bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B19: Functional genomics approach links anchorage-independence with tumor dormancy in ovarian cancer
Authors: Matsumura Noriomi , Yamanoi Koji , Amano Yasuaki , Hamanishi Junzo , Baba Tsukasa , Murphy Susan K. , Konishi Ikuo 
Published: August 2014

Abstract
Although a number of genes are aberrantly regulated in ovarian cancer, little is known about which genes are functionally important. The aim of this study was to identify new genes relevant to anchorage-independent growth of ovarian cancer cells through a genome-wide functional screening approach. We performed lentiviral transduction of a library of 81,000 shRNAs (Cellecta, Inc.) targeting 15,000 genes into an immortalized human ovarian surface epithelium cell line and 7 ovarian cancer cell lines (OVCA420, OVCA433, OVCA429, CAOV3, SKOV8, Tyk-nu and DOV13) which do not generate anchorage-independent colonies in soft agar. Among these, only OVCA420 generated colonies larger than 100 micrometers after shRNA library transduction. We extracted DNA from these colonies, amplified the shRNA constructs with PCR, and inserted the amplicons back into the original lentiviral vector, thus generating a secondary library of 68 shRNAs. Subsequent analysis, performed to examine the reproducible formation of anchorage-independent colonies using the secondary library, identified 5 shRNAs targeting ABHD2, CYB5R3, MR1, ELAC2 and CCL22. Interestingly, population doubling time was increased following transduction of these shRNAs (44.8, 50.1, 43.9, 28.0 and 33.2 hours, respectively) compared to the original or control shRNA-transducted OVCA420 cells (22.4 and 23.7 hours, respectively). Furthermore, side populations detected by efflux of Hoechst 33342 dye were drastically increased (50.5, 46.6, 55.5, 76.5 and 41.1%, respectively) compared to the original or control shRNA-transducted OVCA420 cells (7.3 and 10.4%, respectively). Although these data are not conclusive, they support that a phenotypic change occurs as ovarian cancer cells leave the primary tumor and are suspended in ascites. We found that repression of any one of these particular genes was sufficient to avoid anoikis. This change was accompanied by suppression of cell proliferation and increased efflux of Hoechst 33342 dye, which indicates activation of pumping function, suggesting a change to chemoresistant dormant cells. In summary, our functional genomics approach suggests a molecular mechanism underlying the process of anchorage independence, tumor dormancy and chemoresistance in ovarian cancer.
Citation Format: Noriomi Matsumura, Koji Yamanoi, Yasuaki Amano, Junzo Hamanishi, Tsukasa Baba, Susan K. Murphy, Ikuo Konishi. Functional genomics approach links anchorage-independence with tumor dormancy in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B19.
Abstract B35: Target discovery: Using VBIM technique to identify carboplatin resistance genes in ovarian cancer cells
Authors: Wei Han , Lu Tao 
Published: August 2014

Abstract
Among gynecological cancers, ovarian cancer is the leading cause of death each year. Women are often diagnosed with an advanced stage of the disease as it is frequently without overt or specific symptoms until late in its development. One of the major chemotherapy drugs used to treat ovarian cancer is carboplatin. Carboplatin was introduced in the late 1980s and has since gained popularity in clinical treatment due to its vastly reduced side-effects compared to its parent compound, cisplatin. Although resistance to carboplatin remains a major barrier to the successful treatment of ovarian cancer, the mechanisms of its resistance are poorly understood.
In this study, we used the novel validation-based insertional mutagenesis (VBIM) technique to identify carboplatin resistance genes in ovarian cancer cells and to further confirm and evaluate their role in mediating carboplatin resistance in ovarian cancer cells. In a preliminary screen, we identified three novel proteins whose functions have never been previously linked to carboplatin resistance in ovarian cancer. We name them ovarian cancer carboplatin resistance genes OCCRP-1, 2 and 3. By generating stable A2780 cells in which OCCRP-1 is either overexpressed or knocked down, we confirmed that OCCRP-1 is a carboplatin resistance gene in ovarian cancer cells. Similar work is carrying on for OCCRP-2 and 3 as well.
Our study promises to discover novel mechanisms of gene-mediated carboplatin resistance so that reversal or bypass of this resistance in ovarian cancer can be achieved by developing small chemical inhibitors which ultimately will lead to novel therapeutic approaches for ovarian cancer treatment.
Citation Format: Han Wei, Tao Lu. Target discovery: Using VBIM technique to identify carboplatin resistance genes in ovarian cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B35.
Abstract B47: microRNA-181a plays a critical role in ovarian cancer progression through the regulation of epithelial-mesenchymal transition
Authors: Parikh Aditya , Lee Christine , Joseph Peronne , Marchini Sergio , Baccarini Alessia , Kolev Valentin , Romualdi Chiara , Fruscio Robert , Shah Hardik , Feng Wang , Mullokandov Gavriel , Fishman David , D'Incalci Maurizio , Rahaman Jamal , Kalir Tamara , Redline Raymond , Brown Brian D. , Narla Goutham , DiFeo Analisa 
Published: August 2014

