bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A33: Markov model of VeriStrat© selection criteria for EGFR Inhibitor therapy predicts improved survival for previously treated patients with NSCLC
Authors: Nelson Richard E. , Akerley Wallace 
Published: March 2013

Abstract
Background: EGFR inhibitor therapy extends survival as 2nd or 3rd line treatment of patients with previously treated metastatic non-small cell lung cancer (NSCLC), but a randomized trial of 2nd line therapy in unselected patients showed similar benefit versus conventional chemotherapy. EGFR mutation analysis is useful in choosing therapy, but it is applicable to only a minority of patients due to low frequency of mutation in a North American population and ignores the majority of patients who may benefit with wild type status. Alternative selection strategies are needed. VeriStrat is a protein expression profile utilizing matrix-assisted laser desorption/ionization time of flight mass spectrometry to analyze serum. The test classifies patients as VeriStrat Good or VeriStrat Poor based on likelihood of benefitting from EGFR inhibitor therapy. The objective of this research was to model the anticipated survival of patients using a Veristrat Selection Strategy for 2nd line therapy of NSCLC to the alternative treatment strategies of chemotherapy for all (Chemoall), EGFR inhibitor to all (EGFR-all) l, or to performance status selection (PS selection), a common practice, where those with good performance status receive chemotherapy and those with poor PS receive EGFR inhibitor therapy.
Methods: We developed a Markov model to estimate the expected survival of patients for 4 different treatment strategies for NSCLC: (1) VeriStrat Selection, (2) chemotherapy to all patients, (3) EGFR inhibitor to all patients, and (4) PS selection. Model inputs, taken from published literature, for the base-case analysis (and ranges) were the following: PS 0-1, 50% (35%–65%); VeriStrat Good, 60% (45%–75%); VeriStrat Good if PS &gt;1, 40% (25%–55%); 1-year survival on EGFR inhibitor if VeriStrat Good, 47% (43–50); 1-year survival on EGFR inhibitor if VeriStrat Poor, 12% (8–16) and 1-year survival on chemotherapy, 29% (23–35). Probabilistic sensitivity analysis was performed using 10,000 2nd order Monte Carlo simulations.
Results: In the base case analysis, the median survival for EGFR-all was 8.97 months, Chemo-all was 8.48 months, PS selection was 8.20 months and VeriStrat selection was 10.03 months. In the sensitivity analysis, the VeriStrat selection strategy yielded the longest survival in each of the 10,000 simulations.
Conclusion: These results suggest that VeriStrat-based selection of “standard of care” 2nd line therapy of NSCLC improves survival to a clinically significant degree. This strategy, in the absence of new therapies, appears to improve median survivals by 4–6 weeks.
Abstract A38: Whole methylome explorations of paired lung tumor and non-tumor clinical samples
Authors: Mullapudi Nandita , Suzuki Masako , Fazzari Melissa , Han Weiguo , Spivack Simon D. 
Published: March 2013

