bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract AP31: TARGETING PD–L1/PD1 PATHWAY THROUGH BET PROTEIN INHIBITION IN EPITHELIAL OVARIAN CANCER
Authors: Zhu Hengrui , Bengsch Fee , Svoronos Nikolaos , Rutkowski Melanie R. , Bitler Benjamin G. , Allegrezza Michael J. , Yokoyama Yuhki , Bradner James E. , Conejo-Garcia Jose R. , Zhang Rugang 
Published: June 2017

Abstract
BACKGROUND: Expression of programmed death ligand 1 (PD-L1) is up-regulated in many cancers and has been found to suppress antitumor immunity through binding to its receptor programmed death 1 (PD-1). Blockade of PD-1/PD-L1 signaling axis enhances antitumor immunity in many cancers including epithelial ovarian cancer (EOC). Despite the importance of PD-L1 in tumor immunity, the epigenetic regulation of PD-L1 expression remains poorly understood.
AIMS: To determine the roles of epigenetic components in regulating PD-L1 gene expression and modulating antitumor immunity.
METHODS: Toward this goal, I screened a small molecule library of epigenetic inhibitors and examined their inhibition on PD-L1 expression in EOC cells to identify the positive hits. To further confirm PD-L1 inhibition in vivo, C57BL/6 mice are injected with luciferase expressing mouse ovarian cancer ID8 cells and treated with or without epigenetic inhibitors, PD-L1 expression in both tumor cells and immune cells are examined, tumor growth and survival are also monitored.
RESULTS: BET inhibitors suppresses both constitutive and IFNγ induced PD-L1 expression in EOC cells through targeting BRD4. Further ChIP-seq and ChIP assay demonstrate that BRD4 directly binds to PD-L1 gene promoter and regulated its transcription. BET inhibitor JQ1 suppresses PD-L1 expression in both tumor cells and immune cells including dendritic cells and macrophages in mice bearing ID8 mouse ovarian cancer cells. Moreover, the BET inhibitor suppresses the tumor growth and improves the survival of EOC bearing mice through activating antitumor T cells.
CONCLUSION: Taken together, we demonstrated that BRD4 can directly regulate PD-L1 expression in EOC cells by binding to the promoter of PD-L1 encoding gene, suppressing PD-L1 expression with BET inhibitors blocks PD1/PD-L1 signaling and enhances antitumor immunity in vivo. These findings indicate that pharmacological inhibition of BET proteins represent a new therapeutic strategy for EOC by targeting PD-L1 expression.
Citation Format: Hengrui Zhu, Fee Bengsch, Nikolaos Svoronos, Melanie R. Rutkowski, Benjamin G. Bitler, Michael J. Allegrezza, Yuhki Yokoyama, James E. Bradner, Jose R. Conejo-Garcia, Rugang Zhang. TARGETING PD–L1/PD1 PATHWAY THROUGH BET PROTEIN INHIBITION IN EPITHELIAL OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP31.
Abstract DPOC-002: A NOVEL CELL LINE BASED IMMUNOHISTOCHEMICAL TP53 EXPRESSION PATTERN CONTROL PANEL
Authors: Syed Viqar , Hussain Imran , Johnson Jeptha , Malafronte Patrick , Wells Justin , Zhou Yaling , Xing Deyin , Andersen John D. 
Published: June 2017

Abstract
BACKGROUND: TP53 gene mutation status is known to be manifested through distinct p53 immunohistochemical staining patterns; diffuse, “wild-type” and null. This stratified staining pattern is commonly utilized in subtyping ovarian and endometrial cancer subtypes as well as distinguishing between ovarian low- and high-grade serous carcinoma.
EXPERIMENTAL PROCEDURES: Three ovarian cancer cell lines consistently demonstrating either diffuse, wild-type or null p53 staining were utilized in the construction of an immunohistochemical control panel slide that highlights each TP53 expression pattern. Cell lines were expanded, harvested and resuspended in agarose gel and subsequently sectioned onto a microscope slide (Figure 1A). Procured tissue specimens were submitted along with either standard control tissue or the TP53 cell line control panel to three pathologists of varying experience.
