bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2331: Antioxidant enzymes mediate the survival of ECM-detached ovarian cancer cells
Authors: Versagli Calli A. , Libbing Cassandra 
Published: August 2018

Abstract
Epithelial ovarian cancer (EOC) is the deadliest gynecological cancer and is one of the leading causes of cancer death in women. It has been speculated that the high death rate associated with EOC is due to the fact that approximately 70% of all cases are diagnosed after the disease has already metastasized, thus making the illness more difficult to treat. In order to successfully survive the process of metastasis, EOC cells must be able to survive without anchorage to the extracellular matrix (ECM); however, the molecular mechanisms behind how EOC cells accomplish this feat has yet to be unveiled. Here, we present data that suggest antioxidant enzymes, namely Catalase, Peroxiredoxin 1, and Peroxiredoxin 2 all play a unique role in the survival and proliferation of ECM-detached SKOV3 cells. SKOV3 cells were genetically engineered to be deficient in Catalase, Peroxiredoxin 1, or Peroxiredoxin 2, and all three engineered cell types show abrogated anchorage-independent survival in soft agar. Furthermore, Catalase elimination in ECM-detached SKOV3 cells results in increased cell death at 48 hours, whereas elimination of Peroxiredoxin 1 or Peroxiredoxin 2 in ECM-detached SKOV3 cells results in decreased proliferation at 72 hours. Our current research is working to understand the molecular mechanisms behind the changes in survival and proliferation seen in antioxidant enzyme deficient SKOV3 cells. In aggregate, our data reveal that antioxidant enzymes may serve as attractive targets for the development of chemotherapeutics to eliminate metastatic ovarian cancer.
Citation Format: Calli A. Versagli, Cassandra Libbing. Antioxidant enzymes mediate the survival of ECM-detached ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2331.
Abstract 2333: Genetic characterization of programmed cell death in aneuploid yeast cells
Authors: Onyundo Megan , Sanborn Matthew , Timmel Victoria , Austriaco Nicanor 
Published: August 2018

Abstract
Aneuploidy is the genetic state of a cell that has a chromosomal number that is not an exact multiple of the haploid complement. It is a leading cause of spontaneous abortions and of mental retardation in humans, and is a characteristic defect in cancer. Yeast cells that are aneuploid manifest a diversity of phenotypes including cell cycle defects, genomic instability, protein imbalance, chaperone stress and proteotoxicity. We are investigating the links between aneuploidy on the budding yeast, Saccharomyces cerevisiae and programmed cell death. We have shown that aneuploid yeast cells are more sensitive to ethanol-induced cell death. In addition, we have also shown that caloric restriction protects aneuploid yeast from program cell death. [In addition to funding from the RI-INBRE Program, our laboratory is supported by grant NIGMS R15 GM110578, awarded to N. Austriaco.]
Citation Format: Megan Onyundo, Matthew Sanborn, Victoria Timmel, Nicanor Austriaco. Genetic characterization of programmed cell death in aneuploid yeast cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2333.
Abstract 2338: XAV-939, a Wnt/beta-catenin pathway inhibitor, sensitizes liver cancer cells to sorafenib: Implications in sorafenib resistance
Authors: Vishnoi Kanchan , Ke Rong , Vishwakarma Navin , Rana Ajay , Rana Basabi 
Published: August 2018

