bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PO008: ARID1A prevents H3K27-hyperacetylation at active super-enhancers
Authors: Reske Jake J. , Wilson Mike R. , Chandler Ronald L. 
Published: February 2021

Abstract
Mutations in the multi-subunit SWI/SNF (BAF) chromatin remodeling complex are observed in nearly all types of cancer. The most highly mutated subunit across cancer is ARID1A, which occurs in roughly half of uterine endometrial cancer cases. ARID1A mutations and loss of expression are also common in endometriosis. We have previously demonstrated that ARID1A loss drives transcriptional alterations leading to invasive phenotypes through multiple model systems. Yet, how ARID1A regulates transcription through chromatin regulation is poorly understood. We have generated genome-wide profiles of seven chromatin features associated with transcriptional regulation in human endometrial epithelial cells, in both the presence and absence of ARID1A, in order to identify a mechanism by which ARID1A regulates chromatin. Unbiased genome segmentation using these features revealed that ARID1A interacts with chromatin at highly active and accessible enhancers genome-wide. Out of all tested chromatin features, ARID1A most strongly co-localizes with H3K27ac, a mark of transcriptional activation at proximal and distal enhancers. ARID1A depletion also displayed the greatest effect on genomic H3K27ac as opposed to other histone modifications, H3K18ac, H3K4me1, H3K4me3, and H3K27me3. While the majority of typical enhancers had reduced H3K27ac with ARID1A loss, super-enhancers marked by high basal H3K27ac levels displayed hyperacetylation following ARID1A loss. Moreover, increasing H3K27ac was also associated with heightened eRNA transcription, indicating enhancer hyperactivation. Finally, RNA-seq revealed that genes associated with active super-enhancers were preferentially dysregulated following ARID1A loss. These results suggest that ARID1A-SWI/SNF differentially regulate typical enhancers vs. super-enhancers in the endometrial epithelium, and ARID1A may normally restrict super-enhancer hyperactivation to maintain epithelial identity and prevent endometrial invasion.
Citation Format: Jake J. Reske, Mike R. Wilson, Ronald L. Chandler. ARID1A prevents H3K27-hyperacetylation at active super-enhancers [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO008.
Abstract PO022: Multidimensional longitudinal assessment of patients under treatment for advanced endometrial cancer: a new tool to advance research on human disease
Authors: Dvergsten Erik , Karovic Sanja , Thomeas-McEwing Vasiliki , Kimble Danielle , Guo Pingzhen , Yang Hao , Zhao Binsheng , Schwartz Lawrence H. , Maitland Michael L. 
Published: February 2021

Abstract
Evolutionary biology-based methods to characterize human cancer increasingly inform screening, surveillance, and early stage disease treatment strategies. Advanced metastatic disease presents distinct challenges in research and effective treatment. We have established the Advanced Solid Tumor Registry at the Inova Schar Cancer Institute to systematically track quantitative behavior of advanced solid tumors in a “real world” treatment setting. The study supports collection of serial: plasma samples for ctDNA analysis, computed tomography digital images and semi-automated segmentation of lesions for tumor burden volume measurement, and collection of tumor marker measures among patients receiving routine, longitudinal treatment in a community oncology practice. At submission, the study has enrolled 53 patients, 6 with recurrent metastatic endometrial cancer. Study operations have been enhanced by development of R code and workflow to enable graphical display for individual patients in clinically relevant time. In addition to enhancing clinical decision-making for the individual patients, the collective endometrial cancer patient data currently cover 207 patient-months of observation, 119 circulating marker time-points, 73 CT scans, 27 individual lesions, and 20 different courses of treatment. Treatments included palliative radiation, and: cytotoxic, hormonal, immune-, and targeted therapeutics. We propose this registry represents a new tool to support application of evolutionary science-based methods to clinical care and reciprocally to collect “real world” data with sufficient detail to inform computational science assumptions and inferences in multi-scale modeling projects. In this pilot study, individual cases effectively display multiple observations relevant to understanding treatment response in advanced metastatic disease in the clinical care environment. This project was supported, in part, by R01-CA194783.
