bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4710: Evaluation of the glutaminase inhibitor CB-839 in non-small cell lung cancer
Authors: Boroughs Lindsey K. , Chen Pei-Hsuan , Cai Ling , Rodriguez Mirna , Zhang Winter , Huffman Kenneth E. , Byers Lauren A. , Girard Luc , Gazdar Adi F. , Heymach John V. , White Michael A. , Minna John D. , Emberley Ethan , Pan Alison , Parlati Frank , DeBerardinis Ralph J. 
Published: August 2015

Abstract
Glutamine is an abundant nutrient used by cancer cells to support energetic and biosynthetic pathways. Given that many cancer cells exhibit glutamine dependence, there has been interest in developing inhibitors targeting glutaminase, which catalyzes conversion of glutamine to glutamate. CB-839 is a glutaminase inhibitor with preclinical efficacy in suppressing cancer cell growth in culture and in vivo. It is now in Phase I clinical trials for solid and hematological malignancies, including non-small cell lung cancer (NSCLC).
Here we set out to identify biomarkers predicting sensitivity of NSCLC cells to CB-839, using a highly annotated panel of 81 cell lines. These lines had heterogeneous oncogenotypes and displayed about a 5-fold range in their ability to tolerate glutamine deprivation. Assessing CB-839 sensitivity in ∼40 lines revealed a 5-fold difference in growth suppression among cell lines. There was a strong correlation between CB-839 sensitivity and both glutamine dependence and glutamate secretion. In a subset of 4 representative cell lines, CB-839 suppressed [U-13C]glutamine metabolism in both sensitive and insensitive cells suggesting other mechanisms contribute to CB-839 sensitivity. To identify potential biomarkers predicting CB-839 sensitivity, the glutamine dependence and drug sensitivity phenotypes were correlated with several orthogonal high-content data sets including mutational analysis of commonly-mutated oncogenes and tumor suppressors; sensitivity to chemotherapeutic agents; gene expression arrays; and reverse phase protein arrays (RPPA). Although we did not identify a strong correlation between mutational status and CB-839 sensitivity, expression of phospho-Rb (S807/811) and Smad3 did correlate with drug sensitivity. In addition, sensitivity to glutamine withdrawal correlated with expression of c-Myc and MEK2 protein. While further work is necessary to examine the importance of these proteins in glutamine metabolism, we hypothesize that one or more of these may represent novel biomarkers predicting sensitivity to glutaminase inhibition.
Citation Format: Lindsey K. Boroughs, Pei-Hsuan Chen, Ling Cai, Mirna Rodriguez, Winter Zhang, Kenneth E. Huffman, Lauren A. Byers, Luc Girard, Adi F. Gazdar, John V. Heymach, Michael A. White, John D. Minna, Ethan Emberley, Alison Pan, Frank Parlati, Ralph J. DeBerardinis. Evaluation of the glutaminase inhibitor CB-839 in non-small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4710. doi:10.1158/1538-7445.AM2015-4710
Abstract 4721: Epithelial to mesenchymal transition is not required for breast to lung metastasis but contributes to chemoresistance
Authors: Fischer Kari R. , Durrans Anna , Lee Sharrell , Sheng Jianting , Choi Hyejin , Li Fuhai , Wong Stephen , Altorki Nasser K. , Mittal Vivek , Gao Dingcheng 
Published: August 2015

Abstract
The role of epithelial to mesenchymal transition (EMT) in metastasis is a longstanding source of controversy, largely due to an inability to monitor transient and reversible EMT phenotypes in vivo. We have established a novel and unique EMT lineage tracing system in spontaneous breast to lung metastasis models. In these models, mesenchymal-specific Cre-mediated recombination initiates permanent switch of fluorescent markers in tumor cells undergoing EMT. This allows us to track EMT tumor cells in the primary tumor, circulation and distant organs following the trail of breast to lung metastasis in vivo. We confirmed that within a predominantly epithelial primary tumor, a small portion of tumor cells undergo EMT. Strikingly, lung metastases were mainly comprised of non-EMT tumor cells maintaining their epithelial phenotype. Inhibiting EMT by overexpressing miR-200 did not impact lung metastasis development. However, EMT cells significantly contribute to recurrent lung metastasis formation after chemotherapy. These cells survived cyclophosphamide treatment due to reduced proliferation, apoptotic tolerance, and elevated expression of chemoresistance-related genes. This study suggests the potential of an EMT-targeting strategy, in conjunction with conventional chemotherapies, in the treatment of breast cancer patients.
