bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A67: Understanding HIF1A-mediated therapy in clear cell ovarian cancer
Authors: Price Colles , Gill Stanley , Ho Zandra V. , Davidson Shawn M. , Merkel Erin , McFarland James M. , Leung Lisa , Tang Andrew , Kost-Alimova Maria , Tsherniak Aviad , Jonas Oliver , Vazquez Francisca , Hahn William C. 
Published: September 2020

Abstract
Previously, we have used an integrated approach to use genome-scale screening in RNAi and CRISPR-Cas9 to identify several putative cancer dependencies. From these putative dependencies, we discovered EGLN1 was a significant and selective dependency in ovarian cancer and EGLN1 dependency was further enriched in clear-cell ovarian cancers. Genetic knockout and small-molecule inhibition of EGLN1 reduced cell proliferation and increased apoptosis in vitro and in vivo. We found the function of EGLN1 as a cancer dependency is through its canonical role as a negative HIF1A regulator and knockout of HIF1A, but not HIF2A, rescues genetic knockout and small-molecule inhibition of EGLN1. Genetic and small-molecule suppression of VHL, downstream of EGLN1 in the degradation of HIF1A, similarly reduces proliferation and increases apoptosis, and is rescued by HIF1A knockout. Further, we found that forced expression of a mutated HIF1A that blocks EGLN1-dependent hydroxylation reduces proliferation and promotes apoptosis. Using RNA-sequencing, we identified several putative downstream targets of HIF1A and confirmed that HIF1A directly binds and drives transcription of negative MYC regulator MXI1. Further, we found that knockout of MXI1 reduced the effects of EGLN1-mediated suppression, indicating HIF1A-driven MYC suppression as one mechanism underlying EGLN1 dependency. Further understanding of HIF1A-mediated suppression of ovarian cancer progression will be critical to potential small-molecule therapy.
Citation Format: Colles Price, Stanley Gill, Zandra V. Ho, Shawn M. Davidson, Erin Merkel, James M. McFarland, Lisa Leung, Andrew Tang, Maria Kost-Alimova, Aviad Tsherniak, Oliver Jonas, Francisca Vazquez, William C. Hahn. Understanding HIF1A-mediated therapy in clear cell 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 A67.
Abstract A70: Studying the signaling pathways of tumorigenic epithelial fallopian tube subpopulations during early tumorigenesis
Authors: Russo Angela , Dean Matthew , Lantvit Dan , Burdette Joanna E. 
Published: September 2020

Abstract
Survival rates for high-grade serous ovarian carcinoma (HGSOC) patients have not substantially improved over the past decades, mainly because the disease is only detected at the metastatic stage. The findings of early premalignant lesions in the fallopian tube, but not in the ovary, suggested that HGSOCs may originate from the fallopian tube epithelium (FTE) and metastasize to the ovary. Studying the mechanisms of HGSOC genesis from the correct cell of origin is critical to the early detection of the disease. Our main goal is to determine how genetic and molecular alterations contribute to the early events of HGSOC genesis from FTE. Deletion of PTEN alone in FTE is sufficient to lead to tumor formation and peritoneal dissemination, suggesting that loss of PTEN may play a pivotal role in the early events of the tumorigenic cascade. Herein we show that loss of PTEN in the FTE upregulates markers of tumor-initiating cells (TIC) such as WNT4, LGR5, ALDH1, c-Kit, CD44, and Dll4. We also discovered that the TIC markers are confined in a specific population of cells with increased diameter that we call TICHigh as compared to a smaller population that we call TICLow. In fact, when these two populations are separated by flow cytometry-based sorting, the TICHigh retains all the TIC markers. In addition, using a limiting dilution assay, we found that the TICHigh subpopulation forms tumor at a faster rate in vivo and colonize more the ovary ex vivo. In addition, TICHigh forms bigger spheroids and are more resistant to chemotherapeutic agents, suggesting that more targeted therapy may be developed for these stem-like, tumorigenic subpopulations. We also show that loss of PAX2 is mediating the TICHigh phenotype and that activation of AKT is not sufficient to induce the TIC phenotype whereas p70S6K activation is required. These findings suggest that therapies to re-express PAX2 may prevent development of HGSOC. Together, these findings provide a novel model to study the mechanism of fallopian tube tumor initiation and invasion to the ovary mediated by loss of PTEN, which may help to define early events of human ovarian carcinogenesis.
Citation Format: Angela Russo, Matthew Dean, Dan Lantvit, Joanna E. Burdette. Studying the signaling pathways of tumorigenic epithelial fallopian tube subpopulations during early tumorigenesis [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 A70.
Abstract A73: BCL-XL dependency in a subset of ovarian clear-cell carcinoma cell lines
Authors: Stover Elizabeth H. , Gelbard Maya K. , Matulonis Ursula A. , Meyerson Matthew 
Published: September 2020

