bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract AS30: BRCA1-IRIS inactivation sensitizes ovarian tumors to cisplatin
Authors: Paul Bibbin T. , Blanchard Zannel , Ridgway Mildred , ElShamy Wael M. 
Published: August 2015

Abstract
Ovarian cancer is the first in mortalities among gynecological cancers in the USA, often due to late diagnosis and/or acquired platinum-resistant recurrences. This study investigates whether BRCA1-IRIS is a novel treatment target for ovarian cancers and their platinum-resistant recurrences. Here we show that more than half of ovarian cancer samples analyzed showed BRCA1-IRIS and survivin overexpression and lacked nuclear FOXO3a expression. Normal ovarian epithelial cells overexpressing BRCA1-IRIS formed metastasis in mice when injected in the peritoneal cavity, whereas aggressive ovarian cancer cell lines failed to form tumors or metastases in mice when BRCA1-IRIS was silenced in them. We show that BRCA1-IRIS activates two autocrine signaling loops, BDNF/TrkB and NRG1/ErbB2. These loops are involved in anoikis resistance and metastasis promotion. These loops operate in several ovarian cancer cell lines and BRCA1-IRIS silencing or inactivation using a novel inhibitory peptide renders both non-functional and promoted cell death. In a mouse xenograft model BRCA1-IRIS inactivation using this novel inhibitory peptide resulted in significant reduction in ovarian tumor growth. More importantly, this treatment sensitized ovarian tumors to low Cisplatin concentrations. Taken together, these data strongly suggest that BRCA1-IRIS and/or BDNF/TrkB and NRG1/ErbB2 could serve as rational therapeutic targets for advanced ovarian cancers.
Citation Format: Bibbin T. Paul, Zannel Blanchard, Mildred Ridgway, Wael M. ElShamy. BRCA1-IRIS inactivation sensitizes ovarian tumors to cisplatin [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS30.
Abstract KP02: Functional genomics, cancer biology and targets
Authors: Hahn William C. 
Published: August 2015

Abstract
Recent advances in genomics now make it possible to consider enumerating all of the genetic lesions in specific cancers. These approaches will yield critical information regarding the identification, number, and types of alterations found in human tumors and are increasingly being applied prospectively to patient samples in the clinic. At the same time, complementary approach to decipher the molecular basis of malignant transformation depends upon the application of genome scale tools to annotate the function of genes involved in cancer initiation and progression. Over the past several years, we have developed genome scale loss-of-function libraries and open reading frame expression libraries that permit a systematic evaluation of genes involved in cancer initiation and maintenance. Using these libraries, we have now performed screens in a panel of human ovarian cancer cell lines to systematically identify cancer vulnerabilities. By combining these functional approaches with information derived from mapping the structural abnormalities present in cancer genomes, we have identified several new oncogenes that contribute to cancer development. The ability to systematically manipulate gene expression at genome scale now provides opportunities to investigate the function of genes involved in cancer initiation and maintenance, which will provide a framework for therapeutic strategies.
Citation Format: William C. Hahn. Functional genomics, cancer biology and targets [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr KP02.
Abstract POSTER-BIOL-1309: Beta-catenin regulated ALDH1A1 is a target in ovarian cancer stem cells
Authors: Condello Salvatore , Nagdas Sarbajeet , Morgan Cynthia , Turek John , Hurley Thomas , Matei Daniela 
Published: August 2015