Abstract
Background: Hypermethylation in specific candidate gene promoters has been found during progressive lung carcinogenesis. To explore common methylation events on a genome-wide scale in lung cancer, we analyzed the methylation profiles of paired NSCLC tumor and far adjacent non-tumor samples using the HELP-microarray assay, which yields information on 1.2 million fragments throughout the genome.
Methods: The HELP (HpaII tiny fragment Enriched by Ligation mediated PCR) assay is based on the generation of restriction enzyme libraries generated by methylation sensitive (HpaII) and methylation insensitive (MspI) isoschizomers, in its second generation as a microarray platform. The assay lends itself to low starting amounts of DNA (3 ug) and robust assessment of methylation status by comparing ratios of HpaII- generated-fragments to MspI- generated fragments co-hybridized to a Nimbelgen custom high-density microarrays. The CCGG sites were weighted if neighboring CCGGs were methylated in same direction. Here, 24 pairs of tumor and adjacent non-tumor samples were analyzed using the HELP assay.
Summary of results: At p = 5E-6, we identified 26,138 differentially methylated fragments (corresponding to 2 CpG sites each) in tumor versus non-tumor. The overall trend was consistent with genome-wide hypomethylation and locus specific hypermethylation (localized to CG-island containing promoters). We could identify both known and novel regions of the genome as well as specific gene-promoters that are hypermethylated in tumor versus non-tumor.
Region # loci # signif loci T Hypomethyl T Hypermethyl
Promoter 151,568 576 69% 31%
Gene Body 551,628 9,817 62% 38%
Intergenic 540,473 15,745 97% 3%
Conclusion: An interrogation of methylation status of 1.2 million loci throughout the genome in paired lung tumor/non-tumor specimens reveals many more differential methylation events in gene bodies and intergenic regions than in promoters. That said, many previously unreported differentially-methylated gene promoters were identified. We are able to discover individual methylation events common across different clinical specimens. Based on a set of priors, we have narrowed down promoter-specific hypermethylation events for further validation using tagged Bisulfite Genomic Sequencing. We are also working on the integration of methylome date with other genome-wide epigenetic and expression data from the same clinical samples.
[Funding source: NCI 1RC1 CA145422-01; 1K24-CA139054-01]
Abstract A4: An expression map of long noncoding RNAs in human lung and non-small cell lung cancer
Authors: Becker-Santos Daiana D. , Gibb Ewan E. , Vucic Emily A. , Enfield Katey S.S. , Stewart Greg L. , MacAulay Calum E. , Lam Stephen , Lam Wan L. 
Published: March 2013

Abstract
Background: Although still largely unexplored, long non-coding RNAs (lncRNAS) are emerging as an integral functional component of the human transcriptome. LncRNAs are mRNA-like transcripts of at least 200 nucleotides (nts) with no protein-coding capacity. Similar to their protein-coding counterparts, lncRNAs are frequently spliced and polyadenylated, but act at the RNA level. The range of functions described for lncRNAs is extensive, and includes key biological roles in chromatin remodeling, alternative splicing and mRNA degradation. Given their biological functions, dysregulation of lncRNAs is rising as an important feature of many disorders, including malignant transformation. However, the extent of the contribution of differential lncRNA expression to normal lung tissue and lung cancer has not been investigated in a comprehensive manner.
Hypothesis: We hypothesized that lncRNAs are expressed in a lung tissue-specific manner and that non-small-cell lung cancer (NSCLC) exhibits aberrant lncRNA expression patterns.
Methods: Serial Analysis of Gene Expression (SAGE) libraries were used to characterize polyadenylated transcripts in lung tissue compared to a panel of 25 different normal human tissues, and to a cohort of 12 NSCLCs. To generate lncRNA expression profiles, we developed a lncRNA discovery pipeline to map-tag-to-lncRNA matches. To identify differentially expressed lncRNAs we used a permutation test based statistical analysis. Expression pattern in lung tumors were compared to profiles from a variety of cancer types in order to identify lncRNA changes prominent in lung cancer.
Results: Here we show that large-scale expression profiling through SAGE, is an effective resource for investigating the expression pattern of polyadenylated lncRNAs. Applying a novel lncRNA discovery pipeline we reveal extensive, tissue-specific lncRNA expression in normal lung compared to a panel of several different normal human tissues. Importantly, our study reveals that NSCLC demonstrate significantly altered lncRNA expression patterns and identify highly dysregulated transcripts associated with this malignancy as oppose to other types of cancer.
Conclusion: Collectively, our findings support an important role for tissue-specific lncRNAs in lung cancer. Characterization of the functional role of these transcripts will have a considerable impact on our understanding of lung cancer development and progression, and may reveal clinically important biomarkers.
Abstract A41: SOX11 transcriptionally regulates a cytokine-based gene signature in lung cancer-associated fibroblasts (LCAF) to promote tumor growth
Authors: Vicent Silvestre , Gillespie Anna K. , Vakaa Dedeepya , Khatri Purvesh , Chen Ron , Gevaert Olivier , Clarke Nicole , Plevritis Sylvia , Butte Atul , Sweet-Cordero Alejandro 
Published: March 2013

