bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract NTOC-078: ENGINEERING ADOPTIVE T CELL THERAPY FOR EFFICACY IN OVARIAN CANCER
Authors: Anderson Kristin G. , Bates Breanna M. , Chiu Edison Y. , Greenberg Philip D. 
Published: June 2017

Abstract
Over 20,000 women are diagnosed with ovarian cancer annually—more than half will die within 5 years and this rate has changed very little in the last 20 years, highlighting the need for innovative therapies. Reprogramming immune system cells to target and kill cancer cells represents a promising new treatment strategy. Immune T cells have the potential to control tumor growth without toxicity to healthy tissues when engineered to target proteins uniquely overexpressed in tumors. Recent technological advances have helped identify and validate Wilms' Tumor Antigen 1 (WT1) and mesothelin (MSLN) as valid antigen targets for ovarian cancer; these proteins contribute to malignant and invasive phenotypes and have limited expression in healthy cells. In preclinical studies using either patient-derived cell lines or the mouse ID8 ovarian tumor model, we show that T cells engineered to express either a WT1- or MSLN- specific high-affinity T cell receptor (TCR) can kill human and murine ovarian tumor cells in vitro. Moreover, in a disseminated in vivo murine model, adoptively transferred TCRengineered T cells preferentially accumulated within established ID8 tumors, delayed ovarian tumor growth, and prolonged mouse survival. However, our data also reveal that the tumor microenvironment (TME) limits the persistence and killing capacity of the engineered T cells. Cellular and molecular analyses of human tumor specimens show human therapy will face similar obstacles posed by the TME. Ongoing studies will be discussed that are exploring strategies to overcome elements common to the human and murine TME, including direct modulation of the environment and T cell engineering to promote T cell survival and function.
Citation Format: Kristin G. Anderson, Breanna M. Bates, Edison Y. Chiu, Philip D. Greenberg. ENGINEERING ADOPTIVE T CELL THERAPY FOR EFFICACY IN OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-078.
Abstract NTOC-096: INTRAPERITONEAL CHEMOTHERAPY AFTER PRIMARY OR INTERVAL DEBULKING SURGERY FOR ADVANCED EPITHELIAL OVARIAN CANCER
Authors: Lee Jessica , Curtin John P , Muggia Franco M , Pothuri Bhavana , Boyd Leslie R. , Chern Jing-Yi , Frey Melissa K , Blank Stephanie V 
Published: June 2017

Abstract
PURPOSE: To evaluate the outcomes of intraperitoneal (IP) chemotherapy compared with those of intravenous (IV) chemotherapy in patients with advanced ovarian cancer treated either with neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) or with primary debulking surgery (PDS).
METHODS: Patients diagnosed with FIGO stage III or IV epithelial ovarian, fallopian tube or primary peritoneal carcinoma treated at our institutions with PDS or NACT and IDS from 2006-2014 were identified. Covariates were compared using chi-square analyses, t-tests and Mann-Whitney tests. Survival rates were calculated using the Kaplan-Meier method and compared with log rank tests and Cox multivariate regression models.
RESULTS: Sixty one patients received NACT and underwent IDS with residual disease of ≤ 1 cm; 40 patients (65.6%) received IP chemotherapy and 21 patients (34.4%) were given IV chemotherapy after IDS. The median number of chemotherapy cycles was three (range 3-8), and 34 patients (85.0%) completed the prescribed dose of IP chemotherapy. The median progression free survival was 16.5 months in the IP group and 15.0 months in the IV group (p = 0.88). The estimated median overall survival was 64.0 months in the IP group and 42.0 months in the IV group (p = 0.12).
During the same study period, 148 patients underwent optimal PDS after which 93 patients (83.6%) received IP chemotherapy and 55 patients (37.2%) were given IV chemotherapy. Patients after IP chemotherapy had improved survival outcomes when compared to patients after IV chemotherapy. The median progression free survival was 29.0 months after IP chemotherapy and 16.0 months after IV chemotherapy (p &lt; 0.0001) and the median overall survival was 93.0 months after IP chemotherapy and 43.0 months after IV chemotherapy (p &lt; 0.0001).
CONCLUSIONS: Although IP chemotherapy after PDS showed improved survival, IP chemotherapy after NACT and IDS, while tolerable with high rates of completion, did not demonstrate a survival advantage over IV chemotherapy in our patients.