Citation Format: Kari R. Fischer, Anna Durrans, Sharrell Lee, Jianting Sheng, Hyejin Choi, Fuhai Li, Stephen Wong, Nasser K. Altorki, Vivek Mittal, Dingcheng Gao. Epithelial to mesenchymal transition is not required for breast to lung metastasis but contributes to chemoresistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4721. doi:10.1158/1538-7445.AM2015-4721
Abstract 4762: ITPKA expression in lung and other cancers, regulated via gene body methylation, functions as an oncogene
Authors: Wang Yi-Wei , Ma Xiaotu , Zhang Yu-An , Wang Mei-Jung , Yatabe Yasushi , Lam Stephen , Girard Luc , Chen Jeou-Yuan , Gazdar Adi F. 
Published: August 2015

Abstract
Inositol-Trisphosphate 3-Kinase A (ITPKA), a kinase with limited tissue distribution, is involved in inositol phosphate metabolism. We identified ITPKA as up-regulated in lung and many other types of cancers. Using gain-of-function and loss-of-function approaches, we demonstrated by in vitro and in vivo assays that ITPKA functions as an oncogene to drive the development of lung cancer. We further showed that methylation level in the ITPKA gene body is significantly higher in various types of primary tumors than in corresponding non-malignant tissues, which was positively correlated with its expression. Our study revealed that DNMT3B-mediated methylation of the CpG island in ITPKA gene body regulates its expression via modulation of the binding of transcription activator SP1 to the ITPKA promoter. During the multistage pathogenesis of lung carcinoma, ITPKA gene body methylation first appeared at the in situ carcinoma stage and increased during disease progression. Thus ITPKA expression functions as an oncogene in lung and other cancers. Highly specific and sensitive expression and methylation of ITPKA was present in a wide range of tumor types, suggesting that deregulation of ITPKA may function as a universal or near universal hallmark of malignancy.
Citation Format: Yi-Wei Wang, Xiaotu Ma, Yu-An Zhang, Mei-Jung Wang, Yasushi Yatabe, Stephen Lam, Luc Girard, Jeou-Yuan Chen, Adi F. Gazdar. ITPKA expression in lung and other cancers, regulated via gene body methylation, functions as an oncogene. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4762. doi:10.1158/1538-7445.AM2015-4762
Abstract 4779: RUVBL1 and RUBVL2 are chromatin remodelers that represent prognostic and novel therapeutic targets for a subset of non-small cell lung cancers (NSCLCs)
Authors: Yenerall Paul M. , Kollipara Rahul , Carstens Ryan , Huffman Kenneth , Girard Luc , Rodriguez Jaime , Wistuba Ignacio , Mangelsdorf David , Minna John , Kittler Ralf 
Published: August 2015

Abstract
RUVBL1 and RUVBL2 (collectively referred to as RUVBL1/2) are AAA+ ATPases that function in various chromatin remodeling complexes. We found that RUVBL1/2 are overexpressed (n = 224) and prognostic of patient outcome in NSCLC patients (n = 697) who undergo surgical resection (combined TCGA, KMPlot.com, and SPORE P50CA70907 dataset analyses). To assess the importance and biological functions of RUVBL1/2 in NSCLC, we measured cell growth following depletion of RUVBL1/2 in 24 NSCLC lines, representing a spectrum of oncogenotypes and histologies, and 2 normal human bronchial epithelial cell lines (HBECs) using two independent RNAi reagents. Growth inhibitory phenotypes ranged from 19-87% and were “rescued” by exogenous expression of an RNAi-resistant cDNA construct, indicating “on-target” siRNA effects. Four of the 23 NSCLCs were very sensitive (&gt;75% growth inhibition), while 88% of NSCLCs were more growth inhibited than HBECs, indicating a therapeutic window. To establish molecular biomarkers of RUVBL1/2 dependency, we correlated whole exome mutation