bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-039: PDX and PDX-derived cell line development from peritoneal metastasis of micropapillary serous carcinoma of the ovary
Authors: Thaye Elien De , Vermeulen An , Ceelen Wim , Bocxlaer Jan Van , Wever Olivier De 
Published: August 2018

Abstract
Peritoneal spread is an indicator of poor prognosis in patients with micropapillary serous carcinoma of the ovary. In general, these patients are treated by surgical cytoreduction followed by intraperitoneal chemotherapy. Although this strategy has encouraging efficacy, personalized treatment regimens may potentially further improve efficacy of cancer management. To investigate such a personalized approach, patient-derived xenografts (PDX) and PDX-derived cell lines from peritoneal implants from micropapillary serous carcinoma of the ovary are developed and characterized. Freshly resected peritoneal implants from consenting donors were obtained. A cell suspension was made and immediately subperitoneally implanted in female immunocompromised mice and expanded as peritoneal metastasis (PM)-PDX. A transplantable PM-PDX was established from 1/1 donor. Histology confirmed the micropapillary and cribriform growth pattern, which was further characterized by intraluminal tumor budding. PM-PDX dissociated cells were maintained as a plastic-adherent cell culture up to 20 passages. The PM-PDX derived cell line is characterized by an epithelial morphotype with doubling time of 42 hours and shows a colony formation efficiency of 25-40% independent of estrogen signaling. The cell line is sensitive to the microtubule stabilizing agent paclitaxel (IC50 = 1.485 nM) and the allosteric MEK inhibitor trametinib (IC50 = 1.299 nM). Future work will provide insights on the mutational status of RAS and RAF, important indicators of potential MEK-targeted personalized medicine.
Citation Format: Elien De Thaye, An Vermeulen, Wim Ceelen, Jan Van Bocxlaer, Olivier De Wever. PDX and PDX-derived cell line development from peritoneal metastasis of micropapillary serous carcinoma of the ovary [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-039.
Abstract LB-049: Cancer stem cell-produced lysophosphatidic acid reprograms surrounding tumor cells to a stem-like state
Authors: Rakhshandehroo Taha , Tan Jiali , Grosshart Brandon , Cheresh David 
Published: August 2018

Abstract
Within a tumor, cancer stem cells (CSCs) represent a small yet highly aggressive, metastatic population that enhances the progression of the surrounding non-CSCs. Here we define lysophosphatidic acid (LPA) as a primary factor produced by pancreatic CSCs that converts non-CSCs to a stem-like fate. LPA promotes increased anchorage independence, drug resistance, self-renewal and stem gene expression including Oct4 and Nanog. Cancer stem cells were found to express high levels of the LPA producing enzyme cPLA2 explaining their production of LPA. Pancreatic cancer cells exposed to the drug Gemcitabine showed a dramatic upregulation of the LPA receptor 4 enabling the cells to become drug resistant and tolerant to a range of microenvironmental stresses.
These finding indicate that LPA is a bioactive lipid produced by CSCs that converts surround pancreatic tumor cells to a highly aggressive state. Therapeutic intervention and/or microenvironmental stress will induce non-CSCs to express LPA Receptor 4, thereby making them stress tolerant and drug resistant. Evidence is provided that targeting the LPA receptor pathway may reverse this paracrine effect and thereby reverse cancer progression and drug resistance.
Citation Format: Taha Rakhshandehroo, Jiali Tan, Brandon Grosshart, David Cheresh. Cancer stem cell-produced lysophosphatidic acid reprograms surrounding tumor cells to a stem-like state [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-049.
Abstract LB-067: Identifying novel and druggable targets in a triple negative breast cancer cell line using the Invitrogen LentiArray Human Kinase CRISPR Library
Authors: Gokirmak Tufan , Sharp Jason , Revankar Chetana , Piper David R. 
Published: August 2018