Citation Format: Erik Dvergsten, Sanja Karovic, Vasiliki Thomeas-McEwing, Danielle Kimble, Pingzhen Guo, Hao Yang, Binsheng Zhao, Lawrence H. Schwartz, Michael L. Maitland. Multidimensional longitudinal assessment of patients under treatment for advanced endometrial cancer: a new tool to advance research on human disease [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO022.
Abstract PO030: Understanding the influence of adiposity on the endometrium using human primary endometrial organoids
Authors: Murphy Alina R. , Kim J. Julie 
Published: February 2021

Abstract
Endometrial cancer is the most commonly diagnosed type of gynecological cancer, and obesity is a major risk factor for this disease. Despite rising rates of obesity and endometrial cancer, it is still unclear how obesity alters the benign endometrium and the endometrial hormonal response to promote carcinogenesis. We used an endometrial organoid model to investigate how adiposity predisposes women to develop endometrial cancer. We hypothesized that increased adiposity would directly alter endometrial gene expression and diminish the protective progesterone response of the benign endometrium. Scaffold-free, three-dimensional endometrial organoids consisting of both epithelial and stromal cells from benign endometrial tissue were generated. Organoids were cocultured with different numbers of adipocyte spheroids to represent different levels of adiposity and were treated with a menstrual cycle level of hormones (E2 + P4 +T) over 14 days. Endometrial organoid gene expression was investigated using RNA-seq. Coculturing endometrial organoids with 30 adipocyte spheroids in the presence of E2, P4, and T caused significant differential expression of pathways involved in metabolism, angiogenesis, chromatin modification, and metal ion response, compared to endometrial organoids cultured without adipocyte spheroids. We investigated the metal ion response pathways that were altered and found that many of the most significantly differentially regulated genes in the metal ion response pathways belonged to the metallothionein (MT) family of genes. The expression of MT1A, MT1M, MT1X, and MT2A decreased approximately 50% in endometrial organoids cocultured with 30 adipocyte spheroids. Furthermore, although the results were not statistically significant, we observed a downregulation of the progesterone-responsive genes HSD17B2, IGFBP1, PAEP, PRL, FOXO1, and SPP1 in the endometrial organoids cultured with 30 adipocyte spheroids. Our results show that culturing endometrial organoids in conditions of increased adiposity alters endometrial gene expression and may change the way the endometrium responds to progesterone. Metallothioneins, which are downregulated in the presence of adipocyte spheroids, are important modulators of zinc and copper ions and reactive oxygen species in the cell. Progesterone plays an important protective role against endometrial cancer. In summary, our data show that adipocytes may influence the progesterone response of the benign endometrium. Further investigation into the role of progesterone-driven metallothioneins in the endometrium is currently underway.
Citation Format: Alina R. Murphy, J. Julie Kim. Understanding the influence of adiposity on the endometrium using human primary endometrial organoids [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO030.
Abstract PO033: FGFR2 isoform switching strongly associates with progestin treatment failure in atypical hyperplasia and well-differentiated endometrial cancer
Authors: Sengal Asmerom , Smith Deborah , Rogers Rebecca , Snell Cameron , Williams Elizabeth , Pollock Pamela 
Published: February 2021

Abstract
Introduction: Women with atypical hyperplasia (AH) or well-differentiated endometrioid endometrial carcinoma (EEC) who wish to retain fertility and/or with severe comorbidities that preclude surgery, are treated with progestin. Previously, we reported FGFR2c was associated with aggressive tumour behaviour and poor survival outcome in EEC. The purpose of this study was to estimate the response rate of Levonorgestrel IUD treatment and determine the association of FGFR2b and FGFR2c expression with outcome in women with AH/borderline histology (BL) and EEC treated with progestin.