Abstract
Ovarian cancer is the most lethal gynecological cancer primarily due to advanced stage of disease at diagnosis. Effective therapeutic targets and prognostic biomarkers are still lacking due to insufficient knowledge of the pathways that regulate ovarian cancer progression. Here, we identify miR-181a as a mediator of disease dissemination through the induction of EMT and direct activation of the TGF-β signaling pathway via repression of its functional target, Smad7. High expression of miR-181a and phospho-Smad2 were associated with poor patient outcome and were enriched in recurrent compared to matched-primary tumors. Ectopic expression of miR-181a resulted in increased cellular survival, migration, drug resistance, and in vivo tumor burden, and dissemination. Conversely, targeting this miRNA using a decoy vector resulted in significant decreases in cell survival, migration, and MET in ovarian cancer cell lines. Combined, our findings identify miR-181a as a novel modulator of ovarian cancer dissemination through the induction of EMT and highlight its role as a potential biomarker and therapeutic target for aggressive late-stage ovarian cancer.
Citation Format: Aditya Parikh, Christine Lee, Peronne Joseph, Sergio Marchini, Alessia Baccarini, Valentin Kolev, Chiara Romualdi, Robert Fruscio, Hardik Shah, Wang Feng, Gavriel Mullokandov, David Fishman, Maurizio D'Incalci, Jamal Rahaman, Tamara Kalir, Raymond Redline, Brian D. Brown, Goutham Narla, Analisa DiFeo. microRNA-181a plays a critical role in ovarian cancer progression through the regulation of epithelial-mesenchymal transition. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B47.
Abstract B57: Continuous exposure to epidermal growth factor in ovarian cancer cells causes a persistent increase in N-cadherin expression which then results in multicellular aggregate compaction
Authors: Samudio-Ruiz Sabrina L. , Hudson Laurie G. 
Published: August 2014

Abstract
Ovarian cancer is the leading cause of death arising from gynecological malignancies. Overexpression of the epidermal growth factor receptor (EGFR) or its ligands is associated with poor prognosis. The presence of EGFR activators in patient ascites fluid may lead to constitutive activation of the EGFR and thereby contribute to metastasis and/or resistance to therapy. Acquired chemoresistance following initial chemotherapeutic treatment prevents clinical effectiveness and occurs in a large majority of patients. Thus, our studies evaluated the cellular consequences to prolonged EGF exposure/EGFR activation and how this could contribute to metastasis or chemoresistance. We found that extended exposure to EGF (10 nM, ~40 days) resulted in a change in cell phenotype that was retained even when the EGF ligand was removed for at least 7 days (removal). There was a persistent increase in N-cadherin and vimentin levels in EGF treated and removal cells. This increase in mesenchymal markers in EGF treated cells is associated with a significant increase in multicellular aggregate (MCA) compaction. Furthermore, EGF treated MCAs displayed a significant increase in cell spreading when allowed to adhere to collagen. MCA compaction and enhanced spreading were largely due to elevated N-cadherin levels as we found that knock down of N-cadherin resulted in less compact MCAs and reduced spreading on collagen. MCAs have been shown to be chemoresistant and the compact MCA structure due to prolonged EGF treatment conferred resistance to cisplatin treatment. Our results indicate that prolonged EGFR activation causes a persistent change in mesenchymal marker expression, which regulates MCA compaction and sensitivity to chemotherapeutics. This finding suggests that activators of the EGFR in the tumor environment may drive changes in ovarian cancer cells that contribute to the low patient survival rates.
Citation Format: Sabrina L. Samudio-Ruiz, Laurie G. Hudson. Continuous exposure to epidermal growth factor in ovarian cancer cells causes a persistent increase in N-cadherin expression which then results in multicellular aggregate compaction. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B57.
Abstract IA1: Mining the TCGA
Authors: Levine Douglas A. 
Published: August 2014

