bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5275: An integrated pipeline for TCGA data analysis
Authors: Yu Kaixian , Xu Yun , Tang Ke , Steppi Albert , Zhou Jun , Ouyang Zheng , Zhang Jinfeng 
Published: July 2016

Abstract
The accumulation of publicly available high-throughput experimental data has made analyzing the data a bottleneck in scientific discovery. In this study, we explore a computational, high-throughtput approach for identifying cancer related biological factors using the data available at the Cancer Genome Atlas (TCGA). We developed an integrative genomic analysis (IGA) tool, which performs multiple analysis tasks, including gene/protein level differential expression analysis, gene set level enrichment analysis and network/pathway level comparison. Several data types can be analyzed, including RNA-seq, DNA methylation, miRNA-seq, and proteomics. By varying cancer types, race groups, and data types, we are able to generate a large set of novel findings, which may serve as experimental targets for biologists and biochemists. Interactive reports are generated to facilitate further exploration of the biological significance of findings. With the high-throughput approach and intgrative tools, the bottlenect for us now shifts to publishing these results. We invite researchers in cancer research community to collaborate with us to publish the findings.
Citation Format: Kaixian Yu, Yun Xu, Ke Tang, Albert Steppi, Jun Zhou, Zheng Ouyang, Jinfeng Zhang. An integrated pipeline for TCGA data analysis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5275.
Abstract 53: Epigenetic silencing of krebs cycle metabolism in kidney cancer
Authors: Kho Eun-Young , Livi Carolina B. , Buckhaults Phillip , Carobbio Francesca , Nam Hye-Young , Kirkman Richard , Crossman David , Vayalil Praveen K. , Wei Shi , DeBerardinis Ralph J. , Sudarshan Sunil 
Published: July 2016

Abstract
Mounting evidence points to alterations in mitochondrial metabolism in renal cell carcinoma (RCC) including recent large-scale transcriptomic data demonstrating loss of tricarboxylic acid (TCA) cycle enzyme expression with aggressive tumors. Using a metabolomics/transcriptomics approach, we identified loss of mRNA expression of PGC-1α and ERR-γ is associated with tumor progression and worsened outcomes in RCC patients. PGC-1α both induces and cooperates with ERR-γ to promote TCA cycle enzyme expression. Additionally, PGC-1α reconstitution in RCC cells reverses the glycolytic phenotype and suppresses invasive phenotypes. Loss of PGC-1α and ERR-γ is through DNA and histone repressive silencing of the transcription factor PRDM16. Loss of PRDM16 is among the most prominent transcriptional changes in metastatic tumor sites. PRDM16 expression in RCC cells restorers TCA cycle enzyme expression, mitigates the Warburg phenotype, and suppresses in vivo tumorigenesis. Collectively, our data uncover a transcription factor network epigenetically silenced in renal cancer resulting in suppression of mitochondrial metabolism.
Citation Format: Eun-Young Kho, Carolina B. Livi, Phillip Buckhaults, Francesca Carobbio, Hye-Young Nam, Richard Kirkman, David Crossman, Praveen K. Vayalil, Shi Wei, Ralph J. DeBerardinis, Sunil Sudarshan. Epigenetic silencing of krebs cycle metabolism in kidney cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 53.
Abstract 549: Immune profiling uncovers neo-antigens and TCR repertoire responding to WX-mPD-1 and WX-mPD-L1 immune checkpoint inhibitors in syngeneic mouse xenograft models
Authors: Dong Hua , Lu Yan , Zhang Qiyao , Zhang Lingling , Chen Xiaoyue , Yang Guizhu , Yang Shuqun , He Miao , Tang Xuzhen , Qin Yuxin , Zheng Yong , Cai Jiexing , Cang Yong , Yan Shaoyu , Li Jing , Ji Qunsheng 
Published: July 2016