Abstract
Spheroids are 3D multi-cell aggregates formed in non-adherent culture conditions. In ovarian cancer (OC), they serve as a vehicle for cancer cell dissemination in the peritoneal cavity and protect cells from extracellular stress-induced anoikis. We hypothesized that spheroids are enriched in cancer stem cells and investigated pathways activated under these conditions. Affymetrix-based gene expression profiling of OC cells grown as spheroids vs. monolayers identified β-catenin pathway being upregulated in 3D cultures. Increased expression of β-catenin and target genes (cyclin D1, c-myc) was demonstrated in spheroids vs. monolayers and in successive spheroid generations using OC cell lines and primary cultures. B-catenin function measured as TCF/LEF1 reporter activity was augmented in spheroids vs. monolayers and siRNA mediated β-catenin knock down decreased the number of spheroids (p&lt;0.001). Along with β-catenin, the expression level of ALDH1A1, an OC stem cell marker, was increased in successive spheroid generations. The percentage of ALDH+ cells was significantly higher in spheroids vs. monolayers in IGROV1, A2780, SKOV3, and primary OC cells. B-catenin knock-down decreased ALDH1A1 expression, suggesting that it is a β-catenin target. The percentage of ALDH+ cells and the number of spheroids formed were increased in the cell population dissociated from OC xenografts treated with carboplatin compared to control (44% vs. 2.3%), supporting that ALDH1A1 is a stem cell marker. A37 is a novel ALDH1A1 enzymatic inhibitor (Ki of 5nM). A37 decreased cell viability and spheroid formation by IGROV1 cells (p&lt;0.001). A37 also decreased the percentage of ALDH+ cells under 3D culture conditions. These data support the role of β-catenin regulated ALDH1A1 in the maintenance of OC spheroids and of a stem cell phenotype and propose new ALDH1A1 inhibitors targeting this cell population.
(Funding: US Department of Veterans Affairs and Ovarian Cancer Research Fund)
Citation Format: Salvatore Condello, Sarbajeet Nagdas, Cynthia Morgan, John Turek, Thomas Hurley, Daniela Matei. Beta-catenin regulated ALDH1A1 is a target in ovarian cancer stem cells [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1309.
Abstract POSTER-BIOL-1318: Claudin 4 controls the receptor tyrosine kinase EphA2 pro-oncogenic switch through β-catenin
Authors: Shang Xiying , Lin Xinjian , Howell Stephen B. 
Published: August 2015

Abstract
EphA2, which is expressed in ovarian cancer, is activated by two different mechanisms. Activation by engagement with one of its ephrin ligands is anti-oncogenic whereas activation by phosphorylation of S897 by AKT increases migration, invasion and metastasis. Down-regulation of claudin-4 (CLDN4) produces a loss of E-cadherin and increased β-catenin signaling and a phenotype similar to that produced by oncogenic activation of EphA2. We found that constitutive knockdown of CLDN4 was associated with a 4.5-fold increase in EphA2 mRNA and a 2.5-fold increase in EphA2 protein which was reversed by re-expression of CLDN4. Knockdown of EphA2 blocked the migratory phenotype induced by loss of CLDN4. Knockdown of CLDN4 resulted in a 5.8-fold increase in pEphA(S897), the oncogenic form of the receptor, as well as mislocalization of EphA2 to the interior of the cell. Forced expression of E-cadherin did not reduce total EphA2 or pEphA(S897) whereas re-expression of CLDN4 restored localization and reduced EphA2 and pEphA(S897) even in cells not expressing E-cadherin. Transient siRNA-mediated knockdown of EphA2 and β-catenin, and inhibition of PI3K by LY294002, demonstrated that increased pEphA(S897) in the CLDN4 knockdown cells was attributable to an increase in the level of active dephospho- β-catenin upstream of PI3K and AKT. We conclude that CLDN4 serves to restrain pro-oncogenic signaling from EphA2 by limiting the activity of β-catenin and PI3K and preventing phosphorylation of EphA2 on S897 by AKT. This suggests that interventions directed at enhancing the level or functional activity of CLDN4 may be of therapeutic interest.
Citation Format: Xiying Shang, MD, PhD, Xinjian Lin, MD, Stephen B. Howell, MD. Claudin 4 controls the receptor tyrosine kinase EphA2 pro-oncogenic switch through β-catenin [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1318.
Abstract POSTER-BIOL-1322: Natural anti-glycan IgM recognize P1 glycosphingolipid expressed on ovarian cancer cells
Authors: Jacob Francis , Anugraham Merrina , Pochechueva Tatiana , Tse Brian Wan-Chi , Alam Shahidul , Guertler Rea , Bovin Nicolai V. , Fedier André , Hacker Neville F. , Huflejt Margaret E. , Packer Nicolle , Heinzelmann-Schwarz Viola A. 
Published: August 2015