Citation Format: Jessica Lee MD, John P Curtin MD, Franco M Muggia MD, Bhavana Pothuri MD, Leslie R. Boyd MD, Jing-Yi Chern MD, Melissa K Frey MD, Stephanie V Blank MD. INTRAPERITONEAL CHEMOTHERAPY AFTER PRIMARY OR INTERVAL DEBULKING SURGERY FOR ADVANCED EPITHELIAL OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-096.
Abstract NTOC-111: TARGETING COMPONENTS OF THE STAT3 SIGNALING PATHWAY FOR OVARIAN CANCER THERAPY: IMPLICATIONS FROM 3D CULTURE SYSTEMS
Authors: Walker Sarah R. , Zhang Yixi , Liu Suhu , Giaccone Zachary T. , Frank David A. 
Published: June 2017

Abstract
High grade serous ovarian cancer remains deadly for countless women; therefore, better treatment options are necessary. To identify new targeted therapies for this disease, it is necessary to delineate critical signaling pathways that are driving the pathogenesis of ovarian cancer. Since ovarian cancer in patients grows as three dimensional clusters, particularly within the peritoneum, we examined signaling pathways that were activated with 3D culture in vitro. Comparing the growth of ovarian cancer cell lines in 2D and 3D, we found that the transcription factor STAT3 consistently becomes activated in 3D culture systems. Ovarian cancer cells that lack STAT3 activation when grown in 2D acquire STAT3 activation when grown in 3D. Additionally, ovarian cancer cell lines that have constitutively active STAT3 when grown in 2D display enhanced STAT3 activation when these cells are grown in 3D. STAT3 is often activated through autocrine or paracrine mechanisms via cytokine receptors interacting with the transmembrane signal transducing molecule GP130 and intracellular Jak kinases. Once activated, these kinases tyrosine phosphorylate STAT3, which then translocates to the nucleus, binds to cognate DNA binding sites, and regulates genes that are involved in migration, invasion, and survival. We have found that not only is STAT3 tyrosine phosphorylated in cells grown in 3D, but that STAT3 is functionally active such that STAT3 DNA binding and target gene expression is enhanced in ovarian cancer cells grown in 3D versus 2D. We next determined if STAT3 signaling was necessary for ovarian cancer cell growth in 3D. Using RNA interference directed to STAT3 or GP130, we found that both proteins are necessary for the 3D growth of ovarian cancer cells. In addition, we have found that cells grown in 3D are more resistant to cytotoxic drugs; therefore, we wanted to determine if inhibiting STAT3 would enhance the response to conventional chemotherapy. Using both chemical biology and computational approaches, we have identified small molecule inhibitors of STAT3 that target a number of distinct points in the STAT3 activation pathway. We have found that a subset of these compounds disrupt the morphology of ovarian cancer spheroids. Furthermore, combination of these inhibitors with paclitaxel leads to enhanced loss of viability of cells grown in 3D, raising the possibility of using STAT3 inhibitors alone or in combination with chemotherapeutic drugs for the treatment of ovarian cancer.
Citation Format: Sarah R. Walker, Yixi Zhang, Suhu Liu, Zachary T. Giaccone, and David A. Frank. TARGETING COMPONENTS OF THE STAT3 SIGNALING PATHWAY FOR OVARIAN CANCER THERAPY: IMPLICATIONS FROM 3D CULTURE SYSTEMS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-111.
Abstract NTOC-119: VCP INHIBITORS INDUCE ENDOPLASMIC RETICULUM (ER) STRESS AND SYNERGISTICALLY KILL OVARIAN CANCER CELLS IN COMBINATION WITH SALUBRINAL OR MIFEPRISTONE
Authors: Bastola Prabhakar , Schoenen Frank J. , Chien Jeremy 
Published: June 2017

Abstract
Valosin-containing protein (VCP) or p97, a member of AAA-ATPase protein family, has been linked to several cellular functions including endoplasmic reticulum associated degradation (ERAD), cell division, golgi-membrane reassembly and autophagy. Recent studies have indicated VCP as one of the vulnerabilities in ovarian cancer. Here, we show that treatment with CB-5083, an orally bioavailable compound derived from previously identified quinazoline scaffold-based VCP inhibitor ML240, contributes to cytotoxicity in high-grade serous or clear cell ovarian cancer cell lines. CB-5083 treatment results in increased unfolded protein response (UPR), accumulation of cell cycle proteins as a result of inhibition of proteosomal degradation, cell cycle arrest at G1, and subsequent cell death mediated by both intrinsic and extrinsic apoptotic pathways. These results support an emerging concept that ER stress pathway can be therapeutically targeted in ovarian cancer.
