bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B68: Erythropoietin stimulates ovarian tumor growth via EphB4.
Authors: Pradeep Sunila , Huang Jie , Mora Edna , Wu Sherry Y. , Li Chun , Lopez-Berestein Gabriel , Jackson David , Sood Anil 
Published: May 2016

Abstract
Background: Recombinant human erythropoietin (rhEpo) has been widely used to treat anemia in cancer patients, concerns about its adverse effects on patient survival have emerged. However the lack of correlation between expression of the canonical EpoR and rhEpo's effects on cancer cells prompted us to consider the existence of an alternative Epo receptor.
Methods: We analyzed the membrane-bound portion of the proteome for candidate receptors possessing structural, regulatory, and functional features consistent with Epo binding and tumorigenic signaling. To examine the potential for EphB4 binding to Epo, we generated EpoR-/- MEFs from EpoR-/- mice. We injected A2780-shControl and-shEpoR cells, shEphB4 or -shEpoR/shEphB4 cells in nude mice to study rhEpo induced tumor progression. We also assessed potential effects of tumoral EpoR or EphB4 expression on the effects of ESA treatment in patients with ovarian (N = 175) or breast (N = 88) cancer. Results: Through systems-based approaches we identified EphB4 as an alternate Epo receptor. MST experiments with fluorophore labeled rhEpo demonstrated binding to EpoR with an apparent dissociation constant (KD,app) of 28.0 ± 14.0 nM and EphB4 with a KD,app value of 880.6 ± 128.6 nM. EphB4 and EphrinB2 bound with a KD,app value of 140.5 ± 28.3 nM. We showed that [I125]rhEpo can bind to these cells EpoR-/- MEFs cells.
EphB4 triggered the downstream signaling via STAT3 and promoted rhEpo-induced tumor growth and progression. rhEpo stimulated in vivo growth of A2780-shControl (p&lt;0.01) and-shEpoR cells (p&lt;0.01), but not -shEphB4 or -shEpoR/shEphB4 cells. In human ovarian and breast cancer samples, expression of EphB4 rather than the canonical EpoR correlated with decreased disease-specific survival in rhEpo-treated patients. Conclusion: In this study, we identified a new mechanism that EphB4 as a critical mediator of erythropoietin signaling, which induced tumor progression in ovarian cancer patients. Altogether our study provides a novel and clinically significant dimension to the biology of erythropoietin, which was not appreciated before.
Citation Format: Sunila Pradeep, Jie Huang, Edna Mora, Sherry Y. Wu, Chun Li, Gabriel Lopez-Berestein, David Jackson, Anil Sood. Erythropoietin stimulates ovarian tumor growth via EphB4. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B68.
Abstract B74: Can we repurpose anti-malarial drug quinacrine to treat ovarian cancer?
Authors: Roy Debarshi , Khurana Ashwani , Kalogera Eleftheria , Wen Xuyang , Mondal Susmita , Shridhar Viji 
Published: May 2016

Abstract
Resistance to chemotherapy is a major hurdle that results in the increased mortality associated with ovarian cancer (OvCa). New therapeutics that synergize with cis-carboplatin/paclitaxel in recurrent tumors will have an enormous impact in prolonging the survival of OvCa patients. Due to the enormous cost of designing and testing new drugs, we have adopted the drug repurposing approach and tested the effect of the antimalarial drug quinacrine (QC) in sensitizing drug resistant OvCa cells to carboplatin induced cytotoxicity and determined that it is autophagy dependent. We have discovered that QC, an autophagy modulator exhibited distinct anti-cancer properties in OvCa cell lines in contrast to other anti-malarial/autophagy inhibitor drugs such as hydroxyquinacrine, bafilomycin A and 3-MA. It is well established that autophagy can be a survival mechanism under stress in cancer or a death promoting phenomenon that is cell type and contextual dependent. Here we demonstrate that QC acts to promote chemotherapy induced cell death specifically more in resistant cells in an autophagy dependent manner. Our preliminary data both in vitro and in vivo indicate that QC induced autophagy downregulates p62 and upregulates cathepsin L levels to sensitize the chemoresistant cells to autophagic and caspase mediated cell death in a p53 independent manner. These unexpected findings led us to explore the mechanistic basis of QC-induced upregulation of the cell cycle inhibitor p21 in cells bearing mutant p53. We uncovered that irrespective of p53 status, QC induces p21 expression in an autophagy-dependent p62-Skp2 mediated ubiquitin pathway resulting in cell cycle arrest and cell death. Since QC is already in PhaseI Clinical trial, these studies may spur new treatment strategies to improve OvCa patient outcome and patient care.
Citation Format: Debarshi Roy, Ashwani Khurana, Eleftheria Kalogera, Xuyang Wen, Susmita Mondal, Viji Shridhar. Can we repurpose anti-malarial drug quinacrine to treat ovarian cancer? [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B74.
Abstract IA07: Targeting checkpoint signaling and DNA repair in ovarian cancer.
Authors: Karnitz Larry M. 
Published: May 2016