Abstract
Increasing evidence points to an important role for the tumor microenvironment in cancer progression. However, the role of tumor stroma in the pathogenesis of lung cancer is poorly understood. Desmoplasia is a common pathologic feature of many NSCLC. We noted a similar phenotype in a mouse model of lung cancer driven by expression of oncogenic Kras. Lung cancer-associated fibroblasts (LCAFs) and normal lung fibroblasts (NLFs) from the mouse model of Kras-driven lung cancer were isolated and queried at the functional level using a xenograft model. First, we observed that LCAFs promote tumor growth more favorably than NLFs in vivo when co-injected with mouse tumor cells. Moreover, NLFs passaged in vivo acquire features of LCAFs as indicated by an increased tumor-promoting capacity on mouse and human NSCLC xenografts. In addition, conditioned media from LCAFs stimulated cell proliferation in vitro more significantly than that of NLFs. Expression profiling of NLFs and LCAFs using microarrays uncovered a gene set that includes multiple secreted proteins and genes related to inflammatory processes. Moreover, the SRY-related HMG transcription factor Sox11 was highly up-regulated in LCAFs compared to NLFs. Over-expression and knock-down experiments have confirmed that Sox11 regulates the expression of many of the secreted proteins expressed in LCAFs. The relevance of these findings for human NSCLC is suggested by the observation that the mouse LCAF gene expression signature was predictive of survival in a large cohort of human NSCLC. Besides, Sox11 and several of the secreted proteins expressed in LCAFs, along with their putative receptors, were up-regulated in human NSCLC samples. In conclusion, we have identified a potentially novel regulator of the transition between NLFs and LCAFs and, thus, uncovered a new signaling hub that could be used for therapeutic intervention.
Abstract A7: NOTCH 1 and NOTCH 3 expressions for early stage of non-small cell lung cancer
Authors: Cho Eun Kyung , Lee Jae Hoon , Ha Seung Yeon , Park Sanghui , Lee Jae-ik , Hong Junshik , Jung Minkyu , Sym Sun Jin , Park Jinny , Shin Dong Bok 
Published: March 2013

Abstract
Backgrounds: Notch gene Encode 300kDa single-pass transmembrane receptors. It can variously serve as an oncogene or a tumor suppressor and a repressor or inducer of terminal differentiation. It also regulates cell division, differentiation and survival of stem and/or progenital cells in wide range tissues. We examined Notch 1 and 3 to study the correlation of Notch expression and prognosis for non-small cell lung cancer.
Methods: Paraffin-embedded tissue microarrays were constructed. We analyzed Notch 1 and 3 by immunohistochemical stain on surgical tumor specimens.
Results: Results: One hundred fifty-nine of 185 resected tissues for lung cancer (median age 62 years) were available for immunohistochemical stain. The types of tumor histology were adenocarcinoma; 54, squamous cell carcinoma:79, others;26. 121 patients were taken lobectomy and 38 were done pneumonectomy. Notch 1 and 3 receptors were detected in 119 (74.8%) and 130 (81.7%) of total 159 (M:F=114:45) tumor tissues, respectively. Notch 1 receptors showed higher expressions on squamous cell carcinoma than non-squamous cell carcinoma (58.8% vs. 37.8%, p=0.03). However, it was not correlated with sex, smoking status or advanced stages. Five year-relapse free survival (RFS) and overall survival (OS) were 57.4 % and 59.3 % in 159 patients, respectively. Patients with any expression of Notch1 or 3 have correlated with neither RFS nor OS. 5 year OS for patients who showed Notch 3 expression were 62 % and the others were 47.8%, however, it was not statistically significant (p= 0.165). Both of their expressions were detected in 106 of 159 (66.7%) tumor tissues. Sixteen (10 %) had negative expressions in both of them. The patients with both positive expressions had the tendency of longer OS than both negative patients. Their 5 year OS were 60.8 % vs. 38.2% (p=0.068) and 5 year RFS were 56.5% vs. 49.7 % (p=0.35).
Conclusions: Notch 1 showed higher expression on squamous cell carcinoma. Neither Notch 1 nor 3 have correlated with RFS or OS, but patients with both expressions had the tendency of longer overall survival.
Abstract A9: Pharmacological stimulation of DLL1-Notch signaling as an antitumor immunotherapy
Authors: Huang Yuhui , Lin Luping , Biktasova Asel K. , Malhotra Anshu , Shanker Anil , Carbone David P. , Dikov Mikhail M. 
Published: March 2013

