bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 912: uPA as a topoisomerase-1 protective agent in lung fibroblast cells
Authors: Ge Liang , Gnanamony Manu , Stepanova Victoria , Dinh Dzung H. , Gondi Christopher S. 
Published: August 2018

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the United States, with approximately 53,000 people in the U.S. diagnosed with the disease every year. The Gondi lab has previously shown that poor survival rates in pancreatic cancer are correlated with increased expression of urokinase plasminogen activator (uPA), a serine protease. Our previous data has shown for the first time that uPA binds to topoisomerase-1 (TOPO-1), in addition to the interaction of uPA with various transcription factors. Our current research is aimed at elucidating the mechanism of the interaction between uPA and TOPO-1, with the goal of demonstrating a protective role for uPA in the regulation of TOPO-1 function in the presence of TOPO-1 inhibitors. Methods: Two knock-out lung fibroblast cell lines were used. One cell line was a uPA knock-out line, while the other was a uPA knock-out line with a uPA expression vector transfected into the cells. Transfection was performed using Chariot transfection vector. The cell lines were treated with topoisomerase inhibitors TX1111 and SN38. DNA replication activity was measured using flow cytometry as a surrogate for TOPO-1 activity. Controls included untreated cells, cells treated with empty Chariot, and cells treated with Chariot containing TXC peptide. Results and Discussion: In the presence of topoisomerase inhibitors TX1111 and SN38, uPA knock-out lines demonstrated incomplete cell division relative to controls. In uPA-expressing lines, cell division activity was retained in the presence of topoisomerase inhibitors. Our data demonstrates for the first time that uPA serves a protective role in preventing the inhibition of TOPO-1 by topoisomerase inhibitors. This indicates uPA as a potential new drug target in the treatment of chemoresistant pancreatic cancer. Further studies to be performed include visualizing the degree of DNA-replication using DNA combing, and subsequently expanding this study to pancreatic cancer cells.
Citation Format: Liang Ge, Manu Gnanamony, Victoria Stepanova, Dzung H. Dinh, Christopher S. Gondi. uPA as a topoisomerase-1 protective agent in lung fibroblast 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 912.
Abstract 914: COX-2 expression is associated with chemoresistance through cancer stemness property in head and neck squamous cell carcinoma
Authors: Saito Shin , Ozawa Hiroyuki , Imanishi Yorihisa , Sekimizu Mariko , Watanabe Yoshihiro , Ito Fumihiro , Ikari Yuichi , Nakahara Nana , Kameyama Kaori , Ogawa Kaoru 
Published: August 2018

Abstract
Introduction: COX-2 is one of the two isoforms of cyclooxygenase, an enzyme that catalyzes the conversion of arachidonic acid to prostaglandins. COX-2 is considered to be associated with progression in various cancers, and its expression has been reported to have an impact on poor prognosis in head and neck squamous cell carcinomas (HNSCCs). Furthermore, COX-2 expression has been shown to be associated with resistance to anticancer drugs. However, the precise mechanism of COX-2 for chemoresistance in HNSCC is not fully elucidated. The aim of the present study was to investigate the impact of COX-2 on cancer stem cell property, and to reveal its effect on chemoresistance by in vitro and clinicopathological assays. Methods: We examined the chemoresistance to docetaxel with or without COX-2 inhibitor (celecoxib) in HNSCC cell lines (FaDu, Detroit512) by MTS assays. To evaluate the association of COX-2 expression with stemness property, we assessed alteration of expression levels of the genes related to cancer stem cell (CSC) property after exposure to celecoxib by quantitative real-time PCR. We also performed a sphere formation assay using ultra low attachment dishes and microscopic imaging. Moreover, we analyzed immunohistochemical expressions of COX-2 and clinicopathological factors by using matched samples of pre-treatment biopsy and surgical specimens from hypopharyngeal carcinoma patients who had undergone trans-oral tumor resection with preoperative induction chemotherapy including docetaxel. Results: Cell survival rate under exposure to docetaxel was decreased by addition of celecoxib. COX-2 inhibitor downregulated the expression of Oct3/4 and Nanog. Sphere formation was inhibited by co-culture with COX-2 inhibitor, especially in FaDu cells. Immunohistochemical study in biopsy specimens revealed a negative correlation between COX-2 expression in biopsy specimens and pathological effect of induction chemotherapy in surgical specimens. Conclusion: The present study suggests that COX-2 expression is associated with cancer stemness property, and inhibition of COX-2 has a possibility to enhance chemosensitivity in HNSCCs. Furthermore, initial COX-2 expression in biopsy specimens may predict the effect of chemotherapy in HNSCCs. These results indicate that COX-2 can be an attractive target for the treatment of HNSCC.
Citation Format: Shin Saito, Hiroyuki Ozawa, Yorihisa Imanishi, Mariko Sekimizu, Yoshihiro Watanabe, Fumihiro Ito, Yuichi Ikari, Nana Nakahara, Kaori Kameyama, Kaoru Ogawa. COX-2 expression is associated with chemoresistance through cancer stemness property in head and neck squamous cell carcinoma [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 914.
Abstract 921: High-throughput functional evaluation of variants of unknown significance in ERBB2
Authors: Nagano Masaaki , Kohsaka Shinji , Ueno Toshihide , Kojima Shinya , Ikegami Masachika , Takeda Ikuko , Mano Hiroyuki 
Published: August 2018

