bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA26: Role of mutations in epigenetic regulators in pathogenesis of myeloid malignancies
Authors: Levine Ross 
Published: August 2018

Abstract
Clinical, cytogenetic, and gene-based studies have been used to inform biology and improve prognostication for patients with acute myeloid leukemia (AML), myelodysplasia (MDS), and myeloroliferative neoplasms (MPN). Most recently, a series of candidate gene and whole-genome studies have identified recurrent somatic mutations in AML patients including TET2, ASXL1, DNMT3A, and cohesin complex mutations. Moreover, these mutations can be used to improve risk stratification in AML independent of established clinical parameters. Integrating mutational data with dose-intensity revealed that high-dose daunorubicin improved survival in patients with DNMT3A/NPM1 mutations or MLL translocations relative to treatment with standard-dose daunorubicin, but not in patients wild-type for these alterations. These data provide important clinical implications of genetic alterations in AML by delineating mutation combination genotypes that predict outcome in AML and improve AML risk stratification. Of biologic importance, the TET family of proteins have been shown to place a hydroxyl mark on methylated DNA and lead to DNA demethylation. We and others have found that TET2/IDH mutations lead to loss of DNA hydroxymethylation and a hypermethylation phenotype in leukemia patients. In addition, in vitro and in vivo studies show that TET2 loss or neomorphic IDH1/2 mutations lead to impaired hematopoietic differentiation, increased stem cell self-renewal, and myeloid transformation in vivo. We have also investigated the role of mutant DNMT3A in AML pathogenesis, and shown that these mutations cooperate with other disease alleles to induce leukemic transformation and to confer chemoresistance due to impaired DNA damage sensing. We will present novel data showing how these mutations coopt the epigenetic state of hematopoietic stem/progenitor cells in order to contribute to transformation and that these mutations have biologic and prognostic relevance.
Citation Format: Ross Levine. Role of mutations in epigenetic regulators in pathogenesis of myeloid malignancies [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr IA26.
Abstract A50: EP4 receptor antagonism in paclitaxel-resistant ovarian clear cell carcinomas
Authors: Fan Cong , Reader Jocelyn , Rao Gautam , Staats Paul , Ching Mc Millan , Fulton Amy , Roque Dana 
Published: August 2018

Abstract
Advanced ovarian clear cell carcinoma (OCCC) is associated with a survival disadvantage relative to ovarian serous carcinoma following platinum/taxane-based chemotherapy and optimal cytoreduction. Prostaglandin E2 (PGE2) contributes to disease progression through modulation of several G-protein coupled receptors (EP1-4). Selective EP4 antagonism is preferred over global COX inhibition due to concerns over cardiotoxicity and compensatory upregulation of COX isoenzymes. Class III β-tubulin is a marker for paclitaxel resistance and is widely overexpressed in OCCC. The purpose of this study is to demonstrate that EP4 inhibition may overcome paclitaxel resistance in OCCC that overexpress class III β-tubulin. Expression of EP4 receptor and class III β-tubulin was quantified using immunohistochemistry and Western blot in solid tissues and cell lines. OCCC overexpress class IIIβ-tubulin/EP4 relative to normal ovary. EP4 staining intensity was 2+ in 100% OCCC using an ovarian cancer tissue microarray (62 cores, 13% OCCC); this rate was only 26-56% among other histologies. Standard metabolic growth and migration assays were employed to test the effects of drug treatment and EP4 inhibition. EP4 inhibition reduces growth of paclitaxel resistant cells. Likewise, treatment with EP inhibitors and silencing of EP4 resulted in reduced migration. Selective antagonism of PGE2 through EP4 receptor inhibition may represent a powerful targeted therapy for paclitaxel-resistant OCCC. Further study including simultaneous treatment (EP4 inhibitor + paclitaxel) and larger samples sizes is required.
Citation Format: Cong Fan, Jocelyn Reader, Gautam Rao, Paul Staats, Mc Millan Ching, Amy Fulton, Dana Roque. EP4 receptor antagonism in paclitaxel-resistant ovarian clear cell carcinomas. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A50.
Abstract B07: Targeting DAB2IP in ovarian cancer stem cells
Authors: Zong Xingyue , Ozes Ali R. , Nephew Kenneth P. 
Published: August 2018