RESULTS: Interobserver variability was demonstrated to be similar with the use of the TP53 expression panel (Fleiss kappa= 0.79 vs 0.76) and there was a net decrease in categorization errors. The TP53 cell line expression pattern control panel sections demonstrated consistent clean and easily interpretable diffuse, wild-type and null p53 staining (Figure 1B).
CONCLUSIONS: We developed a novel cell line-based TP53 expression pattern control panel with refined quality assurance potential that would act, as a minimum, a model for antibody optimization. This study suggests the addition of a cell line TP53 control panel could potentially increase the accuracy of identification for ovarian and endometrial cancer subtypes as well as ovarian low grade versus high-grade serous carcinoma distinction. This control panel has the potential to be utilized in other disease states where TP53 expression pattern assists in diagnosis.
Citation Format: Viqar Syed PhD, Imran Hussain, BSc, Jeptha Johnson MD, Patrick Malafronte MD, Justin Wells MD, Yaling Zhou PhD, Deyin Xing MD PhD, John D. Andersen DO. A NOVEL CELL LINE BASED IMMUNOHISTOCHEMICAL TP53 EXPRESSION PATTERN CONTROL PANEL [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr DPOC-002.
Abstract DPOC-007: PROGESTERONE/PR ERADICATES p53–DEFECTIVE CELLS IN THE FALLOPIAN TUBE EPITHELIUM BY INDUCTION OF NECROPTOSIS
Authors: Chu Tang–Yuan 
Published: June 2017

Abstract
Cervical Cancer Prevention Center, Department of Research, Tzu Chi Medical Center, Hualien, Taiwan, Republic of China.
Institute of Medical Sciences, Tzu Chi University, Taiwan, Republic of China.
The fallopian tube (FT) fimbriae, which are regularly exposed to ovulatory carcinogens, have been identified as the origin of high–grade serous ovarian carcinoma (HGSOC), with loss of p53 determined to be a universal and the earliest step of carcinogenesis. In previous studies, we have identified ROS in ovarian follicle is highly mutagenic and toxic to the fallopian tube fimbria that bath in the ovulatory follicular fluid (FF) after ovulation. We also found that loss of p53 renders fimbrial epithelial cells less vulnerable to the ROS stress, and that hemoglobin in ovulated FF could rescue the ROS–stressed fimbrial epithelial cells from apoptosis. Given that both ovulation and retrograde menstruation, the two proven risk factors for HGSOC, are commonplace in menstrual cycles, and that occurrence of tubal p53 signature is frequent but HGSOC is rare, we hypothesize that luteal–phase progesterone (P4) is responsible for clearance of p53–defective epithelial lesions as a natural protection. Herein, we show that P4 and progesterone receptor (PR) induce necroptosis of tubal epithelial cells in p53–null mice and in immortalized p53–deficient human fimbria epithelial cells through the TNF–α/RIPK1/RIPK3/p–MLKL pathway. The clearance acts regularly in the luteal phase of the menstrual cycle, recovering shortly thereafter, and can be augmented with P4 supplementation. With the inhibition of PR, the oviduct epithelium of Trp53–null mice escapes the clearance and, upon repeated ovulation exposures, accumulates DNA double–strand breaks. Through the induction of necroptosis of p53–deficient epithelial cells, luteal phase P4 prevents the transformation of the FT epithelium after ovulation. This protection can be augmented with P4 supplementation.
Citation Format: Tang–Yuan Chu, MD, PhD. PROGESTERONE/PR ERADICATES p53–DEFECTIVE CELLS IN THE FALLOPIAN TUBE EPITHELIUM BY INDUCTION OF NECROPTOSIS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr DPOC-007.
Abstract DPOC-008: LIFESTYLE AND REPRODUCTIVE RISK FACTORS AND OVARIAN CANCER RISK BY p53 AND MAPK EXPRESSION
Authors: Harris Holly R. , Rice Megan S. , Shafrir Amy L. , Poole Elizabeth M. , Hecht Jonathan L. , Terry Kathryn L. , Tworoger Shelley S. 
Published: June 2017

Abstract
BACKGROUND: One recent model of ovarian cancer development divides ovarian cancer into two types. Type II tumors are fast growing, potentially arising from the fallopian tubes, and characterized by tubal precursor lesions with p53 mutations. Type I tumors are slow–growing, arising from the ovary, and characterized by KRAS, BRAF, and PTEN mutations. The purpose of this study was to evaluate the association between selected lifestyle and reproductive risk factors and risk of ovarian cancer defined by expression of p53 (as a marker of Type II disease) and mitogen–activated protein kinase (MAPK), which is upregulated by KRAS and BRAF (as a marker of Type I disease).