Abstract
Clear-cell ovarian carcinoma is a rare histologic subtype of epithelial ovarian cancers. Clear-cell ovarian cancers tend to be less responsive to platinum-based chemotherapy compared to high-grade serous ovarian cancers. In a dataset of large-scale CRISPR knockout and RNAi screens of cancer cell lines (depmap.org), a subset of ovarian clear-cell carcinoma cell lines were sensitive to knockout or knockdown of BCL2L1, encoding antiapoptotic protein BCL-XL. Most clear-cell ovarian cancer cell lines also express BCL2L1 mRNA and protein. We therefore tested a panel of ovarian cancer cell lines for response to BH3 mimetic drugs, which inhibit different members of the BCL-2 family of antiapoptotic proteins. Initial data showed that a subset of ovarian clear-cell carcinoma cell lines was sensitive to single-agent BCL-XL inhibition with A1331852 and dual BCL-2/BCL-XL inhibition with ABT-263. In contrast, these cell lines were relatively insensitive to single-agent BCL-2 inhibition or MCL1 inhibition. We are currently applying BH3 profiling, a functional assay for apoptotic priming, to test the response of ovarian clear-cell carcinoma cell lines to BCL-XL inhibition using a BCL-XL specific peptide, HRK. Collectively, these studies suggest that ovarian clear-cell carcinomas may be sensitive to BCL-XL inhibition, either alone or in combination with chemotherapy.
Citation Format: Elizabeth H. Stover, Maya K. Gelbard, Ursula A. Matulonis, Matthew Meyerson. BCL-XL dependency in a subset of ovarian clear-cell carcinoma cell lines [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 A73.
Abstract B25: SMARCA4/BRG1 and AP-1 co-regulate an epithelial-like signature in small-cell carcinoma of ovary, hypercalcemic type (SCCOHT)
Authors: Orlando Krystal A. , Raab Jesse R. , Douglas Amber K. , Abudu Aierken , Wang Yemin , Negri Gian Luca , Colborne Shane , Morin Gregg B. , Lang Jessica D. , Hendricks William P.D. , Raupach Elizabeth A. , Pirrotte Patrick , Huntsman David G. , Trent Jeffrey M. , Parker Joel S. , Weissman Bernard E. 
Published: September 2020

Abstract
Mutations in SMARCA4 (BRG1), one of the two mutually exclusive ATPases of the SWI/SNF chromatin remodeling complex, occur in &gt;95% of small cell carcinomas of the ovary, hypercalcemic type (SCCOHT), a rare and aggressive form of ovarian cancer. Because of its apparent role as a driver for SCCOHT, we performed integrative multi-omic analyses in a SCCOHT cell line +/- BRG1 re-expression to identify its role in SCCOHT tumorigenesis. After re-expression, BRG1 was recruited to both distal and promoter regions. We also observed increased chromatin accessibility at distal sites enriched for transcription factor binding motifs for AP-1 family members. Of interest, BRG1 re-expression induced an epithelial-like gene and protein expression concomitant with enrichment of AP-1 motifs at the TSS of highly upregulated epithelial genes. To determine the biologic relevance of these changes at AP-1 binding sites, we used a dominant negative AP-1 cell line to demonstrate that the necessity of AP-1 DNA binding activity and BRG1 re-expression for the protein expression of epithelial genes. Our study demonstrates that BRG1 loss may drive SCCOHT tumorigenesis by diminishing an epithelial-like gene and protein signature of its cell of origin driven by altered AP-1 binding.
Citation Format: Krystal A. Orlando, Jesse R. Raab, Amber K. Douglas, Aierken Abudu, Yemin Wang, Gian Luca Negri, Shane Colborne, Gregg B. Morin, Jessica D. Lang, William P.D. Hendricks, Elizabeth A. Raupach, Patrick Pirrotte, David G. Huntsman, Jeffrey M. Trent, Joel S. Parker, Bernard E. Weissman. SMARCA4/BRG1 and AP-1 co-regulate an epithelial-like signature in small-cell carcinoma of ovary, hypercalcemic type (SCCOHT) [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 B25.
Abstract B30: The effect of OCP use on the incidence of precancerous p53 lesions in fallopian tube fimbria
Authors: Greening Kendall , Karnezis Anthony , Cochrane Dawn , Farnell David , Hoang Lien , Hanley Gillian , Huntsman David 
Published: September 2020

