bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract GMM-052: EVIDENCE FOR APOBEC MUTAGENESIS IN CLEAR CELL OVARIAN CARCINOMA
Authors: Serebrenik Artur S. , Jarvis Matthew C. , Argyris Prokopios P. , Brown William B. , Harris Reuben S. 
Published: June 2021

Abstract
Clear cell ovarian carcinoma (CCOC) accounts for 1-12% of ovarian epithelial cancers and, notwithstanding early diagnosis, often has poor clinical outcomes. CCOC genomic sequences show strong cytosine to thymine (C-to-T) transition mutation biases (Wang et al., 2017, Nature Genetics; Maru et al., 2017, Gynecologic Oncology; Shibuya et al., 2018, Genes Chromosomes Cancer). Many of these mutations occur in APOBEC signature motifs (5'-TCA or TCT), implicating at least one of the nine APOBEC DNA cytosine deaminase family members in CCOC mutation and evolution. Three of the nine family members associate with cancer mutagenesis, but only one, APOBEC3B (A3B), correlates in multiple cancer types with worse clinical outcomes including overall and metastasis-free survival.
Here, we further investigate the specific involvement of APOBEC mutagenesis in CCOC. First, we show that tumors positive for APOBEC signature mutations associate with poor clinical outcomes in comparison to those that do not. Second, we perform a comprehensive analysis of mutation signatures from new whole genome sequences and APOBEC expression profiles from tumor and normal tissues, including RTqPCR for mRNA quantification and immunohistochemistry to distinguish APOBEC protein expression in tumor cells from surrounding connective tissue and immune cells. Our results indicate a significant role for APOBEC mutagenesis in CCOC warranting further studies including evaluation of APOBEC as a prognostic biomarker.
Citation Format: Artur S. Serebrenik, Matthew C. Jarvis, Prokopios P. Argyris, William B. Brown, Reuben S. Harris. EVIDENCE FOR APOBEC MUTAGENESIS IN CLEAR CELL OVARIAN CARCINOMA [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-052.
Abstract GMM-056: IGF-AXIS SIGNALING DURING OVULATION IS RESPONSIBLE FOR THE STEMNESS CELL EXPANSION AND TRANSFORMATION OF FALLOPIAN TUBE FIMBRIAL EPITHELIUM
Authors: Chu Tang-Yuan , Hsu Che-Fang , Huang Hsuan-Shun 
Published: June 2021

Abstract
Recent studies have unveiled the fallopian tube fimbria as the major tissue-of-origin and incessant ovulation as the main etiological risk factor of ovarian high-grade serous carcinoma (HGSC) but the mechanism of cancer initiation remains elusive. In a series of study we have found a subset of preovulatory follicular fluids (FF) contain high level of ROS that induce DNA double strand breaks as well as apoptosis to the fimbrial epithelial cells in vitro and in vivo. We also found hemoglobin in pelvis, most likely contributed by retrograde menstruation of previous cycles, reduces the ovulatory ROS level extracellularly and results in a shifting from the apoptotic to the survival fate of ROS-stressed fimbrial epithelial cells. These initiating factors in FF, although may contributes to the TP53 mutation and other early genetic hits in the genesis of HGSC, cannot fully transform the immortalized fimbrial epithelial cells, with loss of p53 and Rb.
In this study, we demonstrated that IGF axis proteins, including IGFBP2- and IGFBP6-bound IGF2 as well as the IGFBP-lytic enzyme PAPP-A are abundantly present in ovulatory FF, and disclosed their effect on the fallopian tube fimbrial epithelium. Upon engaging with glycosaminoglycans (GAG) on the membrane of fimbrial epithelial cells, PAPP-A cleaves IGFBPs and releases bioactive IGF2 in close proximity to its receptor IGF-1R. This leads to stemness activation and clonal expansion of primary and immortalized fimbrial epithelial cells, and to malignant transformation of p53/Rb- and p53/CCNE1-disrupted fimbrial secretory cells. By antibody depletion, we proved each component of this IGF axis is essential and confers the majority of the transformation/regeneration activities in FF. Two signaling pathways, IGF-1R/ AKT/mTOR and IGF-1R/AKT/NANOG, are responsible for the phenotypes. Among them, IGF-1R and NANOG were critical since blocking their expression or function lead to a complete loss of the transformation.
Given that ovulation is an acute inflammatory process inevitably damaging the ovarian surface and the fimbriae, IGF axis in FF takes a role of tissue repair and, in situations when the ROS-induced TP53/Rb mutations accumulated in stem cells, may lead to carcinogenesis of the fallopian tube fimbria.
Citation Format: Tang-Yuan Chu, Che-Fang Hsu, Hsuan-Shun Huang. IGF-AXIS SIGNALING DURING OVULATION IS RESPONSIBLE FOR THE STEMNESS CELL EXPANSION AND TRANSFORMATION OF FALLOPIAN TUBE FIMBRIAL EPITHELIUM [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-056.
Abstract GMM-059: SHEAR STRESS DOWNREGULATION OF MIR-199A-3P DRIVES CHEMORESISTANCE IN OVARIAN CANCER CELLS
Authors: Li Shan-Shan , Ip Carman K. M. , Shum Ho-Cheung , Wong Alice S. T. 
Published: June 2021