METHODS: Epithelial ovarian cancer cases with available tumor blocks and cancer–free controls were identified from the Nurses' Health Study (NHS) and NHS II prospective cohorts, and from the population–based New England Case–Control (NECC) study of ovarian cancer. We performed immunohistochemical assays for p53 and MAPK expression. Age– and multivariable–adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for the association between each lifestyle or reproductive risk factor (e.g. parity, oral contraceptive use, tubal ligation, age at menarche, menopausal status, age at menopause, hormone therapy use, and family history of ovarian cancer) and ovarian cancer using polytomous logistic regression.
RESULTS: 249 cases and 1051 controls from the NHS/NHS II and 77 cases and 857 controls from the NECC study were included in the analyses. Overall there were few significant differences in lifestyle or reproductive risk factors by p53 or MAPK tumor expression. Increasing parity was associated with a greater decreased risk of p53 negative tumors (OR=0.40; 95% CI=0.26–0.62) than p53 positive tumors (OR=0.85; 95% CI=0.46–1.57) (pheterogeneity=0.03). Family history of ovarian cancer was associated with risk of developing MAPK negative (OR=1.87; 95% CI=1.28–2.74) but not MAPK positive tumors (OR=0.76; 95% CI=0.46–1.23) (pheterogeneity&lt;0.01). When p53 and MAPK expression were cross–classified family history was most strongly associated p53+/MAPK– expression (OR=2.46; 95% CI=1.42–4.28).
CONCLUSIONS: These findings provide evidence that parity and family history may be associated with tumor subtypes defined by p53 and MAPK expression. However, in future studies other immunohistochemical markers that more clearly define these subtypes should be considered.
Citation Format: Holly R. Harris, Megan S. Rice, Amy L. Shafrir, Elizabeth M. Poole, Jonathan L. Hecht, Kathryn L. Terry, Shelley S. Tworoger. LIFESTYLE AND REPRODUCTIVE RISK FACTORS AND OVARIAN CANCER RISK BY p53 AND MAPK EXPRESSION [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr DPOC-008.
Abstract KP02: STARING DOWN THE BARREL OF A TUBE AT THE ORIGINS OF OVARIAN CANCER
Authors: Drapkin Ronny 
Published: June 2017

Abstract
There is an emerging consensus that a majority of high-grade serous carcinomas, the most common type of ovarian cancer, are derived from PAX8-expressing cells in the distal fallopian tube. Careful histologic examination of fallopian tubes from BRCA1/2 mutation carriers has led to the identification of a morphological continuum that begins with a benign secretory cell, transitions to identifiable precursor lesions, and culminates in serous carcinoma. We have previously demonstrated the biologic plausibility of this hypothesis by showing that dysregulation of BRCA1/2 and TP53 in PAX8-expressing mouse or human fallopian tube secretory epithelial cells (FTSECs) can induce tumors that are genomically and phenotypically identical to human high-grade serous ovarian cancers.
While PAX8 serves as the basis for many of the fallopian tube-based models we have developed, little is known about its role during neoplastic transformation. PAX8 is a lineage-defining transcription factor that directs the development of the Müllerian duct (the female reproductive tract). Its expression is retained by nearly all high-grade serous carcinomas but it remains unknown whether alterations in the PAX8 cistrome contribute to ovarian carcinomas. Using whole transcriptome shotgun sequencing (RNA-Seq) after PAX8 knockdown and ChIP-Seq, we show that FTSECs and high-grade serous carcinomas are distinguished by marked reprogramming of the PAX8 cistrome. Interestingly, the majority of PAX8 binding peaks are found in intronic and intergenic regions of the genome rather than promoters. Genes that are significantly altered between FTSECs and carcinoma lines are enriched near PAX8 binding sites. These sites are also near TEAD binding sites, and these transcriptional changes may be related to PAX8 interactions with the TEAD/YAP1 signaling pathway. These data suggest that transcriptional changes after transformation in ovarian cancer are closely related to epigenetic remodeling in lineage-specific transcription factors.
