bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A9: A whole-locus sequencing approach to identify polymorphisms associated with juvenile-onset granulosa cell tumor susceptibility in SWR mice
Authors: Dorward Ann M. , Smith Kerri N. , Rabie Zoha , Yaskowiak Edward S. , Reinholdt Laura G. 
Published: August 2014

Abstract
Genes that are fundamental for normal development and regulation of the mammalian ovary have been identified through genetic investigations of unusual cases of altered fecundity, infertility or ovarian pathology in model species. In the SWR/Bm (SWR) inbred mouse, we have mapped three distinct loci on Chromosome (Chr) 4 (Gct1) and Chr X (Gct4, Gct6) that have a deleterious effect on ovarian development leading to the formation of juvenile-onset granulosa cell (GC) tumors. GC tumors in SWR female mice have strong parallels with juvenile-type GC tumors that appear in infants and young girls based on endocrinological, histological and malignant criteria. As such, the genetic and epigenetic determinants for tumorigenic processes operative in SWR mice will provide novel information for translational investigations of human juvenile-type GC tumors.
The Gct1 allele derived from the SWR strain (Gct1SW) is unique in its support of androgen-sensitive GC tumor-susceptibility, with the expectation that a unique mutation underlies this trait. The X-linked Gct4 locus is a modifier locus for early-onset GC tumorigenesis, acting in conjunction with the Gct1 allele to enhance or diminish tumor susceptibility with a strong paternal, parent-of-origin effect. The X-linked Gct6 locus harbors a tumor suppressor for GC tumorigenesis, with a unique allele contributed by the Castaneus mouse strain. Forward genetic crosses and congenic strain mapping have resolved the candidate gene intervals for Gct1, Gct4 and Gct6 to 1.31, 1.34 and 1.02 Mb, respectively. It was our goal to evaluate all potential protein-coding or regulatory sequence polymorphisms between the GC tumor-sensitive SWR inbred strain and SWR-derived congenic strains that are resistant to androgen-inducible GC tumorigenesis. The individual locus regions were subsequently captured in a custom library approach prior to high-throughput, next generation sequencing. Informatics analyses of all polymorphisms are underway in the search for unique variants that will be investigated for their causal role in GC tumor susceptibility in this mouse model. For the Gct1SW locus, protein-coding variants have been excluded by our analysis, suggesting that regulatory variant(s) support the juvenile-onset GC tumor susceptible phenotype.
Citation Format: Ann M. Dorward, Kerri N. Smith, Zoha Rabie, Edward S. Yaskowiak, Laura G. Reinholdt. A whole-locus sequencing approach to identify polymorphisms associated with juvenile-onset granulosa cell tumor susceptibility in SWR mice. [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 A9.
Abstract B29: The role of C-Terminal Binding Proteins in BRCA1 silencing and genetic instability of ovarian cancer cells
Authors: Liu Shubai , Yang Junzheng , May Taymaa , Hua Yuanyuan , Lu Shi , Elias Kevin , Drapkin Ronny , Welch William , Crum Christopher , Berkowitz Ross S. , Ng Shu-Wing 
Published: August 2014