Method: BaseScope RNA ISH and immunohistochemistry assays were deployed to detect (FGFR2b and FGFR2c mRNA) and (FGFR2 protein and progesterone receptors), respectively in 89 diagnostic biopsies of patients with AH/BL and EEC treated with progestin. Kaplan Meier Curve and Cox regression model analyses were performed to evaluate the predictive value of FGFR2b and FGFR2c in this cohort.
Results: The complete resolution rate (CRR) and overall response rate (ORR) at any time point in the whole cohort were 26/82 (32%) and 35/82 (43%), respectively. When stratified by histologic diagnosis CRR was 47.5% and 17% and ORR 63% and 24% for AH/BL and EEC, respectively. The recurrence rate was 28.7%. FGFR2c expression was documented in 12/72 (15%) cases. Both univariable and multivariable Cox regression analyses showed women with FGFR2c expression were 5-fold more likely to progress compared with FGFR2b positive women (HR 5.4, P&lt;0.0001) and (HR, 5, P&lt;0.001), respectively.
Conclusion: Progestin treatment is less effective in patients with EEC. Notably, FGFR2c expression appears to be strongly associated with progestin treatment failure.
Citation Format: Asmerom Sengal, Deborah Smith, Rebecca Rogers, Cameron Snell, Elizabeth Williams, Pamela Pollock. FGFR2 isoform switching strongly associates with progestin treatment failure in atypical hyperplasia and well-differentiated endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO033.
Abstract PO042: ROR2 is epigenetically regulated in endometrial cancer
Authors: Liu Dongli , Enriquez Luis , Daniels Benjamin , O'Mara Tracy , Tang Katrina , Ford Caroline 
Published: February 2021

Abstract
BACKGROUND: The Wnt signalling receptor ROR2 has been identified as a potential target in numerous cancers, however its exact role remains controversial. ROR2 has been shown to play distinct roles in regards to tumorigenesis in different tumour types. Our previous study suggested a potential tumour suppressor role for ROR2 in endometrial cancer (EC), however the mechanism associated with ROR2 repression in EC remains unclear. ROR2 has been found to be epigenetically inactivated in colorectal cancer. OBJECTIVE: The aim of this study was to investigate the role of ROR2 in EC, and to determine if ROR2 expression in EC was regulated epigenetically. METHODS: The correlation between ROR2 mRNA expression levels and clinicopathological parameters, including overall survival (OS) was analysed in The Cancer Genome Atlas Uterine Corpus Endometrial Carcinoma (TCGA-UCEC, n=546) cohort and GEO datasets (GSE17025, n=91). Immunohistochemistry (IHC) of ROR2 was performed on a large EC patient cohort (Australia-wide population-based Australian EC Study, ANECS, n=499). The correlation between ROR2 staining intensity (0-3) and clinicopathological parameters as well as 5-year progression free survival (PFS) and OS was analysed. Cox regression was also applied to analyse the impact of selected covariates (age, BMI, FIGO stage and grade) on the PFS and OS. Four EC cell lines (KLE, MFE-296, Ishikawa and ARK-1) and eight clinical EC samples were analysed for ROR2 methylation via COmbined Bisulphite Restriction Analysis (COBRA) and bisulphite genomic sequencing (BGS). RESULTS: ROR2 promoter methylation or reduced ROR2 expression were both found to correlate with lower OS, high grade and serous EC in the TCGA-UCEC and GEO dataset at p&lt;0.05 level. In our ANECS cohort, the same trend of correlation was observed of ROR2 expression and grade (p=0.062). No significant correlation was observed for ROR2 expression with OS or PFS in this cohort at univariate or multivariable survival analysis. ROR2 was epigenetically silenced by promoter methylation in KLE and ARK-1 cell lines. There was also a significant correlation between ROR2 expression level and promoter methylation in our patient cohort (r=-0.79, p=0.02). CONCLUSION: ROR2 plays a tumour suppressor role in EC and is epigenetically suppressed with the development of disease. It may therefore be a diagnostic or therapeutic candidate for EC.
