bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract AS28: Phase Ib/II with expansion of patients at the mtd study of olaparib plus weekly (metronomic) carboplatin and paclitaxel in relapsed ovarian cancer
Authors: Rivkin SE , Iriarte D , Sloan H , Wiseman C , Moon J 
Published: August 2015

Abstract
BACKGROUND: To establish the maximum-tolerated dose (MTD) and evaluate dose-limiting toxicities (DLTs) and response to therapy of combination therapy with carboplatin/paclitaxel and olaparib, an oral tablet inhibitor of poly ADP ribose polymerase (PARP), in advanced (Stage III or IV) relapsed ovarian cancer.
METHODS: Eligibility required measurable disease, adequate organ function and ECOG performance status of ≤ 2. Patients had to have failed first line platinum containing chemotherapy. All patients were tested for BRCA 1 and 2 mutations. Patients received the metronomic therapy of paclitaxel 60mg/m2 IV and carboplatin AUC 2 IV weekly, 3 weeks out of 4 and increasing doses of olaparib until the maximum tolerated dose was obtained. Olaparib started at 50 mg bid administered orally for 3 consecutive days (D1-D3), every week for each cycle. Patients were assessed for toxicity and response according to the protocol. Patients received combination therapy until DLT or disease progression.
RESULTS: The maximum tolerated dose was found to be olaparib 150 mg bid administered orally, three (D1-D3) consecutive days of each week of each cycle. Total number of patients enrolled in the phase 1b part of this study was 14. Median age was 58 (range 42-77). The median number of prior therapeutic regimens was 4 (range 3-8). Median number of cycles on study to date is 9.3 and the mean is 7.3. There were no grade 4 toxicities. The most common grade 3 toxicities were neutropenia (11), leukopenia (7), lymphopenia (4), anemia (4), fatigue (1) and MDS (1). There was no evidence of GI, cardiac, hepatic, pulmonary or dermatologic toxicities in any of these patients. Two patients had an allergic reaction prior to participating in the trial and once enrolled were desensitized to carboplatin for each study visit. One patient had a mild allergic reaction to the chemotherapy on trial, but did not require desensitization. 4 patients had a complete response (CR), 3 had partial response (PR), 3 had stable disease (SD), 2 had progressive disease (PD) and 2 were not evaluable. Of the 4 CR's three were BRCA mutant and 1 had no known BRCA mutation. Of the PD's one was BRCA mutant.
CONCLUSION: Olaparib, an oral tablet can be safely administered with a weekly regimen of carboplatin and paclitaxel in heavily pretreated, ovarian cancer patients. This is early preliminary data. This study is ongoing with a planned total expansion of 40 additional patients at the MTD.
Citation Format: Rivkin SE, Iriarte D, Sloan, H, Wiseman, C, Moon J,. Phase Ib/II with expansion of patients at the mtd study of olaparib plus weekly (metronomic) carboplatin and paclitaxel in relapsed 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 AS28.
Abstract KP01: Identification of genes and pathways that prevent genome instability
Authors: Kolodner Richard 
Published: August 2015

Abstract
The genome of many cancers is characterized by ongoing genome instability; however, the causes of genome instability in cancer are not well understood. To understand the control genome instability, we developed three types of genetic assays for measuring the rate of accumulating gross chromosomal rearrangements (GCRs) in the yeast Saccharomyces cerevisiae - one that detects GCRs containing breakpoints in single copy sequences, a second that detects GCRs mediated by segmental duplications, and a third that detects GCRs mediated by Ty elements which are similar to mammalian LINE elements. Initial studies characterizing these three types of assays found that there are specific pathways that suppress duplication-mediated GCRs and identified sequences that are hotspots for the formation of GCRs. We have subsequently used these three assays to perform a genetic screen of the non-essential genes in S. cerevisiae to identify the genetic network that acts to prevent genome instability. This screen involved three steps: a novel bioinformatics screen to identify and prioritize candidate genome instability suppressing genes; a biological genetic screen to identify which of the predicted genes actually suppress genome instability; and a biological genetic screen to identify interacting genes. As a result of these screens, we have identified 184 genes in which defects cause increased GCRs and an additional 459 genes in which mutations only cause increased GCRs when combined with a second mutation thus defining multiple pathways that prevent GCRs. Control experiments indicated that this approach led to the identification of greater than 95% of the non-essential genes that act to suppress genome instability. In a second screen, we identified 44 essential genes in which defects caused increased GCRs. We are now beginning to use the S. cerevisiae genome instability suppressing genes to predict the mammalian genome instability genetic suppressing network.
Citation Format: Richard Kolodner, PhD. Identification of genes and pathways that prevent genome instability [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 KP01.
Abstract POSTER-BIOL-1303: ARID3B alters tumor cell adhesion by binding to the promoter regions in fzd5 and other wnt pathway genes
Authors: Bobbs Alexander , Hallas William Morgan , Gellerman Katrina , Joseph Stancy , Dahl Karen Cowden 
Published: August 2015