Abstract
Objective: Ovarian cancer is the leading cause of mortality from gynecological malignancy in Western countries. High-grade serous ovarian carcinoma (HGSOC) is characterized by genetic instability and frequently harbors defects in genes such as BRCA1 for homologous recombination (HR) pathway. Our group recently demonstrated that the transcriptional co-repressors, C-Terminal Binding Proteins (CtBP1 and CtBP2), are overexpressed in epithelial ovarian carcinoma and CtBP2 overexpression is associated with poor patient survival. We sought to relate the expression of CtBP to genetic instability and chemoresponse in HGSOC cells.
Methods: Gene expression profiling was performed for the control and CtBP2-knockdown ovarian cancer cell lines. Chromatin Immunoprecipitation (ChIP)-qPCR assays and a BRCA1 promoter-luciferase reporter assay were performed to compare the binding of CtBP complex to BRCA1 promoter and the activity of BRCA1 promoter in the ovarian cancer cells. Cell cycle status of the cell lines was determined by flow cytometry. DNA double-strand breaks (DSB) were determined by comet assay.
esults: Analysis of gene expression profiles revealed potential functions of CtBP2 in silencing the expression of a panel of genes such as BRCA1 and Fanconi anemia complementation group gene FANCD2 that are involved in HR pathway, cell cycle checkpoints, and genetic instability. ChIP analyses and the luciferase assays strongly suggest that the CtBP2 complex binds to the BRCA1 promoter and represses BRCA1 transcription. Ovarian cancer cell lines with knockdown of either CtBP1 or CtBP2 showed increased expression of BRCA1 protein. CtBP2-knockdown ovarian cancer cells showed increased apoptosis and arrest in cell cycle. These cell lines also showed a significant increase in DSB after gamma irradiation than wild-type control cells in a comet assay.
Conclusions: CtBP1 and CtBP2 function in the suppression of a panel of target genes such as BRCA1 and FANCD2 that are involved in cell cycle checkpoints and HR pathway. CtBP-mediated BRCA1 silencing may be a significant contributing mechanism for genetic instability and clinicopathologic development of HGSOC. Targeting this epigenetic mechanism may enhance the sensitivity of HGSOC to DNA damaging agents and contribute to improved outcome of ovarian cancer patients.
Citation Format: Shubai Liu, Junzheng Yang, Taymaa May, Yuanyuan Hua, Shi Lu, Kevin Elias, Ronny Drapkin, William Welch, Christopher Crum, Ross S. Berkowitz, Shu-Wing Ng. The role of C-Terminal Binding Proteins in BRCA1 silencing and genetic instability of 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 B29.
Abstract B3: HSP27 is required for invasion and metastasis triggered by hepatocyte growth factor
Authors: Pavan Simona , Musiani Daniele , Torchiaro Erica , Migliardi Giorgia , Erriquez Jessica , Olivero Martina , Renzo Maria Flavia Di 
Published: August 2014

Abstract
The Hepatocyte Growth Factor (HGF) also known as Scatter Factor, activates cancer cell invasion and metastasis. We show that in ovarian cancer cells HGF induced the phosphorylation of the small heat shock protein of 27KDa (HSP27) by activating the p38MAPK. HSP27 is increased in many cancers at advanced stage including ovarian cancer and associated with cancer resistance to therapy and poor patients' survival. The phosphorylation of HSP27 regulates both its chaperone activity and its control of cytoskeletal stability. We show that HSP27 was necessary for the motility in vitro and the remodeling of actin filaments induced by HGF. In vivo, HSP27 silencing impaired the ability of the highly metastatic, HGF-secreting ovarian cancer cells to give rise to spontaneous metastases. This was due to defective motility across the vessel wall and reduced growth. Indeed, HSP27 silencing impaired both the ability of ovarian cancer cells to form experimental haematogenous metastases and to grow as subcutaneous xenografts. Moreover, HSP27 suppression resulted in the sensitization of xenografts to low doses of the chemotherapeutic Paclitaxel, likely because HSP27 protected microtubules from bundling caused by the drug. Altogether, these data show that the HSP27 is required for the pro-invasive and pro-metastatic activity of HGF and suggest that HSP27 might be not only a marker of progression of ovarian cancer, but also a suitable target for therapy. Grant sponsors: This work has been supported by grants to M.F.D.: 2012 IG grant and 2010 Special Program Molecular Clinical Oncology 5xMille of the Italian Association of Cancer Research (AIRC), Project n° 9970, and Grant of the CARIPLO Foundation.
Citation Format: Simona Pavan, Daniele Musiani, Erica Torchiaro, Giorgia Migliardi, Jessica Erriquez, Martina Olivero, Maria Flavia Di Renzo. HSP27 is required for invasion and metastasis triggered by hepatocyte growth factor. [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 B3.
Abstract B48: Targeting chemo-resistance in CCNE1-amplified ovarian cancer
Authors: Taylor-Harding Barbie , Agadjanian Hasmik , Aspuria Paul Joseph , Mizuno Takako , Cheon Dong-Joo , Orsulic Sandra , Karlan Beth , Walsh Christine , Wiedemeyer Wolf Ruprecht 
Published: August 2014

