bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA22: miRNA and lung cancer: Early detection in high-risk subjects
Authors: Sozzi Gabriella , Boeri Mattia , Verri Carla , Roz Luca , Suatoni Paola , Croce Carlo M. , Pastorino Ugo 
Published: March 2013

Abstract
Background: Lung cancer remains the major cause of cancer mortality in the world. In addition to primary prevention, earlier detection and more targeted treatments, tailored on the biological characteristics of the tumor and its microenvironment, could significantly reduce morbidity and mortality for this disease. The real efficacy of lung cancer screening by spiral-computed tomography (CT) in heavy smokers is still to be defined since, in spite of a proved capacity to detect small asymptomatic nodules, the frequency of false positive CTs as well as unnecessary treatments is very high if compared to the limited mortality reductions. The development of biomarkers able to identify tumors in a pre-clinical phase and to track the different aggressiveness of lung tumors is of paramount importance. microRNAs (miRNAs) represent a recently identified class of regulatory molecules and several studies showed that miRNA are involved in lung tumor development and progression and also circulate in plasma and serum of lung cancer patients.
Materials and Methods: We analyzed miRNA profiles of lung tumors, normal lung tissues and plasma samples from cases with variable prognosis identified in two independent spiral-CT screening trials where multiple plasma samples, collected from one to four years before radiological detection of the disease were available.
Results: We found miRNA expression profiles associated with aggressiveness of the disease and poor survival in tumors and also in normal lung tissues of the patients, thus proving the critical influence of a smoking-related lung microenvironment on tumor progression. Specific microRNA signatures were identified in plasma samples collected up to two years before spiral-CT detection of the disease, thus able to catch the earlier biological phases of disease development. We also defined a plasma signature that discriminates subjects according to aggressiveness of their future tumors, and in particular the occurrence of early metastatic but spiral-CT invisible lung tumors or small spiral-CT detected lesions with aggressive potential. Of interest plasma miRNas involved in the signatures of lung cancer risk and of aggressive disease more closely reflected miRNAs expressed in the normal lung rather than those characterizing the tumor samples of patients, supporting the concept that normal lung microenvironment has a critical influence on tumor development and aggressiveness.
Conclusion: These results open up the prospective of using plasma miRNAs as non invasive lung cancer biomarkers.
Abstract IA23: A systems approach to the discovery of lung cancer biomarkers
Authors: Hanash Samir 
Published: March 2013

Abstract
We have implemented a systems approach for the discovery of lung cancer biomarkers. Applications include risk assessment, early detection, and predicting response to treatment. The approach which includes genomic, proteomic, metabolomic, and immune profiling integrates data from human biospecimens, a large number of lung cancer cell lines grown under various conditions and several genetically engineered mouse models of lung cancer. An important component of the human studies consists of profiling of pre-diagnostic plasmas available through longitudinal cohort studies, particularly useful for the discovery and validation of blood based risk and early detection markers. Findings include molecular signatures and networks for lung cancer sub-types. Mouse model studies yielded an NKX2.1 signature relevant to early detection, an EGFR network signature for EGFR driven lung cancer and a neuroendocrine signature for small cell lung cancer which were validated in human samples. Integration of proteome and transcriptomic profiling of lung cancer cell line yielded several signatures and a marker panel that predict survival for early stage lung cancer. Mining of the large and continuously expanding sets of data currently being collected benefits from an organized collaborative effort.
Abstract IA4: Defining the mechanisms of tumorigenesis by mutant EGFR using mouse models
Authors: Politi Katerina A. 
Published: March 2013