Abstract
Erb-b2 receptor tyrosine kinase 2 (ERBB2) gene amplification is present in a wide variety of human cancers. ERBB2-targeted therapies have been developed and improved the outcome in patients with ERBB2-positive cancers. Recently, the advent of next-generation sequencing technology has enabled to identify numerous ERBB2 somatic mutations across a variety of cancers, but many of the mutations are still variants of unknown significance (VUS) that await further investigation of clinical relevance. In addition, the sensitivities of those ERBB2 mutations to ERBB2-targeted drugs have not been evaluated systematically. Here we assessed comprehensively the transforming activities as well as drug sensitivities of ERBB2 mutations in a high-throughput manner using the mixed-all-nominated-in-one (MANO) method. We evaluated 55 non-synonymous ERBB2 mutations which are reported recurrently in COSMIC database, and discovered several novel activating mutations which probably drive tumorigenesis. Furthermore, ERBB2 mutations showed varying drug sensitivities to ERBB2-targeted inhibitors. Thus, the MANO method may be a novel approach for assessing VUS, and our findings in this study will be beneficial to deliver personalized medicine to cancer patients harboring ERBB2 mutations.
Citation Format: Masaaki Nagano, Shinji Kohsaka, Toshihide Ueno, Shinya Kojima, Masachika Ikegami, Ikuko Takeda, Hiroyuki Mano. High-throughput functional evaluation of variants of unknown significance in ERBB2 [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 921.
Abstract 927: TCPA: An open access resource for cancer functional proteomics data
Authors: Li Jun , Liang Han 
Published: August 2018

Abstract
In recent years, tremendous efforts have been made to systematically characterize the molecular profiles of tumor tissues from individuals with cancer, laying a critical foundation for elucidating the molecular basis of tumorigenesis and developing biomarker-based diagnostic, prognostic and therapeutic approaches. In particular, cancer genomic data at the DNA or RNA level are being accumulated at an unprecedented speed. However, comprehensive cancer proteomic data have been relatively limited. Using reverse phase protein arrays (RPPA), we have generated a large collection of cancer protein expression data (&gt;8,000 samples of 32 cancer types from The Cancer Genome Atlas and &gt;650 independent cell lines across 19 lineages). To facilitate access of the broader research community to these RPPA datasets, we have developed a user-friendly data portal, TCPA (The Cancer Proteome Atlas), which can be accessed at http://tcpaportal.org.

TCPA currently has two web applications, one is for patient cohort data and the other is for cell line data. Both of them provide three types of modules: (i) “Summary”: the summary module help users check the detailed information about all the datasets curated in our database and provide a user-friendly interface for downloading the data. (ii) “Analysis”: this module provides common used analyses such as correlation, differential, survival and drug sensitivity analysis; and (iii) “Visualization” module provides approaches to examine the global patterns in a specific dataset. share some major analytic and visualization modules.

In summary, TCPA represents a highly valuable resource dedicated to cancer functional proteomic data. Compared with other proteomic databases, the primary advantage of TCPA is the availability of quantitative protein expression data over many large cohorts of well-characterized TCGA patient tumors. Moreover, TCPA provides an unprecedented opportunity to validate the findings from TCGA RPPA data through independent sample cohorts and to help select model tumor cell lines for further functional investigation. These unique features of TCPA greatly increase the utility of TCGA proteomic data for both basic research and clinical applications.
Citation Format: Jun Li, Han Liang. TCPA: An open access resource for cancer functional proteomics data [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 927.
Abstract 931: Discovery of ABBV-744, a first-in-class highly BDII-selective BET bromodomain inhibitor
Authors: Sheppard George S. , Wang Le , Fidanze Steven D. , Hasvold Lisa A. , Liu Dachun , Pratt John K. , Park Chang H. , Bui Mai-Ha , Faivre Emily J. , Huang Xiaoli , Lin Xiaoyu , Wilcox Denise M. , Shen Yu , Albert Daniel H. , Magoc Terrance J. , Rajaraman Ganesh , Kati Warren M. , McDaniel Keith F. 
Published: August 2018