Abstract
ARID3B is a DNA-binding protein from the AT-rich interactive domain family that is overexpressed in ovarian cancer and promotes tumor progression in a xenograft model of ovarian cancer in nude mice. Prior to this study, direct ARID3B target genes had not been identified, and relatively little was known about ARID3B's function or consensus binding site. In this study, we identified and confirmed the first gene targets of ARID3B by chromatin immunoprecipitation, microarray, and quantitative real-time PCR. Based on the binding sites that were determined in this study, we defined a novel ARID3B binding site that was tested in an electrophoretic mobility shift assay. Analysis of ARID3B binding regions revealed that ARID3B regulates genes in key cellular pathways that are involved in cancer progression and drug resistance, including EGFR, NOTCH, TNF, centromere proteins, and the Wnt signaling pathway. We have focused on Wnt signaling, and showed that ARID3B binds to the promoter regions of Wnt5A and its receptor FZD5, along with downstream components of the pathway: APC and MYC. FZD5 is commonly over-expressed in ovarian cancer cell lines, and is further upregulated by excess ARID3B. Upregulation of either ARID3B or FZD5 increased adhesion to extra-cellular matrix components Collagen IV, Fibronectin, Laminin, Tenascin, and Vitronectin. These results establish that Wnt signaling is targeted by ARID3B, and provide key insights into how ARID3B affects tumor progression.
Citation Format: Alexander Bobbs, William Morgan Hallas, Katrina Gellerman, Stancy Joseph Karen Cowden Dahl. ARID3B alters tumor cell adhesion by binding to the promoter regions in fzd5 and other wnt pathway genes [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-1303.
Abstract POSTER-BIOL-1306: DNA methylation changes during epithelial-to-mesenchymal transition in ovarian cancer cells
Authors: Cardenas Horacio , Vieth Edyta , Lee Jiyoon , Liu Yunlong , Nephew Kenneth P. , Matei Daniela 
Published: August 2015

Abstract
Epithelial-to-mesenchymal transition (EMT) is an important step in the process of metastasis and has been linked to cancer cell stemness. We hypothesize that aside from defined genetic changes associated with EMT, epigenetic mechanisms are involved and have not been fully elucidated. We determined DNA methylation in SKOV3 ovarian cancer (OC) cells during EMT induced by TGF-ß using the Infinium HumanMethylation450 array. Methylation levels of CpG sites were expressed as ß-values ranging from 0 (totally unmethylated) to 1 (totally methylated). Methylation of 468 and 390 sites changed (P&lt;.01, ANOVA and FDR&lt;0.05) after 48h and 120h of TGF-ß stimulation. The majority of changes (81%) reflected TGF-ß-induced increase in methylation. Methylation of 160 sites changed similarly at 48 and 120 h indicating that 34% of initial changes were sustained. The number of methylation changes decreased significantly after TGF-ß removal from the cell cultures, demonstrating that removal of TGF-ß stimulation reversed the methylation changes at most sites and restituted the baseline methylome. These results were consistent with those of the principal component and hierarchical clustering analyses. TGF-ß increased overall (average of all CpG sites) DNA methylation, total DNA methyltransferase activity, and amounts of DNMT1 protein and mRNA. The average methylation of CpG islands located in or near promoters increased in 193 genes at 24h and 494 at 120h, while no changes were observed after TGF-ß removal. Pathway analysis identified methylation changes in genes belonging to functional networks relevant to EMT and cancer progression, including: cellular movement, cell cycle, organ morphology, cellular development, and cell death and survival. Treatment of OC cells with the DNA methylation inhibitor SGI-110 prevented TGF-ß-induced EMT in association with an inhibition of the TGF-ß-induced downregulation of E-Cadherin. Results demonstrate that DNA methylation is a dynamic process involved in regulation of genes implicated in EMT and metastasis.
Citation Format: Horacio Cardenas, Edyta Vieth, Jiyoon Lee, Yunlong Liu, Kenneth P. Nephew, Daniela Matei. DNA methylation changes during epithelial-to-mesenchymal transition in 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-1306.
Abstract POSTER-BIOL-1331: Nucleotide excision repair mutations confer sensitivity to platinum but not PARP-inhibitors in epithelial ovarian cancer
Authors: Ceccaldi Raphael , O'Connor Kevin , Mouw Kent W. , Li Adam Y. , Matulonis Ursula A. , D'Andrea Alan D. , Konstantinopoulos Panagiotis A. 
Published: August 2015