Abstract
Ovarian cancer is leading cause of deaths among all gynecological malignancies. The presence of intrinsic and acquired drug resistance are major challenges in the treatment and clinical management of ovarian cancer. Ovarian cancer cells typically cluster into tumor spheroids and float in the ascitic fluid, which are characteristic of the aggressiveness of these tumor cells. We have recently developed a three-dimensional microfluidic platform with tumor spheroids and continuous fluidic flow to closely emulate the physiological condition in the ascites of ovarian cancer patients. Using this model, we showed for the first time that clinically relevant levels of ascitic shear stress induced drug resistance in ovarian tumor spheroids. Such chemoresistance was mediated through the increased expression of ABC-binding cassette transporter G2 and P-glycoprotein. By profiling the microRNAs (miRNAs) expression patterns under flow conditions, we identified miR-199a-3p as a critical mechanosensitive miRNA that was downregulated under shear stress through regulating the miRNA biogenesis machinery. miR-199a-3p expression was found to be inversely correlated with enhanced drug resistance properties and chemoresistant ovarian cancer sublines. Ectopic expression of miRNA-199a-3p could reverse the shear stress-induced expression of ABC-binding cassette transporter G2 and P-glycoprotein in ovarian tumor spheroids, confirming that the effect was miR-199a-3p specific. Taken together, these findings highlight the importance of shear stress-mediated decrease of miR-199a-3p in the regulation of drug response in ovarian cancer, which provide new insights in the understanding of cancer biology and potential effective treatment.
Citation Format: Shan-Shan Li, Carman K. M. Ip, Ho-Cheung Shum, Alice S. T. Wong. SHEAR STRESS DOWNREGULATION OF MIR-199A-3P DRIVES CHEMORESISTANCE IN OVARIAN CANCER CELLS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-059.
Abstract NT-086: PRELIMINARY IDENTIFICATION OF LACTATE DEHYDROGENASE INHIBITORS TOWARDS ANTICANCER DRUG DEVELOPMENT
Authors: Emmanuel Adegbite , Sanya Joseph O , Olubiyi Olujide O 
Published: June 2021

Abstract
In tumor cells undergoing rapid cellular division, significantly increased quantities of lactic acid are produced in an anaerobic respiration via the Cori cycle. While this produces a lower of the pH in the local environment, the hepatic conversion of the generated lactate into glucose places a huge energy demand on the body which makes the patient weaker and results in cancer cachexia in all ovarian malignancies. Thus, instead of producing acetyl CoA, the dividing tumorous cells synthesize lactic acid catalyzed by the enzyme lactate dehydrogenase (LDH). LDH's involvement in tumor initiation and metabolism primarily involves a state of fermentative glycolysis catalyzed by the A form of the enzyme which allows tumorous cells convert the majority of their glucose stores into lactate even under anaerobic conditions which invariably shifts the utilization of glucose metabolites from simple energy production to an active promotion of accelerated cell growth and replication. This makes LDH a vital target for malignant ovarian drug development. And in the present work a combination of virtual screening, database scouting and biophysical analysis of binding site properties have been employed in analysis the interaction of about 30,000 compounds with LDH. Using a synthetic NADH inhibitor, as a reference, only four compounds were found to demonstrate stronger binding features than the inhibitor. This preliminary in silicon screening represents the foundational effort in a ovarian cancer drug discovery project aimed at generating specific inhibitors of LDH for use in ovarian cancer therapeutics.
Note: This abstract was not presented at the symposium.
Citation Format: Adegbite Emmanuel, Joseph O Sanya, and Olujide O Olubiyi. PRELIMINARY IDENTIFICATION OF LACTATE DEHYDROGENASE INHIBITORS TOWARDS ANTICANCER DRUG DEVELOPMENT [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-086.
Abstract NT-097: QUANTITATIVE HIGH-THROUGHPUT SCREENING USING AN ORGANOTYPIC MODEL IDENTIFIES TWO KINASE INHIBITORS THAT INHIBIT OVARIAN CANCER METASTASIS
Authors: Kenny Hilary A. , Lal Madhu , Shen Min , Nahotko Dominik , Fazal Sarah , Chen Siquan , Chiang Chun-Yi , Kara Betul , Yamada S. Diane , Brimacombe Kyle , Marugan Juan , Ferrer Marc , Lengyel Ernst 
Published: June 2021