Abstract
The BET family of proteins consists of BRD2, BRD3, BRD4 and BRDT, with each of these proteins containing two distinct bromodomains (BDI and BDII). ABBV-075, like other first generation BET family bromodomain inhibitors currently under clinical development, binds to each of the 8 bromodomains with similar affinity and inhibits the proliferation of cancer cells that represent a wide range of tumor types. We hypothesized that selectively targeting specific subsets of the BET bromodomain might abolish this broad spectrum profile such that only the tumor types that are highly addicted to the subtype specific BET bromodomain-mediated transcription would remain sensitive to these selective agents. Both BDI and BDII are highly conserved across BET family members (&gt; 70% identity), suggesting that the generation of compounds that are selective for the BDI bromodomains or the BDII bromodomains might be achievable. Structure-based design targeting the Asp144/His 437 and Ile146/Val439 sequence differences (BRD4 BDI/BDII numbering) led to the identification of structural analogs of ABBV-075 demonstrating greater than 100X selectivity for BRD4 BDII over BRD4 BDI. Further elaboration led to compounds with improved BDII-selectivity and oral bioavailability and the identification of the clinical asset ABBV-744. Disclosures: All authors are employees or former employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.
Citation Format: George S. Sheppard, Le Wang, Steven D. Fidanze, Lisa A. Hasvold, Dachun Liu, John K. Pratt, Chang H. Park, Mai-Ha Bui, Emily J. Faivre, Xiaoli Huang, Xiaoyu Lin, Denise M. Wilcox, Yu Shen, Daniel H. Albert, Terrance J. Magoc, Ganesh Rajaraman, Warren M. Kati, Keith F. McDaniel. Discovery of ABBV-744, a first-in-class highly BDII-selective BET bromodomain inhibitor [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 931.
Abstract 938: Detection of actionable mutations in plasma cfDNA samples from patients with non-small cell lung carcinoma using a novel amplicon-based Firefly NGS assay
Authors: Wang Lin , Weng Li , Chen Xiao , Li Min , Guo Qiaomei , Yu Wenjun , Wittkop Tobias , Wang Hongyan , Fahem Malek , Lin Shengrong , Zhao Grace Q. , Lou Jiatao 
Published: August 2018

Abstract
Background: Detection of EGFR, KRAS and BRAF mutations can help guide cancer treatment for non-small cell lung cancer (NSCLC) patients. To identify an easy to use, accurate, multiplex molecular diagnostic assay, we evaluated the performance of a novel next-generation sequencing (NGS)-based cell-free DNA (cfDNA) assay, Firefly assay, which employs a concatemer-based noise suppression mechanism with an amplicon workflow.
Methods: Performance of amplicon based Firefly assay, with a panel covering EGFR, BRAF, and KRAS mutations designed for targeted therapy selection of NSCLC was first evaluated using a cfDNA reference standard and blank control samples. This panel was then used to analyze plasma cfDNA samples from 134 NSCLC cancer patients and 50 non-cancerous controls, and results were compared with tumor tissue ARMS and cfDNA ddPCR results.
Results: Firefly assay demonstrated superior sensitivity and specificity with median detection of 100% at allele frequency of 0.1% for 20ng of cfDNA and zero false positive in all blank control samples. In cfDNA from plasma collected before treatment, EGFR mutation detection by Firefly assay was 94% concordant with tumor tissue ARMS. Firefly assay demonstrated strong per-variant detection-rate concordance (98%) and allele frequency concordance (R2 = 0.95) when compared with cfDNA ddPCR result.
Conclusions: The amplicon based Firefly assay offers multiplex capacity, de novo variant detection, high sensitivity and specificity. Thus, Firefly assay is a kitable NGS solution for cfDNA analysis, which can help guide targeted therapy selection, drug resistance detection, and disease monitoring in NSCLC and other cancer patients.
Citation Format: Lin Wang, Li Weng, Xiao Chen, Min Li, Qiaomei Guo, Wenjun Yu, Tobias Wittkop, Hongyan Wang, Malek Fahem, Shengrong Lin, Grace Q. Zhao, Jiatao Lou. Detection of actionable mutations in plasma cfDNA samples from patients with non-small cell lung carcinoma using a novel amplicon-based Firefly NGS assay [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 938.
Abstract 950: New strategy to sensitize pancreatic and bladder cancer to gemcitabine
Authors: Bayle Simon , Vena Francesca , Monastyrskyi Andrii , Roush William , Duckett Derek 
Published: August 2018