Abstract
The marked platinum sensitivity of epithelial ovarian cancer (EOC) is thought to be related to underlying defects in the homologous recombination (HR) DNA repair pathway, which are present in approximately 50% of tumors with high-grade serous histology. However, repair of platinum-induced DNA damage does not always involve the HR pathway. More than 90% of platinum-DNA lesions are intrastrand cross-links which are repaired by the nucleotide excision repair (NER) pathway. We curated the TCGA ovarian cancer dataset and identified 22 tumors (7%) with nonsynonymous or splice site NER gene mutations among the 316 sequenced high grade serous ovarian tumors. All NER mutations were mutually exclusive and 8 (36%) were accompanied by heterozygous loss of the respective NER gene. In 12 (55%) of the 22 cases, there were no concomitant HR alterations identified. In vitro functional evaluation of two NER mutations (ERCC6-Q524* and ERCC4-A583T), identified in patients with advanced stage tumors and extreme response to first-line platinum therapy, showed that both mutations conferred platinum, but not PARPi, or doxorubicin sensitivity, and did not affect HR activity. Interestingly, ERCC6-Q524* was not associated with heterozygous loss but sensitized cells to platinum in a dominant negative fashion. Our findings suggest a novel mechanism of platinum sensitivity in EOC that involves NER gene mutations, which may occur independently of HR alterations. Unlike tumors with defective HR, tumors harboring only NER mutations may be sensitive to platinum but not PARP inhibition. Dissociation of platinum and PARPi sensitivity in this setting may have important implications for PARPi trials for both HR-proficient and HR-deficient EOCs.
Citation Format: Raphael Ceccaldi, Kevin O’Connor, Kent W. Mouw, Adam Y. Li, Ursula A. Matulonis, Alan D. D’Andrea, Panagiotis A. Konstantinopoulos. Nucleotide excision repair mutations confer sensitivity to platinum but not PARP-inhibitors in epithelial 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-1331.
Abstract POSTER-BIOL-1337: Omentum promotes suppression against peritoneal tumors
Authors: Meza-Perez Selene , Garcia-Hernandez Maria de la Luz , Silva-Sanchez Aaron , Rangel-Moreno Javier , Mudunuru Uma , Lord Edith M , Randall Troy D. 
Published: August 2015