Abstract
Deficiencies in immune function are one of mechanisms for tumor escape from host immune surveillance, and therapies aimed at overcoming these defects are of major importance in cancer immunotherapy. However, the underlying causes of these defects are multiple and remain not fully understood. We report a previously undescribed mechanism for tumor-associated defects in T cell function mediated by reducing levels of Delta-like (DLL) 1 and DLL4 in the hematopoietic microenvironment, and show that elevated levels of circulating vascular endothelial growth factor (VEGF) characteristic for cancer patients is one of the mediators of this effect. Remarkably, selective activation of DLL1-Notch signaling alone by over-expression of DLL1 in bone marrow precursors or by soluble multivalent DLL1 treatment significantly enhances tumor-specific immune responses and inhibits tumor growth in multiple tumor models. The data suggest that tumor growth suppresses T cell differentiation and function via inhibition of DLL-mediated Notch signaling in the hematopoietic compartment. Our findings uncover a novel molecular mechanism of immune suppression and suggest a pharmacologic intervention based on activation of DLL1-Notch signaling to reverse this effect, stimulate immune responses and suppress tumor growth. Given that recently DLL1 was also implicated in abnormal tumor vessel formation and growth inhibition [Zhang JP, ea. Cancer Lett. 2011;309:220–227], systemic stimulation of Notch by multivalent DLL1 might represent an efficient therapeutic strategy targeting multiple mechanisms of tumor growth.
Abstract B11: EGFR polymorphism as a predictor of clinical outcome in advanced lung cancer patients treated with EGFR-TKI
Authors: Jung Minkyu , Lee Chul Ho , Park Hyung Soon , Lee Ji Hyun , Kim Joo Hang , Kang Young Ae , Kim Se Kyu , Chang Joon , Kim Dae Jun , Cho Byoung Chul 
Published: March 2013

Abstract
Background: Mutations in the epidermal growth factor receptor (EGFR) have been confirmed as predictors of efficacy for EGFR-tyrosine kinase inhibitors (TKIs). We investigated whether polymorphisms of the EGFR gene were associated with clinical outcome in NSCLC patients treated with EGFR-TKI.
Methods: A polymorphic dinucleotide repeat (CA simple sequence repeat 1 [CA-SSR1]) in intron one and single nucleotide polymorphisms in the promoter region (SNP -216 GG or GT) were evaluated in 71 NSCLC patients by PCR-RFLP and DNA sequencing. Genetic polymorphisms were correlated with clinical outcomes of EGFR-TKIs.
Results: SNP-216G/T polymorphisms were associated with the efficacy of EGFR-TKI. The response rate for the SNP-216G/T was significantly higher than that for the GG (62.5% vs. 27.4%, P=0.044). SNP-216G/T genotype was also associated with longer progression-free survival compared with GG genotype (16.7 months vs. 5.1 months, P=0.005). However, Genotypes for the CA-SSR1 was not associated with the efficacy of EGFR-TKI.
Conclusions: SNP-216G/T polymorphism is potential predictor for clinical outcome in NSCLC patients treated with EGFR-TKI.
Abstract B13: FGFR2 as a therapeutic target in squamous cell lung carcinoma
Authors: Liao Rachel G. , Hammerman Peter , Sivachencko Andrey , Greulich Heidi , Getz Gad , Liu Qingsong , Gray Nathanael , Meyerson Matthew 
Published: March 2013