Abstract
Sorafenib is the only FDA-approved drug currently available for the treatment of advanced hepatocellular carcinoma (HCC). However, development of sorafenib-resistance in patients poses a major challenge to make this treatment successful in long-term. There is an urgent need to explore the mechanisms underlying sorafenib-resistance and to develop strategies towards overcoming sorafenib-resistance. Aberrant activation of Wnt/β-catenin signaling in HCC is suggested to maintain tumor initiating cells, drug-resistance, tumor progression, and metastasis. Combining β-catenin inhibitors with sorafenib might thus be an effective therapeutic strategy to target drug-resistant HCC. To explore this, we used wnt/β-catenin pathway inhibitor XAV-939 in combination with sorafenib to study their effect on the apoptotic potential of HCC cell lines Huh7, Hep3B and HepG2. XAV-939 was demonstrated to effectively reduce the expression of β-catenin in wild-type expressing Huh7 and Hep3B cells. Flow cytometric analysis of these cells pre-treated with XAV-939 followed by sorafenib treatment showed a significant increase in apoptosis in a time dependent manner. Furthermore, these cells revealed increased mitochondrial depolarization which was accompanied by a parallel increase in cytosolic cytochrome c release and downregulation of pro-survival protein Mcl-1. These effects of XAV-939 were further validated following knockdown of endogenous β-catenin, which showed a potentiation of sorafenib effects with β-catenin knockdown. Further, to understand the mechanism associated with sorafenib-resistance, we developed sorafenib-resistant HCC cells by repeated exposure to increasing concentration of sorafenib. To our surprise the combination of sorafenib and XAV-939 was ineffective in increasing the apoptotic potential of these resistant cells, suggesting a differential role of wnt/β-catenin axis in sorafenib-resistance. Taken together, these results suggested that combination of wnt/β-catenin pathway inhibitor and sorafenib could be effective in sensitizing HCC cells to apoptosis initially, but might be ineffective once these cells acquire sorafenib-resistance.
Citation Format: Kanchan Vishnoi, Rong Ke, Navin Vishwakarma, Ajay Rana, Basabi Rana. XAV-939, a Wnt/beta-catenin pathway inhibitor, sensitizes liver cancer cells to sorafenib: Implications in sorafenib resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2338.
Abstract 2343: Comprehensive evaluation of antibody-drug conjugate targets for drug development across tumor types: Analysis from TCGA
Authors: Groisberg Roman , Rosznik Jason , Meric-Bernstam Funda , Subbiah Vivek 
Published: August 2018

Abstract
Introduction: Cancer cells over-express proteins on their cell surface that can be exploited as drug targets and has led to development of two successful Anti-body Drug Conjugates (ADCs), Brentuximab and Trastuzumab Emtansine. Because a strong correlation exists between mRNA levels and protein expression we analyzed RNAseq data from TCGA to look at known ADC targets as a proof-of-concept to discovering new therapeutic targets.
Methods: We used mRNA expressions (transcripts per million, TPM) from publicly available RNA sequencing data from the Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) project to analyze the expression of ADC targets in tumor and normal tissues. We chose thirty-seven targets with known ADCs in clinical development. Graphs were generated to show distribution of each gene's expression across all tumor and normal tissue types in TCGA and GTEx. Potential targets were determined based on tumor expression of at least two times the highest expression in any normal tissue. Proteins known to be secreted in the blood stream at high levels were excluded as they are unlikely to make a good ADC target (eg. AFP, FOLH1).
Results: Using ERBB2 as the prototype gene, we were able to detect over-expression in all tumors that have HER-2 ove-rexpression in the literature including breast, bladder, NSCLC, Gastroesophageal, endometrial, HNSCC, ovarian, and colon cancer. Other genes with overexpression in select tumors including BSG (RCC, Melanoma, ACC), CD70 (RCC, DLBCL, mesothelioma, cervical), ENPP3 (RCC, endometrial, breast, lung adeno), FGFR2 (breast, gastric), FOLR1 (ovarian, lung adeno), GPNMB (lung, melanoma, HNSCC, renal), MSLN (lung adeno, mesothelioma, ovarian), SLC39A6 (breast), TDGF1 (thymoma, testicular, adrenocortical) were discovered as well. Tumors exhibited a significantly higher expression compared to normal tissue for ERBB2: breast cancer vs normal breast: p &lt; 0.001; bladder cancer vs normal bladder: p &lt; 0.001; lung adenocarcinoma vs normal lung: p &lt; 0.001; ovarian cancer vs normal ovary: p &lt; 0.001.
Conclusion: Overall, this large-scale analysis from TCGA reveals that RNA-seq can be used as an initial screen to identify novel targets for ADCs. Further analysis will identify previously unappreciated targets that can be exploited for drug development across diverse cancers. Further confirmation with protein expression is warranted.
Citation Format: Roman Groisberg, Jason Rosznik, Funda Meric-Bernstam, Vivek Subbiah. Comprehensive evaluation of antibody-drug conjugate targets for drug development across tumor types: Analysis from TCGA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2343.
Abstract 2344: Identification and validation of synthetic lethal cancer pairs from genome-wide CRISPR screens
Authors: Schwartz Benjamin , Jing Junping , Stronach Euan , Cooper David , Wilson Boris , Middleton Sarah , Khaladkar Mugdha , Dong Coco , Shabon Usman , Rao Yanhua , Riesenberg Stefanie 
Published: August 2018