Abstract
Background: High-grade serous ovarian carcinoma (HGSOC) accounts for &gt;70% of ovarian cancer-related deaths and is the most common ovarian cancer histotype, most originating from precancerous p53 lesions in the fallopian tube (FT) fimbria. Use of oral contraceptive pills (OCPs) for 5 years or more is associated with a &gt;40% reduction in risk of HGSOC, but the mechanism is unknown. We hypothesize that OCP use reduces the incidence of p53 lesions. Our preliminary data show higher incidence of p53 lesions in post- compared to premenopausal women; therefore we aim to quantify p53 lesions in postmenopausal women who previously did or did not use OCPs. This will provide insight into the protective effects of OCPs against HGSOC.
Preliminary Results: We determined the presence of p53 lesions by immunohistochemistry (IHC) in FT of women up to 40 years old (n=27) and &gt;60 years old (n=24) who underwent salpingectomies for noncancer reasons. p53 lesions were identified in 3/27 cases of the younger cohort (11%) and in 10/24 of the older cohort (42%). Thus, we conclude an increased incidence of p53 lesions in older compared to younger women.
Proposed Design: IHC for p53 will be performed on FT fimbria of women &gt;55 years old who received salpingectomy for noncancer reasons. Based on an assumed reduction in p53 lesions of 35% in women who used OCPs for 5 years or more compared to nonusers (25 vs. 42%), analysis of 190 cases from each group will provide &gt;80% power (p&lt;0.05). Cases will be identified through Population Data BC and blind analysis by p53 IHC will be performed at the Vancouver General Hospital. Data will be flowed back to Pop Data BC to compare to OCP data.
Conclusion: Our preliminary study found that 42% of postmenopausal women had p53 lesions, informing this study design. The study registered through this abstract will be the first to examine the impact of OCPs on the earliest known precursors of HGSOC.
Citation Format: Kendall Greening, Anthony Karnezis, Dawn Cochrane, David Farnell, Lien Hoang, Gillian Hanley, David Huntsman. The effect of OCP use on the incidence of precancerous p53 lesions in fallopian tube fimbria [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 B30.
Abstract B33: Reproductive factors and risk of ovarian cancer: The Singapore Chinese Health Study
Authors: Lei Ming , Adambekov Shalkar , Wang Renwei , Yuan Jianmin , Lopa Samia , Linkov Faina 
Published: September 2020

Abstract
Background: Ovarian cancer (OC) is the deadliest gynecologic cancer, with varying incidence across geographic regions. Asian population is underrepresented in etiologic and epidemiologic investigations in the area of ovarian cancer. We explored association between ovarian cancer incidence and several lifestyle, dietary, reproductive, and hormonal risk factors in the Singapore Chinese cohort study.
Methods: A population of 34,028 Singaporean Chinese women aged 45-74 were enrolled in the Singapore Chinese Health Study between 1993 to 1998, and followed through Dec. 31, 2010. Data on demographics, tobacco use, dietary and reproductive factors were collected. Cases of OC were determined via linkage to Singapore Cancer Registry. Poisson regression model was performed and hazard ratios (HR) and 95% confidence intervals (CI) were estimated for each variable. Established risk factors and variables showing a significant result in univariate analysis were included in the multivariate analysis.
Results: 128 cases of OC were identified. No dietary factors were associated with OC incidence in this population, nor was tobacco/alcohol use. In univariate analysis, significant results included later age of menopause (RR=2.38, 95%CI 1.23-4.30), later age of first birth (RR=0.43, 95%CI 0.17-0.93) and longer period of menstruating (RR=1.48, 95%CI 1.02-2.18), parity (RR=0.37, 95%CI 0.22-0.65), and oral contraceptives use (RR=0.54, 95% CI 0.33-0.84). In multivariate analysis, higher number of children was associated with decreased ovarian cancer risk (1-2, 3-4, 5+ vs nulliparity: RR=0.45, 95%CI 0.26-0.8; RR= 0.35, 95%CI 0.20-0.51 RR= 0.32, 95%CI 0.18-0.60, respectively).
Conclusions: Parity, contraceptive use, and later age of first birth decreased the risk of OC incidence, while later age at menopause and longer menstruating period increased ovarian cancer risk in Singaporean Chinese cohort. This finding is consistent with findings in Western populations. Future studies are needed to determine risk factors associated with ovarian cancer histologic types and identify markers of elevated risk, especially in Asian populations.
Citation Format: Ming Lei, Shalkar Adambekov, Renwei Wang, Jianmin Yuan, Samia Lopa, Faina Linkov. Reproductive factors and risk of ovarian cancer: The Singapore Chinese Health Study [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 B33.
Abstract B35: Dietary flaxseed supplementation in ovarian cancer: Elucidating the molecular actions of its biologically derived active compounds
Authors: Pal Purab , Hales Karen , Hales Dale Buchanan 
Published: September 2020