Abstract
The Cancer Genome Atlas (TCGA) has recently completed its first formal analysis of the genomic and clinical data from the ovarian carcinoma project. This analysis has confirmed previous knowledge and discovered new insights into this challenging disease. Now is the time for the research community to take hold of this high-quality, robust data set and apply it to translational and basic biologic questions. This session will review the nuts and bolts of The Cancer Genome Atlas comprehensive genomic profiling projects with special emphasis on the completed ovarian project. The sample inclusion criteria, clinical data, and molecular platforms will be reviewed in detail. The TCGA biospecimens pipeline will be discussed. Numerous analytical tools for individuals to download raw data and use previously processed data will be provided. Case studies of individual research projects that use TCGA data will be examined. This session will be useful for any scientists, surgeons, or physicians who are interested in learning more about the NIH-sponsored TCGA project. This session will also be beneficial for individuals interested in figuring out how to practically use the large volumes of data generated by TCGA to enhance ongoing and planned research projects. The goal of this session is to demonstrate how TCGA data can serve as a reliable resource for the greater research community.
Citation Format: Douglas A. Levine. Mining the TCGA. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr IA1.
Abstract IA14: Exploiting the translational and functional opportunities for homologous recombination deficiency
Authors: Edmondson Richard John 
Published: August 2014

Abstract
Cancer is a disease of DNA, and the processes by which cells repair DNA damage are critical, not only in causing the disease but also in determining how the cancer cell will respond to treatment. Of the six major pathways by which DNA damage is repaired, homologous recombination (HR) is perhaps the best studied in ovarian cancer. This pathway is responsible for repairing double strand breaks and uses at least forty proteins, including both BRCA1 and BRCA2.
We have shown that 50% of high grade serous cancers are defective in homologous recombination and this group are more likely to be sensitive to platinum chemotherapy and have a better prognosis than tumours which are competent for the pathway. As may be expected, this group also includes all the tumours occurring in women with germline mutations of BRCA1 and BRCA2.
HR status has also been suggested to be predictive of response to PARP inhibitors and it is proposed that this is an example of synthetic lethality in which inactivation of one pathway is not harmful to a cell but inhibition of two (one by the PARP inhibitor and the other the underlying HR defectiveness) will render the cell non viable. We have confirmed in a large panel of ovarian cancer primary cultures and cell lines that HR defectiveness is indeed a very strong predictor of ex vivo drug sensitivity with positive and negative predictive values close to 100%. These data provide the basis for developing biomarker directed therapy for PARP inhibitors and provide a rationale for increasing the indication for these drugs to tumours other than those caused by germline mutations.
Challenges still exist however and current work is seeking to investigate the interplay of the different DNA damage repair pathways and how these may be used to further refine the biomarkers currently available.
Citation Format: Richard John Edmondson. Exploiting the translational and functional opportunities for homologous recombination deficiency. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr IA14.
Abstract IA2: Cell lines as ovarian cancer models: Insights from molecular profiles in TCGA and CCLE
Authors: Schultz Nikolaus 
Published: August 2014

Abstract
Cancer cell lines are frequently used as in vitro tumor models. Recent molecular profiles of hundreds of cell lines from the Cancer Cell Line Encyclopedia (CCLE) and thousands of tumor samples from The Cancer Genome Atlas (TCGA) now allow a systematic genomic comparison of cell lines and tumors. We analyzed a panel of 47 ovarian cancer cell lines and identified those that have the highest genetic similarity to ovarian tumors. Our comparison of copy-number changes, mutations and mRNA expression profiles revealed pronounced differences in molecular profiles between commonly used ovarian cancer cell lines and high-grade serous ovarian cancer tumor samples. We identified several rarely used cell lines that more closely resemble cognate tumor profiles than commonly used cell lines, and we propose these lines as the most suitable models of ovarian cancer. Our results indicate that the gap between cell lines and tumors can be bridged by genomically informed choices of cell line models for all tumor types. The genomic profiles of these ovarian cancer cell lines and tumor samples can be explored and analyzed via the cBioPortal for Cancer Genomics (cbioportal.org).
Citation Format: Nikolaus Schultz. Cell lines as ovarian cancer models: Insights from molecular profiles in TCGA and CCLE. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr IA2.
Abstract IA9: Pathway-directed therapy
Authors: Levine Douglas A. 
Published: August 2014

Abstract
The Cancer Genome Atlas (TCGA) has recently completed its first formal analysis of the genomic and clinical data from the ovarian carcinoma project. The landscape of ovarian cancer is changing due to our improved understanding of risk factors, histopathology, and cancer genomics. Ovarian cancer is a unique disease with extensive activation of canonical cancer pathways. This session will update the latest advances in ovarian cancer research with a focus on pathway-based therapeutics. The incorporation of biomarkers to predict clinical outcome and for the selection of molecularly targeted agents will be examined. Throughout the session examples will be provided from recent literature and clinical trials. At the conclusion of the session, the participants should have a better understanding of the latest molecular progress and the application to screening, prevention, and therapeutic stratification.
Citation Format: Douglas A. Levine. Pathway-directed therapy. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr IA9.
The CDK4/6 Inhibitor LY2835219 Overcomes Vemurafenib Resistance Resulting from MAPK Reactivation and Cyclin D1 Upregulation
Authors: Yadav Vipin , Burke Teresa F. , Huber Lysiane , Van Horn Robert D. , Zhang Youyan , Buchanan Sean G. , Chan Edward M. , Starling James J. , Beckmann Richard P. , Peng Sheng-Bin 
Published: August 2014