Abstract
Although most canonical somatic cancer mutations have now been cataloged, only a fraction are amenable to drug discovery efforts. These are limited to targets with gain of function mutations and druggable protein domains. Examples include kinases such as FLT3 and metabolic enzymes such as IDH1/2. However, excluded from this list are undruggable protein targets with gain of function mutations, such as KRAS, or tumor suppressors which acquire loss of function mutations, such as APC.
The concept of synthetic lethality is being used to address this gap in cancer discovery. Cells which carry these directly undruggable somatic mutations become susceptible to inhibition of secondary targets. This susceptibility is specific in context to cells carrying the cancer associated mutation, offering both a novel approach for establishing efficacy as well as a potential therapeutic window for normal cells. The successful development of PARP inhibitors for BRCA mutant ovarian and breast cancers has provided the first clinical validation of this idea.
Pooled, genome-wide knock out experiments are being pursued to systematically discover more of these types of synthetic lethalities. Typically, a sgRNA library is used to transfect a CAS9 expressing cancer cell line, and sequencing of the guides over time identifies lethalities specific to the cell line. Once this experiment is repeated over hundreds of cell lines, one can use the genomic information of the cell lines, such as mutations or copy number aberrations, to identify potential new combinations of molecular lethality.
We have analyzed pooled CRISPR knockout data in a large panel of cancer cell lines generated from two independent sources (Broad Institute and Open Targets) to identify these types of lethality. Besides identifying targets for prevalent cancer mutations, we have also identified lethal combinations based on genes aberrantly deleted/silenced in cancers, termed “collateral lethality.” These include pairs of paralogs, many of which code enzymes with redundant functions.
In this presentation we will outline our analysis strategies and methods, and describe the development of a downstream experimental validation pipeline, using a specific target/predictor pair to exemplify our approach.
Citation Format: Benjamin Schwartz, Junping Jing, Euan Stronach, David Cooper, Boris Wilson, Sarah Middleton, Mugdha Khaladkar, Coco Dong, Usman Shabon, Yanhua Rao, Stefanie Riesenberg. Identification and validation of synthetic lethal cancer pairs from genome-wide CRISPR screens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2344.
Abstract 2345: The genomic landscape of small cell carcinoma of the oesophagus
Authors: Wang Feng , Liu Dongbing , Zhao Qi , Chen Gang , Liu Xinming , Wang Yingnan , Su Hong , Qin Yanru , He Yifu , Zou Qingfeng , Liu Yanhui , Lin Youen , Sheng Hui , Hu Jiajia , Liu Zexian , Zuo Zhixiang , Bei Jinxin , Xu Ruihua 
Published: August 2018

