitinib maintenance in the HCC827 GR5 NSCLC cell line harbouring MET amplification as acquired resistance mechanism. We demonstrated that resistant cells can proliferate and survive regardless of the presence of gefitinib, whereas the absence of the drug significantly enhanced cell migration and invasion. Moreover, the continuous exposure to gefitinib prevented the epithelial-mesenchymal transition (EMT) with increased E-cadherin expression and down-regulation of vimentin and N-cadherin. Importantly, the inhibition of cellular migration was correlated with the suppression of EGFR-dependent Src, STAT5 and p38 signaling as assessed by a specific kinase array, western blot analysis and silencing functional studies. On the contrary, the lack of effect of gefitinib on EGFR phosphorylation in the H1975 cells (EGFR-T790M) correlated with the absence of effects on cell migration and invasion. In conclusion, our findings suggest that certain EGFR-mutated patients may still benefit from a second-line therapy including gefitinib based on the specific mechanism underlying tumor cell resistance.

TERT is of great importance for genome integrity and plays a crucial role in cancer initia- tion and progression. Many molecular epidemiology studies have demonstrated genetic vari- ations in the TERT gene as risk factors for many cancer types [5,10]. Mocellin et al. have summarized eighty-five studies of TERT polymorphisms enrolling 490901 subjects with a total of 24 tumor types, and have demonstrated the polymorphisms rs2736098, rs2736100, and rs2853676 significantly associated with risk of lung cancer [10]. What is more, several studies have reported that the polymorphism rs2736100 displayed significant correlation with lung cancer risk in never-smoking females [28–30]. Accumulating evidence has demon- strated that the molecular pathogenesis and treatment response of lung cancer differs by smoking status. Lung cancers arising in never smokers are suggested to have different molec- ular carcinogenic pathways and distinct profiles of oncogenic mutations; for example, lung cancer patients in never smokers are much more likely to carry mutations of epidermal growth factor receptor (EGFR) [31,32]. Functional and mechanistic studies have indicated that TERT plays an important role in regulating oncogenic signaling pathways and acts as a transcriptional regulator of EGFR expression, implying its potential role in the progression of lung cancers arising in never smokers [17,18,33]. In the current study, we did not observe sig- nificant association between rs2736100 and clinical outcomes of platinum-based chemother- apy, both in overall patients and in smoking status subgroups. However, the polymorphism rs4975605 showed a significant influence on clinical benefit after platinum-based treatment, and exhibited a much stronger effect in never-smoking female subgroup. This suggested that the variants rs4975605 displayed significant impact on the rate of progressive disease (PD) in advanced NSCLC patients following first-line platinum-based treatment. Futher analysis found that heterozygous rs4975605 exhibited significant influence on PFS in never-smoking female subgroup (adjusted HR, 1.50; 95%CI, 1.03–2.19; P = 0.037), suggesting its significant impact on advanced NSCLC progression.

Collection of biospecimens and outcomes data complied with the Helsinki Declaration and was approved by the Wayne State University School of Medicine Institutional Review Board. Tumor materials used in this research were from patients who provided written informed consent. Fresh-frozen tumor specimens were collected prospectively from patients who underwent a surgical resection for diagnosed or suspected lung cancer. All patients who were candidates for surgical resection of their lung cancer, either biopsy proven or suspected, were consented for specimen collection. Only patients whose tumors were confirmed to be NSCLC were included in this analysis. Specimens from patients with a final diagnosis of small cell carcinoma (N=16) or a small cell component of NSCLC (N = 2), carcinoid tumors (N = 6), or mesothelioma (N = 3) were excluded. Specimens were kept frozen at -80°C in aliquots of approximately 0.1 g. Specimen procurement procedures were developed to reduce the resection to freezing time interval to less than 30 min. The quality of extracted analytes was assured by performing integrity analysis. The overall procurement period ranged from 1985 to 2001. Formalin-fixed and paraffin-embedded specimens were reviewed to verify diagnosis and to determine tumor cell content. Specimens were uniquely identified by laboratory numbers that allowed cross-referencing with clinical data from the tumor registry and chart review without disclosure of patient identity. Demographic and clinical outcomes data collected included the dates of birth, diagnosis (defined as the date of first pathologic verification of malignancy), surgical resection (same as the date of specimen procurement), and date of last follow-up or death; sex, race, tumor histology, pathological and clinical tumor stage (version 6), performance status, weight loss (defined as >5% during the 3 months proceeding surgery), and self-reported smoking history (defined as life-time never smoker for those who had smoked <100 cigarettes, former smoker for those who had quit cigarette smoking for more than one year, and smoker for all others). One of the patients included in this analysis had preoperative chemotherapy and radiation and one had preoperative radiation. None of the patients had adjuvant therapy. A standardized protocol for patients’ follow-up evaluation was not specified.