Abstract
The putative oncogene CCNE1 (cyclin E1) is frequently amplified in human high-grade serous ovarian cancer. CCNE1-amplified cancers tend to be wildtype for BRCA1 and BRCA2 and are associated with shorter survival and resistance to platinum-based chemotherapy. Cyclin E1 is an activating cofactor for cyclin-dependent kinases (CDK), which stimulate cell cycle progression through phosphorylation of the retinoblastoma (RB) protein and subsequent induction of E2F transcriptional activity (cyclin E1-RB-E2F signaling). Since BRCA1 and BRCA2 are known target genes of E2F transcription factors, we hypothesize that cyclin E1 signaling actively contributes to high DNA repair capacity and chemo-resistance in a BRCA1/2-dependent manner. We predict CCNE1-amplified ovarian cancers to exhibit an “anti-BRCAness” phenotype. In two independent gene expression datasets, generated by TCGA and The Women's Cancer Program at Cedars-Sinai, we found that CCNE1-amplified ovarian cancers maintain higher levels of BRCA1 than CCNE1-wildtype tumors. Moreover, we have employed genetic and pharmacological targeting approaches in order to assess if inhibition of cyclin E1-dependent signaling can induce BRCAness and restore chemo-sensitivity. Here, we show that pharmacological CDK inhibitors (CDKi) effectively shut down E2F-mediated transcription, resulting in downregulation of BRCA1 and BRCA2 in CDKi-treated cells. Long-term exposure of ovarian cancer cell lines to CDKi selected for cells with reduced dependency on cyclin E1, and genomic profiling revealed de novo DNA copy number changes which compensate for loss of cyclin E1 function. Importantly, CDKi-resistant subclones retained lower levels of BRCA1 and were significantly more sensitive to cisplatin than parental cell lines. Collectively, our results suggest that cyclin E1 signaling is required for BRCA1 expression and chemo-resistance. Currently available CDKi such as Dinaciclib, which is in a phase 3 clinical trial, may be useful to specifically sensitize CCNE1-amplified ovarian cancers to cisplatin.
Citation Format: Barbie Taylor-Harding, Hasmik Agadjanian, Paul Joseph Aspuria, Takako Mizuno, Dong-Joo Cheon, Sandra Orsulic, Beth Karlan, Christine Walsh, Wolf Ruprecht Wiedemeyer. Targeting chemo-resistance in CCNE1-amplified 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 B48.
Abstract B78: Osteopontin-c splicing isoform is a key molecule in ovarian cancer progression
Authors: Tilli Tatiana M. , Mello Kivvi D. , Franco Vanessa , Robbs Bruno , Wanderley João Luiz , Rass Fabrício , Viola João P B , Weber Georg , Castronovo Vincent , Bellahcène Akeila , Gimba Etel R P , Gimba Etel 
Published: August 2014