Abstract
Ovarian cancer is the leading cause of death from gynecologic malignancies. Failure to eliminate ovarian cancer stem cells (OCSCs) by the end of conventional chemotherapy contributes to tumor relapse and metastasis. Understanding the molecular features of OCSCs may allow for effective targeting and eradicating these cells and tumor remission. We reported tumor-initiation and expansion capacity by ALDH+ OCSCs after platinum-based treatment of ovarian cancer xenografts. In addition, loss of DAB2IP in prostate and colon cancer promoted CSC-like features, suggesting a critical role in modulating CSC maintenance. DAB2IP, a novel member of Ras GTPase-activating (GAP) protein family, was identified as a potent tumor suppressor that interfered with many aspects of cancer progression and was frequently downregulated in tumors. In the current study, we aimed to elucidate the tumor-suppressor role of DAB2IP in ovarian cancer in the context of OCSCs and explore epigenetic approaches to upregulate its expression. OCSCs and non-CSCs subpopulations were isolated from multiple high-grade serous ovarian cancer cell lines (Kuramochi, OVCAR3, and COV362). Reduced (p&lt;0.05) DAB2IP expression in OCSCs compared to non-CSC counterparts was observed, suggesting that DAB2IP suppresses OCSC maintenance. Overexpression of DAB2IP in OCSCs derived from Kuramochi decreased (p&lt;0.05) OCSC population, and DAB2IP overexpression inhibited stemness-related phenotypes, including reduced (P&lt;0.05) spheroid formation ability after 14-day incubation under stem cell conditions and decreased (P&lt;0.05) colony formation. Decreased expression of stem cell markers (Oct4, Nanog, and Twist) in DAB2IP-overexpressing cells was also observed, indicating potential key effectors downstream of DAB2IP. Furthermore, elevated DAB2IP expression in OCSCs decreased (p&lt;0.05) cisplatin IC50 and cell migration capacity in transwell assay, suggesting DAB2IP plays a role in OCSC function. Aberrant DNA promoter methylation and histone modifications were previously shown to be two major mechanisms of DAB2IP inactivation in cancer. We treated OCSCs with next-generation DNMT inhibitor guadecitabine and EZH2 inhibitor GSK-126, either alone or in combination. Single-agent guadecitabine or GSK-126 decreased ALDH expression with greater (p&lt;0.05) effect in combination. Single GSK-126 was sufficient to increase DAB2IP expression (p&lt;0.05) with additional increase when combined with guadecitabine, correlating with decreased ALDH expression. Collectively, our data suggested a possible combination epigenetic therapy to eliminate OCSCs, potentially through targeting DAB2IP, an important OCSC regulator.
Citation Format: Xingyue Zong, Ali R. Ozes, Kenneth P. Nephew. Targeting DAB2IP in ovarian cancer stem cells. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B07.
Abstract B26: Immune-active microenvironment in SCCOHT: Rationale for therapy with immune checkpoint blockade
Authors: Oudenhove Elke Van , Jelinic Petar , Ricca Jacob , Olvera Narciso , Merghoub Taha , Levine Douglas A. , Dmitriy Zamarin 
Published: August 2018

Abstract
Introduction: Small cell carcinoma of the ovaries, hypercalcemic type (SCCOHT) is a rare and very aggressive malignancy with limited treatment options. SCCOHT is described as an epigenetically altered SMARCA4-mutated monogenic disease, but the exact mechanism of SCCOHT tumorigenesis is not clear. Immune checkpoint-targeting antibodies have not been considered as a suitable treatment option for SCCOHT, because this cancer is characterized by a small number of mutations. Anecdotal reports of patients with SCCOHT responding to PD-1 blockade have challenged this view. We aimed to characterize the immune microenvironment of SCCOHT in order to evaluate a rationale for therapy with PD-1/PD-L1 targeting antibodies.
Methods: To test whether SCCOHT tumors were identified by the immune system, we examined PD-L1 expression and T cell populations within tumor samples. The immune landscape was profiled using quantitative immunofluorescence and gene expression profiling.
Results: Most tumors showed PD-L1 expression and prominent T cell infiltration, with PD-L1 being primarily limited to tumor-infiltrating immune cells. Gene expression analyses revealed upregulation of genes related to T-cell infiltration and cytolytic function in the PD-L1-high tumors. We hypothesize that PD-L1 upregulation in SCCOHT is an adaptive immune response to T-cell infiltration, as has been previously reported for several other cancer types.
Conclusions: Our findings provide an impetus for further investigation of PD-1/PD-L1 as a potential therapy for patients with SCCOHT. More generally, these results challenge the prevailing view that tumor immunogenicity is primarily driven by mutational burden, calling for identification of additional immune pathways involved in tumor recognition.
Citation Format: Elke Van Oudenhove, Petar Jelinic, Jacob Ricca, Narciso Olvera, Taha Merghoub, Douglas A. Levine, Zamarin Dmitriy. Immune-active microenvironment in SCCOHT: Rationale for therapy with immune checkpoint blockade. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B26.
Abstract B38: Synergistic effects of SHP2 and PI3K inhibitors in GAB2-overexpressing ovarian cancer
Authors: Cheung Hiu Wing 
Published: August 2018