Abstract
Breast cancer is the most commonly diagnosed cancer among women in worldwide and the second leading cause of death by cancer after lung cancer. Breast cancer can be broadly grouped into three main groups: HR+ (estrogen receptor positive and/or progesterone receptor positive), HER2+ (human epidermal growth factor receptor 2 positive) and triple-negative (HR- and HER2-). Hormone and anti-HER2 targeted therapies are available for receptor positive breast cancer types. However, because triple-negative breast cancer (TNBC) does not have estrogen, progesterone or HER2 receptors, there are no such targeted therapies available for this type of cancer. Currently, oncologists are resort to treating TNBC patients with traditional chemotherapy drugs, surgery and radiation. Thus, due to its poorer prognosis and fewer treatment options in comparison to other type of breast cancers, search for specific molecular targets and developing novel treatments for TNBC is one of the highest priorities of current breast cancer research. Protein kinases are involved in cell signaling cascades leading to cell proliferation, migration and survival in all cell types, and their dysregulation often leads to cancer. Due to their oncogenic roles, protein kinases have become a main focus of the targeted drug discovery efforts. Therefore development of novel high-throughput screening platforms that enable the identification of protein kinases or for that matter any gene, essential for tumor proliferation and viability is expected to advance oncogenic drug discovery efforts. In this study, we developed a loss-of-function screen for identifying essential kinases in a TNBC cell line, MDA-MB-231, using the Invitrogen™ LentiArray™ Human Kinase CRISPR Library. This arrayed lenti virus library targets 840 kinases with up to 4 different gRNAs per protein kinase for complete gene knockout. Our initial pilot screen identified polo-like kinase 1 (PLK1), checkpoint kinase 1 (CHK1) and cyclin-depended kinase 9 (CDK9) as essential kinases in MDA-MB-231 cell line and our current efforts focus on expanding this loss-of-function screen to the full kinase library and validation of the hits. Target identification and validation remains a significant challenge to translate to clinical trial outcomes and these generalized, functional genomic approaches may provide the next-generation platform to effectively bridge these gaps.
Citation Format: Tufan Gokirmak, Jason Sharp, Chetana Revankar, David R. Piper. Identifying novel and druggable targets in a triple negative breast cancer cell line using the Invitrogen LentiArray Human Kinase CRISPR Library [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-067.
Abstract LB-070: Design and modular development of I-PARTS: An integrated platform for anti-cancer radiation therapeutics screening
Authors: Papineni Rao V. , Costes Sylvain , Ray Shayoni , McLaughlin William , Lukaniec Brendan , Kruger Kurt , Kanugi Keith 
Published: August 2018

Abstract
Tumor irradiation during cancer treatment induces cell death by apoptosis, mitotic death, and clonogenic death. With expanded global access to cancer radiotherapy, there is a need to discover agents with anti-cancer and radiation sensitizing properties. in vitro high-throughput screening (HTS) systems routinely used to screen agents for cytotoxicity assays unfortunately do not directly measure clonogenic potential and fail to accurately predict the efficacy of an agent either in subsequent preclinical animal model testing or in clinical trials. Clonogenic assays unlike colorimetric and metabolic assays for determining cell viability and apoptosis, are less susceptible to artifacts. We are addressing these requirements through an integrated I-PARTS platform development and optimization. Here, the design and the prototype of a fully enclosed imaging/X-ray irradiation system will be presented. The proof of principle experimentation to obtain high content information on the cellular response to specific primary human cells (normal or tumors) to a variety of radiation doses and fraction modality will be described. The initial approaches taken towards the establishment of an integrated platform to screen anti-cancer drugs will be discussed.
Citation Format: Rao V. Papineni, Sylvain Costes, Shayoni Ray, William McLaughlin, Brendan Lukaniec, Kurt Kruger, Keith Kanugi. Design and modular development of I-PARTS: An integrated platform for anti-cancer radiation therapeutics screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-070.
Abstract LB-075: Structural stabilization of protein fragments by membrane anchoring for generation of cell-permeable protein mimetics
Authors: Tarasova Nadya , Stefanisko Karen , Khavrutskii Lyuba , Tarasov Sergey 
Published: August 2018