status, whole transcriptome mRNA levels, and a number of other parameters to sensitivity to RUVBL1/2 depletion. Sensitivity to RUVBL1/2 knockdown did not correlate with the mutation status or expression of any genes. However, sensitivity to RUVBL1/2 depletion did correlate with doubling time. Flow cytometry analysis in NSCLC lines sensitive to RUVBL1/2 KD revealed that RUVBL1/2 depletion resulted in a G2/M arrest (but not apoptosis), and a decrease in cell cycle related transcripts, such as CDKN3, AURKA, CIT and CDC20, whereas resistant cell lines do not exhibit these changes. Initial ChIP-seq analysis suggests that RUVBL1/2 preferentially occupies cell cycle related genes and are depleted in nucleosome free regions (i.e. transcription start sites). These results, combined with results from others demonstrating the necessity of ATP hydrolysis for RUVBL1/2's function(s), indicate that the chromatin remodelers RUVBL1/2 are potential therapeutic targets in a subset of NSCLCs. (Supported by UTSW Green Center Fellowship, CPRIT RP120732, SPORE P50CA70907)
Citation Format: Paul M. Yenerall, Rahul Kollipara, Ryan Carstens, Kenneth Huffman, Luc Girard, Jaime Rodriguez, Ignacio Wistuba, David Mangelsdorf, John Minna, Ralf Kittler. RUVBL1 and RUBVL2 are chromatin remodelers that represent prognostic and novel therapeutic targets for a subset of non-small cell lung cancers (NSCLCs). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4779. doi:10.1158/1538-7445.AM2015-4779
Abstract 4794: Identification of FOXM1 driven gene network as a prognostic marker in breast cancer
Authors: Chu In-Sun , Kim Seon-Kyu , Roh Yun-Gil , Leem Sun-Hee 
Published: August 2015

Abstract
A transcription factor FOXM1 is known to play a key role in cell cycle progression where endogenous FOXM1 expression peaks at S and G2/M phases. It was previously reported that expression level of FOXM1 in breast cancer was strongly correlated with patient survival, since FOXM1 influenced endocrine therapy and chemo-response effect. The aim of this study is to estimate prognostic value of FOXM1 gene and to identify novel markers interconnected with FOXM1 to predict heterogeneous breast cancer behaviors.
Microarray gene expression profiling was performed using gene expression data obtained from 317 Korean patients with breast cancer to identify a signature associated with FOXM1. Various statistical methods, including the leave-one-out cross validation, were applied to identify a gene expression signature able to predict breast cancer outcome. The predictive value of the signature was verified in the two larger independent cohorts obtained from a public database. Unsupervised cluster analysis of gene expression data from the Korean cohort showed highly concordant subtypes of Caucasian cohort. Significant differences in overall and disease specific survival between the subgroups divided by the expression signature of FOXM1-associated genes were observed (log-rank test, each P &lt;0.001, respectively). Multivariate Cox regression analysis revealed that the expression signature of FOXM1-associated genes was a strong predictor of breast cancer outcomes. Our findings were verified in the two independent patient cohorts and confirmed that the signature produced consistent prediction patterns. Finally, gene network analyses in the signature revealed that, FOXO1, CCNK, MYC, BRD4 and EIF4G1 could be important mediators interconnected with FOXM1 in the breast cancer behavior.
The expression signature of FOXM1 and its associated genes represents a promising diagnostic tool for the identification of breast cancer patients that have a high risk of poor clinical behavior.
Note: This abstract was not presented at the meeting.