Abstract
Recent research strongly suggests a role of plasma-derived anti-P1 antibodies (AGA) in ovarian cancer, as demonstrated by three independent glycan-based immunoassays. The level of these antibodies was lower in ovarian cancer patients and therefore discriminate cancer patients from healthy women. Here we investigate in a separate Australian cohort (n=155) whether IgM or IgG to P1 accounts for this discrimination and whether plasma matched ascites samples contain AGA. We also aimed to identify the P1 antigen in cancer tissue and cultured cells that are recognized by naturally occurring anti-P1 IgM and to investigate the potential function in respect to cell migration.
Our results demonstrated that the IgM to P1 discriminates patients with ovarian cancer from healthy controls (p=0.0002) and that lower anti-P1 antibody levels are associated with a slightly higher risk for early relapse. Mass spectrometry identified P1 and structurally related epitopes in fresh tissue specimens and cultured cells. Ovarian cancer cell line IGROV1 was identified to be P1-positive while others (n=7) including human ovarian surface epithelial cells were negative determined by comprehensive flow cytometry. Epitope-mapped and characterized affinity purified anti-P1 antibodies from ascites were shown to bind P1-expressing cancer cells. IGROV1 was cell-sorted into two subpopulations, P1–high (66.1%) and P1-low (33.3%) and we found a significantly higher migration rate in P1-high expressing cells.
Plasma-and ascites-derived natural anti-P1 IgM bind to the corresponding selfantigen expressed on the ovarian cancer cell surface. These findings are in concordance with the literature on natural IgM as part of the innate immune system recognizing carbo-neo-epitopes. These results deliver the first evidence that P1 may also be involved in cell migration and therefore may have a role in metastasis.
Citation Format: Francis Jacob, Merrina Anugraham, Tatiana Pochechueva, Brian Wan-Chi Tse, Shahidul Alam, Rea Guertler, Nicolai V. Bovin, André Fedier, Neville F. Hacker, Margaret E. Huflejt, Nicolle Packer, Viola A. Heinzelmann-Schwarz. Natural anti-glycan IgM recognize P1 glycosphingolipid expressed on ovarian cancer cells [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1322.
Abstract POSTER-BIOL-1323: Elevated MGAT3 expression in ovarian cancer cells is epigenetically regulated and correlates with expression of bisecting GlcNAc-modified proteins
Authors: Jacob Francis , Anugraham Merrina , Kohler Reto , Nixdorf Sheri , Everest-Dass Arun Vijay , Fedier André , Heinzelmann-Schwarz Viola , Packer Nicolle H. 
Published: August 2015

Abstract
Changes in the glycosylation of membrane proteins are a common feature of malignant transformation including ovarian cancer development. Of particular interest are N-linked glycans because these cell surface glycans mediate various cellular functions in cell-cell communication, cell adhesion, and cell motility. However the nature of these changes, their underlying molecular mechanisms, and the biological function of these glycans are poorly understood. In the present study, N-glycans were released from extracted membrane glycoproteins from ovarian cancer and normal ovarian epithelial cell lines and analysed using electrospray ionisation mass spectrometry; RT-qPCR measured gene expression of related glycosyltransferases; bisulfite sequencing analysed DNA methylation of the corresponding genes.
We identified characteristic glycan features unique to membrane proteins of ovarian cancer cells. Among those ovarian cancer specific N-glycans were the ‘bisecting N-acetyl-glucosamine (GlcNAc)’ type. The bisecting GlcNAc is the product of the enzyme MGAT3 (beta-1,4-N-acetylglucosaminyltransferase 3) and the expression of the MGAT3 gene was elevated in ovarian cancer cell lines (SKOV3, IGROV1, A2780, OVCAR3) as compared to normal ovary surface epithelial (HOSE) cells. This elevated MGAT3 expression in ovarian cancer cells correlated with DNA hypomethylation at the transcription start site (TSS) of the MGAT3 promotor, which contains a large CpG island with 204 CpG dinucleotides located -600/+800bp relative to the TSS. This finding suggests that MGAT3 expression is epigenetically regulated. This was validated by the finding that the treatment of HOSE cells with the DNA-methyltransferase inhibitor 5-Aza increased MGAT3 expression and corresponded to a reduction in DNA methylation at the TSS.
Taken together, we conclude that the elevated MGAT3 expression in ovarian cancer cells correlates with the presence of the resultant specific N-glycan substructures and with the epigenetic regulation of the associated enzymes by DNA methylation. These findings may stimulate the development of novel anti-glycan targeted drugs and clinical diagnostic tools for ovarian cancer
Citation Format: Francis Jacob, Merrina Anugraham, Reto Kohler, Sheri Nixdorf, Arun Vijay Everest-Dass, André Fedier, Viola Heinzelmann-Schwarz, Nicolle H. Packer. Elevated MGAT3 expression in ovarian cancer cells is epigenetically regulated and correlates with expression of bisecting GlcNAc-modified proteins [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1323.
Abstract POSTER-BIOL-1325: Ovarian cancer-associated CDK12 mutations disable its kinase activity and cause defects in homologous recombination
Authors: Joshi Poorval M. , Sutor Shari L. , Huntoon Catherine J. , Karnitz Larry M. 
Published: August 2015