Abstract
Targeting protein-protein interactions can provide plentiful opportunities for the discovery of novel drug candidates and powerful chemical biology tools. However, the majority of these interactions are ‘undruggable”, and we still know very little about the structural mechanisms and functions for the vast majority of them. We have developed a rational approach that allows for the straightforward development of cell-permeable metabolically stable inhibitors of protein-protein interactions. The approach is based on structural stabilization of peptides by membrane anchoring. Biophysical data suggests that proximity to the membrane facilitates interactions of hydrophobic side chains of amphiphilic peptides with the bilayer and stabilizes natural fold of not only helical but also stretched and hairpin-type peptides. Membrane tethering is achieved through straightforward derivatization of peptides with fatty acids of appropriate length that depends on peptide's hydrophobicity. Lipidation facilitates cell entry and allows intracellular delivery of peptides up to 14-16 residues long. Negative charges can interfere with the entry, while positive charges generally have little effect. Wide applicability of this method was confirmed by generation of selective and highly potent dominant negative inhibitors of RAS oncogenes, β-catenin, STAT1, STAT3 and STAT5 N-domains, Il10R1, IFNGR1 and other non-druggable targets. Rational design of inhibitors can be accomplished even in the absence of the target tertiary structure by using conservation of certain sequence parts during the evolution. High throughput generation of selective chemical biology tools allows for effective interrogation of protein-protein interactions leading to discovery of mechanistic details of molecular signaling that could not be obtained with the help of genetic approaches.
Citation Format: Nadya Tarasova, Karen Stefanisko, Lyuba Khavrutskii, Sergey Tarasov. Structural stabilization of protein fragments by membrane anchoring for generation of cell-permeable protein mimetics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-075.
Abstract LB-082: ONC201 sensitizes resistant breast cancer cells to TRAIL through death receptor 5 upregulation
Authors: Ralff Marie D. , Wagner Jessica , El-Deiry Wafik S. 
Published: August 2018

Abstract
ONC201 is a potent inducer of cancer cell death through the tumor necrosis factor related apoptosis inducing ligand (TRAIL) pathway. ONC201 and its structural analogs comprise a novel class known as the imipridones. The compound is being tested clinically against a range of solid tumors and hematological malignancies. We found that both triple negative and non-triple negative breast cancer cells are sensitive to ONC201. This was initially surprising, as the majority of non-triple negative breast cancer cells are resistant to TRAIL. In TRAIL-sensitive cells, ONC201 induced cell death in a TRAIL-dependent manner. In TRAIL-resistant cells, the effects of ONC201 are not pro-apoptotic but are rather anti-proliferative. Here we further investigate the effects of ONC201 in TRAIL-resistant breast cancers from multiple molecular subtypes. ONC201 has been previously shown to induce transcriptional upregulation of TRAIL receptor death receptor 5 (DR5). A known mechanism of TRAIL resistance in breast cancer is low cell surface DR5 expression. We hypothesized that pre-treatment with ONC201 would upregulate DR5 and lead to TRAIL sensitization in resistant cells. Our results confirm our hypothesis and show that treatment with ONC201 transcriptionally upregulates DR5 and increases its expression at the cell surface. In addition, pre-treatment with ONC201 sensitizes TRAIL-resistant breast cancer cells to the pro-apoptotic effects of TRAIL. Caspase-8 and PARP are cleaved when cells are treated with the combination of ONC201 and TRAIL, but not when treated with either compound alone. Annexin-V PI staining and quantitation of subG1 DNA content via flow cytometry further confirmed these results. Knockdown of DR5 abrogated TRAIL sensitization by ONC201. Natural killer (NK) cells are known to use TRAIL to kill targets like tumor cells. We are exploring the hypothesis that pre-treatment of tumor cells with ONC201 would increase their killing by NK cells. We are currently investigating the importance of the TRAIL pathway and DR5 upregulation by imipridone compounds in this sensitization to NK cell induced apoptosis. In summary, these results describe a novel mechanism by which ONC201 sensitizes breast cancer cells to the effects of apoptosis inducing ligand TRAIL. They also provide preclinical rationale for the testing of the compound against breast cancers in the clinic.
Citation Format: Marie D. Ralff, Jessica Wagner, Wafik S. El-Deiry. ONC201 sensitizes resistant breast cancer cells to TRAIL through death receptor 5 upregulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-082.
Abstract LB-090: Activation of KITENIN/ErbB4-mediated signaling contributes to acquisition of cetuximab resistance in colorectal cancer cells
Authors: Park So-Yeon , Yang Yi , Zhou Rui , Bae Woo Kyun , Chung Ik Joo , Kim Kyung Keun , Kim Hangun 
Published: August 2018