Abstract
The goal of our study is to elucidate the anti-ovarian cancer molecular mechanisms promoted by a flaxseed-supplemented diet in the laying hen. A flaxseed-supplemented diet generates a myriad of biologically active compounds that work synergistically to attack ovarian tumors. Our laboratory has demonstrated that flaxseed diet reduces the occurrence and severity of ovarian cancer in laying hen—the only spontaneous animal model for ovarian cancer. Flax diet in chicken induces the CYP1A1 pathway of estrogen metabolism increasing production of 2-hydroxy and 2-methoxy metabolites. 2-methoxyestradiol (2ME) is produced by the Catechol-O-Methyl transferase (COMT) enzyme from 2-hydroxyestradiol—a pathway that reduces estrogen toxicity, which is protective against ovarian cancer. Flaxseed is also a rich source of omega-3 fatty acids, mostly a-linoleic acid (ALA), which is converted into docosahexaenoic acid (DHA) in the gut. We have recently shown that flaxseed diet induces apoptosis and inhibits angiogenesis in the chicken ovarian tumors. 2ME promotes apoptosis and inhibits angiogenesis via activation of p38-MAPK; DHA has potent antiangiogenic and anti-inflammatory actions, however not dependent on the p38-MAPK pathway. To further investigate the molecular mechanisms of the antiangiogenic actions of flax diet, a qRT-PCR array analyzing 84 key genes involved in angiogenesis was performed. Nine key genes were significantly downregulated with flax diet. These genes are involved in hypoxia-induced endothelial cell migration, proliferation, differentiation, and lymphangiogenesis. Using human ovarian cancer cells, DNA damage was studied by TUNEL staining; DNA content and cell cycle progression were studied by PI staining and flow cytometry; apoptosis was measured by cleavage of caspase-3 by Western blot. 2ME treatment induced phosphorylation at ser139 of histone H2A (gH2Ax), a known marker for dsDNA breaks, along with phosphorylation at ser10 of histone H3 (pHH3) and ser14 of histone H2B (pHH2B). 2ME is known to bind at/near the colchicine binding site of the growing microtubules and therefore arresting cells at G2/M phase. 2ME effects were equivalent in ERa positive and negative human ovarian cancer cells. Also, the selective GPR30 agonist and antagonist, G1 and G15, did not modulate the effects of 2ME. Therefore, the anticancer actions of 2ME are not dependent on or mediated through the estrogen receptors. (NIH RO1AT005295)
Citation Format: Purab Pal, Karen Hales, Dale Buchanan Hales. Dietary flaxseed supplementation in ovarian cancer: Elucidating the molecular actions of its biologically derived active compounds [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 B35.
Abstract B60: Pro-HGF and its activator confer a sustained transformation activity in ovulatory follicular fluid
Authors: Huang Hsuan Shun , Chu Tang-Yuan 
Published: September 2020