Abstract
PURPOSE: The purpose of this study was to determine whether a) high-grade serous ovarian cancer-associated CDK12 kinase domain mutations affect catalytic activity, b) loss of CDK12 affects BRCA1 expression levels and Homologous Recombination (HR) in ovarian cancer, c) tumor-associated CDK12 mutations cause HR defects in ovarian cancer, and d) loss of CDK12 sensitizes ovarian cancer to chemotherapy and Poly(ADP-ribose) Polymerase [PARP] inhibitors.
EXPERIMENTAL PROCEDURES: We compared the kinase activities of wild-type CDK12 and tumor-associated CDK12 kinase domain mutants using in-vitro kinase assays. To determine the impact of CDK12 activity on HR, we assessed RAD51 foci formation and HR using a DR-GFP construct. To analyze the effect of tumor-associated CDK12 mutations on HR, CDK12-depleted OVCAR-8 cells were reconstituted with either wild-type CDK12 or the tumor-associated CDK12 mutant (G909R), irradiated and stained for RAD51 foci. We performed clonogenic assays using ovarian cancer cell lines (OVCAR-8, OVCAR-5 and OVCAR-3) to measure sensitivity to DNA cross-linking agents (melphalan and cisplatin) and the PARP inhibitor, veliparib, in the presence or absence of CDK12 activity. CDK12 depletion was carried out using at least two independent short-interfering RNAs (siRNAs).
RESULTS: We showed that many, but not all, ovarian cancer-associated CDK12 kinase domain mutations severely disrupted kinase activity. Moreover, we found that disabling CDK12 activity in ovarian cancer cells decreased BRCA1 levels and disrupted HR. Additionally, the tumor-associated CDK12 G909R mutant did not restore impaired RAD51 foci formation in CDK12-depleted OVCAR-8 cells. Finally we show that CDK12 depletion sensitized multiple ovarian cancer cells to the DNA cross-linking agents melphalan and cisplatin and to the PARP inhibitor veliparib.
CONCLUSION: Ovarian cancer-associated CDK12 mutations disrupt kinase activity and cause defects in HR, suggesting that ovarian tumors harboring deleterious CDK12 mutations may predict sensitivity to chemotherapeutic agents, including PARP inhibitors.
Citation Format: Poorval M. Joshi, Shari L. Sutor, Catherine J. Huntoon, Larry M. Karnitz. Ovarian cancer-associated CDK12 mutations disable its kinase activity and cause defects in homologous recombination [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1325.
Abstract POSTER-BIOL-1329: The ovary is an alternative site of origin for high-grade serous ovarian cancer in mice
Authors: Kim Jaeyeon , Coffey Donna M. , Ma Lang , Matzuk Martin M. 
Published: August 2015

Abstract
The tumor suppressor p53 is the most frequently mutated gene in high-grade serous carcinoma (HGSC), the most common and deadliest ovarian cancer. It remains unknown, however, whether p53 mutation can cause HGSC. To address this, we have incorporated a p53 activating mutation, p53R172H, into conditional Dicer-Pten double-knockout (DKO) mice, generating triple-mutant (TKO) mice. Like DKO mice, TKO mice develop metastatic HGSCs originating from the fallopian tube. Besides, even when fallopian tubes are removed in TKO mice, ovaries alone can spur their own metastatic HGSCs, indicating that p53 mutation can drive HGSC arising from the ovary. To further confirm the ability of p53 mutation to induce ovarian HGSC, we have generated p53R172H-Pten double-mutant (DMu) mice, one genetic control line for TKO mice. As anticipated, these DMu mice develop metastatic HGSCs from the ovary, which spread to the abdominal cavity before killing the mice, just like fallopian tube-deficient TKO mice. Our study therefore shows that the ovary, as well as the fallopian tube, can be a source of high-grade serous ovarian cancer.
(Grant support: Marsha Rivkin Ovarian Cancer Challenge Grant; Ovarian Cancer Research Fund (OCRF); F32 NCI National Research Service Award (NRSA); and K99/R00 NCI Pathway to Independence Award)
Citation Format: Jaeyeon Kim, Donna M. Coffey, Lang Ma, Martin M. Matzuk. The ovary is an alternative site of origin for high-grade serous ovarian cancer in mice [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1329.
Abstract POSTER-BIOL-1332: Molecular, cellular and clinical interaction between MDSC and ovarian cancer stemness
Authors: Kryczek Ilona , Cui Tracy X. , Zhao Lili , Vatan Linda , Szeliga Wojciech , Liu Rebecca , Zou Weiping 
Published: August 2015