Citation Format: Dongli Liu, Luis Enriquez, Benjamin Daniels, Tracy O'Mara, Katrina Tang, Caroline Ford. ROR2 is epigenetically regulated in endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO042.
Abstract PO047: AVB-500, a receptor tyrosine kinase AXL inhibitor, improves response to olaparib in uterine serous cancer
Authors: Toboni Michael D. , Mullen Mary , Tankou Jo'an , Noia Hollie , Oplt Alyssa , Wilke Daniel , Khabele Dineo , Kuroki Lindsay , Hagemann Andrea , McCourt Carolyn , Thaker Premal , Mutch David , Powell Matthew , Fuh Katherine 
Published: February 2021

Abstract
Objectives: We determined whether inhibition of GAS6/AXL with AVB-500 in combination with olaparib could improve response in HR-proficient (HRP) uterine serous cancer (USC). Methods: Two USC cell lines (ARK1 & ARK4) were radiated with 10Gy, and RAD51 foci were identified by immunofluorescence (IF). These were treated with AVB-500 (Aravive Biologics, Houston, TX) in combination with the poly ADP ribose polymerase (PARP) inhibitor, olaparib. Colony forming assays were assessed after 4 days of treatment with either AVB-500 alone, olaparib alone or combination treatment (olaparib + AVB-500). Colonies were stained and absorbance was obtained to calculate relative cell survival using Graph Pad Prism. In vivo studies were performed using NOD-SCID mice injected with 1 × 107 ARK1 cells intraperitoneally followed by treatment q3 days for 14-day treatment period. Treatment groups were vehicle control, AVB-500 alone, olaparib alone and olaparib with AVB-500. Results: ARK1 and ARK4 cells were found to have an increase in gamma-H2AX and RAD51 foci after radiation that was consistent with HRP. In clonogenic assays, colonies were stained and absorbance was obtained for each experimental arm. Olaparib + AVB-500 had significantly less absorbance than the olaparib only group for ARK1s (0.417nm vs 0.756nm, p=0.001) as well as in ARK4s (0.186nm vs 0.641nm, p=0.003). In an intraperitoneal model with ARK1 tumors, the olaparib + AVB-500 treated group had less tumor weight than those treated with olaparib alone (0.008g vs 0.138g, p=0.002) and AVB-500 alone (0.008g vs 0.145g, p=0.0006) after a 14-day treatment period. Conclusions: AVB-500 in combination with olaparib demonstrates an improved response than olaparib alone with a greater decrease in tumor burden. This was demonstrated in two HRP cell lines. Additional therapeutic and mechanistic experiments are ongoing.
Citation Format: Michael D. Toboni, Mary Mullen, Jo'an Tankou, Hollie Noia, Alyssa Oplt, Daniel Wilke, Dineo Khabele, Lindsay Kuroki, Andrea Hagemann, Carolyn McCourt, Premal Thaker, David Mutch, Matthew Powell, Katherine Fuh. AVB-500, a receptor tyrosine kinase AXL inhibitor, improves response to olaparib in uterine serous cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO047.
Abstract PR003: Multi-tissue transcriptome-wide association study identifies genetic mechanisms underlying endometrial cancer susceptibility
Authors: O'Mara Tracy A. , Kho Pik Fang , Partida Gabriel Cuellar , Spurdle Amanda B. , Glubb Dylan M. 