Since CB-5083 induces CHOP-dependent apoptosis, we tested the extent to which VCP inhibitors act synergistically with salubrinal, a compound that inhibits GADD34 and enhances eIF2α phosphorylation. Results from Sulforadamine B and clonogenic assays indicate that VCP inhibitors and salubrinal act synergistically across various concentrations of drug combination. Based on recent studies indicating that mifepristone, a steroidal antagonist to progesterone and glucocorticoid, induce ER stress and subsequent cell death, we also tested the potential drug synergies between VCP inhibitors and mifepristone. Our results indicate these drugs act synergistically across various concentrations in ovarian cancer cells. Analysis of TCGA RNA-sequencing datasets indicate VCP expression is down-regulated in cisplatin-resistant tumor samples compared to cisplatin-sensitive cancer. This data is consistent with the fact that tumors with lower expression of VCP shows significant association with poor progression-free survival and overall survivor. Finally, our results indicate that cells with lower expression of VCP are more sensitive to VCP inhibitors than those with higher expression. Considering that cisplatin-resistant tumor samples have lower expression of VCP, VCP inhibitors may be a good therapeutic candidate to treat cisplatin-resistant ovarian cancer. Collectively, our results provide evidence that VCP inhibitors can be used as a single agent and can be synergized with compounds that prolong or induce ER stress in ovarian cancer.
Citation Format: Prabhakar Bastola, Frank J. Schoenen, Jeremy Chien. VCP INHIBITORS INDUCE ENDOPLASMIC RETICULUM (ER) STRESS AND SYNERGISTICALLY KILL OVARIAN CANCER CELLS IN COMBINATION WITH SALUBRINAL OR MIFEPRISTONE [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-119.
Abstract TMEM-017: COLLAGEN TYPE XI ALPHA 1 (COL11A1) IS A NOVEL STROMAL MEDIATOR OF CHEMORESISTANCE
Authors: Rada Miran , Eldred Catherine , Sage Jessica , Orsulic Sandra , Cheon Dong-Joo 
Published: June 2017

Abstract
Despite an initial satisfactory response to platinum and taxane-based regimens, approximately 80% of ovarian cancer patients will succumb to chemoresistant recurrent disease. Thus, there is a dire need to understand the mechanism by which tumor cells develop resistance to subsequent therapies after first-line cisplatin treatment.
We previously identified that collagen type XI, alpha 1 (COL11A1) is a novel biomarker associated with poor survival, metastasis, and chemoresistance in ovarian cancer. COL11A1 is expressed in a subset of α-SMA-positive cancer-associated fibroblasts (CAFs) adjacent to tumor cells. COL11A1 expression in peritumoral CAFs increases during ovarian cancer progression, with the highest expression in recurrent tumors. However, the functional significance of stromal COL11A1 in ovarian cancer progression and chemoresistance is largely unknown.
To determine the role of stromal COL11A1 in chemoresistance, we generated COL11A1-overexpressing TRS3 ovarian fibroblasts, co-cultured them with A2780 and OVCAR3 ovarian cancer cells, and measured cancer cell sensitivity to cisplatin. Our data showed that ovarian cancer cells become resistant to cisplatin when cultured in direct contact with COL11A1-overexpressing fibroblasts as well as in fibroblast conditioned media. Furthermore, full-length COL11A1 protein, extracted from A204 cell line, increased cisplatin resistance in ovarian cancer cells, suggesting that COL11A1 is sufficient to induce chemoresistance. Interestingly, culture of cancer cells on full-length COL11A1 protein resulted in increased number of ALDHhigh cancer stem-like cells and activation of Akt, the principal mediator of pro-survival signaling. To further dissect the mechanism by which COL11A1 leads to cisplatin resistance in tumor cells, we performed RNA-seq analysis of tumor cells after COL11A1 overexpression. Our data showed that COL11A1 did not change the levels of genes involved in cisplatin transport and DNA repair pathway in cancer cells, which are well-established mechanisms to confer cisplatin resistance. Rather, COL11A1 increased the expression of pro-inflammatory genes, some of which are known to confer chemoresistance in ovarian cancer. Consistently, our Western data showed that COL11A1 activates NF-kB signaling in cancer cells, a central pathway regulating pro-inflammatory genes. Collectively, our data suggest that COL11A1 contributes to chemoresistance possibly due to an increased survival of ALDHhigh cancer stem-like cells through activation of pro-inflammatory signaling.