Abstract
Squamous cell lung carcinoma (lung SCC)) is the second most common subtype of non-small cell lung cancer, with 40,000 new cases diagnosed every year in the United States. Unlike lung adenocarcinoma, few targetable genomic events are known drivers of lung SCC, and therefore, therapeutic options are limited for patients with this disease. As part of The Cancer Genome Atlas (TCGA) project, we have analyzed the entire coding sequence of 196 lung SCCs for mutated genes which may be amenable to targeted therapeutics. In the 196 patient samples analyzed to date, we have observed mutations in the Fibroblast Growth Factor Receptor 2 (FGFR2) kinase gene in ten cases, or 5% of samples. The observed FGFR2 mutations are present in both the extracellular domain and the kinase domain of the protein, an observation that is consistent with activating mutations in FGFR2 that are known to drive endometrial cancer. We therefore hypothesized that these mutations are oncogenic and may be driving transformation in a subset of lung SCC patients. Expression of mutated FGFR2 in NIH-3T3 cells led to anchorage-independent colony formation, which was inhibited by treatment with the pan-FGFR inhibitor FIIN-1. A known mechanism of FGFR2 activation is the constitutive dimerization of receptors with mutated extracellular domains via intermolecular disulfide bond formation, and we have observed this phenomenon in two of our ECD mutants as well. These data suggest that both ECD and kinase mutations in the FGFR2 gene are sufficient to transform cells. This finding, along with recently published data suggesting that FGFR1 amplification is also able to drive lung SCC development, demonstrates that the FGFR family may be a promising therapeutic target in lung SCC.
Abstract B20: Thyroid transcription factor 1 is embedded in a microRNA network
Authors: Mu David 
Published: March 2013

Abstract
Thyroid transcription factor 1 (TTF-1 or NKX2-1) is an essential fetal lung developmental factor which can be recurrently activated by gene amplification in adult lung cancer. These findings imply that TTF-1 is a gain-of-function oncogene selected for gene amplification due to an undefined biological pressure in lung cancer cells. However, recent data in the literature showed that TTF-1 suppressed lung cancer progression in a mouse model system and that the chromosomal area harboring the TTF-1 amplicon also underwent allelic DNA loss in lung cancer. Despite the complexity surrounding TTF-1 in lung cancer, characterization of TTF-1 gene regulatory mechanisms is warranted as lung adenocarcinomas frequently amplified for TTF-1 are the most common histologic type of lung cancer. We have discovered the first microRNA that directly regulates TTF-1 by interacting with its 3′-untranslated region. By gene expression profiling, we identified other putative targets of the microRNA. In line with the microRNA/target relationship, the expression patterns of the microRNA and TTF-1 were in an inverse relationship in human lung cancer. Exploration of human lung cancer genomics data uncovered that TTF-1 gene amplification was significantly associated with DNA copy number loss at one of the two genomic loci encoding the precursor RNA of mature microRNA. This implies the existence of genetic selection pressure to lose the repressive microRNA that would otherwise suppress amplified TTF-1. We detected a signaling loop between transforming growth factor beta (TGFβ and the microRNA and this loop reinforced suppression of TTF-1, consistent with the concept that TTF-1 possesses anti-epithelial mesenchymal transition (EMT) activity. Paradoxically, the microRNA also targets an EMT-promoting gene HMGA2 which is known to be repressed by TTF-1. Our data suggest that there is a group of microRNAs that are directly regulated by TTF-1, reinforcing our hypothesis that TTF-1 in embedded in a microRNA network. In summary, these data connect the lung transcriptional program to the microRNA network.
Abstract B21: E7050, a Met kinase inhibitor, reverses three different mechanisms of hepatocyte growth factor-induced resistance to tyrosine kinase inhibitors in EGFR mutant lung cancer cells
Authors: Nakagawa Takayuki , Takeuchi Shinji , Yamada Tadaaki , Kita Kenji , Yano Seiji 
Published: March 2013