Abstract
The cancer cells, stromal cells and stroma in the tumor microenvironment contribute to cancer metastasis and drug resistance. Therefore we applied an organotypic, robust and reliable assay for quantitative high throughput screening (qHTS) in drug discovery. This 1536-well HTS culture contains primary human mesothelial cells, fibroblasts, fibronectin and collagen type I and reproduces the human ovarian cancer (OvCa) metastatic microenvironment. The qHTS assay identifies small molecule compounds that inhibit OvCa adhesion/migration/invasion to the organotypic metastatic microenvironment.
Over 44,000 small molecules were screened in the primary qHTS assay. A counter screen was performed to eliminate any compounds toxic to the mesothelial cells or fibroblasts within the metastatic microenvironment. The activity of hit compounds was confirmed using five OvCa cell lines, and validated in secondary in vitro and in vivo biological assays. The active compounds directly inhibit at least two of three OvCa functions: adhesion, invasion and growth. In vivo, these compounds prevent OvCa adhesion/invasion and metastasis, and improve survival in mouse models.
Collectively, these data indicate that the three compounds, two tyrosine kinase inhibitors and one novel compound, identified using an complex organtoypic culture of the tumor microenvironment for qHTS are potential therapeutics for OvCa metastasis.
Citation Format: Hilary A. Kenny, Madhu Lal, Min Shen, Dominik Nahotko, Sarah Fazal, Siquan Chen, Chun-Yi Chiang, Betul Kara, S. Diane Yamada, Kyle Brimacombe, Juan Marugan, Marc Ferrer and Ernst Lengyel. QUANTITATIVE HIGH-THROUGHPUT SCREENING USING AN ORGANOTYPIC MODEL IDENTIFIES TWO KINASE INHIBITORS THAT INHIBIT OVARIAN CANCER METASTASIS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-097.
Abstract NT-100: PARPI-INDUCED ALDH1A1 EXPRESSION CONTRIBUTES TO PARPI RESISTANCE IN OVARIAN CANCER CELLS
Authors: Liu Lu , Cai Shurui , Han Chunhua , Benerjee Ananya , Wu Dayong , Cui Tiantian , Xie Guozhen , Zheng Yanfang , Wang Qi-En 
Published: June 2021

Abstract
Ovarian cancer (OC) is one of the most lethal female malignancy which accounts for just 2.5% of female cancer cases but 5% of deaths because of low survival. 90% of OC are epithelial ovarian cancer (EOC), with an overall 5-year relative survival rate of 47% and only 29% for patients diagnosed with distant-stage. 20% of OC cases are estimated to be due to inherited mutations that confer elevated risk, especially cancer susceptibility genes BRCA1 and BRCA2. PARP inhibitors (PARPi) are novel and promising cancer-targeted drugs. PAPRi are approved by FDA for clinical treatment of advanced EOC patients with BRCA1/2 gene mutation. However, patients gradually gained resistance to PARPi with continuously increased recurrence rate (&gt;90%). Thus, understanding the mechanism underlying PARPi resistance is an urgent need for improving the PARPi efficacy. Aldehyde dehydrogenase (ALDH) activity is considered as a cancer stem cell (CSC) marker and also relative to drug resistance. However, the relationship between ALDH activity and PAPPi resistance remains unclear. In this study, we generated two olaparib-resistant EOC cell lines by continuously treating BRCA2-mutated PEO1 and Kuramochi cell lines for 6 months, and found that these resistant cell lines exhibited higher ALDH activity compared to their corresponding parent cell lines. In addition, short-term treatment of PEO1 and Kuramochi cells with olaparib (7 days) also increased the ALDH+ cell population in these cells, and olaparib-induced ALDH--to-ALDH+ conversion contributed to the expansion of the ALDH+ cell population after olaparib treatment. qRT-PCR analysis demonstrated that ALDH1A1 is the major gene in the ALDH gene family that was induced by olaparib. Overexpression of ALDH1A1 increased olaparib resistance in a panel of EOC cells lines including both BRCA2-muated and BRCA2-wild type cell lines. In summary, our data indicate that olaparib is able to induce ALDH1A1 gene expression, which results in the enhanced ALDH activity. The enhanced ALDH activity can contribute to olaparib resistance in BRCA2-mutated EOC cells.
Citation Format: Lu Liu, Shurui Cai, Chunhua Han, Ananya Benerjee, Dayong Wu, Tiantian Cui, Guozhen Xie, Yanfang Zheng, and Qi-En Wang. PARPI-INDUCED ALDH1A1 EXPRESSION CONTRIBUTES TO PARPI RESISTANCE IN OVARIAN CANCER CELLS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-100.
Abstract NT-117: INHIBITION OF PARG, SENSITIZES OVARIAN CANCER CELLS TO PARP INHIBITORS AND DNA DAMAGING AGENTS
Authors: Matanes Emad , Baloch Tahira , Octeau David , Kessous Roy , Kogan Liron , Laskov Ido , Gotlieb Walter , Yasmeen Amber 
Published: June 2021