Abstract
We previously found that the scaffold/adaptor growth factor receptor bound 2 (GRB2)-associated binding protein 2 (GAB2) is frequently amplified and overexpressed in primary high-grade serous ovarian cancers (HGSOCs) and cell lines. Ovarian cancer cell lines overexpressing GAB2 are dependent on GAB2 for activation of ERK1/2 and AKT signaling, consistent with its role in regulating the protein tyrosine phosphatase SHP2 (encoded by the PTPN11 gene) and the p85 regulatory subunit of phosphoinositide 3-kinase (PI3K). In this study, we investigated whether ovarian cancer cell lines overexpressing GAB2 are sensitive to combinatorial SHP2 and PI3K inhibition. Analysis of gene expression profiles reveals that primary HGSOCs overexpressing GAB2 are associated with increased ERBB, RAS, and MAPK activity signatures. Inhibition of SHP2 by an allosteric inhibitor SHP099 selectively inhibits ERK1/2 activity, proliferation, and survival of ovarian cancer cell lines with GAB2 amplification/overexpression. Treatment with SHP099 has a synergistic effect with multiple PI3K pathway inhibitors such as BKM120, a pan-class I PI3K inhibitor, at suppressing proliferation and survival of ovarian cancer cells overexpressing GAB2 in part through induction of apoptosis. Combinatorial SHP2 and PI3K inhibition more effectively activates both pro-apoptotic proteins BIM and BAD and inhibits expression of transcription factor c-MYC, a master regulator of cancer stem cells, compared with individual inhibitor, and sensitized cancer cells to chemotherapeutic drugs paclitaxel and cisplatin. Combinatorial SHP2 and PI3K inhibition also suppresses spheroid formation of ALDH-positive ovarian cancer stem cells. Together, our findings identify a previously unrecognized role of SHP2 in promoting proliferation and survival of ovarian cancer cells in which GAB2 is amplified and/or overexpressed, and suggest that combinatorial SHP2 and PI3K inhibition may be a promising therapeutic approach for HGSOCs with GAB2 amplification/overexpression.
Citation Format: Hiu Wing Cheung. Synergistic effects of SHP2 and PI3K inhibitors in GAB2-overexpressing ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B38.
Abstract B40: High-throughput screening of new potential targets for high-grade serous ovarian cancer treatment
Authors: Dai Jun , Erkan Erdogan Pekcan , Zhang Kaiyang , Kaipio Katja , Lamminen Tarja , Huhtinen Kaisa , Hynninen Johanna , Grenman Seija , Carpen Olli Mikael , Hautaniemi Sampsa , Vähärautio Anna 
Published: August 2018

Abstract
High-grade serous ovarian cancer (HGSOC) is the most common cause of gynecologic-cancer-associated death. Although HGSOC is initially extremely sensitive to platinum-based chemotherapy, relapse and progression to chemotherapy resistance are frequently seen, resulting in the low 5-year survival rate of this disease. Therefore, we aim to establish a feasible methodology that combines genome editing and single-cell RNA-seq to high-throughput screen new potential targets that could be utilized alone or combined with platinum for HGSOC treatment. Firstly, we constructed several inducible Cas9-expressed HGSOC cell lines, including both platinum-sensitive and -resistant cells. Secondly, we transduced these cell lines with a pooled sgRNA lentivirus consisting of 105 non-target scrambled sgRNAs and sgRNAs against 188 genes (10 sgRNAs per gene) that are currently targets of FDA/EMA approved drugs or drugs undergoing clinical trials in ovarian cancer treatment. Our analysis of multiple HGSOC dissociated tumors by single-cell RNA-seq has revealed intertumoral heterogeneity in expression of these drug targets in vivo. The majority of these 188 genes, approximately two thirds, are expressed in low level in most epithelial ovarian cancer (EOC) cells. Only 4 genes (AKT1, IL6, C1QA, INHBA) show relatively high expression, and only in a small subset of EOC cells. Also, the remaining drug target genes that are expressed show intertumoral heterogeneity, e.g., high expression of PARP-1 in tumors that are potentially deficient in homologous recombination repair. To elucidate the functionality of these drug targets, we will next analyze the transcriptomic effects of specific gene CRISPR/Cas9 knockouts in these HGSOC cell lines by droplet-based single-cell RNA-seq. From the data, we will compare the differences between platinum-sensitive and -resistant cell lines after the gene knockouts to identify the correlations between specific genetic perturbations and platinum resistance. As a future perspective, we will continue optimizing our platform for screening other potential targets. Overall, this study provides a comprehensive and unbiased approach for potential HGSOC target screening.
Note: This abstract was not presented at the conference.
Citation Format: Jun Dai, Erdogan Pekcan Erkan, Kaiyang Zhang, Katja Kaipio, Tarja Lamminen, Kaisa Huhtinen, Johanna Hynninen, Seija Grenman, Olli Mikael Carpen, Sampsa Hautaniemi, Anna Vähärautio. High-throughput screening of new potential targets for high-grade serous ovarian cancer treatment. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B40.
Abstract IA07: Targeting micrometastasis for the treatment of ovarian cancer
Authors: Ahmed Ahmed Ashour 
Published: August 2018