Citation Format: In-Sun Chu, Seon-Kyu Kim, Yun-Gil Roh, Sun-Hee Leem. Identification of FOXM1 driven gene network as a prognostic marker in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4794. doi:10.1158/1538-7445.AM2015-4794
Abstract 4798: Genomic alterations in ERBB2 define a subset of pleomorphic invasive lobular breast cancer
Authors: Hirshfield Kim M. , Sanders Renee , Feld Heather K. , Barnard Nicola , Liang Li , Zhong Hua , Bhanot Gyan , Sahota Amrik S. , Brooks Andrew , Rodriguez-Rodriguez Lorna , Ganesan Shridar 
Published: August 2015

Abstract
Background. Pleomorphic invasive lobular carcinoma represents a unique histologic subset of breast cancer with poorer outcomes as compared with classic invasive lobular carcinoma of the breast. With the recent finding of ERBB2 alterations in recurrent invasive lobular carcinoma, the goal of this study is to define the relationship of ERBB2 alterations in the distinct subset of pleomorphic invasive lobular carcinomas.
Methods. Using the provisional invasive breast cancer data set of 962 cases in The Cancer Genome Atlas (TCGA), all breast cancers with CDH1 alterations were identified and pathologic review was performed. Independent identification of ERBB2 genomic alterations was done. The frequency and nature of genomic alterations in ERBB2, PTEN, PIK3CA, and TP53 were determined. FFPE specimens from an additional 18 cases from our own institution have been evaluated using the combination of the RainDance ThunderBolts™ Cancer Panel for validation.
Results. Of 116 TCGA breast cancers with CDH1 alterations, 86 were invasive lobular breast cancer. Within this subset, 21 pleomorphic lobular breast cancers were identified based on morphologic review. Nine ERBB2 mutations (42.9%) and three amplifications (14.3%) were found in pleomorphic invasive lobular carcinoma, but none in classic invasive lobular carcinoma (p value 1.92e-9). There were no significance differences in the frequency of TP53, PTEN or PIK3CA alterations in pleomorphic invasive lobular carcinoma as compared to classic invasive lobular carcinoma. Data from the additional 18 validation cases will be presented.
Conclusions. Genomic alterations in ERBB2 strongly associate with the finding of pleomorphic invasive lobular but not classic invasive lobular histology. The presence of ERBB2 alterations has therapeutic implications specific to this rare breast cancer subset that could impact outcomes. Comprehensive genomic profiling identifies ERBB2 mutations that are not detected with standard clinical immunohistochemistry or FISH.
Citation Format: Kim M. Hirshfield, Renee Sanders, Heather K. Feld, Nicola Barnard, Li Liang, Hua Zhong, Gyan Bhanot, Amrik S. Sahota, Andrew Brooks, Lorna Rodriguez-Rodriguez, Shridar Ganesan. Genomic alterations in ERBB2 define a subset of pleomorphic invasive lobular breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4798. doi:10.1158/1538-7445.AM2015-4798
Abstract 4805: Whole genome sequencing of primary breast cancers and matched distant metastases
Authors: Tang Man-Hung , Dahlgren Malin , Brueffer Christian , Winter Christof , Chen Yilun , Olsson Eleonor , Sjöström Martin , Bendahl Pär-Ola , Niméus-Malmström Emma , Saal Lao H. , Borg Åke , Gruvberger-Saal Sofia K. 