Abstract
BACKGROUND: Poly(ADP-ribose) glycohydrolase (PARG) is responsible poly(ADP-ribose) (PAR) catabolism, which is synthesized by poly(ADP-ribose) polymerases (PARPs) at the site of DNA single-strand breaks (SSB). Faulty PAR formation or disintegration inhibits SSB repair. PARP inhibitors (PARPi) exploit the synthetic lethality between SSB repair and homologous recombination (HR) double strand break (DSB) repair. The most effective PARPi traps PARP at the SSB site, causing a double strand break during DNA synthesis that the cell cannot repair. The trapping of PARP can also be achieved through PARG inhibition. Due to the high rate of HR defects in epithelial ovarian cancer, the aim of this study is to evaluate the effect of a PARG inhibitor (PARGi) on epithelial ovarian cancer cell lines, alone and in combination with PARPi or cisplatin.
METHODS: PARG protein levels were assessed in 74, unselected, snap-frozen, tumors kept in our bio-bank by western blotting and immuno-histochemistry (IHC), as well as in the TCGA database. PARG was knocked down in two cell lines resistant to PARP inhibition, OVCAR3 and SKOV3. The knockdowns were subjected to cell migration and cell proliferation assays, as well as single cell analysis. BRCA1 mutated and BRCA1 wild-type cell lines were exposed to clinically relevant doses of PARGi, PARPi, or cisplatin, separately or in various combination. Therapeutic efficacy was assessed using colony formation assay. Western Blotting was used to detect the levels of PARG and PARP proteins in the cell lines.
RESULTS: PARG mRNA was expressed in 30% of tumors in TCGA. PARG protein was also detected in 30% of the biobank tumors analyzed. PARG knockdowns exhibited reduced rates of cellular proliferation and significant G2/M cell cycle arrest. In PARG over expressed ovarian cancer cell lines, PARG inhibitor similarly reduced cell migration (OVCAR3 and SKOV3: 75% reduction, SNU-251: 48% reduction).
CONCLUSION: PARG inhibition appears to be a viable, complementary strategy to PARP inhibition in HR-deficient cancers. The effect of BRCA1 on the efficacy of PARG inhibition, as well as various treatment combinations, are currently under investigation.
Citation Format: Emad Matanes, Tahira Baloch , David Octeau, Roy Kessous, Liron Kogan, Ido Laskov, Walter Gotlieb, Amber Yasmeen. INHIBITION OF PARG, SENSITIZES OVARIAN CANCER CELLS TO PARP INHIBITORS AND DNA DAMAGING AGENTS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-117.
Abstract NT-118: SEQUENTIAL THERAPEUTIC TARGETING OF OVARIAN CANCER HARBORING DYSFUNCTIONAL BRCA1
Authors: Baloch Tahira , Kessous Roy , Octeau David , Kogan Liron , Laskov Ido , Witcher Michael , Gotlieb Walter H. , Yasmeen Amber 
Published: June 2021