Abstract
Background & Aims—Small cell carcinoma of the oesophagus (SCCE) is a deadly malignancy but its genetic characteristics remain unknown and treatment is commonly adopted from therapies for its histologically identical counterpart, small cell lung cancer (SCLC). We conducted a large-scale genomic analysis of SCCE to determine the mutational landscape of this deadly disease.
Methods—We performed whole-exome sequence of tumour and para normal esophageal tissues from 55 patients with SCCE who underwent surgery at seven institutions in China. Comprehensive analyses were carried out to identify key genetic events in SCCE, including significant mutations, copy number variation, pathway disruption. We also performed ultra-deep targeted sequencing on 20 specimens and microarray assays on 24 specimens to validate somatic mutations and copy number variations respectively. Using an unsupervised hierarchical clustering approach, the genomic characteristics of SCCE were compared with other types of malignancies including oesophageal squamous cell carcinoma, oesophageal adenocarcinoma and et al. In vitro proliferation and migration assays were conducted to assess the function of PDE3A.
Results—The mutational spectrum of SCCE was dominated by C&gt;T/G&gt;A transitions and the mutational signatures classified the patients into 3 groups. We identified three novel significantly mutated genes (PDE3A, PTPRM and CBLN2) and mutations in five other well-known tumour-associated genes (TP53, RB1, NOTCH1, FAT1 and FBXW7). Non-silent alterations of chromatin remodeling genes were detected in 96.4%. Moreover, pathway enrichment analysis revealed that genes involved in the cell cycle, p53, Notch and Wnt signaling were frequently altered in SCCE. Mutations in NOTCH family correlated with shorter overall survival. Furthermore, comparison analysis of mutation signatures revealed that SCCE tumours were more closely related to oesophageal squamous cell carcinoma, rather than oesophageal adenocarcinoma and SCLC, suggesting that current therapies for SCCE may be inadequate. Functional characterizations suggested that PDE3A acts as a novel oncogene.
Conclusions—Our findings reveal key somatic alterations in SCCE, and provide insights to better understand the pathogenesis of SCCE and to develop better treatment strategies for patients with the condition.
Citation Format: Feng Wang, Dongbing Liu, Qi Zhao, Gang Chen, Xinming Liu, Yingnan Wang, Hong Su, Yanru Qin, Yifu He, Qingfeng Zou, Yanhui Liu, Youen Lin, Hui Sheng, Jiajia Hu, Zexian Liu, Zhixiang Zuo, Jinxin Bei, Ruihua Xu. The genomic landscape of small cell carcinoma of the oesophagus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2345.
Abstract 2350: Efficient survival multifactor dimensionality reduction method for genome-wide association study
Authors: Gui Jiang , Ji Xuemei , Amos Christopher I. 
Published: August 2018

Abstract
The problem of identifying associations between SNPs and case-control outcome has been studied extensively and a number of new techniques have been developed. Little progress has been made, however in the analysis of SNP effect in relation to censored survival data. We present an extension of the two class multifactor dimensionality reduction (MDR) algorithm that enables detection and characterization of epistatic SNP-SNP interactions in the context of survival outcome. The proposed an Efficient Survival MDR (ES-MDR) method handles censored data by modifying MDR's constructive induction algorithm to use logrank Test. We applied ES-MDR to genetic data of over 470,000 SNPs from the OncoArray Consortium. We use onset age of lung cancer and case-control (n=27,312) status as the survival outcome and divided data into training and testing sets. We also adjust for subject's age, gender and smoking status. From training set, we identified strong association from SNPs in BRCA1 and IL17RC genes with lung cancer onset age. This result is validated in the testing set.
Citation Format: Jiang Gui, Xuemei Ji, Christopher I. Amos. Efficient survival multifactor dimensionality reduction method for genome-wide association study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2350.
Abstract 2354: Candidate non-coding driver mutations in super-enhancers and long-range chromatin interaction networks across 1,800 whole cancer genomes
Authors: Reimand Juri 
Published: August 2018