Citation Format: Miran Rada, Catherine Eldred, Jessica Sage, Sandra Orsulic and Dong-Joo Cheon. COLLAGEN TYPE XI ALPHA 1 (COL11A1) IS A NOVEL STROMAL MEDIATOR OF CHEMORESISTANCE [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr TMEM-017.
Abstract TMEM-018: IN VITRO MODELS OF HGSC BASED ON MURINE OVIDUCTAL EPITHELIAL ORGANOIDS
Authors: Zhai Yali , Fearon Eric R. , Cho Kathleen R. 
Published: June 2017

Abstract
Mouse models of high-grade serous carcinoma (HGSC) arising from oviductal epithelium provide excellent in vivo systems with which to define the cellular and molecular events associated with HGSC development and progression. However, tumors in mice typically develop over months rather than weeks, and tumor progression in vivo cannot be easily monitored. Murine organoid models that closely mimic the biology of fallopian tube epithelium would facilitate research exploring HGSC pathogenesis.
We have developed Ovgp1-iCreERT2 mice in which the Ovgp1 promoter controls expression of tamoxifen (TAM)-inducible Cre recombinase in the oviductal epithelium – the murine equivalent of human fallopian tube epithelium. We have established long-term, 3-dimensional oviductal epithelial organoid cultures from Ovgp1-iCreERT2;R26LSL-EYFP double transgenic mice, and show that the organoids contain both ciliated and secretory cells, and express oviductal epithelial markers including cytokeratin 8, ER, PAX8 and OVGP1. Organoids treated in vitro with 4-hydroxy-tamoxifen (4-OH-TAM) activate the EYFP reporter.
Oviductal epithelial organoids established from Ovgp1-iCreERT2;Brca1del/fl; Trp53mut/fl;Rb1fl/fl (BPR) mice and treated in vitro with 4-OH-TAM show selection for the recombined tumor suppressor gene alleles by passage 6, accompanied by morphological and behavioral changes associated with neoplastic transformation. Stable organoid cultures can also be established from the oviductal epithelium of BPR mice treated in vivo with Tamoxifen (TAM).
We show that long-lived 3-dimensional organoids can be generated from normal oviductal tissue; can undergo Cre-mediated recombination in vitro to inactivate tumor suppressor genes relevant to human HGSC pathogenesis; and can acquire properties associated with neoplastic transformation in a relatively short period of time (weeks). As we have already generated Ovgp1-iCreERT2 mice with various combinations of constitutional and Cre-inducible mutant tumor suppressor gene (Trp53, Rb1, Brca1, Pten, Nf1, Apc) and oncogene (PIK3CA, KRAS) alleles, the roles of specific genetic alterations in HGSC pathogenesis can be explored in a relatively rapid and controlled experimental system.
Citation Format: Yali Zhai, Eric R. Fearon, and Kathleen R. Cho. IN VITRO MODELS OF HGSC BASED ON MURINE OVIDUCTAL EPITHELIAL ORGANOIDS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr TMEM-018.