Abstract
B-RAF selective inhibitors, including vemurafenib, were recently developed as effective therapies for melanoma patients with B-RAF V600E mutation. However, most patients treated with vemurafenib eventually develop resistance largely due to reactivation of MAPK signaling. Inhibitors of MAPK signaling, including MEK1/2 inhibitor trametinib, failed to show significant clinical benefit in patients with acquired resistance to vemurafenib. Here, we describe that cell lines with acquired resistance to vemurafenib show reactivation of MAPK signaling and upregulation of cyclin D1 and are sensitive to inhibition of LY2835219, a selective inhibitor of cyclin-dependent kinase (CDK) 4/6. LY2835219 was demonstrated to inhibit growth of melanoma A375 tumor xenografts and delay tumor recurrence in combination with vemurafenib. Furthermore, we developed an in vivo vemurafenib-resistant model by continuous administration of vemurafenib in A375 xenografts. Consistently, we found that MAPK is reactivated and cyclin D1 is elevated in vemurafenib-resistant tumors, as well as in the resistant cell lines derived from these tumors. Importantly, LY2835219 exhibited tumor growth regression in a vemurafenib-resistant model. Mechanistic analysis revealed that LY2835219 induced apoptotic cell death in a concentration-dependent manner in vemurafenib-resistant cells whereas it primarily mediated cell-cycle G1 arrest in the parental cells. Similarly, RNAi-mediated knockdown of cyclin D1 induced significantly higher rate of apoptosis in the resistant cells than in parental cells, suggesting that elevated cyclin D1 activity is important for the survival of vemurafenib-resistant cells. Altogether, we propose that targeting cyclin D1–CDK4/6 signaling by LY2835219 is an effective strategy to overcome MAPK-mediated resistance to B-RAF inhibitors in B-RAF V600E melanoma. Mol Cancer Ther; 13(10); 2253–63. ©2014 AACR.
Abstract A05: Functional genetic approach identifies cancer-specific requirement for BUB1B/BubR1 in human brain tumor isolates and genetically transformed cells
Authors: Ding Yu , Hubert Christopher , Herman Jacob , DeLuca Jennifer , Olson James , Paddison Patrick 
Published: August 2014

Abstract
Cancer cells give rise to distinctive and complimentary capabilities that enable them to continuously grow. These capabilities may as well generate additional vulnerabilities and can be targeted for therapy. To identify new candidate therapeutic targets for glioblastoma multiforme, we combined functional genetics and glioblastoma network modeling to identify kinases required for the growth of patient-derived brain tumor-initiating cells (BTIC) but that are dispensable to proliferating human neural stem cells (NSC). This approach yielded BUB1B/BUBR1, a critical mitotic spindle checkpoint player, as the top-scoring glioblastoma lethal kinase. Knockdown of BUB1B inhibited expansion of BTIC isolates, both in vitro and in vivo, without affecting proliferation of NSCs or astrocytes. Mechanistic studies revealed that BUB1B's GLE2p-binding sequence (GLEBS) domain activity is required to suppress lethal kinetochore-microtubule (KT-MT) attachment defects in glioblastoma isolates and genetically transformed cells with altered sister KT dynamics, which likely favor KT-MT instability. These results indicate that glioblastoma tumors have an added requirement for BUB1B to suppress lethal consequences of altered KT function and further suggest that sister KT measurements may predict cancer-specific sensitivity to BUB1B inhibition and perhaps other mitotic targets that affect KT-MT stability.
Significance: Currently, no effective therapies are available for glioblastoma, the most frequent and aggressive brain tumor. Our results suggest that targeting the GLEBS domain activity of BUB1B may provide a therapeutic window for glioblastoma, as the GLEBS domain is nonessential in untransformed cells. Moreover, the results further suggest that sister KT distances at metaphase may predict sensitivity to anticancer therapeutics targeting KT function.
Citation Format: Yu Ding, Christopher Hubert, Jacob Herman, Jennifer DeLuca, James Olson, Patrick Paddison. Functional genetic approach identifies cancer-specific requirement for BUB1B/BubR1 in human brain tumor isolates and genetically transformed cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr A05.