Published: February 2021

Abstract
To date, genome-wide association studies (GWAS) of endometrial cancer have identified 16 genetic risk regions; however, candidate susceptibility genes at these regions are yet to be confirmed. We performed a transcriptome-wide association study (TWAS) to identify candidate endometrial cancer susceptibility genes and provide evidence to support previously identified candidate genes. To maximise statistical power, we used a multi-tissue TWAS approach, integrating the largest endometrial cancer GWAS (12,906 cases and 108,979 controls of European ancestry) with cis-expression quantitative trait loci (eQTLs) from 48 tissues. Identified genes were prioritised by colocalisation analysis to reduce false positive findings. We found seven candidate endometrial cancer susceptibility genes, six of which had previously been identified as candidate susceptibility genes by parallel functional analyses. The remaining identified gene was a lncRNA located at a potentially novel endometrial cancer genetic risk region. Using phenome-wide association approaches, we found these genes associate with traits related to endometrial cancer risk factors, including cardiovascular phenotypes, diabetes, and hormone levels. This analysis additionally identified associations with traits related to bone health, haematopoiesis and liver function, providing avenues for future study. Comparing genetically predicted endometrial cancer gene expression with drug-induced gene expression profiles from the Connectivity Map database, we identified 14 drug repurposing candidates including tubulin inhibitors, a drug class already in use for treatment of advanced endometrial cancer. In summary, using TWAS we have identified candidate endometrial cancer susceptibility genes and provided evidence to prioritise existing candidates. Follow-up analyses have revealed further potential risk factors for endometrial cancer and compounds that could be repurposed for endometrial cancer treatment.
Citation Format: Tracy A. O'Mara, Pik Fang Kho, Gabriel Cuellar Partida, Amanda B. Spurdle, Dylan M. Glubb. Multi-tissue transcriptome-wide association study identifies genetic mechanisms underlying endometrial cancer susceptibility [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PR003.
Abstract PR004: Multi-dimensional biomarker analyses identify pembrolizumab responders in advanced stage, high grade endometrial cancer
Authors: Fuh Katherine , Lomonosova Elena , Pachynski Russell , Malkova Olga , Oh Stephen , Hagemann Andrea , McCourt Carolyn , Powell Matthew , Fantl Wendy , Thaker Premal 
Published: February 2021

Abstract
Objectives: The recent FDA approval of pembrolizumab for the treatment of recurrent, tissue agnostic cancers with Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) has led to the treatment of a selected cohort of endometrial cancer (EC) patients. Methods: We designed a study to ascertain tumor immune modulatory effects of pembrolizumab in the front-line setting for advanced stage III/IV surgically-resectable endometrial cancers regardless of MSI-H or dMMR status. The primary objectives were to determine the safety of treatment with pembrolizumab by radiographic imaging and to determine progression-free survival at 6 months. Exploratory objective was to compare the immune response before and after treatment. In an open label, single-arm Phase I trial, 8 EC patients were treated with 2 doses of preoperative pembrolizumab IV prior to surgery followed by carboplatin and paclitaxel and 4 doses of pembrolizumab 200mg/kg q3 weeks IV. Peripheral blood was collected from EC patients at baseline level before treatment and post 2 doses of pembrolizumab treatment. Blood from healthy controls (HC) was also collected. Both were processed for high-dimensional single-cell mass cytometry (CyTOF) using an optimized lymphoid and myeloid panel. Results: Patients who responded to therapy showed lower frequency of circulating CD8+ naïve T cells but higher frequency of CD8+ effector T cells after the treatment than the poor responders. We observed post-therapy expansion of populations of CD8+ and CD4+ T cells expressing co-stimulatory receptor ICOS in responders but not in poor responders. Granzyme+CD8+ and Granzyme+CD4+ T cell populations were expanded after pembrolizumab treatment in responders but were decreased in poor responders. Higher frequency of CD27+Fas- CD4+ T cells at baseline and increased frequency of CD27-Fas+CD4+ T cells post-treatment were observed in responders but not in the poor responders. Furthermore, we identified that circulating MDSCs were reduced after pembrolizumab treatment in responders. Conclusions: Our results suggest that peripheral blood analysis may provide valuable insights into responses to anti-PD-1-targeted therapies in patients with endometrial cancers.
Citation Format: Katherine Fuh, Elena Lomonosova, Russell Pachynski, Olga Malkova, Stephen Oh, Andrea Hagemann, Carolyn McCourt, Matthew Powell, Wendy Fantl, Premal Thaker. Multi-dimensional biomarker analyses identify pembrolizumab responders in advanced stage, high grade endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PR004.