Published: August 2015

Abstract
Metastatic disease is the main cause of death for breast cancer patients, but it is still unclear whether primary tumor characteristics are predictive of the metastasis phenotype. Our aim was to investigate, by analyzing chromosomal structural variation, the clonal similarities between primary breast tumors and their matched distant metastases. For 11 patients, we performed low-coverage (∼10x) whole-genome sequencing on 11 primary breast tumors and 13 matched distant metastases to enumerate chromosomal rearrangements. The tumor genomes (n = 24) harbored a median of 85 (range 18-405) chromosomal rearrangements per tumor, with a median of 82 (26-310) in primaries compared to 87 (18-405) in distant metastases. Similarity between tumors was assessed based on presence or absence of chromosomal rearrangements. Concordance between matched primaries and distant metastases from the same patient was high, with a median of 89% rearrangements being shared (range 61-100%). Nearly all of the rearrangements were patient-specific, with very little overlap when comparing all possible pairings of tumors from different patients (median 3%). The tumors exhibited different genomic patterns of rearrangements: some carried events scattered throughout the genome while other tumors had events in densely clustered foci - chromothripsis-like hotspots - at a few chromosomal locations. Irrespective of the type of rearrangement profile of the tumor genomes, the patterns were highly conserved between the primary tumor and metastasis from the same patient, although in general metastases acquired additional rearrangement events. Our study suggests that analysis of structural variation in tumor genomes could be useful for identifying tumor origin, facilitating cancer detection via measurement of rearrangements in circulating tumor DNA, and estimating degree of relatedness between primary tumors and metastases. Moreover, our finding that distant metastases have a close clonal relationship to the primary tumor at the level of chromosomal structure is most consistent with chromosomal rearrangements being early events in breast cancer progression that remain stable during the development from a primary tumor to its distant metastasis.
Citation Format: Man-Hung Tang, Malin Dahlgren, Christian Brueffer, Christof Winter, Yilun Chen, Eleonor Olsson, Martin Sjöström, Pär-Ola Bendahl, Emma Niméus-Malmström, Lao H. Saal, Åke Borg, Sofia K. Gruvberger-Saal. Whole genome sequencing of primary breast cancers and matched distant metastases. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4805. doi:10.1158/1538-7445.AM2015-4805
Abstract 4814: Inferring liver cancer evolution from spatial and temporal genomic heterogeneity
Authors: Gao Qiang , Wang Zhi-Chao , Xi Rui-Bin , Fan Jia 
Published: August 2015

Abstract
Background & Aims: The molecular pathogenesis of primary liver cancer is extremely complex and heterogeneous, which was further complicated by multiple carcinogenesis. We aimed to elucidate the pathogenesis of multifocal primary liver cancer by genomic profiling.
Methods: A patient with synchronous hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) who underwent resection and experienced post-operative intrahepatic metastases (IMs) was enrolled. Multiregion whole-exome sequencing was applied on the three primary tumors and two IMs to infer tumor clonality and evolution. The mutational and expression profiles, clinical relevance (n = 236) and functional implications of the identified potential driver gene FAT4 in HCC were investigated.
Results: In total, we identified 12, 184, 126, and 54 of protein coding mutation in the cirrhotic liver, two HCCs (designated as HCC-A and HCC-B) and one ICC respectively. The mutational data of the two HCCs and one ICC showed almost no overlaps, suggesting that they developed through an accumulation of complete different sets of genetic alterations. For each tumor, multiregion sequencing data showed varied intratumoral heterogeneity (18.1% in HCC-A, 15.7% in HCC-B, 45.6% in ICC). The mutational profile of two IMs showed obvious similarity with HCC-A (87.6% and 87.7% shared with HCC-A respectively), rather than HCC-B and ICC tumors, indicating that they originated from HCC-A. Notably, FAT4 was the only gene that mutated in both HCCs and the two IMs, but in different locations (HCC-A and two IMs have the same G to A mutation at the coding position 2530, while HCC-B genomes have the A to C mutation at the coding position 14804). Prevalence screen revealed that FAT4 was mutated in over 15% of HCC patients and also several HCC cell lines. Significant down-regulation of FAT4 mRNA and protein expression was found in HCC, and loss of FAT4 independently correlated with early recurrence in HCC patients. In HCC cell lines, knockdown of FAT4 promoted and re-expression of FAT4 reduced cell growth and invasion.
Conclusions: Spatial and temporal dissection of genomic alterations during the progression of liver cancer may help elucidate the basis for its dismal prognosis. FAT4 acts as a putative tumor suppressor that is frequently inactivated in human HCC.
Citation Format: Qiang Gao, Zhi-Chao Wang, Rui-Bin Xi, Jia Fan. Inferring liver cancer evolution from spatial and temporal genomic heterogeneity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4814. doi:10.1158/1538-7445.AM2015-4814