Citation Format: Ronny Drapkin. STARING DOWN THE BARREL OF A TUBE AT THE ORIGINS OF OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr KP02.
Abstract MIP-043: OVARIAN CARCINOMA CDK12 MUTATIONS IMPAIR GENE-SPECIFIC POL II ELONGATION AND FAITHFUL REPAIR OF DNA DOUBLE STRAND BREAKS
Authors: Ekumi Kingsley M. , Paculova Hana , Lenasi Tina , Pospichalova Vendula , Bösken Christian A. , Rybarikova Jana , Bryja Vitezslav , Geyer Matthias , Blazek Dalibor , Barboric Matjaz 
Published: June 2017

Abstract
The Cdk12/CycK complex is a novel transcription elongation-associated kinase that promotes expression of a subset of RNA polymerase II (Pol II) genes, including those of the DNA damage response (DDR) network. CDK12 is mutated in many cancers, particularly in high-grade serous ovarian carcinoma (HGS-OvCa), where it is one of only nine genes with statistically recurrent somatic mutations. However, the influence of these mutations on the kinase and their link to cancerogenesis remain ill-defined. Here, we show that most CDK12 mutations interfere with formation of the complex, rendering the kinase inactive. By examining the mutations within the Cdk12/CycK structure, we find that they likely provoke structural rearrangements detrimental to Cdk12 activation. Our mRNA expression analysis of the patient samples containing the CDK12 mutations identifies coordinated down-regulation of key DDR genes, particularly those of the homologous recombination (HR) repair pathway. Moreover, we note that production of nascent HR gene transcripts is compromised significantly upon CDK12 and CYCK knockdown. Indeed, Cdk12 occupies these genes and promotes phosphorylation of the Pol II's C-terminal domain (CTD) at Serine 2 (Ser2-P), the hallmark of effective transcription elongation, indicating that the down-regulated genes are directly controlled by Cdk12/CycK. Functionally, we demonstrate that the mutant Cdk12 proteins fail to stimulate the faithful repair of DNA double strand breaks via HR. In summary, we provide molecular basis of how mutated CDK12 ceases to function in ovarian carcinoma. We propose that CDK12 is a tumor suppressor of which the loss-of-function mutations could elicit defects in HR-mediated and possibly other DNA repair pathways, leading to genomic instability underlying the genesis of HGS-OvCa.
Citation Format: Kingsley M. Ekumi, Hana Paculova, Tina Lenasi, Vendula Pospichalova, Christian A. Bösken, Jana Rybarikova, Vitezslav Bryja, Matthias Geyer, Dalibor Blazek and Matjaz Barboric. OVARIAN CARCINOMA CDK12 MUTATIONS IMPAIR GENE-SPECIFIC POL II ELONGATION AND FAITHFUL REPAIR OF DNA DOUBLE STRAND BREAKS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr MIP-043.
Abstract MIP-059: MITOCHONDRIAL DYNAMICS AND DYSFUNCTION IN OVARIAN CANCER
Authors: Shin Dong-Hui , Dier Usawadee , Timmins Patrick F. , Kesterson Joshua , Phaeton Rebecca , Hempel Nadine 
Published: June 2017

Abstract
Altered mitochondrial function remains a key feature of many tumor cells and drives pathways such gene expression, metabolic and stress responses, cell cycle progression and resistance to apoptosis. Many chemotherapeutics activate programmed cell death and it is thought that mitochondrial dysfunction may be one mechanism by which cancer cells evade killing by these compounds. Screening the metabolic profiles of ovarian cancer cell lines and patient ascites-derived tumor cells reveals that ovarian cancers fall into unique bioenergetic subgroups. For example, Ovarian Clear Cell Carcinomas (OCCC) display high oxygen consumption rate and glycolytic flux compared to the more common high grade serous adenocarcinoma (HGSA) subtype. In addition, we show that a portion of HGSAs have severe mitochondrial dysfunction, that is marked by a decrease in mitochondrial respiration, a lack of response to the uncoupler FCCP and a concomitant reliance on alternate metabolic pathways. Moreover, this is accompanied by enhanced chemoresistance to Cisplatin and Taxol. The cause of mitochondrial dysfunction has been attributed to a number of factors, including deregulation in mitochondrial fission/fusion dynamics. Moreover, fission is an integral component of apoptotic and authophagy pathways. Interestingly, the observed HGSA mitochondrial dysfunction correlates with aberrant fusion/fission dynamics and expression of a low molecular weight variant of the mitochondrial fission protein Drp1. The potential significance of Drp1 in ovarian cancer etiology is highlighted by TCGA data, where more than 15% of HGSA samples display significant increases in Drp1 mRNA levels, and associated amplification of the Drp1 gene DNM1L. Whether this represents the shorter, potentially dominant-negative Drp1 variant identified in our work is currently under active investigation. Our data suggest that compromised mitochondrial function and fission/fusion dynamics may be a hallmark of a previously unidentified subgroup of highly chemoresistant EOCs and that this is associated with aberrant expression of the fission protein Drp1. Studies are underway to identify the molecular identity and regulation of short Drp1, and the mechanistic links to alterations in fission, metabolic switching and chemoresistance.
