bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B27: Cellular retinoic acid binding protein 2 (CRABP2) is a novel biomarker and potential therapeutic target for high-grade serous ovarian carcinomas
Authors: Feng Yi , Gillette Michael , Kuhn Eric , Klinkebiel David , Mitchell Marilyn A. , Doberstein Kai , Chaves-Moreira Daniele , Sato Sho , Xu Haineng , Bomwell Brett , Hirsch Michelle S. , Reyes Carolina , Karpf Adam R. , Birrer Michael J. , Skates Steven J. , Carr Steven A. , Drapkin Ronny 
Published: September 2020

Abstract
Ovarian cancer ranks fifth in cancer deaths among women in the United States, accounting for more deaths than any other gynecologic cancer. There is an unmet medical need for biomarkers that can detect high-grade serous ovarian carcinoma (HGSOC) at an early stage. Our laboratory evaluated the biomarker potential of cellular retinoic acid binding protein 2 (CRABP2). Using Western blots (WB) and immunohistochemistry (IHC), we show that CRABP2 is expressed and secreted by HGSOC cells and tissues and is absent in normal fallopian tube (FT) epithelium. CRABP2 expression was associated with poor overall survival in patients with HGSOC. Proteomic analyses quantified specific secretion of CRABP2 in conditioned media from HGSOC cell lines, primary ascites-derived tumor cells, and serum from HGSOC patients. Expression of CRABP2 was positively associated with CRABP2 copy number amplifications by mining The Cancer Genome Atlas database. In addition, DNA methylation studies identified a putative enhancer downstream of CRABP2 that is hyper-methylated in fallopian tube epithelia (FTE) tissue and hypomethylated in HGSOC cells and tissues that expressed CRABP2. Inhibition of DNA methylation with DNA methytransferase (DNMT) inhibitors resulted in robust expression of CRABP2 protein in FT cell lines. Finally, a finding supported by CRABP2 knockdown experiments showed that CRABP2 loss triggers cell death in HGSOC cell lines. In conclusion, CRABP2 may serve as a novel biomarker for HGSOC with clinical potential as a therapeutic target.
Citation Format: Yi Feng, Michael Gillette, Eric Kuhn, David Klinkebiel, Marilyn A. Mitchell, Kai Doberstein, Daniele Chaves-Moreira, Sho Sato, Haineng Xu, Brett Bomwell, Michelle S. Hirsch, Carolina Reyes, Adam R. Karpf, Michael J. Birrer, Steven J. Skates, Steven A. Carr, Ronny Drapkin. Cellular retinoic acid binding protein 2 (CRABP2) is a novel biomarker and potential therapeutic target for high-grade serous ovarian carcinomas [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B27.
Abstract B34: LINC00886, a risk locus-associated long noncoding RNA, promotes ovarian cancer progression
Authors: Nakamura Koji , Reid Brett M. , Sellers Thomas A. , Karreth Florian A. 
Published: September 2020

Abstract
Background: Recent genome-wide association studies (GWAS) have identified a plethora of SNPs that cluster at loci associated with increased epithelial ovarian cancer (EOC) risk. The functional validation of genes in such risk loci focused primarily on the protein-coding space while long noncoding RNAs (lncRNAs) were disregarded. Given the emerging evidence that lncRNAs can act as oncogenes and tumor suppressors, we seek to evaluate the functional role of EOC risk locus-associated lncRNAs in EOC development.
Methods: We interrogated GWAS for EOC and the FANTOM-CAT database for lncRNAs to identify EOC risk-associated SNPs that lie within lncRNA regulatory regions. We first prioritized the lncRNAs that are associated with EOC risk loci using public databases including GTEx and TCGA. To assess the oncogenic potential of these lncRNAs, we performed in vitro functional assays such as proliferation, colony formation, anchorage-independent growth and migration by overexpressing and silencing candidate lncRNAs in fallopian tube secretory epithelial and ovarian cancer cells. To validate our findings in vivo, we intraperitoneally injected OVCAR-8 cells into immunocompromised mice and evaluated tumor growth. LncRNA subcellular localization was evaluated based on qPCR from cytoplasmic and nuclear RNA. Further, we investigated expression changes upon lncRNAs overexpression in OVCAR-8 and FT282 cells by RNA sequencing (RNA-seq) and predicted shared microRNAs (miRNA) binding sites using LncBase Predicted v.2 and TargetScanHuman 7.2.