Abstract
Purpose: The metastasis of ovarian cancer to the omentum is associated with poor clinical outcomes. Although the omentum has immune function due to the activities of milky spots, the role of the omentum in anti-tumor immunity has not been rigorously addressed. We hypothesize that the omentum directly modulates anti-tumor immunity to metastasized tumor cells.
Experimental procedure: We examined metastases and immunological function in mice that expresses SV40 T antigen oncogene under the Mullerian Inhibitory Substance type II Receptor promoter (MISIIR-Tag). In separate experiments we also implanted 3 x 106 EG7.1.15 cells (murine thymoma that express chicken ovalbumin (OVA)) intraperitoneally (i.p.) to induce peritoneal tumors. We used flow cytometry to analyze cells from the omentum and peritoneal exudate from mice with or without tumors.
Results: Omental tumor growth induced by EG7.1.15 cells is associated with an increase in CD4+CD25+FoxP3+ T regulatory cells (Tregs) and CD103+ DCs, while tumor-specific CD8+ T cells are reduced. Although tumor-specific CD8+ T cells generated in the periphery prior to tumor onset prevent omental and peritoneal tumor growth, tumor-specific CD8+ T cells generated after tumors are established in the omentum are unable to mediate tumor clearance. The induction of tolerance requires the omentum, is dependent on FoxP3+ Tregs, is tumor antigen-specific and takes place in as few as 6 days. The metastasis of ovarian tumor cells into the omentum also correlates with an increase in Tregs. Deleting Tregs in both models reduces tumor burden.
Conclusions: Metastasis of tumor cells to the omentum leads to immunological tolerance rather than immunity – even when tumor cells express foreign antigens. Thus, the omentum has an immunological activity that prevents, rather than promotes, immunity to peritoneal tumors.
Citation Format: Selene Meza-Perez, Maria de la Luz Garcia-Hernandez, Aaron Silva-Sanchez, Javier Rangel-Moreno, Uma Mudunuru, Edith M Lord PhD, Troy D. Randall. Omentum promotes suppression against peritoneal tumors [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-1337.
Abstract POSTER-BIOL-1341: MUC16 (CA125) knockdown as a potential strategy to decrease tumor growth
Authors: Felder Mildred , Kapur Arvinder , Rakhmilevich Alexander L. , Qu Xiaoyi , Connor Joseph , Patankar Manish S. 
Published: August 2015

Abstract
MUC16 (CA125), a membrane spanning mucin, promotes proliferation and metastasis of ovarian cancer cells. Here, we demonstrate that MUC16 protects cancer cells from cytolysis by NK cells and macrophages. SCID mice implanted with MUC16-positive and MUC16-knockdown human ovarian tumors have a median survival of 75 and 181 days, respectively. Animals bearing MUC16-positive tumors developed ascites fluid and were moribund because of high tumor volume. In contrast, none of the mice with MUC16-knockdown tumors developed ascites. Decreased growth of MUC16-knockdown tumors correlated with increased cytolysis by murine splenocytes from naïve and anti-CD40 antibody treated mice. Murine NK cells showed a 2.5-fold higher preference for MUC16-knockdown cells. Unstimulated and LPS or IFN-γ-activated peritoneal macrophages from SCID mice also preferentially inhibited proliferation of MUC16-knockdown targets. Even in SCID/Beige mice, where cytolysis by resident NK cells is impaired, median survival MUC16-positive tumor-bearing animals was 75 days as compared to 189 days for animals with MUC16-knockdown tumors. All ten SCID/Beige mice with MUC16-knockdown tumors showed significant macrophage infiltration throughout the tumor nests and only two of the ten developed ascites. In contrast, 80% of SCID/Beige mice with MUC16-positive tumors had significant ascites and macrophages were predominantly found in the stroma. Finally, knockdown of MUC16 increased the susceptibility of cancer cells to natural cytotoxic responses of human NK cells, and increased their susceptibility to ADCC and lysis in the presence of immunocytokines. Therefore, strategies that decrease the expression of immunosuppressive MUC16 coupled with NK or macrophage-based immunotherapies should be investigated for the treatment of ovarian cancer.
Citation Format: Mildred Felder, Arvinder Kapur, Alexander L. Rakhmilevich, Xiaoyi Qu, Joseph Connor, Manish S. Patankar. MUC16 (CA125) knockdown as a potential strategy to decrease tumor growth [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-1341.
Abstract POSTER-BIOL-1344: Epigenetic regulation of SPARC in ovarian cancer
Authors: Matthews Dylan P. , Taylor Sherine , Said Neveen A. 
Published: August 2015