Abstract: Immuno checkpoint inhibitors have ushered in a new era with respect to the treatment of advanced non-small-cell lung cancer. Many patients are not suitable for treatment with epidermal growth factor receptor tyrosine kinase inhibitors (eg, gefitinib, erlotinib, and afatinib) or with anaplastic lymphoma kinase inhibitors (eg, crizotinib and ceritinib). As a result, anti- PD-1/PD-L1 and CTLA-4 inhibitors may play a novel role in the improvement of outcomes in a metastatic setting. The regulation of immune surveillance, immunoediting, and immunoescape mechanisms may play an interesting role in this regard either alone or in combination with current drugs. Here, we discuss advances in immunotherapy for the treatment of metastatic non-small-cell lung cancer as well as future perspectives within this framework.

Objective: To report the demographic data and clinical outcomes of non-small-cell lung cancer patients exposed to erlotinib in any line of treatment. Methods: This was a retrospective cohort study of non- small-cell lung cancer patients from a reference general hospital and a private oncology clinic, who received erlotinib from 2005 to 2011. Statistical analysis was performed and we evaluated demographic data and response to treatment, by correlating the results of this first cohort published in Brazil with results of current literature. Results: A total of 44 patients were included; 65.9% were diagnosed with adenocarcinoma, and 63.6% had metastatic disease. The mean age was 63.3 years. The median follow-up was 47.9 months. Epidermal growth factor receptor mutation screening was performed in 22.7% of patients (n=10), with mutation present in 30% of patients. The median overall survival was 46.3 months, and there was a higher probability of survival at 60 months for females compared to males (29.4% versus 15.8%; p=0.042). The other variables did not present significant statistical difference. Conclusion: We collected the largest cohort of patients with non-small-cell lung cancer who have used erlotinib in Brazil to date, and demonstrated that outcomes of patients treated at our clinic during the study period were consistent with the results of current literature in similar patients.

The development of new diagnostic, prognostic and predictive markers could significantly enhance its early detection outcome. Results from the Collaborative Advanced Stage Tissue Cancer (CASTLE) network are particularly awaited. In fact, this study aims to collect tumor, plasma and serum samples from stage IV NSCLC patients before treatment to test a panel of biomarkers in order to predict response (NCT01574300). Early detection is particularly crucial for tumors without clinical symptoms during the initial stages of their development, such as lung cancer. Stage IIIB/IV NSCLC patients have a poor prognosis and the majority of them, not presenting a drugable molecular alteration, have a median survival around 12 months using platinum based chemotherapy doublets [7]. The era of molecular targeted therapy in lung cancer started in 2004, when activating mutations in the epidermal growth factor receptor (EGFR) and their

Because lymphocytes play an important role in tumor eradication[11] and macrophages are associated with tumor progression[12, 13], we presumed that patients with higher lymphocyte- to-monocyte ratio (LMR) might have better prognosis in EGFR-mutant NSCLC patients receiving first-line EGFR-TKIs. The LMR was found to be a prognostic factor in hematological cancer [14, 15] and in several types of solid tumors. [16–18] In addition, elevated LMR was found to be an independent prognostic factor in patents with early-stage lung cancer after com- plete resection[19] and in patients with advanced-stage lung cancer who were undergoing plat- inum-based chemotherapies.[20] However, to the best of our knowledge, the prognostic significance of baseline and trend of LMR in EGFR-mutant NSCLC patients receiving first-line EGFR-TKIs has not been established. We conducted a retrospective analysis to investigate the influence of baseline and trend of LMR on PFS and OS.