Results: We identified 5 candidate risk locus-associated lncRNAs (CATG00000115318.1, HAGLR, LINC00886, CATG00000117550.1, and CTD-2521M24.8). Functional assays showed that LINC00886 promoted cancer cell proliferation and colony formation in vitro. Overexpression of LINC00886 in OVCAR-8 cells significantly promoted peritoneal dissemination in a xenograft model. LINC00886 was mainly localized to the cytoplasm, suggesting it could function by decoying miRNAs. Interestingly, we observed that LINC00886 overexpression increased the levels of several oncogenes, of which several (ROR2, TNFSF14, GPNMB, LTB, and ZBTB20) share miRNA binding sites with LINC00886.
Conclusion: LINC00886, a risk loci-associated lncRNA, promotes an aggressive phenotype in ovarian cancer, suggesting an oncogenic function. We are currently investigating the molecular mechanism of LINC00886 as a ceRNA in ovarian cancer progression.
Citation Format: Koji Nakamura, Brett M. Reid, Thomas A. Sellers, Florian A. Karreth. LINC00886, a risk locus-associated long noncoding RNA, promotes ovarian cancer progression [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B34.
Abstract B40: Characterization of TP53 mutations in Pap test DNA of women with and without serous ovarian cancer
Authors: Krimmel-Morrison Jeffrey D. , Lian Shenyi , Zhang Yuezheng , Fredrickson Jeanne , Nachmanson Daniela , Baker Kathryn T. , Radke Marc R. , Hun Enna , Norquist Barbara , Emond Mary J. , Swisher Elizabeth M. , Risques Rosa Ana 
Published: September 2020

Abstract
Objective: The development of Pap tests as a molecular diagnostic for serous ovarian cancer is a promising concept, but previous studies reported limited sensitivity. In addition, the presence of cancer-associated somatic mutations in normal tissue is increasingly recognized as a specificity challenge for mutational tests. We aimed to determine the diagnostic performance of Pap tests for ovarian cancer detection using ultra-accurate deep sequencing.
Methods: We used CRISPR-DS, a novel duplex sequencing method that employs CRISPR-based target enrichment to increase efficiency and reduce DNA input. We performed ultra-accurate deep sequencing (mean 2000x) of the TP53 gene in 30 Pap tests from 21 women without cancer and 9 women with serous ovarian cancer with known TP53 driver mutations. Mutations were annotated using the Seshat web service and compared to those in the UMD TP53 cancer database.
Results: The tumor-derived mutation was identified in 3 of 9 Pap tests from women with ovarian cancer (33% sensitivity). In addition, 221 low-frequency (≲0.001) mutations were identified in the coding region of TP53 in Pap tests from women with ovarian cancer (94 mutations) and without ovarian cancer (127 mutations). In both groups these mutations showed evidence of positive selection as indicated by clustering in exons 5 to 8, preferential location in hotspot codons and CpG dinucleotides, common presence in cancer database, impact on protein activity, and predicted pathogenicity. These “cancer-like” features were significantly more frequent in mutations identified in women with ovarian cancer than in women without cancer.
Conclusions: Pap tests have low sensitivity for ovarian cancer detection and carry abundant low-frequency TP53 mutations. These mutations are more frequently pathogenic in women with ovarian cancer and determining whether their presence is associated with an increased gynecologic cancer risk warrants further study.
Citation Format: Jeffrey D. Krimmel-Morrison, Shenyi Lian, Yuezheng Zhang, Jeanne Fredrickson, Daniela Nachmanson, Kathryn T. Baker, Marc R. Radke, Enna Hun, Barbara Norquist, Mary J. Emond, Elizabeth M. Swisher, Rosa Ana Risques. Characterization of TP53 mutations in Pap test DNA of women with and without serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B40.
Abstract B46: Trends in stage at diagnosis for ovarian, fallopian tube, and serous primary peritoneal cancers, 2004–2015
Authors: Townsend Julie S. , Puckett Mary C. , Stewart Sherri L. 