Abstract
Mutations in exons encoding the epidermal growth factor receptor (EGFR) are found in 10–15% of lung adenocarcinomas. The two most common mutations: a point mutation in exon 21 that leads to substitution of an arginine for a leucine at position 858 and small in-frame deletions in exon 19 are associated with sensitivity to the specific tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. Approximately 70% of tumors harboring EGFR mutations respond to treatment with these drugs, however 30% of these tumors exhibit primary resistance to treatment with these agents. Moreover, responses are transient and, on average, within a year of initiating treatment patients who initially respond eventually develop TKI-inhibitor-resistant disease. Drug resistance, in most cases, is due to a secondary mutation in EGFR (EGFR T790M). Other less frequent mechanisms of resistance include MET amplification, PIK3CA mutations and transformation to small cell lung cancer. However, the mechanism of resistance is still unknown in approximately 30% of cases. More effective treatment of patients with EGFR mutant lung cancer requires a better understanding of the mechanisms of primary and acquired resistance to EGFR TKIs and the development of strategies to overcome this resistance.
To study these problems in vivo, we developed tetracycline-inducible transgenic mouse models of EGFR mutant lung cancer. Expression of lung cancer associated EGFR mutants gives rise to lung adenocarcinomas with bronchioloalveolar carcinoma features that are dependent upon the continuous activity of mutant EGFR for survival. Thus, treatment of the mice with erlotinib leads to tumor regression and long-term treatment with the drug gives rise to drug-resistant tumors that harbor some of the alterations observed in human TKI-resistant tumors such as the T790M mutation. Current efforts to use these mouse models to: 1) study mechanisms of primary and acquired resistance to EGFR TKIs and 2) evaluate new therapies to overcome resistance to first generation TKIs will be discussed.
Abstract IA7: Somatic genome alterations in human lung cancers
Authors: Meyerson Matthew 
Published: March 2013

Abstract
Cancer is a disease of the genome. High-throughput genome analysis tools now enable the detection of somatic alterations in cancer cells including point mutations, copy number alterations, translocations, and infections. Our approaches include next-generation sequencing of cancer genomes, exomes, and transcriptomes as well as single nucleotide polymorphisms (SNP) array analysis of copy number.
As part of “The Cancer Genome Atlas” or TCGA project of the National Institutes of Health, which aims to characterize the genomes of 10,000 human cancers, we are performing genomic analysis of lung carcinomas. In this presentation, I will discuss analysis of the genomes of squamous cell lung carcinomas. New results regarding mutations, genomic structure, and classification will be presented.
Abstract IA9: The molecular pathology of adenocarcinoma versus histopathological classification
Authors: Brambilla Elisabeth 
Published: March 2013

Abstract
Recent therapeutic advances have led to a revolution in the lung cancer field in discovering therapeutically tractable oncogene dependency with major implications for patient evaluation and approach to diagnosis. A recently published IASLC/ATS/ERS classification of lung adenocarcinoma addresses these issues fully based on the molecular features of histological subtypes of adenocarcinoma (1). As deduced from their molecular signatures, pathological patterns are the most achieved translation of the full genomic space (expression profiles, gene copy number alterations, and likely epigenetics space …). Therefore the functional clusters of genes defining a phenotypic population dictates the survival and contains targets of therapies in adenocarcinoma supporting the contention that each of the pathological and molecular features contains this information (2, 3). The new classification of adenocarcinoma has a high prognostic interest validated on further independent series of the literature (4). Molecular pathology recapitulates both differentiation markers and biomarkers of therapeutic sensitivity.
A stepwise accumulation of genetic and molecular abnormalities is sustaining the morphological transition between preinvasive and invasive and metastatic process in adenocarcinoma.
Now that lung cancer therapies personalized for individual patients is based on the histologic type of lung cancer and molecular status, the pathologist role using the knowledge on molecular pathology is to allow the histomolecular classification on small biopsies and cytology, the only specimens available in advanced treatable cases of adenocarcinoma (5).
A few differentiation markers (TTF-1, P63, P40, mucines) met the need for subclassification of cases with adenocarcinoma components (adenocarcinoma per se, large cell carcinoma, sarcomatoid carcinoma and NSCLC/NOS) driving their molecular analysis (6).
TTF-1 positive solid and cribriform tumor with signet ring are strongly associated with susceptibility for EML4-ALK fusion for ALK positivity candidate for crizotinib therapy, whereas Ras mucinous adenocarcinoma (previously mucinous BAC) are essentially TTF-1 negative, amphiregulin positive with IGFR activated pathway which are strongly resistant to gefitinib alone but are restored to sensitivity by IGFR inhibitors (7). Articulation between molecular pathology and histopathological features will in the future be the first organizers of therapeutical decisions (7).
Conclusion: As the molecular changes directly influence the therapy today and even more in the future, we think this should be reflected in the taxonomy as well as in the term given in the WHO classification. Histopathological classification would tend to predict that the molecular characteristics of the tumors together with their immunohistochemical and morphological appearance will dictate therapy in the future. Gefitinib is less effective in non adenocarcinoma NSCLC harboring EGFR mutations (8).
Abstract PR1: Integrating expression data improves mutational significance analysis of lung squamous carcinoma
Authors: Hernandez Bryan , Hammerman Peter , Imielinski Marcin , Lawrence Michael , Stojanov Petar , Getz Gad , Meyerson Matthew 
Published: March 2013