Abstract
Pancreatic Ductal Adenocarcinoma (PDAC), the major histological subtype of pancreatic cancer displays few symptoms for early detection and the majority of PDAC patients are diagnosed with advanced or metastatic disease. PDAC patients with advanced disease lack durable responses to chemotherapy and have a dismal prognosis. Gemcitabine is the cornerstone of care for advanced and metastatic PDAC. While the underlying mechanisms leading to gemcitabine resistance are likely to be multifactorial, there is a strong association between activating gemcitabine metabolism pathways and clinical outcome. Accordingly, strategies that lead to upregulation of signaling pathways and enzymes involved in generating the active metabolite may lead to improved outcome in PDAC.
We have developed a potent, selective, small molecule inhibitor of casein kinase-1 delta (CK1δ) and demonstrated that inhibition of CK1δ activity specifically compromises the growth, survival and invasion of breast cancer cells that overexpress CK1δ. Notably, our lead compound, SR-3029 provokes pre-clinical tumor regression of triple negative breast cancer (TNBC), including lung metastatic TNBC and basal-like PDX breast cancer models. We observed that CK1δ is upregulated in other cancers including bladder cancer and demonstrated that SR-3029 acts in synergy with DNA damaging cytotoxic agents. Notably, the combination of gemcitabine with SR-3029 resulted in synergistic antiproliferative activity and impaired colony formation in both pancreatic and bladder cancer cells. Mechanistic studies demonstrate that silencing CK1δ or inhibition of CK1δ activity by SR-3029 induces a significant upregulation of deoxycytidine kinase (DCK; rate limiting enzyme for gemcitabine activation) both at the RNA and protein levels, which results in increased cellular DCK and its active gemcitabine metabolite. We evaluated the effect of SR-3029 alone and in combination with gemcitabine in an orthotopic pancreatic tumor mouse model and observed much improved tumor growth inhibition with combination treatment, concomitant with increased expression of DCK.
In conclusion, our study suggests that CK1δ plays signaling roles in DNA metabolism and the combination of CK1δ inhibition with gemcitabine holds promise as a future therapeutic option for metastatic pancreatic cancer as well as other cancers.
Citation Format: Simon Bayle, Francesca Vena, Andrii Monastyrskyi, William Roush, Derek Duckett. New strategy to sensitize pancreatic and bladder cancer to gemcitabine [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 950.
Abstract 963: Screening of neoantigen-specific T cells in head and neck cancer and establishment of T-cell receptor-engineered T cells with cytotoxic reactivity
Authors: Ren Lili , Matsuda Tatsuo , Deng Boya , Kiyotani Kazuma , Kato Taigo , Park Jae-Hyun , Seiwert Tanguy , Vokes Everett , Agrawal Nishant , Nakamura Yusuke 
Published: August 2018

Abstract
Neoantigen-reactive T cells are considered to be crucial mediators for anti-tumor activity in adoptive T cell transfer (ACT) immunotherapy although the efficacy of ACT using in vitro expanded tumor-infiltrating T lymphocytes (TILs) has been limited. Since characterization of T cell receptor (TCR) repertoires of TILs before and after in vitro expansion has not well investigated, we in present study performed whole exome sequencing (WES) and transcriptome analysis, and selected candidate neoantigen epitopes to induce cytotoxic T lymphocytes (CTLs) in 20 patients with head and neck cancer (10 frozen tissues and 10 freshly resected tumors). 36 potential neoantigen peptides including missense somatic mutations were examined for induction of neoantigen-reactive cytotoxic T cells in vitro using patients' derived dendritic cells. We have so far confirmed three neoantigen-reactive T cells and obtained the sequence information of a pair of TCR alpha and beta chains, which were identical to those identified in resident dominant TILs in the original tumors. We cloned the TCR genes into T lymphocytes and constructed the neoantigen-reactive T-cell receptor-engineered (TCR-engineered) T cells, which showed HLA-restricted neoantigen-reactive cytotoxic activity. In addition, we compared the TCR composition of TILs before/after in vitro expansion in 10 fresh head and neck cancers, and found that TCR clonotypes in original TILs and in vitro expanded TILs are drastically different except for those between expanded CD8 cells and resident TILs in three tumors, which had unusually high mutational burden due to mutations in the mismatch repair genes (MSH2, MSH6) or a DNA polymerase (POLE) gene. Our data also suggest that some expanded TILs are likely to be cancer-specific T cells and may be good cell sources for ACT immunotherapy and that the mutational load might be a good biomarker to screen effective TIL treatment. We demonstrate establishment of an effective and rapid protocol to generate neoantigen-specific T cells and to identify neoantigen-specific TCRs for individual patients, which makes TCR-engineered T cells applicable for the clinical use.
Citation Format: Lili Ren, Tatsuo Matsuda, Boya Deng, Kazuma Kiyotani, Taigo Kato, Jae-Hyun Park, Tanguy Seiwert, Everett Vokes, Nishant Agrawal, Yusuke Nakamura. Screening of neoantigen-specific T cells in head and neck cancer and establishment of T-cell receptor-engineered T cells with cytotoxic reactivity [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 963.