Abstract
Background: We have previously reported the tumor suppressor effect of Secreted protein acidic and rich in cysteine (SPARC) in ovarian cancer in vitro and in vivo. We reported that SPARC suppresses ovarian cancer cells interactions with the surrounding environmental cues within the peritoneal milieu. We also reported that the expression of SPARC was decreased in established ovarian cancer cell lines and micro-dissected ovarian cancer cells from advanced tumors consistent with hypermethylation of its promoter. However, the mechanisms of epigenetic regulation of SPARC in ovarian cancer (and other morbidities) are unraveled.
Experimental Procedures: In silico analysis, human ovarian cancer tissue microarrays, a panel of established human ovarian cancer cell lines and in vitro ovarian cancer cell models were used. Genetic and pharmacologic manipulation of NFκB subunits and DNA methyl transferases (DNMTs) were used to investigate their involvement in the transcriptional regulation of SPARC expression and function.
Results: In silico mapping of SPARC promoter identified consensus binding sites for subunits (RelA and NFκB1). Pharmacologic inhibition of NFκB as well as knockdown of p65-RelA and p50 subunits restored SPARC expression and function in ovarian cancer cells. Treatment of ovarian cancer cells with demethylating agent 5’-azacytidine and knockdown of DNMTs (DNMT1, DNMT3a and DNMT3b) indicated that NFκB-mediated SPARC repression is due to promoter methylation through DNMT3a. In ovarian cancer tissue microarrays, SPARC expression in cancer cells significantly and progressively decreased in advanced stage. The expression of SPARC in cancer cells inversely correlated with nuclear p65-RelA and DNMT3a expression.
Conclusion: Our findings indicate that activated NFκB integrates inflammatory signals to exert epigenetic pressure suppressing tumor-SPARC through promoter methylation. Pharmacologic inhibitors of NFκB as well as anti-inflammatory agents may provide a significant therapeutic opportunity.
Citation Format: Dylan P. Matthews, Sherine Taylor, Neveen A. Said. Epigenetic regulation of SPARC 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-1344.
Abstract POSTER-CTRL-1208: A dualistic model for the origin of high-grade serous carcinoma: BRCA mutation status, histology and tubal intraepithelial carcinoma
Authors: Howitt Brooke E , Hanamornroongruang Suchanan , Lin Douglas , Conner James E , Schulte Stephanie , Garber Judy , Crum Christopher P , Meserve Emily E 
Published: August 2015

Abstract
Extra-uterine high-grade serous carcinoma (HGSC) is linked to the fimbria via serous tubal intraepithelial carcinoma or STIC. Women with deleterious BRCA1/2 germ-line mutations (BRCA+) are at high risk for HGSC and ~5% of risk reducing salpingo-oophorectomies harbor a STIC. However, STIC is found in only~40% of the HGSC population and less frequently in endometrioid variants of HGSC (Roh 2009). Consecutively tested women with untreated HGSC, with detailed fallopian tube examination (SEE-FIM protocol), who had germ-line BRCA testing were studied. STIC status was determined by histologic exam, and tumors were classified as predominately SET (&gt; 50% solid, endometrioid-like, or transitional, Soslow 2012) or classic histology. SET features trended towards a higher frequency in BRCA+ vs BRCA- women (50 vs 28%, p = .11). BRCA- subjects with SET morphology were significantly younger than those with classic HGSC (mean 56.2 vs 64.8 years; p=0.04), with a generally better clinical outcome. STIC was significantly more frequent in BRCA- tumors (66 vs 31%, p = 0.017) and more frequent in classic HGSCs in BRCA- (83 vs 22%, p = 0.003) women. Overall, several co-variables – histology, BRCA status, age, coexisting STIC, response to therapy - suggest two categories of HGSC with differences in speed of development, progression, outcome, histology, and possibly, precursor type. We introduce a dualistic HGSC model with a faster evolving tumor type that is not linked to a long-standing STIC. Resolving the nature of this second pathway is germane to both resolving the precursors and expectations from both screening and prevention of HGSC.
Citation Format: Brooke E Howitt MD, Suchanan Hanamornroongruang MD, Douglas Lin MD PhD, James E Conner MD PhD, Stephanie Schulte MD, Judy Garber MD, Christopher P Crum MD, Emily E Meserve MD MPH. A dualistic model for the origin of high-grade serous carcinoma: BRCA mutation status, histology and tubal intraepithelial carcinoma [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-CTRL-1208.