Abstract
Myeloid derived suppressor cells (MDSCs) and cancer stem cells (CSCs) are important cellular components in the cancer microenvironment, and may affect cancer phenotype and patient outcome. The nature of MDSCs and their interaction with CSCs in ovarian carcinoma are unclear. We examined the interaction between MDSCs and CSCs in patients with ovarian carcinoma. We demonstrate that MDSCs inhibit T cell activation, enhance CSC gene expression, sphere formation and cancer metastasis. MDSCs trigger microRNA101 expression in cancer cells; microRNA101 subsequently represses the co-repressor gene C-terminal binding protein-2 (CtBP2), and CtBP2 directly targets stem cell core genes resulting in increased cancer cell stemness, and increasing metastatic and tumorigenic potential. Increased MDSC density and tumor microRNA101 levels, and decreased tumor CtBP2 expression independently predict poor survival. Collectively, the work identifies a novel immune associated cellular, molecular and clinical network involving MDSCs/microRNA101/CtBP2/stem cell core genes, which extrinsically controls cancer stemness and impacts patient outcome.
Citation Format: Ilona Kryczek, Tracy X. Cui, Lili Zhao, Linda Vatan, Wojciech Szeliga, Rebecca Liu, Weiping Zou. Molecular, cellular and clinical interaction between MDSC and ovarian cancer stemness [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1332.
Abstract POSTER-BIOL-1336: Investigating the role of phosphodiesterase 10A as a novel target in ovarian cancer
Authors: Silva Luciana Madeira da , Lee Kevin , Piazza Gary A. , Bachaboina Lavanya , Rocconi Rodney P. , Scalici Jennifer 
Published: August 2015

Abstract
Cyclic nucleotide phosphodiesterases (PDEs) play major roles regulating cell signaling by hydrolyzing the second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Phosphodiesterase 10A (PDE10A) is one of 21 PDEs encoded in the human genome. Its predominant expression in the brain striatum has guided intensive investigations on the therapeutic potential of PDE10A in psychiatric and neurological disorders, leading to several PDE10A inhibitors in clinical trials for schizophrenia and Hungtington's disease. Recently, we described for the first time an oncogenic role for PDE10A in colorectal cancer (N. Li et al. 2014 Oncogene 1-11). Our published data showed that PDE10A is overexpressed in colon tumor cells when compared to normal colonocytes, and that pharmacological inhibition or genetic knockdown of PDE10A suppresses colon tumor growth. Here, we are investigating the role of PDE10A in ovarian cancer and its potential as a novel therapeutic target. We detected expression of PDE10A in several ovarian cancer cell lines (SKOV3, SKOV3ip1, A2780, A2780-CP70, OV-90, ES-2 and TOV112D) by western-blotting and quantitative RT-PCR. In addition, our preliminary analysis revealed PDE10A expression in tumors and matched normal tissues from eight patients of ovarian cancer. Finally, we developed novel small molecule compounds targeting PDE10A which potently inhibit growth of all these ovarian cancer cell lines at low micromolar or sub-micromolar concentrations. Future work will focus on i) expanding the cohort of ovarian cancer patient tissues to analyze expression levels of PDE10A by western-blotting, quantitative RT-PCR and immunohistochemistry; ii) genetic silencing of PDE10A by siRNA/shRNA to investigate its role regulating cell proliferation, apoptosis, and cGMP/cAMP cell signaling in ovarian cancer; iii) investigate the signaling pathways suppressed by our novel PDE10A inhibitors. Our studies will determine the potential of using PDE10A as a novel therapeutic target for the treatment and chemoprevention of ovarian cancer.
Citation Format: Luciana Madeira da Silva, Kevin Lee, Gary A. Piazza, Lavanya Bachaboina, Rodney P. Rocconi, Jennifer Scalici. Investigating the role of phosphodiesterase 10A as a novel target in ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1336.