Abstract
Introduction: PD-1 and PD-L1antibodies have shown impressive clinical benefits to cancer patients. However, still a significant number of patients fail to respond to those checkpoint inhibitors. To understand the underlying mechanism, we performed genomic and immune profiling of both tumor tissues and cytotoxic T cells isolated from syngeneic mouse xenograft models treated with in-house WuXi anti-mouse PD-1(WX-mPD-1) and anti-mouse PD-L1 (WX-mPD-L1) antibodies.
Material and methods: Syngeneic mouse xenograft models from melanoma cell lines, CloudmanS91 and B16-F10, were used to evaluate the anticancer efficacy of WX-mPD-1 and WX-mPD-L1 antibodies. Cancer cells and xenograft tumors before and after treatment were collected for RNASeq profiling, from which mRNA expression and DNA mutations were called and neo-antigens were predicted. FACS analysis and TCR sequencing were also performed to examine the tumor infiltrating lymphocytes (TILs) population and TCR repertoire diversity, respectively.
Results: Among forty-eight established syngeneic models, nine had been tested with WX-mPD-1 and WX-mPD-L1 antibodies as single agent or in combination. More importantly, we have investigated the expression, mutation loads, neo-antigens for responsive model from CloudmanS91 and partially responsive model from B16-F10. CloudmanS91 model had 8 fold increases in mutation loads compared with B16-F10 model. Neo-antigens identified in CloudmanS91 cells were further knocked out to dissect their roles in activating immune response to WX-mPD-1 and WX-mPD-L1 antibodies in vivo.
Conclusions: WX-mPD-1 and WX-mPD-L1 antibodies as well as syngeneic tumor models are useful tools for pre-clinical combination and MoA studies for cancer immunotherapy. Analysis of Neo-antigen and TCR repertoire helps us better understand immune response to these antibodies in preclinical settings, and suggest novel approaches to enhance the current immunotherapeutic interventions.
Citation Format: Hua Dong, Yan Lu, Qiyao Zhang, Lingling Zhang, Xiaoyue Chen, Guizhu Yang, Shuqun Yang, Miao He, Xuzhen Tang, Yuxin Qin, Yong Zheng, Jiexing Cai, Yong Cang, Shaoyu Yan, Jing Li, Qunsheng Ji. Immune profiling uncovers neo-antigens and TCR repertoire responding to WX-mPD-1 and WX-mPD-L1 immune checkpoint inhibitors in syngeneic mouse xenograft models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 549.
Abstract 55: Glucose supports EGFR-mutated lung adenocarcinoma survival by sustaining EGFR stability
Authors: Rho Jin Kyung , Choi Yun Jung , Choi Chang-Min , Lee Jae Cheol 
Published: July 2016

Abstract
Tumor cells are genetically unstable, driven by genetic mutations that stimulate cancer cell proliferation and survival. These genetic mutations are generally linked to particular types of cancer. Oncogenic epidermal growth factor receptor (EGFR) is frequently mutated in non-small cell lung cancer (NSCLC), which is essential for NSCLC development and growth. However, the precise roles of EGFR in lung cancer metabolism are still unclear. Here we show that glucose (Glc) metabolism is critical for EGFR stability required for tumor growth and survival. EGFR mutation leads to a robust increase in Glc uptake, lactate production and glycolytic flux. Moreover, EGFR-mutated NSCLC cell lines are much more sensitive than EGFR WT to inhibition of Glc metabolism through EGFR degradation, suggesting that EGFR mutant NSCLCs rely more heavily than EFGR WT on aerobic glycolysis. Knockdown of EGFR in EGFR-mutated NSCLCs results in a decrease in expression level of genes that encode glycolysis enzymes, indicating that EGFR mutation leads to an increase in Glc metabolism and Glc dependence for growth and survival. Furthermore, inhibition of Glc metabolism shows a significant decrease in intracellular ATP, oxygen consumption and level of TCA cycle intermediates. Indeed, the addition of pyruvate dramatically rescues apoptotic cell death caused by EGFR degradation upon inhibition of Glc metabolism, suggesting that Glc to fuel the TCA cycle is essential for tumor survival. In addition, the inhibition of Glc metabolism overcomes T790M-mediated resistance to EGFR-TKIs. Together, our data suggest that the EGFR mutation mediates the reprogramming of Glc metabolism and this metabolic alteration represents an attractive target for new therapy of EGFR-mutated NSCLC.
Citation Format: Jin Kyung Rho, Yun Jung Choi, Chang-Min Choi, Jae Cheol Lee. Glucose supports EGFR-mutated lung adenocarcinoma survival by sustaining EGFR stability. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 55.
Abstract 559: Small molecule T-reg inhibitors for cancer immunotherapy
Authors: Kumar Suresh , Wu Jian , Wang Liquing , Wang Feng , Kodrasov Matthew P. , Agarwal Saket , Sokirniy Ivan , Yeckley Thomas , Weinstock Joseph , Mattern Michael R. , Hancock Wayne W. 
Published: July 2016