Abstract
Unlike many other solid tumors, high-grade serous ovarian cancer seldom spreads outside the abdominal cavity. The most common cause of death is malnutrition secondary to intestinal obstruction because of abdominal metastasis. Understanding the key mechanisms involved in driving abdominal metastases is important for the development of novel strategies to prevent metastasis. In this talk, I will present our recent work on preventing ovarian cancer metastasis by targeting Salt Inducible Kinase 2 (SIK2).
Citation Format: Ahmed Ashour Ahmed. Targeting micrometastasis for the treatment of ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA07.
Abstract IA14: Exploiting synthetic lethality in the treatment of gynecologic cancers
Authors: Lord Christopher J. 
Published: August 2018

Abstract
PARP inhibitors represent the first synthetic lethal treatment for cancer and are now approved for the treatment of serous ovarian cancers. Despite this advance, drug resistance to PARP inhibitors is a growing problem and in most patients has an unknown etiology. I will discuss efforts to understand PARP inhibitor resistance and to devise therapeutic approaches that limit the impact of revertant BRCA1/2 mutations. I will also discuss recent data describing synthetic lethal interactions between ARID1A defects in gynecologic cancers and novel DNA repair inhibitors, including ATR inhibitors currently undergoing clinical trial assessment.
Citation Format: Christopher J. Lord. Exploiting synthetic lethality in the treatment of gynecologic cancers. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA14.
Abstract IA16: PapGene, PapSEEK, and PapDREAming for early detection of ovarian cancer
Authors: Shih Ie-Ming 
Published: August 2018

Abstract
Advances in genomic technologies are revolutionizing how we understand pathogenesis in ovarian cancer. These technologies are critical in developing innovative strategies to diagnose cancer earlier by detecting rare mutant alleles or aberrant methylation marks among a pool of normal DNA. Studies integrating these technologies provide the fundamental scientific underpinning for designing future standards of care to reduce the burden of ovarian cancer through early detection and prevention. This presentation will focus on two related topics. One is to summarize the recent research findings from the Johns Hopkins Ovarian Cancer Early Detection (JHOCD) group in deciphering the major molecular alterations involving in ovarian cancer in situ lesions (serous tubal intraepithelial carcinoma, STIC) and its precursors (including serous tubal intraepithelial lesion, STIL and so-called “p53” signatures) in fallopian tubes. The clinicopathologic and molecular studies we have done have helped define the precursor lesions in many high-grade serous carcinomas (HGSC) of the ovary, the most common and aggressive type of ovarian epithelial cancer. The other focus is to discuss the promise and challenges in applying genetic and epigenetic methods to detect ovarian HGSC. In an effort to replicate the success of cervical cancer screening, several approaches for the early detection of ovarian cancers have been proposed. JHOCD team has first reported the feasibility of using cervical cytology samples to detect ovarian carcinomas. We have extended this original study by determining whether different sample collection methods including cervical cytology specimens, uterine lavage/brush, and blood, alone or in combination with each other or serum CA-125 levels, can achieve a better sensitivity and specificity. The objective of JHOCD is to facilitate the proposed clinical studies to assess the clinical benefit in applying the aforementioned molecular diagnostics for early ovarian cancer diagnosis in high-risk women (including those carrying BRCA mutations).
Citation Format: Ie-Ming Shih. PapGene, PapSEEK, and PapDREAming for early detection of ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA16.
Abstract IA27: Functional genetic architecture of serous ovarian cancer
Authors: Francis Kyle , Burston Helen , Mokady Daphna , Wagner Melany , Medrano Mauricio , Rottapel Robert 
Published: August 2018

Abstract
The degree of genetic aberrations characteristic of high-grade serous ovarian cancer (HGSC) makes identification of the molecular features that drive tumor progression difficult. Here, we perform genome-wide RNAi screens and whole-kinome proteomics to identify genes that are critical to their survival. We report that the tetraspanin CD151 contributes to survival of a subset of HGSC cell lines associated with a ZEB transcriptional program and supports the growth of HGSC tumors. Moreover, we show that high CD151 expression is prognostic of poor clinical outcome. We have identified essential kinases that manage biosynthetic stress indicative of the ovarian cancer transformed state. These data suggest that targeting pathways that underlie adaptation to cellular stress states rather than driver oncogenes may provide new therapeutic avenues for treating HGSC.
Citation Format: Kyle Francis, Helen Burston, Daphna Mokady, Melany Wagner, Mauricio Medrano, Robert Rottapel. Functional genetic architecture of serous ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA27.