Abstract
BACKGROUND: Ovarian cancer is the most lethal gynecologic cancer. High grade serous ovarian cancer (HGSC) is the most common and deadly histological subtype. The current standard treatment protocol involves primary debulking surgery followed by platinum-based combination chemotherapy. PARP inhibitors(PARPi) are the first approved personalized treatments used in BRCA1-mutated recurrent ovarian cancer patients and have shown promising clinical results. Previously published data in collaboration with Dr. Witcher's lab, we described a significant reduction in PARP1 protein levels in patients after giving standard carboplatinum-paclitaxel chemotherapy that is effecting the clinical efficacy of PARP inhibitors in clinical trials. PARP inhibitors are currently administered after standard chemotherapy, when PARP levels are the lowest which was clearly shown in the previous published paper. Applying novel strategy and following the sequence of administration, giving PARP inhibitors first followed by standard chemotherapy might improve response rates. This study aims to evaluate this strategy (in vitro) in the pre-clinical models.
METHODS: BRCA1 mutated (UWB1.287, SNU-251), epigenetically silenced (OVCAR8), and wild-type BRCA1 (OVCAR3, SKOV3, A2780P & A2780R) cell lines were exposed to clinically relevant doses of PARPi, either followed by standard chemotherapy, or the inverse sequence. Therapeutic efficacy was assessed using colony formation assay. Apoptotic index was evaluated by cell cycle analysis and apoptotic assays using flow cytometry. Western Blotting was used to detect the levels of relevant apoptotic and cell cycle proteins.
RESULTS: Exposure to PARPi prior to standard chemotherapy sensitized BRCA1 mutated or epigenetically silenced BRCA1 cell lines to lower doses of Cisplatin (CP) or Paclitaxel (PT). Similarly, pre-treatment with PARPi prior to chemotherapy induced apoptosis more effectively in the same cell lines. Similar results were observed in BRCA1 wild-type cell lines and cell lines in which BRCA1 functionality was restored.
CONCLUSION: Pre-treatment of cell lines with PARPi followed by standard chemotherapy is more efficient (in vitro) in inhibiting growth and inducing apoptosis than the present sequence of chemotherapy followed by PARPi.
Citation Format: Tahira Baloch, Roy Kessous, David Octeau , Liron Kogan, Ido Laskov, Michael Witcher, Walter H. Gotlieb and Amber Yasmeen. SEQUENTIAL THERAPEUTIC TARGETING OF OVARIAN CANCER HARBORING DYSFUNCTIONAL BRCA1 [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-118.
Abstract TMIM-064: AMPKA-LIKE PROTEINS IN OVARIAN CANCER TUMORIGENESIS AND NECROPTOSIS
Authors: Jamroze Anmbreen , Chesnokov Mikhail , Chefetz Ilana 
Published: June 2021

Abstract
In our previous research we characterized novel ALDH1A inhibitors (1A1, 1A2, 1A3) 673A that specifically target Ovarian Cancer Stem cells (OvCSC) and trigger cell programmed necrosis (necroptosis). Following ALDH1A inhibition CD133+ (A2780) FACS sorted cells we detected increase in phospho LKB1 while its major downstream target AMPKa did not exhibit changes in phosphorylation level. In addition to AMPKa, which is most known downstream target of LKB1, there are 11 AMPKa-like proteins that can be phosphorylated by LKB1. These proteins have been studied mostly in brain development.
To detect AMPKa-like relevancy to high grade serous ovarian cancer, we next analyzed TCGA data. Surprisingly we identified many alterations in all 12 genes, including LKB1 (STK11).
We only focused on alterations that exhibit gene amplifications or mRNA upregulation. Based on TCGA data, all AMPKa-like genes have many alterations in ovarian tumors suggesting importance of these genes to ovarian cancer tumorigenesis. We next continued to analyze combinations of any two genes to test their co-occurrence or mutual exclusivity. We detected 9 gene combinations, in which amplification or mRNA upregulation in AMPKa-like genes co-occur (p&lt;0.5) in patient tumors. We next validated expression of AMPKa-like genes in ovarian cancer cell lines and confirmed their expression in PEO-4, Ovcar8, and Ovsaho. We next treated Ovsaho, PEO4 and OvCAR8 cells with ALDH1A inhibitor 673A for 8 and 14 hr, and profiled expression of AMPKa-like genes following ALDH1A inhibition. We detected significant changes in AMPKa-like genes, suggesting their role in cell programmed necrosis.
To confirm our bioinformatic findings, we established cell lines that mimic patient tumors with most frequent co-occurrence of AMPKa genes. We have been studying these cell lines in terms of cell proliferation, stemness and role in cell death.
Citation Format: Anmbreen Jamroze, Mikhail Chesnokov, Ilana Chefetz. AMPKA-LIKE PROTEINS IN OVARIAN CANCER TUMORIGENESIS AND NECROPTOSIS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr TMIM-064.