Citation Format: Dong-Hui Shin, Usawadee Dier, Patrick F. Timmins, Joshua Kesterson, Rebecca Phaeton and Nadine Hempel. MITOCHONDRIAL DYNAMICS AND DYSFUNCTION IN OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr MIP-059.
Abstract MIP-060: EPIGENETIC DYSREGULATION OF A HISTONE MARK REVEALS A METABOLIC VULNERABILITY IN OVARIAN CANCER
Authors: Hood Jagmohan , Novak Marián , MacDuffie Emily , Lester Jenny , Parkash Vinita , Mills Gordon B. , Karlan Beth Y. , Oren Moshe , Drapkin Ronny 
Published: June 2017

Abstract
High-grade serous ovarian cancer (HGSOC) is frequently complicated by the inevitable development of therapeutic resistance, and thus remains an incurable disease. Recent insights supporting the fallopian tube epithelium (FTE) as the tissue of origin and serous tubal intraepithelial carcinomas (STICs) as the precursor lesion for the majority of HGSOCs provide a necessary context to study the mechanisms that drive the development and progression of HGSOC. Understanding these key molecular processes is essential to inform the development of next generation therapies. In this study we investigated the role of the ubiquitin ligase RNF20 and histone H2B monoubiquitylation (H2Bub1) in serous tumorigenesis. H2Bub1, catalyzed largely by RNF20, is an epigenetic mark with tumor suppressor properties. Conversely, the loss of RNF20/H2Bub1 has been linked with cancer progression. By analyzing the TCGA data we found that heterozygous loss of RNF20 defines the majority of HGSOC tumors. Our IHC results show that H2Bub1 is lost or downregulated in a large proportion of STICs and invasive HGSOC tumors, implicating RNF20/H2Bub1 loss as an early event in serous ovarian cancer tumorigenesis. Functionally, we demonstrated that shRNA-mediated RNF20 knockdown, with concomitant H2Bub1 downregulation, was sufficient to increase cell migration and clonogenic growth of immortalized tubal epithelial cells as well as cells derived from invasive HGSOC. Subsequent proteomic profiling (RPPA), of RNF20/H2Bub1-depleted cells revealed pronounced changes in the steady-state levels of a number of metabolic and signaling pathways. In particular, two of the top differentially expressed proteins were glutaminase (GLS) and glutamate dehydrogenase (GLUD1/2), key enzymes in the glutamine metabolism pathway. These changes are predicted to result in elevated levels of glutamate that can fuel the TCA cycle, amino acid biogenesis, and/or glutathione production. We hypothesize that loss of RNF20/H2Bub1 rewires glutamine metabolism in cancer cells and leads to an increase in transamination and glutathione production which fuels the progression of HGSOC. In conclusion, our study identifies that loss of H2Bub1 is an early epigenetic event in HGSOC progression, which rewires glutamine metabolism and may represent a unique therapeutic vulnerability.
Citation Format: Jagmohan Hood, Marián Novak, Emily MacDuffie, Jenny Lester, Vinita Parkash, Gordon B. Mills, Beth Y. Karlan, Moshe Oren, and Ronny Drapkin. EPIGENETIC DYSREGULATION OF A HISTONE MARK REVEALS A METABOLIC VULNERABILITY IN OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr MIP-060.