I read the recent article by Bacchi et al. in a recent issue of your esteemed journal with great interest (1). The article is highly thought provoking. Over the past few years, new data have emerged that reveal the emerging role of epidermal growth factor (EGF) and its receptor (EGFR) in the personaliza- tion of non-small cell lung cancer (NSCLC) treatment.

Epidermal growth factor receptor (EGFR), member of the human epidermal growth factor receptor (HER) family, plays a critical role in regulating multiple cellular processes including proliferation, differentiation, cell migration and cell survival. Deregulation of the EGFR signal- ing has been found to be associated with the development of a variety of human malignancies including lung, breast, and ovarian cancers, making inhibition of EGFR the most promising molecular targeted therapy developed in the past decade against cancer. Human non small cell lung cancers (NSCLC) with activating mutations in the EGFR gene frequently experience significant tumor regression when treated with EGFR tyrosine kinase inhibitors (TKIs), although acquired resistance invariably develops. Resistance to TKI treatments has been associated to secondary mutations in the EGFR gene or to activation of additional bypass sig- naling pathways including the ones mediated by receptor tyrosine kinases, Fas receptor and NF-kB. In more than 30–40% of cases, however, the mechanisms underpinning drug-resis- tance are still unknown. The establishment of cellular and mouse models can facilitate the unveiling of mechanisms leading to drug-resistance and the development or validation of novel therapeutic strategies aimed at overcoming resistance and enhancing outcomes in NSCLC patients. Here we describe the establishment and characterization of EGFR TKI- resistant NSCLC cell lines and a pilot study on the effects of a combined MET and EGFR inhibitors treatment. The characterization of the erlotinib-resistant cell lines confirmed the association of EGFR TKI resistance with loss of EGFR gene amplification and/or AXL overex- pression and/or MET gene amplification and MET receptor activation. These cellular models can be instrumental to further investigate the signaling pathways associated to EGFR TKI- resistance. Finally the drugs combination pilot study shows that MET gene amplification and MET receptor activation are not sufficient to predict a positive response of NSCLC cells to a cocktail of MET and EGFR inhibitors and highlights the importance of identifying more reliable biomarkers to predict the efficacy of treatments in NSCLC patients resistant to EGFR TKI.

remains unknown. Firstly the increase in platelet count may promote tumor cells growth and angiogenesis. Platelets re- lease various cytokines, including vascular endothelial growth factor (VEGF) and platelet- derived growth factor (PDGF), during blood clotting. The VEGF and PDGF fam- ily of proteins has a significant role in regulating angio- genesis. The invasiveness of the cancer cells may be en- hanced by the plasma components in stored platelets [24]. Additionally, bevacizumab, an inhibitor of VEGF, is able to reduce this promotive effect. Moreover, platelets promote the formation of capillary- like structures by endothelial cells, via integrins mediating cell- cell adhesion [25]. Sec- ondly, platelets enhance tumor metastasis by protecting the tumor cells from the host’s immune system. Platelets ex- pressing immunoregulatory proteins, including glucocor- ticoid- induced tumor- necrosis factor receptor- related pro- tein, may protect the cancer [26].