Abstract
ErbB4/KITENIN signaling plays a role in epidermal growth factor receptor (EGFR)-independent EGF pathways mediating the invasiveness and tumorigenesis of colorectal cancer cells. However, whether alterations in ErbB4/KITENIN signaling play a role in the resistance to anti-EGFR therapy remains unclear. Here, we established cetuximab-resistant DLD1 and HT29 cells, and analyzed changes in ErbB4/KITENIN signaling. c-Jun, a final effector in ErbB4/KITENIN-mediated signaling, was upregulated, whereas KITENIN levels remained constant in both cetuximab-resistant cell lines. The phosphorylation of EGFR and ErbB4 was increased in cetuximab-resistant cells, suggesting that ErbB4/KITENIN signaling contributed to the acquisition of cetuximab resistance in the cells. Silencing of KITENIN and/or ErbB4 increased cetuximab sensitivity in cetuximab-resistant cells. This study is the first to report the activation of ErbB4/KITENIN-mediated signaling in cetuximab-resistant colorectal cancer cells and the potential clinical application of ErbB4/KITENIN-targeting therapy for overcoming anti-EGFR resistance.
Citation Format: So-Yeon Park, Yi Yang, Rui Zhou, Woo Kyun Bae, Ik Joo Chung, Kyung Keun Kim, Hangun Kim. Activation of KITENIN/ErbB4-mediated signaling contributes to acquisition of cetuximab resistance in colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-090.
Abstract LB-093: ERK mutations and amplification confer resistance to ERK-inhibitor therapy
Authors: Jaiswal Bijay S. , Durinck Steffen , Stawiski Eric W. , Yin Jianping , Wang Weiru , Lin Eva , Moffat John , Martin Scott E. , Modrusan Zora , Seshagiri Somasekar 
Published: August 2018

Abstract
MAPK pathway inhibitors targeting BRAF and MEK have shown clinical efficacy in patients with RAF and/or RAS mutated tumors. However, acquired resistance to these agents has been an impediment to improved long-term survival in the clinic. In such cases, targeting ERK downstream of BRAF/MEK has been proposed as a potential strategy for overcoming acquired resistance. Preclinical studies suggest that ERK inhibitors are effective at inhibiting BRAF/RAS mutated tumor growth and overcome BRAF or/and MEK inhibitor resistance. However, as with other MAPK pathway inhibitors, treatment with ERK inhibitors is likely to cause resistance in the clinic. In this study, we have used in vitro modeling, structural biology and genomic analysis to understand development of resistance to ERK inhibitors and the mechanisms leading to it. We have identified mutations in ERK1/2, amplification and overexpression of ERK2, and overexpression of EGFR/ERBB2 as mechanisms of acquired resistance. Structural analysis of ERK showed that specific compounds that induced on-target ERK mutations were impaired in their ability to bind mutant ERK. We show that in addition to MEK inhibitor, ERBB-receptor and PI3K/mTOR pathway inhibitors are effective in overcoming ERK-inhibitor resistance. These findings suggest that combination therapy with MEK or ERBB-receptor or PI3K/mTOR and ERK inhibitors may be an effective strategy for managing the emergence of resistance in the clinic.
Citation Format: Bijay S. Jaiswal, Steffen Durinck, Eric W. Stawiski, Jianping Yin, Weiru Wang, Eva Lin, John Moffat, Scott E. Martin, Zora Modrusan, Somasekar Seshagiri. ERK mutations and amplification confer resistance to ERK-inhibitor therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-093.
Abstract LB-097: Linking prostate cancer cell AR heterogeneity to distinct castration and Enzalutamide responses
Authors: Li Qiuhui , Chen Xin , Deng Qu , Chao Hsueh-Ping , Tracz Amanda , Kirk Jason , Zhao Ruizhe , Rycaj Kiera , Tang Dean G 
Published: August 2018