Published: September 2020

Abstract
Introduction: Timely diagnosis is key to reducing distant stage ovarian cancer. The purpose of this study was to examine trends in the proportion of women diagnosed with ovarian cancer by stage and predictors of distant stage diagnosis, comparing two time periods: 2004–2009 and 2010–2015.
Methods: We analyzed newly diagnosed malignant ovarian, fallopian tube, and serous primary peritoneal cancers reported to population-based central cancer registries funded by CDC’s National Program of Cancer Registries (NPCR) or the NCI’s Surveillance, Epidemiology, and End Results Program (SEER). We conducted a descriptive analysis examining demographic and clinical characteristics by SEER summary stage at diagnosis (localized, regional, distant, unstaged). We compared women diagnosed between 2004–2009 and 2010–2015 by stage, histology, race/ethnicity, and stage. We built a logistic regression model to examine predictors of a distant stage diagnosis.
Results: In 2004, 18% of women were diagnosed at regional stage, which increased to 23% in 2015. There was a slight increase in local stage tumors (14% to 15%). Unstaged tumors declined from 10% to 7% over the same time period, and distant stage tumors declined from 58% to 56%. Only American Indian/Alaska Native (AI/AN) women did not experience a statistically significant decline in distant stage tumors over the two time periods. A greater proportion of serous tumors were diagnosed in the 2010–2015 time period compared to the first (53.2% vs. 50.5%). Predictors of distant stage diagnosis included being diagnosed between 2004–2009, older age (those over age 65), residence in the southern and western U.S., black race, serous histology, and residence in high-poverty census tracts.
Conclusion: In the 2010–2015 time period, a smaller proportion of ovarian cancers were distant or unstaged at diagnosis compared to 2004–2009, and most subpopulations of women experienced a decline in distant ovarian cancer. More efforts are needed to increase timely diagnosis and access to specialized care in the southern and western US, high-poverty areas, and among black women.
Citation Format: Julie S. Townsend, Mary C. Puckett, Sherri L. Stewart. Trends in stage at diagnosis for ovarian, fallopian tube, and serous primary peritoneal cancers, 2004–2015 [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B46.
Abstract B47: Physical activity and survival following diagnosis with ovarian cancer
Authors: Wang Tianyi , Townsend Mary , Eliassen Heather , Terry Kathryn , Song Mingyang , Tworoger Shelley 
Published: September 2020

Abstract
Among the limited studies assessing the association between physical activity and ovarian cancer survival, results have been inconsistent. Therefore, we investigated the relation of pre- and postdiagnosis physical activity with risk of death among women with ovarian cancer in two prospective cohort studies, the Nurses’ Health Study (NHS) and NHSII. Analyses included 1,113 women with confirmed invasive, stage I-III epithelial ovarian cancer (611 ovarian cancer specific deaths). We used Cox proportional hazards regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for ovarian cancer-specific mortality by physical activity levels, adjusting for age and year of diagnosis, tumor stage, histologic subtype, body mass index, and nonsteroidal anti-inflammatory use (postdiagnosis models only). Neither prediagnosis physical activity (assessed a median of 12 months before diagnosis) nor postdiagnosis physical activity (assessed a median of 19 months after diagnosis) was significantly associated with risk of ovarian cancer death. For example, comparing women participating in ≥27 vs. &lt;3 MET-hours/week of physical activity, HRs were 1.19 (95%CI: 0.91-1.56) for prediagnosis activity and 0.74 (95%CI: 0.51-1.08) for postdiagnosis activity. In analyses stratified by tumor stage, higher physical activity before and after diagnosis was associated with lower ovarian cancer-specific mortality among stage I/II patients (≥27 vs. &lt;3 MET-hours/week, HR=0.43, 95%CI: 0.21-0.88 for prediagnosis activity, HR=0.31, 95%CI: 0.13-0.72 for postdiagnosis activity), while an increased risk of death or no association was observed among stage III patients (≥27 vs. &lt;3 MET-hours/week, HR=1.37, 95%CI: 1.02-1.84 for prediagnosis activity, HR=0.84, 95%CI: 0.56-1.25 for postdiagnosis activity). Results did not vary significantly by histologic subtype (serous vs. nonserous/unknown). Future analyses will evaluate prediagnosis physical activity reported at least four years prior to ovarian cancer diagnosis and postdiagnosis physical activity within four years after diagnosis. Overall, our analyses suggest that, among all stage I-III ovarian cancer patients, higher levels of physical activity, either before or after diagnosis, are not associated with improved survival. However, physical activity in women with early-stage disease may be related to improved outcomes.