Angiogenesis, which is the formation of new blood vessels from the endothelium of existing vasculature, plays a pivotal role in tumor growth, progression and metastasis [3]. A series of angiogenic factors are overexpressed in tumors, such as vascular endothelial growth factor (VEGF) and its receptors, fibroblast growth factor (FGF) and its receptors, hepatocyte growth factor (HGF), interleukins (ILs-1, 6, and 8) and stromal cell derived factor 1, transforming growth factorβ (TGFβ) and endothelin [4]. There are 18 mammalian FGF ligands and 4 FGF receptors (FGFR1-4) [5,6]. Basic FGF (bFGF), also known as FGF-2, is the most extensively studied peptide. bFGF is able to bind FGFR1, FGFR2, and FGFR3, leading to auto-phosphory- lation of intracellular tyrosine residues, which are involved in instigating tumor cell prolifera- tion and invasion in various tumor types [7]. The expression of MMP-1, HGF, Bcl2, survivin, MMP-9 and MMP-13 is up-regulated through bFGF and results in a gain of invasive and anti- apoptotic properties [8–11]. Deregulation of FGF signaling in tumors has been reported in var- ious tumor types. A number of studies have explored the prognostic value of bFGF in lung can- cer patients, but the results were contradictory, and therefore a consensus has not been

Uma análise do estadiamento internacional para o câncer do pulmão, utilizado mundialmente nos últimos dez anos, mostrou problemas em duas áreas. O primeiro problema diz respeito ao mapa dos linfonodos mediastinais criado pelo Prof. Tsuguo Naruke, do Instituto de Câncer do Japão, e recomendado pelo American Joint Commitee on Cancer

those, another seventy genes have also been associated with the development of lung cancer. Such genes are described on a site that is host to a gene archive (http://www.bioinformatics. org/LuGenD/index.htm), which is of funda- mental importance for the understanding of the genetic programming involved in the onset and development of lung cancer. Three repre- sentatives of this archive—CYP1A1, CYP2A6 and CYP2E1—are P450 cytochrome family members and participate in the metabolism of various drugs, including tobacco-derived substances, such as 4-(methylnitrosamino)-1-(3-pyridyl)-1 -butanone and N’-nitrosonornicotine. Genetic variations in this family members increase the risk of developing lung cancer. In this edition of the Brazilian Journal of Pulmonology, Honma et al. describe a study which evaluates the distri- bution of the CYP1A1*2A allele in 200 patients with lung cancer and 264 negative controls. (11)

Tumors whose paraffin blocks were located and contained enough material for new sections were included in the survey. We required adequate tissue and data for stag- ing each lesion by its tumor location, and determining lesion size, level of invasion into adjacent tissues, lymph node involvement, and distant metastasis. Clinical data and tumor staging were obtained from patients’ records.

who have never smoked. Among nonsmokers, passive smoking and exposure to other carcino- gens are risk factors for the development of the tumor. In both cases, the hereditary component is determinant, since it confers a greater genetic predisposition to the individuals. Genes such as p53, p14ARF, p16INK4a, RB, FHIT and RASSF1A are related to lung cancer. (6-10) In addition to

Objective: Lung cancer is a global public health problem and is associated with high mortality. Lung cancer could be largely avoided by reducing the prevalence of smoking. The objective of this study was to analyze the effects of social, behavioral, and clinical factors on the survival time of patients with non-small cell lung cancer treated at Cancer Hospital I of the José Alencar Gomes da Silva National Cancer Institute, located in the city of Rio de Janeiro, Brazil, between 2000 and 2003. Methods: This was a retrospective hospital cohort study involving 1,194 patients. The 60-month disease-speciic survival probabilities were calculated with the Kaplan-Meier method for three stage groups. The importance of the studied factors was assessed with a hierarchical theoretical model after adjustment by Cox multiple regression. Results: The estimated 60-month speciic- disease lethality rate was 86.0%. The 60-month disease-speciic survival probability ranged from 25.0% (stages I/II) to 2.5% (stage IV). The performance status, the intention to treat, and the initial treatment modality were the major prognostic factors identiied in the study population. Conclusions: In this cohort of patients, the disease-speciic survival probabilities were extremely low. We identiied no factors that could be modiied after the diagnosis in order to improve survival. Primary prevention, such as reducing the prevalence of smoking, is still the best method to reduce the number of people who will suffer the consequences of lung cancer.