Abstract
Expression of androgen receptor (AR) in prostate cancer (PCa) is heterogeneous but the functional significance of AR heterogeneity in regulating PCa biology and response to androgen/AR-targeted therapies remains unclear. Screening of ~200 castration-resistant PCa (CRPC) cores identified 3 AR expression patterns: nuclear (nuc-AR), mixed nuclear/cytoplasmic (nuc/cyto-AR), and low/no expression (AR-/lo). Xenograft CRPC modeling demonstrated that, although the AR+ CRPC responded to Enzalutamide, the AR-/lo CRPC was completely refractory to Enzalutamide. Genome editing-derived isogenic AR+ and AR-KO (knockout) PCa cells showed contrasting tumor-regenerating capacities and responses to castration and Enzalutamide. Whole-genome RNA-Seq and biochemical analyses coupled with experimental combinatorial therapy identified novel signaling pathways and BCL-2 as a critical therapeutic target in both AR+ and AR-/lo CRPC. Our study links AR heterogeneity to distinct castration/Enzalutamide responses and suggests the urgency in developing therapeutics to target AR-/lo PCa cells/clones.
Citation Format: Qiuhui Li, Xin Chen, Qu Deng, Hsueh-Ping Chao, Amanda Tracz, Jason Kirk, Ruizhe Zhao, Kiera Rycaj, Dean G Tang. Linking prostate cancer cell AR heterogeneity to distinct castration and Enzalutamide responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-097.
Abstract LB-118: A conserved checkpoint molecule signature offers novel targets for tumor specific regulatory T cell manipulation
Authors: Freeman Zachary T. , Hovleson Daniel H. , Pearson Alexander T. , Zhai Jingyi , Ghasemzadeh Ali , Nirschl Thomas R. , Jiang Hui , Tomlins Scott A. , Drake Charles G. 
Published: August 2018

Abstract
Regulatory T (Treg) cells play an important role in modulating the tumor microenvironment, leading to the suppression of anti-tumor immune responses. Tumor Tregs could be targeted by taking advantage of the differential expression of immune checkpoints on these cells as compared to other T cell subsets. While the elevated expression of checkpoints such as CTLA-4 on Tregs compared to conventional T cells is well-characterized, less is known about the collective landscape of Treg specific checkpoint expression specific in the tumor microenvironment. We identified a network of Treg-associated checkpoint markers including those previously associated with Treg function (CTLA4, ICOS) as well as several additional checkpoints (BTLA, LAG3, TIGIT, TNFRSF9) by characterizing the expression of 28 checkpoint molecules across 7,608 bulk tumor samples (31 tumor types) from TCGA. We then utilized whole transcriptome RNA sequencing of purified peripheral and tumor Treg cell populations across 4 different tumor types (glioblastoma multiforme, prostatic adenocarcinoma, urothelial transitional cell carcinoma, renal clear cell carcinoma) to characterize the Treg specific expression of checkpoint molecules. Peripheral and tumor Tregs demonstrate differential checkpoint expression landscapes, with tumor Tregs uniquely discriminated by collective expression of TNFRSF9 (4-1BB), HAVCR-2 (TIM-3), and LAG-3. This discriminatory signature was conserved across the 4 profiled tumor types, was associated with changes in Treg biology, and was confirmed in published data from three additional cancer cohorts (breast, colorectal, and non-small-cell-lung cancers). Furthermore, normalized TNFRSF9 expression in TCGA was also associated with a worse survival outcome, suggesting that elevated Treg TNFRSF9 expression may be a poor prognostic factor across a wide range of tumors. Taken together, these data highlight the potential of targeting TNFRSF9 expressing Tregs in the tumor as a novel immunotherapeutic approach for several types of cancer.
Citation Format: Zachary T. Freeman, Daniel H. Hovleson, Alexander T. Pearson, Jingyi Zhai, Ali Ghasemzadeh, Thomas R. Nirschl, Hui Jiang, Scott A. Tomlins, Charles G. Drake. A conserved checkpoint molecule signature offers novel targets for tumor specific regulatory T cell manipulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-118.