Abstract
DNA damage and replication stress activate the ATR-Chk1 checkpoint signaling pathway in which ATR phosphorylates multiple substrates including the kinase Chk1. The ATR-Chk1 signaling pathway regulates DNA repair and cell cycle arrest and promotes the survival of tumor cells exposed to genotoxic chemotherapies. Accordingly, the ATR-Chk1 pathway has emerged as an attractive therapeutic target to increase the antitumor activities of chemotherapy agents, and selective ATR and Chk1 inhibitors have been developed. However, it remains unclear whether ATR and Chk1 inhibition are equally effective with genotoxic chemotherapies that have different mechanisms of action. Here, we compared ATR versus Chk1 inhibition in ovarian cancer cells exposed to agents (cisplatin, topotecan, gemcitabine, and PARP inhibitor) with different mechanisms of action that are used to treat this disease. We found that Chk1 inhibition selectively sensitized to gemcitabine, whereas ATR inhibition broadly sensitized to all chemotherapy agents. Importantly, ATR inhibition also robustly sensitized to PARP inhibitors even in cells with defective HR. These findings suggest that combining ATR inhibitors with these chemotherapy agents may a viable therapeutic strategy in HR-proficient and-deficient tumors.
Citation Format: Larry M. Karnitz. Targeting checkpoint signaling and DNA repair in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr IA07.
Abstract IA16: Endometriosis-related ovarian cancer.
Authors: Shih Ie-Ming 
Published: May 2016

Abstract
Endometriosis-related ovarian neoplasms (ERONs) include clear cell carcinoma, endometrioid carcinoma, and, least frequently, seromucinous carcinomas. They belong to a unique group of ovarian tumors in that unlike other histotypes of ovarian cancer, these tumors are frequently associated with endometriosis, especially the lesions presenting as ovarian endometriotic cysts or endometriomas. ERONs usually present as large, unilateral, cystic neoplasms. In general, ERONs tend to behave in an indolent fashion because many of the diseases present at early clinical stages. When confined to the ovary, they have an excellent prognosis, but advanced stage tumors have a poor outcome. It has been demonstrated that ERONs can develop from endometriotic cyst epithelium through sequential stages of tumor progression. The microenvironment of an endometriotic cyst is highly inflammatory, and the cyst contains abundant iron-induced reactive oxygen species that are thought to be genotoxic and mutagenic. Chronic exposure of cystic epithelium to this microenvironment likely facilitates the accumulation of somatic molecular genetic changes that ultimately transform the cells and lead to tumor development. Molecular analyses of ERONs, including genome-wide analysis, have identified several alterations associated with aberrant activation or inactivation of pathways involving ARID1A, PI3K, Wnt, PP2A and mismatch repair. Specifically, canonical Wnt signaling pathway defects and microsatellite instability are more frequently detected in endometrioid carcinomas than in clear cell carcinomas. Among all of the molecular genetic changes identified to date, inactivating mutations of the ARID1A tumor suppressor gene are most common in ERON. Interestingly, ARID1A mutations are rarely observed in other types of ovarian cancer. ARID1A participates in the SWI/SNF chromatin remodeling complex, which plays a fundamental role in a variety of cellular processes, including DNA damage repair, telomere maintenance, transcription and DNA synthesis and methylation. The molecular events that dictate the development of different ERONs remain elusive, but studies using genetically engineered mouse models demonstrate that co-deletion of ARID1A and PTEN results in ovarian endometrioid carcinoma, while co-deletion of ARID1A and PIK3CA leads to formation of clear cell-like ovarian neoplasms in mice. However, deletion of ARID1A by itself is insufficient to drive ovarian tumor formation. Understanding the molecular changes and pathogenesis involved in the development of ERON is fundamental for future translational studies aimed at designing new diagnostic tests for outcome prediction and at identifying critical molecular features for target-based therapy.
Citation Format: Ie-Ming Shih. Endometriosis-related ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr IA16.
Abstract IA20: Biomarkers for risk prediction, screening, and early diagnostics.
Authors: Urban Nicole , Hawley Sarah , Janes Holly , Karlan Beth Y. , Drescher Charles W. , Daly Mary B. , Anderson Garnet L. 
Published: May 2016