Abstract
Introduction: Osteopontin (OPN) is a glyphosphoprotein overexpressed in ovarian carcinoma (OC) and is involved in tumorigenesis and metastasis. Alternative splicing of OPN primary transcript generates 3 isoforms, named as OPNa, OPNb, and OPNc. Objective: This study aimed to characterize the expression profile and functional role of each OPN splicing isoform (OPN-SI) in OC. Methodology: The expression patterns of OPN-SI and a series of genes involved in key cancer pathways were analyzed by real-time PCR. In vitro and in vivo functional assays were performed using the ovarian cancer cell line OvCar-3, stably overexpressing the three OPN-SI and conditoned medium secreted by these cells. Results: OPNc, but not OPNa and OPNb, was specifically expressed on OC samples. OPNc splice variant significantly activated OvCar-3 cell proliferation, migration, invasion and anchorage independent cells growth, besides inducing tumor formation in nude mice. We also found that these features are mainly mediated by PI3K/Akt signaling pathway. By using a real time PCR Cancer Gene Array, we found that OvCar-3 OPNc-overexpressing cells are also able to modulate the expression of 34 genes involved in key cancer pathways. Notably, tumors formed by OPNc-overexpressing cells present high expression levels of typical angiogenic markers, such as VEGF-A, VEGFR-2 and CD34. Based on these data, we also investigated the molecular mechanisms by which OPNc stimulates angiogenic processes. Our data showed that OPNc overexpression activates VEGF-A expression and secretion, besides upregulating the expression of c-Fos, c-Jun and phospho-c-Jun. OPNc role on activating the phosphorylation of c-Jun is mediated by the integrin receptor (αvβ3), in an RGD-dependent manner. In addition, OPNc-conditioned medium is able to induce HUVEC endothelial cell proliferation, migration and adhesion. Conclusion: In summary, our data demonstrate that OPNc is able to activate sereral aspects of OC progression, including angiogenesis, mainly by the PI3K/Akt pathway, indicating that this splice variant could be a putative target for further studies aiming to investigate this molecule for new therapeutic approaches for OC.
Citation Format: Tatiana M. Tilli, Kivvi D. Mello, Vanessa Franco, Bruno Robbs, João Luiz Wanderley, Fabrício Rass, João P B Viola, Georg Weber, Vincent Castronovo, Akeila Bellahcène, Etel R P Gimba, Etel Gimba. Osteopontin-c splicing isoform is a key molecule in ovarian cancer progression. [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 B78.
Abstract IA10: Comprehensive proteomic analyses of TCGA ovarian cancer specimens: Update from CPTAC
Authors: Rodland Karin D. 
Published: August 2014

Abstract
The Cancer Genome Atlas project included ovarian serous cystadenocarcinoma as one of the first four tumor types examined, and TCGA has currently completed comprehensive genomic analyses of over 500 HGSOC tumor specimens, including complete exome sequencing, SNP and methylation analysis, as well as mRNA and miRNA profiling. The Clinical Proteomics Tumor Analysis Consortium (CPTAC) has collaborated with TCGA to provide equally comprehensive proteomic analysis of the same tumors analyzed by TCGA, including quantitative global proteomics, phosphoproteomics, and glycoproteomics. The objective of this study is to further understanding of the execution of genome-level aberrations at the protein level, and to identify functional changes associated with clinical outcome that may provide new insights into the mechanisms of disease progression, factors contributing to chemoresistance, and potentially the identification of new therapeutic targets. Initial analysis of a subset of the TCGA ovarian tumors at Pacific Northwest National Laboratory and Johns Hopkins Medical Institutes has provided preliminary evidence of pathway-level dysregulation associated with platinum resistance and poor clinical outcome.
Citation Format: Karin D. Rodland. Comprehensive proteomic analyses of TCGA ovarian cancer specimens: Update from CPTAC. [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 IA10.
Abstract IA21: Panel Discussion: Survivorship Issues
Authors: Levine Douglas A. 
Published: August 2014

Abstract
This one-of-a-kind discussion panel with a mix of both scientists and survivors, will help to bridge the gap between researchers and patients. The main goal is for scientists to appreciate issues of important priority to patients and understand where the ultimate fruits of their labors reside. Scientists will gain a better understanding of the complex issues surrounding first in human studies and the balance of efficacy and toxicity that face patients and doctors on a daily basis. Survivors and clinicians will appreciate the complex environment of drug development in the laboratory and how to take a lead compound through to clinical testing from a human trials perspective. We will discuss issues faced when trying to overcome barriers in improving ovarian cancer outcome and survival. Financial aspects of clinical trials and correlative science continually plague decision-making processes. In addition, how scientists can help advocates in bringing effective drugs into market even when the market share may be small. Scientists will have the opportunity to hear patient stories of diagnosis and treatment as well as specific survivorship issues and healthcare needs of survivors. The balance between efficacy and quality of life will also be discussed.
Citation Format: Douglas A. Levine. Panel Discussion: Survivorship Issues. [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 IA21.
Abstract IA22: Causes and consequences of cancer-associated thrombocytosis
Authors: Sood Anil K. , Stone Rebecca L. , Afshar-Kharghan Vahid 
Published: August 2014