Citation Format: Tianyi Wang, Mary Townsend, Heather Eliassen, Kathryn Terry, Mingyang Song, Shelley Tworoger. Physical activity and survival following diagnosis with ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B47.
Abstract B66: Paracrine interactions with microenvironmental fibroblasts promote ovarian cancer metastasis through downregulation of miR-4454
Authors: Dasari Subramanyam , Pandhiri Taruni , Grassi Tommaso , Visscher Daniel W. , Multinu Francesco , Agarwal Komal , Mariani Andrea , Shridhar Viji , Mitra Anirban K. 
Published: September 2020

Abstract
Metastasis causes poor prognosis and yet remains the least understood aspect of cancer. To identify key regulators of ovarian cancer metastasis that drive early colonization and are also essential for advanced metastasis, we have applied a novel, comprehensive approach of combining the analysis of an organotypic 3D culture model of early metastasis with ovarian cancer patient tumors. Using matched primary and metastatic tumors from 42 OC patients, we have compared the fully formed metastatic tumors with the primary tumor of the same patient. Since this is an end-point analysis and reveals little about the intermediated regulatory steps, we have also studied the changes occurring during early metastatic colonization as a result of the interactions with the metastatic microenvironment by using an organotypic 3D culture model of omental metastasis. By combining these two approaches, we have identified key master regulators of metastasis that are essential for early metastatic colonization and remain important in the fully formed metastatic tumor. We specifically focused on microRNAs because of their pleotropic effects through translational inhibition of multiple targets, and also our previous studies have demonstrated their important role in metastasis. Using this approach, we identified a novel microRNA miR-4454, downregulated in the metastasizing ovarian cancer cells through their specific paracrine interactions with fibroblasts in the metastatic microenvironment. The downregulation of miR-4454 promoted high-grade serous ovarian cancer cell migration, invasion, proliferation, and clonogenic growth as well as metastasis in xenografts. The targets of miR-4454 were identified by RNA-seq in high-grade serous ovarian cancer cells overexpressing the microRNA. SPARC and BAG5 were found to be the functional effectors of miR-4454. SPARC activated FAK signaling and promoted metastasis, while BAG5 inhibited apoptosis and helped the metastasizing cancer cells tide over adverse conditions in the microenvironment. Since miR-4454 is essential for early metastatic colonization as well as in advanced metastasis, targeting it is a promising approach to treat metastatic ovarian cancer.
Citation Format: Subramanyam Dasari, Taruni Pandhiri, Tommaso Grassi, Daniel W. Visscher, Francesco Multinu, Komal Agarwal, Andrea Mariani, Viji Shridhar, Anirban K. Mitra. Paracrine interactions with microenvironmental fibroblasts promote ovarian cancer metastasis through downregulation of miR-4454 [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B66.