Abstract
In contrast to lung adenocarcinoma in which a driving and potentially targetable genetic aberration can be identified in excess of 50% of tumors, only 10% can be found in squamous cell lung cancer, the second most common type of lung cancer, none of which are druggable by an approved targeted therapy. Our limited knowledge regarding targetable genetic alterations in squamous cell lung cancer is the result of a lack of detailed genomic study of this disease and the lack of experimental validation of identified putative therapeutic targets. We have analyzed exome sequencing data to identify novel driving mutations in 184 lung squamous cell carcinomas using previously successful methods (Integrated genomic analyses of ovarian carcinoma, Nature 2011), but these analyses are confounded by an unusually high mutation rate, 8-9/Mb on average, some reaching as many as 80/Mb. Many of the most significantly mutated genes in the analysis are unlikely related to the pathogenesis of the disease based on a lack of expression in lung and known role in cancer, suggesting that genes which are not expressed (or minimally expressed) escape negative selection and result in a higher mutation density as compared with expressed genes.
Here, we present a method integrating expression and mutation data in order to more accurately determine the significance of a mutated gene based on the expression subclass in which it falls and the frequency at which it's mutated relative to our expectation; unexpressed genes are likely much more tolerant of mutations and should therefore have a higher expected background mutation rate. Analyses of this kind have removed many of the genes putatively irrelevant in this cancer type and have identified many biologically plausible novel genes that to date are unlinked with lung squamous cell carcinoma. We believe this method refines an already powerful analysis for identifying significantly mutated genes in cancer with a particularly high potential for separating signal and noise in the most highly mutated cancer types.
This abstract is also presented as Poster A17.
Abstract A1: Functional significance of miR-10b in tamoxifen resistance of breast cancer cells
Authors: Ahmad Aamir , Reddy Kaladhar B. , Sarkar Fazlul H. 
Published: March 2013

Abstract
Tamoxifen is a conventional treatment option for breast cancer patients diagnosed with estrogen receptor (ER)-positive tumors. However, a significant number of these patients eventually develop resistance to tamoxifen during therapy, and thus the management of such tamoxifen-resistant patients remains a clinical challenge. In an effort to identify novel targets for the treatment of tamoxifen-resistant tumors, we observed increased expression of microRNA 10b (miR-10b) in ER-positive MCF-7 cells-derived tamoxifen-resistant cells (MCF7TR). The miR-10b has been implicated in invasion and metastasis but its role, if any, in drug resistance of breast cancer cells has never been investigated. To ascertain the mechanistic role of miR-10b in tamoxifen resistance, we downregulated its levels in MCF7TR cells and in addition we also overexpressed miR-10b by transfecting MCF-7 cells with pre-miR-10b. We found that the downregulation of miR-10b in MCF7TR cells led to increased sensitivity to tamoxifen whereas overexpression of miR-10b in MCF-7 cells led to increased resistance to tamoxifen. During our mechanistic investigation, we found that increased expression of miR-10b downregulated the expression of HDAC4 in MCF7TR cells. Inactivation of HDAC4 using HDAC4-specific siRNA transfection in MCF-7 cells led to the acquisition of tamoxifen resistance. Moreover, further reduction of HDAC4 in MCF7TR cells by HDAC4-specific siRNA transfection resulted in further enhancement of tamoxifen resistance. In summary, we have identified miR-10b-HDAC4 nexus as one of the molecular mechanism of tamoxifen resistance, and thus targeting this nexus could become a novel targeted therapeutic approach for the treatment of tamoxifen-resistant breast cancer.
Abstract A20: DARPP-32-mediated EGFR protein stability leads to gefitinib resistance in gastric cancer
Authors: Zhu Shoumin , Belkhiri Abbes , El-Rifai Wael 
Published: March 2013