Abstract
Purpose: Hepatocyte growth factor (HGF) induces resistance to reversible and irreversible epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR mutant lung cancer cells by activating Met and downstream PI3K/Akt pathway. In addition, HGF accelerates expansion of minor clones with Met amplification and facilitates EGFR-TKI resistance. Purpose of this study is to determine whether E7050, a Met kinase inhibitor, could overcome these three resistant mechanisms to EGFR-TKIs.
Experimental design: Effect of E7050 on HGF-induced resistance to reversible (gefitinib), irreversible (BIBW2992), and mutant selective (WZ4002) EGFR-TKIs was determined using EGFR-mutant human lung cancer cell lines, PC-9 and HCC827 with exon 19 deletion, and H1975 with T790M secondary mutation. As an in vivo models, PC-9 cells mixed with HGF producing fibroblasts, MRC-5, were subcutaneously inoculated into SCID mice and therapeutic effect of E7050 combined with gefitinib was examined.
Results: We found that E7050 circumvented resistance to all of reversible, irreversible, and mutant selective EGFR-TKIs induced by exogenous and/or endogenous HGF in EGFR mutant lung cancer cell lines, by blocking Met/Gab1/PI3K/Akt pathway in vitro. E7050 also prevented emergence of gefitinib resistant HCC827 cells induced by continuous exposure to HGF. In vivo model, E7050 combined with gefitinib dramatically regressed the tumor growth, associating with inhibiting Akt phosphorylation in cancer cells.
Conclusions: E7050, a Met kinase inhibitor, reverses three different mechanisms of gefitinib resistance induced by HGF, suggesting usefulness of E7050 for overcoming HGF-induced resistance to gefitinib and new generation EGFR-TKIs.
Abstract B3: Relevance of genotyping non-small-cell lung cancer patients on response to platinum-basedchemotherapy and tyrosine kinase inhibitors
Authors: Campos-Parra Alma D. , Cruz Graciela , Zuloaga Carlos , Aviles Alejandro , Vázquez Manríquez María E. , Borbolla-Escoboza José R. , Cardona Andrés , Abelardo Meneses , Arrieta Oscar 
Published: March 2013

Abstract
Background: Subdividing non-small cell lung cancer (NSCLC) based on molecular alterations such as EGFR, KRAS and ALK genes is important for selecting treatment involving EGFR and EML4-ALK tyrosine kinase inhibitors (TKI). However, little information is available comparing patients' response and progression-free survival in the presence or absence of EGFR, KRAS mutations or the EML4-ALK fusion gene when being treated with chemotherapy.
Methods: NSCLC patients were treated with chemotherapy and/or TKIs. Tests were performed for EGFR and KRAS gene mutation as well as EML4-ALK fusion genes. Progression-free survival and overall survival association with type of treatment and mutational status was analyzed.
Results: The factors associated with a response to chemotherapy were the presence of EGFR and KRAS mutation (p = 0.006 and p = 0.028, respectively). Factors associated with TKI response were adenocarcinoma (HR 2.7: 1.6–4.6 95%CI; p&lt;0.001), EGFR mutation (HR 0.5: 0.3–0.8 95%CI; p = 0.009) and wild-type KRAS (HR 1.7: 1.1–2.8 95%CI; p = 0.013). Mean progression-free survival in the chemotherapy group was 5.3 months (4.8–5.7 95%CI).
Conclusion: EGFR and KRAS mutation status appeared to subdivide NSCLC patients into TKI and chemotherapy response groups.