Abstract B78: Improving chemotherapy response of immunologically cold high-grade serous ovarian cancer with loss of PTEN using STING agonist
Authors: Shakfa Noor , Lightbody Elizabeth , Afriyie-Asante Afrakoma , Kannen Vinicius , Koti Madhuri 
Published: September 2020

Abstract
High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy, with high rates of chemotherapy resistance and poor outcomes. We previously showed that tumors from chemotherapy-resistant patients show an immunologically cold phenotype, exhibiting lower density of CD8+ T cells and low expression of interferon genes. Subsequently, using the ID8-Trp53−/− murine model of HGSC, we further demonstrated the potential of Stimulator of Interferon Genes (STING) pathway activation in enhancing response of HGSC to carboplatin chemotherapy. Currently, we aim to better characterize the effect of cancer cell genotype on response to treatment in HGSC. The evolution of the tumor immune microenvironment (TIME) as immunologically hot or cold can be to some extent dictated by cancer cell-specific genetic alterations. While loss of the tumor suppressor TP53 is a universal mutation (&gt;96% of cases), previous reports in HGSC have shown that patients with BRCA1 mutations (~25% of cases) have higher CD8+ T-cell infiltration and higher chemosensitivity. In contrast, loss of PTEN (seen in ~20% of cases) is associated with poor outcomes and chemoresistance. We hypothesized that HGSC tumors with loss of PTEN expression can benefit via immunomodulatory treatment approaches that activate the STING pathway following chemotherapy. C57/BL6 mice were implanted with either ID8-Trp53−/−; Brca1−/− cells or ID8-Trp53−/−; Pten−/− cells and subjected to one of three treatment groups: vehicle, carboplatin, or carboplatin + STING agonist. Characterization of the TIME generated from ID8-Trp53−/−; Brca1−/− cells, and those from ID8-Trp53−/−; Pten−/− cells, through local and systemic immune profiling, showed significant immunologic differences between different genotypes. Addition of STING agonist significantly increased chemosensitivity and improved overall response in ID8-Trp53−/−; Pten−/− injected mice compared to those treated with carboplatin alone. This study helps to determine the potential of STING pathway activation in inducing an activated tumor immune state in genotypes of HGSC that result in a “cold” TIME, such as loss of PTEN, to augment responses to chemotherapy and prolong survival.
Citation Format: Noor Shakfa, Elizabeth Lightbody, Afrakoma Afriyie-Asante, Vinicius Kannen, Madhuri Koti. Improving chemotherapy response of immunologically cold high-grade serous ovarian cancer with loss of PTEN using STING agonist [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B78.
Abstract B80: Predictive treatment response models for epithelial ovarian cancer: Comparison of 2D, 3D, and in vivo models
Authors: Nourmoussavi Melica , Carmona Euridice , Mes-Masson Anne-Marie 
Published: September 2020

Abstract
Introduction: Epithelial ovarian cancer (EOC) is still a deadly disease, with a 5-year overall survival of 45%. Current research focuses on the development of new targeted and personalized therapies to improve survival in these patients. The drug discovery pipeline is dependent on preclinical models, which have mostly focused on 2D systems because of time and cost efficiency. However, it is currently unclear whether they accurately reflect patient response and whether other in vitro models may better predict therapeutic response. Preliminary data from our laboratory suggest that the sensitivity to carboplatin chemotherapy varies between 2D and 3D in vitro models. We hypothesize that the 3D model will more closely reflect therapeutic response. The primary objective of this study is to characterize the sensitivity to carboplatin of our EOC cell lines in 2D monolayers and 3D spheroids and compare them to their in vivo response using our xenograft mouse models.
Methods: We are injecting NOD-RAG mice with 7 EOC cell lines (TOV112D, TOV21G, OV4485, OV4453, OV1946, OV90, OV3133). At 200mm3, weekly carboplatin treatments (group1 = control, group 2= 25mg/kg, group 3= 50mg/kg, group 4= 75mg/kg) are given up to 6 cycles. Tumor volume and survival curves are used to categorize chemosensitivity between cell lines. Furthermore, the same cell lines are seeded in ultra-low attachment microplates to form spheroids over 48hr and are thereafter treated with 24hr of carboplatin. Flow cytometry analyses are done to classify cell lines.
Results: The results for the 2D models using clonogenic assays (IC50) of the 7 cell lines have previously been published. Thus far, we have completed a first set of in vivo experiments for TOV21G showing a nonsignificant tumor growth suppression after 6 doses (no difference between the 3 treated and the nontreated group). Tumor growth suppression for OV90 was statistically significant with 50mg/kg and 75mg/kg of carboplatin after 6 doses. This demonstrates thus far that the most resistant cell line in 2D is more sensitive in an in vivo model.
Conclusion: The results will help define the most reliable preclinical model with the highest translational potential to predict treatment response.
Citation Format: Melica Nourmoussavi, Euridice Carmona, Anne-Marie Mes-Masson. Predictive treatment response models for epithelial ovarian cancer: Comparison of 2D, 3D, and in vivo models [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B80.