Abstract TMEM-029: AGING INCREASES SUSCEPTIBILITY TO OVARIAN CANCER METASTASIS IN A MURINE ALLOGRAFT MODEL
Authors: Loughran Elizabeth , Leonard Annemarie , Phan Ryan , Tarwater Laura , Hilliard Tyvette , Asem Marwa , Liu Yueying , Yang Jing , Klymenko Yuliya , Johnson Jeff , Shi Zonggao , Leevy Matthew , Ravosa Matthew , Stack M. Sharon 
Published: June 2017

Abstract
Ovarian cancer (OvCa) is the leading gynecological malignancy in women in the United States. OvCa metastasizes uniquely, spreading through the peritoneal cavity and generating widespread metastatic sites. The vast majority of OvCa cases occur in women over 40 and the median age at diagnosis is 63 (SEER). Despite age being a significant risk factor for the development of OvCa, there is a paucity of studies addressing the role of aging in OvCa metastasis. To our knowledge, there are no reports utilizing old mice to investigate the effects of age on metastasis in vivo. We designed a study using a C57BL/6 model of aging where young (Y) mice are 3-6 months of age and aged (A) mice are 20-23 months of age, corresponding to young (20-30 years) and aged (60-67 years) humans. Using the C57BL/6 syngeneic ID8 mouse ovarian surface epithelial cell line, we tested the effect of aging on metastatic success in vivo. An allograft study was carried out with Y and A mice that were intraperitoneally injected with 3.7x106 ID8 RFP-tagged cells. The mice were imaged once a week starting at 4.5 weeks post injection and were sacrificed for dissection at 8 weeks post injection. Live imaging suggested OvCa metastasis was more efficient in the aged animals than in the young animals. After dissection, the abdominal organs were imaged ex vivo and tumor burden was quantified. The aged mice displayed heavier tumor burden in the gonadal fat compared to the young. Interestingly, no difference in metastasis to the omentum was detected. To investigate why gonadal fat is more receptive to metastasis in the aged animals, periovarian adipose from 4 young and 4 aged healthy non-tumor bearing mice was isolated for RNAseq analysis. Several immune pathways involving B cells were found to be significantly upregulated in the RNA from aged animals. Studies will be conducted to elucidate the status of B cells in aging periovarian adipose, including immunohistochemistry for CD45 and other B cell markers upregulated in the RNAseq dataset.
Citation Format: Elizabeth Loughran, Annemarie Leonard, Ryan Phan, Laura Tarwater, Tyvette Hilliard, Marwa Asem, Yueying Liu, Jing Yang, Yuliya Klymenko, Jeff Johnson, Zonggao Shi, Matthew Leevy, Matthew Ravosa and M. Sharon Stack. AGING INCREASES SUSCEPTIBILITY TO OVARIAN CANCER METASTASIS IN A MURINE ALLOGRAFT MODEL [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr TMEM-029.
Abstract TMEM-033: DEVELOPING A MONKEY MODEL FOR SPONTANEOUS TYPE I OVARIAN CANCER
Authors: Felder Mildred , Kapur Arvinder , Simmons Heather , Abbott David , Patankar Manish S. 
Published: June 2017

Abstract
The goal of this research project is to investigate if Non-Human Primates (NHP) can serve as model for endometriosis-associated Type I ovarian cancer. Endometriosis is a spontaneously occurring condition in both women and rhesus macaques. Endometriosis is likely caused by aberrant retrograde menstruation of endometrial epithelium that implants and grows on the serosal surfaces of the ovaries, uterus, urinary bladder, intestines and abdominal peritoneum. Several studies have shown direct association between endometriosis and two histological subtypes of Type I ovarian cancer- clear cell ovarian carcinoma (CCOC) and low grade serous endometrioid ovarian cancer (EnOC). Genetically altered mouse models for Type I and II ovarian cancer and are contributing significantly to our understanding of the biology of this malignancy. Since rodents do not have menstrual cycles, there are no mouse models for spontaneous endometriosis and Type I ovarian tumors. On the other hand, between 10-30% of female rhesus macaques of reproductive age develop endometriosis. A survey of pathology reports at the Wisconsin National Primate Research Center (WNPRC) identified cases of ovarian and peritoneal neoplasia in monkeys that also had endometriosis. This is a typical feature of CCOC and EnOC in humans where tumors are found adjacent to atypical endometriotic lesions. We are conducting immunohistological analysis to study the molecular phenotype of endometriosis and the ovarian and peritoneal neoplasia in the rhesus macaque. We will discuss our findings on the expression of important molecular markers of ovarian cancer (CA125, EpCAM, mesothelin, ARID1A, and others) in the non-human primate reproductive organs as well as in endometriotic explants and in ovarian and peritoneal neoplasms from the female rhesus. The data we will present and our on-going efforts to sequence the genome and transcriptome of normal and aberrant reproductive tissue samples of female rhesus monkeys will be essential in determining if the rhesus can be used as a model for CCOC and EnOC.
Citation Format: Mildred Felder, Arvinder Kapur, Heather Simmons, David Abbott, and Manish S. Patankar. DEVELOPING A MONKEY MODEL FOR SPONTANEOUS TYPE I OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr TMEM-033.