Abstract
Objective: We developed and validated a hybrid risk classifier combining serum markers and epidemiologic risk factors to identify post-menopausal women at elevated risk for invasive fallopian tube, primary peritoneal, and ovarian epithelial carcinoma. The marker component of the classifier uses HE4 in addition to CA125. We have previously reported that HE4 may be useful as a confirmatory test for early diagnosis of ovarian cancer, when rising CA125 is used as a first-line screen.
Methods: To select epidemiologic risk factors for use in the classifier, Cox proportional hazards analyses were conducted using 74,786 Women's Health Initiative (WHI) Observational Study (OS) participants. To construct a combination classifier, 210 WHI OS cases and 536 matched controls with serum marker measurements were analyzed; validation employed 143 cases and 725 matched controls from the WHI Clinical Trial (CT) with similar data.
Results: Analyses identified a combination risk classifier composed of two elevated-risk groups: 1) women with either CA125 or HE4 exceeding a 98% specificity threshold; and 2) women with intact fallopian tubes, prior use of menopausal hormone therapy for at least two years, and either a first degree relative with breast or ovarian cancer or a personal history of breast cancer. In the WHI OS population, it classified 13% of women as elevated risk, identifying 30% of ovarian cancers diagnosed up to 7.8 years post-enrollment (Hazard Ratio [HR]=2.6, p&lt;0.001). In the WHI CT validation population, it classified 8% of women as elevated risk, identifying 31% of cancers diagnosed within 7 years of enrollment (HR=4.6, p&lt;0.001).
Conclusion: CA125 and HE4 contributed significantly to risk prediction in a classifier combining serum markers with epidemiologic risk factors. The hybrid risk classifier may be useful to identify post-menopausal women who would benefit from timely surgical intervention to prevent epithelial ovarian cancer.
Citation Format: Nicole Urban, Sarah Hawley, Holly Janes, Beth Y. Karlan, Charles W. Drescher, Mary B. Daly, Garnet L. Anderson. Biomarkers for risk prediction, screening, and early diagnostics. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr IA20.
Abstract 03: The impact of chromosomal translocation locus and fusion oncogene coding sequence in synovial sarcomagenesis
Authors: Jones Kevin B. , Barrott Jared J. , Jin Huifeng , Haldar Malay , Capecchi Mario R. 
Published: May 2016

Abstract
Synovial sarcoma, the most common soft-tissue sarcoma in young adults bears a t(X;18) translocation that generates a fusion between SS18 (formerly SYT) and an SSX gene. SS18-SSX1 and SS18-SSX2 differ by only 13 amino acids. Clinically, SS18-SSX1 is more common, portends a worse prognosis, and demonstrates increased prevalence of biphasic histology. We conditionally expressed each fusion in otherwise identical mouse models, unexpectedly finding SS18-SSX2 to be more sarcomagenic than SS18-SSX1 and equally prone to biphasic histology. This suggested that coding sequence does not account for clinical differences between the fusions. Reanalysis of patient series found a gender bias in the prevalence of SS18-SSX2-expressing tumors, suggesting an X-linked effect and implicating the loss of native SSX2 by translocation as a hinderance to SS18-SSX2-driven synovial sarcomagenesis in males. Next, we confirmed that human synovial sarcomas almost universally express native SSX2, but not SSX1 and knock-down of native SSX2 in human synovial sarcoma cell lines blunted proliferation whereas overexpression of SSX2 enhances cell proliferation. In conclusion, we hypothesize that SSX2 facilitates sarcomagenesis in SS18-SSX1-expressing tumors and because our model of SS18-SSX2-expressing mice does not disrupt native SSX2 it recapitulates the prevalence and phenotype of SS18-SSX1 tumors.
Citation Format: Kevin B. Jones, Jared J. Barrott, Huifeng Jin, Malay Haldar, Mario R. Capecchi. The impact of chromosomal translocation locus and fusion oncogene coding sequence in synovial sarcomagenesis. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 03.
Abstract 44: Building patient-specific predictors of drug responses from cell line genomics
Authors: Szeto Christopher W. , Benz Stephen , Vaske Charlies 
Published: May 2016

Abstract
Hundreds of model cancer cell lines from diverse tissues have now been comprehensively assayed using several different genome-scale technologies. Additionally, many of these model lines have been challenged with dozens of clinically available oncotherapies. Here we present a set of high-throughput technologies suitable for turning these diverse datasources into actionable, patient-specific diagnostic predictors of response.
First, we computationally integrate diverse -omics data from the DNA, mRNA and protein levels into a pathway model of the cellular state. Next, parallel compute clusters are used to develop and evaluate accurate predictive models upon these pathway activity levels. Finally, these predictive models are used to suggest therapies in a patient-specific manner.
Here we show results from applying these technologies to learning a simple 50-gene signature for response to the the tyrosine kinase inhibitor Dasatinib. This signature utilizes features from the TP53/FOXM1, FOS/JUN & MYC pathways. We note that the exceptional responders to Dasatinib are enriched for nervous-system cancer cell lines. We applied our predictive signature to glioblastoma multiforme samples to correctly indicate which specific GBM patients may have respond to Dasatinib.
Citation Format: Christopher W. Szeto, Stephen Benz, Charlies Vaske. Building patient-specific predictors of drug responses from cell line genomics. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 44.
Abstract 45: Detection of focal somatic copy number variants in whole genome, whole exome, and targeted next-generation sequencing data of tumor/normal pairs
Authors: Aldrich Jessica , Keats Jonathan J. , Liang Winnie S. , Carpten John D. , Craig David W. 
Published: May 2016