Abstract
A comprehensive understanding of the mutations that drive tumorigenesis and disease progression is essential to understanding tumor biology and designing precision therapies. The landscape of driver mutations in the protein-coding genome has been well-characterized by large exome-sequencing studies. Surprisingly, many tumors do not have mutations in any known protein-coding driver. Non-coding driver mutations are hypothesized to explain many of these cases, but aside from a few regions, like the TERT promoter, our understanding of drivers in the complex regulatory genome remains limited. To fill this gap, we analyzed 150,000 cis-regulatory modules with clustered transcription factor binding sites in 1,844 whole cancer genomes from the ICGC-TCGA PCAWG project. Using a new statistical method, ActiveDriverWGS, we identified dozens of frequently mutated regulatory elements (FMREs) enriched in non-coding SNVs and indels (FDR&lt;0.05) with many structural rearrangements and focal copy number alterations in additional samples. The FMREs were enriched in super-enhancers, long-range chromatin interactions and H3K27ac marks derived from primary tumors, suggesting a gene regulatory role of these mutations through three-dimensional genome organization. The interaction network of chromatin loops and FMREs revealed putative target genes located dozens to hundreds of kilobases away from the mutated regulatory elements. We found known and putative oncogenes and tumor suppressors whose expression significantly correlated with mutations in FMREs, suggesting novel oncogenic mechanisms. Most of the FMREs were also confirmed by additional driver discovery methods, lending confidence to our statistical approach. We also validated ActiveDriverWGS on protein-coding sequence and accurately recovered known driver genes. The non-coding regulatory genome is characterized by diverse mutational processes, regional hypermutations and technically challenging areas with suboptimal sequencing coverage. Thus our findings, most of which are reported for the first time, should be carefully vetted and experimentally validated in future studies. Our integrative analysis of somatic mutations, cis-regulatory regions and long-range chromatin interaction networks is a novel framework for cancer discovery and reveals the currently largest set of potential non-coding drivers in a pan-cancer cohort.
Citation Format: Juri Reimand. Candidate non-coding driver mutations in super-enhancers and long-range chromatin interaction networks across 1,800 whole cancer genomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2354.
Abstract 2358: Uncovering novel mechanisms of resistance in AML using integrative functional genomics
Authors: Ramos Azucena , Barea Luis R. Millan , Puissant Alexandre , Fenouille Nina , Alexe Gabriela , Stegmaier Kimberly , Hemann Michael T. 
Published: August 2018

Abstract
Treatment options that effectively cure patients diagnosed with acute myeloid leukemia (AML) continue to represent an area of unmet need in oncology clinical care. While remission rates in AML patients can reach upwards of 90% under the current frontline therapy paradigm, nearly all patients relapse with treatment refractory disease less than 5 years after diagnosis. Relapse driven by therapy resistant cells that persist in the body after treatment (defined as minimal residual disease, or MRD) is the principal source of fatality in AML patients. Therefore, understanding how and where these leukemic cells survive treatment in vivo may help advance the rational development of highly synergistic combination therapies for the treatment of AML. Using a functional genomic approach (in vivo RNAi) and a new mouse model of AML chemoresistance (ChemoR) generated in our labs, we have identified several putative mediators of therapy resistance. Transcriptional profiling of the ChemoR model allowed us to generate a chemoresistance gene signature that we overlapped with the results of the shRNA screen to identify high-confidence genes of interest. The top genes from a ranked list of the most highly overexpressed (OE) genes in ChemoR cells and the top depleted genes from the shRNA screen in the context of therapy treatment were selected as high interest hits and subsequently tagged for individual follow-up experiments. Early validation studies suggest that some of our hits protect leukemic cells resident only at specific anatomical niches from therapy, while other proteins appear to be general chemosensitizers both in vivo and in vitro, and in both murine and human AML. Subsequent work will focus on elucidating the mechanisms by which these proteins promote resistance to frontline therapies in AML.
Citation Format: Azucena Ramos, Luis R. Millan Barea, Alexandre Puissant, Nina Fenouille, Gabriela Alexe, Kimberly Stegmaier, Michael T. Hemann. Uncovering novel mechanisms of resistance in AML using integrative functional genomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2358.