Abstract
The etiology of ovarian high-grade serous ovarian cancers (HGSC) originating from the epithelium of fallopian tube fimbriae is elusive. Based on the incessant ovulation hypothesis, our previous studies found that ROS released during ovulation, collaborated with hemoglobin from retrograde menstruation, caused oxidative damage and DNA breaks to the fimbrial epithelial cells. Repeated exposures of ovulatory follicular fluid could induce tumorigenesis of in Trp53-null mice and transform human fimbrial epithelial cells (FE25) immortalized by E6/E7. In addition to mutagenic ROS, we later identified IGF-axis proteins abundantly present in follicular fluid (FF) are largely responsible for the stemness activation and transformation of FE25 cells. However, FF-IGF signal does not confer other key phenotypes induced by FF, such as mitogenesis and cell migration. In this study, we further clarified the role of HGF, another growth factor abundantly present in FF. Treating FE25 cells with pure HGF and IGF2 could fully recapitulate the anchorage-independent growth (AIG) activity of FF with equal colony number of 55±12 and 60±6, respectively. Inhibitor of HGF cMET receptor, AMG337, greatly reduced the AIG activity to 8±5 colonies. HGF is known to be activated by a cascade of activation by cleavage of its precursor pro-HGF and the precursor (pro-HGFA) of its activating protein HGFA. We found FF contains a high level of these pro-form proteins and a low amount of the cleaved active forms. Interestingly, these pro-form HGF axis proteins are extremely stable in FF. After one-month incubation at 37 degrees Celsius, they could still be activated and exerted AIG of FE25 cells. Once encountering the cell surface, protease cleavage is initiated to activated pro-HGFA to HGFA, which then cleaves pro-HGF to HGF. Via the c-MET/AKT/ERK signaling, the activated HGF confers the mitogenic and transformation activity of FF. In FF, HGF seems to cooperate with IGF2 to sustain a long-term proliferation of fimbrial epithelial cells initiated by ROS-induced mutagenesis and clonally expanded by IGF axis signaling. A reservoir of durable pro-forms of HGFA and HGF are responsible for this sustained transformation activity. Thus, the mutagenic, clonogenic, and sustained mitogenic activities in FF strongly support the incessant ovulation theory with ovulatory carcinogens to be the culprit.
Citation Format: Hsuan Shun Huang, Tang-Yuan Chu. Pro-HGF and its activator confer a sustained transformation activity in ovulatory follicular fluid [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 B60.
Abstract B79: Effect of HIPEC on immune microenvironment in epithelial ovary cancer
Authors: Rizwan Arshi , Ray Mukurdipi 
Published: September 2020

Abstract
Introduction: Women with epithelial ovary cancer with impaired immunity develop life-threatening clinical disease, implying that these patients have some form of altered immune response against disease prognosis. Frequent findings of tumor-associated lymphocytes as well as differential immunologic markers from tumor specimen after surgery for EOC are explicit evidence of immunologic sensitivity to this. Despite several treatment modalities, the majority of these patients will eventually relapse. However, several i.p. therapies have been advocated to command the disease progress. In this context, hyperthermia is one of the effective i.p. therapies to boost the therapeutic efficacy, showing its impact by killing tumor cells as well as inducing an efficient anticancer immune response, therefore providing insight into hyperthermic intraperitoneal chemotherapy (HIPEC)-associated immunotherapy, a new therapeutic treatment for cancer.
Rationale: In a vast majority of the cases the disease is confined to the peritoneal cavity for a long time. Even in recurrent cases, disease remains confined to peritoneal cavity only. Intraperitoneal administration of chemotherapy results in high peritoneal to plasma ratios for pick concentration of chemotherapeutic drugs. Mechanisms of immune activation: Surface molecular expression—Heated tumor cells increase the surface expression of MHC class I, making the tumor cells more sensitive to lysis by CD8+T (T cytotoxic) cells. Expression of HSPs—Heated tumor cells release heat shock protein (HSPs), which activate natural killer (NK) cells and antigen-presenting cells (APCs), cross present the antigen to CD8+T cells. Exosome production—Heated tumor cells release exosomes, containing potential antigens, and antigen-presenting cells, cross present the antigen to CD8+ T cells. Direct effect on immune cells, NK cells, CD8+ T cells and dendritic cells (DC), tumor vasculature—Increases the permeability of tumor vasculature. Changed vasculature within the tumor may help immune cell mobilization.
Conclusion: HIPEC elicits antitumor immune responses by enabling tumor cells to stimulate the immune system through increased surface expression of MHC class I, release of HSPs, exosomes, directly activating intratumoral immune cells and improving immune-cell trafficking.
Note: This abstract was not presented at the conference.
Citation Format: Arshi Rizwan, Mukurdipi Ray. Effect of HIPEC on immune microenvironment in epithelial ovary 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 B79.