Abstract
Background: Gastric cancer is an aggressive tumor that is often resistant to chemotherapeutics. The 17q amplicon genes, including dopamine and cAMP-regulated phosphoprotein MW 32 kDa (DARPP-32), are overexpressed in two-thirds of gastric adenocarcinomas and may induce chemotherapy resistance via abrogation of apoptosis. EGFR plays an important role in tumor growth and activation of the PI3K pathway. Gefitinib (Iressa) is a specific and effective EGFR inhibitor that has shown antitumor activity in clinical trials against several gastrointestinal cancers, including gastric cancers. However, molecular mechanisms that mediate resistance to gefitinib remain poorly understood.
Methods and Results: The expression of DARPP-32 in the multistep carcinogenesis cascade was examined using IHC analysis on 533 samples. The composite expression score, calculated from immunostaining patterns, progressively increased significantly from normal or gastritis to metaplasia, dysplasia, and adenocarcinoma (p&lt;0.001). Using clonogenic survival assays, and ATP-GLO cell viability assays, we found that overexpression of DARPP-32 leads to a 3-fold increase in gefitinib resistance in MKN-28 cells (25 μM gefitinib, treated overnight, P&lt;0.01). We also found that DARPP-32 expressing MKN-28 cells had activated the PI3K-AKT pathway as compared to control cells. We next examined the binding of DARPP-32 to EGFR and ERBB3. The three-way co-immunoprecipitation experiments demonstrated the existence of DARPP-32, EGFR, and ERBB3 in the same protein complex. The enhanced EGFR-ERBB3 heterodimerization promotes phosphorylation of ERBB3, then activated the PI3K-AKT pathway, as indicated by p-p85 (Tyr458) subunit of PI3K and p-AKT (Ser473) levels. Following treatment with gefitinib (25 μM) overnight, MKN-28 cells expressing DARPP-32 displayed stable protein levels of EGFR. In contrast, control cells exhibited a significant reduction in EGFR protein levels, suggesting that DARPP-32 promotes stability and suppresses degradation of EGFR protein. After the gefitinib treatment of DARPP-32-expressing MKN-28 cells, p-ERBB3 and activated PI3K-AKT pathway were maintained at higher levels than in control cells. The knockdown of endogenous DARPP-32 by lentiviral DARPP-32 shRNA in SNU-16 cell lines reversed these signaling effects and increased sensitivity to gefitinib (p&lt;0.01).
Conclusion: Our results suggest that DARPP-32 overexpression may participate in the transition to intestinal metaplasia and progression to neoplasia. The in vitro studies indicate that DARPP-32 plays a role in increasing the stability of EGFR protein by delaying gefitinib-induced EGFR degradation; maintaining EGFR-ERBB3 heterodimerization promotes phosphorylation of ERBB3, which regulates the PI3K/Akt pathway. DARPP-32 may have potential as a predictive biomarker in gastric cancer prognosis and clinical response to treatment.
Abstract A21: Dual-kinase inhibition of EGFR/ERBB2 as a therapeutic strategy in prostate cancer
Authors: Jathal Maitreyee K. , Mooso Benjamin A. , D'Abronzo Leandro S. , Ghosh Paramita M. 
Published: March 2013