Abstract
Platelets represent one of the largest storage pools of angiogenic and oncogenic growth factors in the human body. The observation that thrombocytosis (platelet count &gt;450,000/μL) occurs in patients with solid malignancies was made over 100 years ago. However, mechanisms of paraneoplastic thrombocytosis and the role that platelets play in abetting cancer growth are unclear. We have used clinical data coupled with sophisticated mouse models to identify the mechanisms and biological implications of paraneoplastic thrombocytosis. Thrombocytosis was significantly associated with advanced disease and shortened survival. Plasma levels of thrombopoietin and interleukin-6 were significantly elevated in patients who had thrombocytosis as compared with those who did not. In mouse models, increased hepatic thrombopoietin synthesis in response to tumor-derived interleukin-6 was an underlying mechanism of paraneoplastic thrombocytosis. Tumor-derived interleukin-6 and hepatic thrombopoietin were also linked to thrombocytosis in patients. Silencing thrombopoietin and interleukin-6 abrogated thrombocytosis in tumor-bearing mice. Anti–interleukin-6 antibody treatment significantly reduced platelet counts in tumor-bearing mice and in patients with epithelial ovarian cancer. In addition, neutralizing interleukin-6 significantly enhanced the therapeutic efficacy of paclitaxel in mouse models of epithelial ovarian cancer. The use of an antiplatelet antibody to halve platelet counts in tumor-bearing mice significantly reduced tumor growth and angiogenesis. Biologically, platelets were detected within the tumor microenvironment and affected tumor growth and response to chemotherapeutic agents. These findings support the existence of a paracrine circuit wherein increased production of thrombopoietic cytokines in tumor and host tissue leads to paraneoplastic thrombocytosis, which fuels tumor growth. Blocking the stimulatory effects of platelets may have implications for new therapeutic approaches.
Citation Format: Anil K. Sood, Rebecca L. Stone, Vahid Afshar-Kharghan. Causes and consequences of cancer-associated thrombocytosis. [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 IA22.
Abstract IA17: Exploiting the synthetic lethal properties of selective PI3K-β inhibition in PTEN deficient cells with GSK2636771
Authors: Greshock Joel 
Published: August 2014

Abstract
The phosphoinositide 3-kinase (PI3K) pathway is among the most commonly mutated pathways in human cancer. The majority of first-generation PI3K inhibitors currently in clinical trials inhibit multiple PI3K isoforms. The PIK3CB gene encodes p110β isoform, which has been reported to be required for pathway activation in phosphatase and tensin homolog (PTEN) deficient cancer cells. The observed dependence of PTEN-deficient tumors on p110β provides an opportunity for identification of a novel isoform-selective therapeutic with a synthetic lethal effect. During an extensive knowledge-based lead identification and optimization effort, we identified substituted benzimidazole GSK2636771 as a potent, orally bioavailable, PI3Kβ-selective inhibitor. The observed enzymatic potency for PI3Kβ is approximately 1000 and 10 fold higher than the potency against PI3Kα and PI3δ respectively. Pre-clinical data demonstrate the synthetic lethal relationship between PTEN deficiencies and PI3K-β inhibition. PTEN-deficient cells dosed with GSK2636771 show concentration dependent decreases in cellular levels of phosphorylated AKT (pAKT), and PRAS40 both in-vitro and in-vivo. A 3-day proliferation assay performed on a large panel of cell lines (n=80) grown in-vitro demonstrates selective growth inhibition in PTEN-deficient cells at lower concentrations of GSK2636771. In-vivo studies in PTEN-deficient prostate cancer models also show dose dependent tumor growth delay. PTEN is commonly mutated, deleted, or epigenetically silenced in a wide range of solid tumors. Loss of PTEN protein is particularly frequent in prostate (50%), endometrial (57%), and triple negative breast cancers (30%). Prospective selection of patients with this protein loss serves as a development path through the course of study P3B115717 (NCT01458067), a Phase I/IIa first-time-in-human study with GSK2363771. This study is currently in dose-escalation.β
Citation Format: Joel Greshock. Exploiting the synthetic lethal properties of selective PI3K-β inhibition in PTEN deficient cells with GSK2636771. [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 IA17.