Abstract
We describe the development and validation of an analysis pipeline for detection of focal somatic copy number aberrations from next-generation sequencing (NGS) data. In the clinical setting, tumor samples may be derived from historical tissue or from recently collected fresh frozen biopsies. DNA extracted from samples preserved as formalin-fixed, paraffin-embedded (FFPE) tissue are often highly degraded. We describe challenges inherent to sequencing different tissue sources and algorithmic approaches for optimizing detection of focal alterations in these samples with a high degree of accuracy. The first area of optimization takes into account clonal or fragment coverage based on user-defined intervals by accounting for coverage between paired-end reads. Normalized log2 fold-changes between tumor and normal samples are then calculated and a smoothing window is applied. In addition, we utilize tumor allele frequencies of known heterozygous germline SNPs identified within the normal to both evaluate potential false positives and correct biases. Lastly, a segmentation algorithm (circular binary segmentation as implemented in DNAcopy package1) is applied to summarize the individual log2 fold-changes into intervals with a constant copy number state. The results from the segmentation algorithm are then annotated and reformatted into the VCF format. We have analytically optimized and validated our algorithm across a series of samples with known alterations for implementation on both clinical and research samples.
1. Seshan VE and Olshen A. DNAcopy: DNA copy number data analysis. R package version 1.40.0.
Citation Format: Jessica Aldrich, Jonathan J. Keats, Winnie S. Liang, John D. Carpten, David W. Craig. Detection of focal somatic copy number variants in whole genome, whole exome, and targeted next-generation sequencing data of tumor/normal pairs. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 45.
Abstract IA10: Extracellular RNA: A next frontier of biomarker research for precision medicine
Authors: Tewari Muneesh 
Published: May 2016

Abstract
Development of effective, minimally invasive biomarker approaches for cancer is critical for enabling precision oncology. Whereas circulating tumor DNA (ctDNA) is one such approach that is now beginning to reach the clinic after an extended period of development, circulating extracellular RNA (exRNA) is a more recent discovery and represents a new frontier for precision medicine biomarker development. I will review the recent history of extracellular circulating RNA, beginning with the discovery of circulating microRNAs and extending to consider other classes of RNA found in human plasma. I will compare and contrast ctDNA and exRNA approaches, and highlight current challenges as well as possibilities for development of circulating exRNAs as biomarkers for precision oncology.
Citation Format: Muneesh Tewari. Extracellular RNA: A next frontier of biomarker research for precision medicine. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr IA10.
Abstract IA15: “Next-gen” genomics-based clinical trials
Authors: Siu Lillian L. 
Published: May 2016

Abstract
Next generation sequencing (NGS) technologies have gained increasing clinical applications as a strategy to screen and identify patients for genomic based clinical trials in oncology. Molecular characterization programs using NGS have been established in many cancer centers worldwide, including some that comprise part of nation-based efforts. With a growing number of patients whose tumors have undergone molecular profiling, there is an urgent need to justify these activities and translate genomic findings into clinically relevant outcome. Molecular profiling offers information beyond the histopathological classification of tumors, subdividing them into smaller genomic subsets ranging from those harboring common recurrent aberrations to others with rare variants of uncertain significance. The current era of genomic based clinical trials is populated by “umbrella” and “basket” trials which allocate patients with druggable genomic signatures to specific genotype-drug matched groups that remain histology-based (“umbrella” trials) or are histology-agnostic (“basket” trials). The pros and cons of these clinical trial designs, and their ability to bring the value of precision medicine to bear, will be discussed. Looking beyond the present clinical trials framework, it is unlikely that genomics is sufficient as a standalone strategy to fully characterize the complex molecular landscape of cancer. “Next-gen” clinical trials need to target the dynamic status of tumors and take into consideration intratumoral heterogeneity in their design. The extension of profiling algorithms to include transcriptomics and epigenetics is attractive to encompass other alterations that can lead to unchecked tumor growth. A systems biology approach should be considered to understand signaling pathway interactions and decipher mechanisms of oncogenic dependence, especially in tumors which lack readily actionable profiles. There are close interactions between the genome and the immunome such that NGS may inform the selection of patients most likely to benefit from immune-based therapies. “Next-gen” clinical trials must be capable of interrogating cancer in a multifaceted and dynamic manner in order to achieve substantial incremental benefits in therapeutic outcome.
Citation Format: Lillian L. Siu. “Next-gen” genomics-based clinical trials. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr IA15.