Abstract
Androgen withdrawal therapy (AWT) remains the cornerstone of advanced prostate cancer (PCa) therapy; however, patients on this therapy eventually relapse, caused by the advent of castration-resistant PCa. This stimulates investigation into additional therapeutic targets that may delay or impede the development of CRPC. The EGFR family of receptor tyrosine kinases is intimately involved in prostate cancer (PCa) development. EGFR/ErbB1 and HER2/ErbB2 have been clinical targets in androgen-dependent PCa but targeting each individually encourages compensatory signaling by a third member, HER3/ErbB3. Activated HER3/ErbB3 contributes to the onset of castrate-resistant PCa (CRPC), presently an incurable condition. We previously showed that dual EGFR/HER2 inhibition sensitizes PCa cells to androgen withdrawal by suppressing ErbB3 (Clin Cancer Res. 2011 Oct 1;17(19):6218–28). Based on these results, we hypothesized that the dual EGFR/HER2 inhibitor lapatinib (‘Tykerb’, Lap) may sensitize PCa cells to AWT. Athymic nu/nu mice were subcutaneously implanted with CWR22 (androgen-dependent) or CWR22Rv1 (CRPC) tumors derived from human prostate tumors. Tumor-bearing mice were either castrated or left intact, and were treated with the FDA-approved, reversible, dual-kinase, small-molecule inhibitor lapatinib or vehicle alone. Castration prevented tumor growth in CWR22 tumor-bearing mice, both those treated with lapatinib or vehicle, but in intact mice, lapatinib actually stimulated tumor growth. In CWR22Rv1 tumor-bearing mice, lapatinib was ineffective, both in intact or castrated animals. Therefore we further investigated the effect of dual EGFR/ErbB2 inhibitors in PCa. Comparison of various cells showed that lapatinib was effective in LNCaP cells and its CRPC derivatives, but was ineffective in other lines, including PC-346C cells which express a wild-type androgen receptor (AR), whereas LNCaP cells and its derivatives express a mutant AR (T877A). In the latter cell line, lapatinib increased cell growth similar to that seen in CWR22 tumors. Hence, we investigated the effect of other dual EGFR/HER2 inhibitors in PCa cells. In contrast to lapatinib, dacomitinib (PF00299804, Pfizer, PF), an irreversible, small-molecule, dual-kinase inhibitor currently in several clinical trials for a variety of tumors, was more effective and completely inhibited cell growth in the majority of cell lines. When combined, PF and Lap decreased tumor cell viability, increased cell cycle arrest, increased apoptosis, and downregulated ErbB3 protein. These preclinical data support the hypothesis that dual-kinase inhibition may be a viable therapeutic strategy. They also indicate that prostate cancer patients must be carefully preselected, based on their tumor type, and offered personalized therapeutic regimens in order to ensure maximum efficacy of dual-kinase inhibitory treatment.
Abstract A33: Modeling clinical resistance to RAF inhibitors in an in vivo melanoma model provides insights into prevention of resistance
Authors: Thakur Meghna Das , Salangsang Fernando , Pryer Nancy , McMahon Martin , Stuart Darrin 
Published: March 2013

Abstract
Small-molecule RAF inhibitors such as vemurafenib have demonstrated proof-of-concept that BRAFV600E is a key driver of proliferation and survival in melanoma, as evidenced by tumor regression and prolonged survival in patients in late stage clinical trials. Unfortunately, in many patients the tumor response can be short lived as resistance to the inhibitor rapidly develops. Understanding the mechanisms that underlie drug resistance will be critical to providing improved treatment options for these patients.
Here we model the emergence of resistance to vemurafenib in an early passage primary human melanoma xenograft model, which recapitulates a more physiologically relevant microenvironment, genetic diversity, and selective pressure compared to in vitro models. The selection of resistance in vivo also provides the opportunity to model drug pharmacokinetics which better replicates the selective pressure observed in patients.
Long-term continuous treatment of the homozygous BRAFV600E primary melanoma xenografts with RAF inhibitors resulted in the appearance of resistant tumors over the course of 4 to 6 weeks. Pharmacodynamic (PD) analysis of individual tumors indicated that the MAPK pathway is suppressed by the compounds in resistant tumors, although the degree and duration of suppression is less than in sensitive tumors. Furthermore, there is heterogeneity in the kinetics of pathway inhibition and recovery between tumors. Biochemical analyses indicate that BRAFV600E protein levels are upregulated across all resistant tumors and in some cases there is DNA amplification of the mutant BRAF. Taken together with the PD data, this suggests there is a great deal of tumor cell heterogeneity, and that tumors are able to rapidly adapt to the selective pressure being applied. Both in vivo drug withdrawal studies as well as in vitro analyses of tumor derived cell lines indicate that the resistant cells have become dependent on the presence of the inhibitor for their survival. Based on these observations it appears that resistant tumor cells are less fit than sensitive tumor cells in the absence of drug and therefore we tested an intermittent dosing regimen. Intermittent dosing (4 weeks on / 2 weeks off) of RAF inhibitors prevented the evolution of resistance for the duration of the study (4 months). These data could have significant implications in optimizing dose schedules to prevent the emergence of clinical resistance.