Abstract
Immune evasion is a hallmark feature of tumors as they employ various strategies to suppress the immune system's ability to recognize and destroy cancer cells. T cell checkpoint inhibitors such as anti-PD1 and anti-CTLA-4 antibodies spearhead the immune response against a variety of tumors. Numerous studies suggest that the complex immunosuppressive milieux require the development of additional therapeutic agents to potentiate active drugs and thereby broaden the utility and increase the therapeutic indices of revolutionary immune-oncology treatment modalities. The presence of immunosuppressive regulatory T cells (Tregs) in tumors, keeping tumoricidal Teffector cells in check, signals poor prognosis. Thus, depletion of Tregs or impairment of Treg function is an attractive therapeutic approach for cancer. USP7, a deubiquitylase enzyme implicated as a critical node in several cancer signaling pathways, has recently emerged as an essential factor in maintaining Treg functions. Progenra identified small molecule USP7 inhibitors and employed them to show that Treg specific inhibition of USP7 results in impairment of Treg function leading to immune activation, commensurate with the ablation of Foxp3, a transcription factor that is a target of USP7 and is essential to Treg activation. This USP7 inhibitor class was subsequently lead optimized, and selected USP7 inhibitors were evaluated in ADME/PK studies and shown to impair Treg functions and to exhibit powerful anti-tumor activity against syngeneic lung tumor models in immunocompetent mice. In addition, Progenra's USP7 inhibitors significantly augmented the antitumor activity of anti-PD1 antibody, CAR T cell therapy, and cancer vaccines. These studies provide a strong rationale for the use of USP7 inhibitors in combination therapy protocols to improve the efficacy of currently approved cancer immunotherapy agents.
Citation Format: Suresh Kumar, Jian Wu, Liquing Wang, Feng Wang, Matthew P. Kodrasov, Saket Agarwal, Ivan Sokirniy, Thomas Yeckley, Joseph Weinstock, Michael R. Mattern, Wayne W. Hancock. Small molecule T-reg inhibitors for cancer immunotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 559.
Abstract 570: Long-term efficacy and downstream mechanism of anti-Annexin A2 monoclonal antibody in a pre-clinical model of aggressive human breast cancer
Authors: Sharma Mahesh C. , Tuszynski George P. , Blackman Marc R. , Sharma Meena 
Published: July 2016

Abstract
Abstract:
There are considerable direct evidences to support that calcium binding protein ANX A2 is a potential target for aggressive breast cancer. The most compelling evidence is based on the fact that ANX A2 overexpress specifically in aggressive triple negative human breast cancer (TNBC) cell lines as well as in human breast cancer tissues. Previously, we and others have demonstrated a unique role of ANX A2 in cancer invasion including breast cancer. Moreover we demonstrated that anti-ANX A2 monoclonal antibody (anti-ANX A2mAb)-mediated immunoneutralization of ANX A2 inhibited invasive human breast growth in a xenograft model. We further evaluated long-term effect of multiple treatments of anti-ANX A2mAb and its mechanism of inhibition of human breast tumor growth. We now show that three treatments of anti-ANX A2mAb showed significant inhibition of breast tumor growth in immunodeficient mice and anti-tumor response was started from day 94. After treatments, we followed tumor growth for 172 days and our results demonstrated 67% inhibition of tumor growth without detectable adverse effects. Biochemical analysis demonstrated anti-ANX A2mAb treatment caused significant inhibition of tissue plasminogen activator (tPA) synthesis in the tumor microenvironment. This led to disruption of plasmin generation that consequently inhibited activation of MMP-9 and MMP-2. These results suggest that ANX A2 plays an important role in aggressive breast tumor growth by regulating proteolytic pathway in the tumor microenvironment. ANX A2 may represent a new target for the development of therapeutics for the treatment of aggressive breast cancer.
Citation Format: Mahesh C. Sharma, George P. Tuszynski, Marc R. Blackman, Meena Sharma. Long-term efficacy and downstream mechanism of anti-Annexin A2 monoclonal antibody in a pre-clinical model of aggressive human breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 570.
Abstract 593: Highly cytotoxic EGFR/CD16A TandAbs specifically recruit NK cells to potently kill various types of solid tumors
Authors: Ellwanger Kristina , Reusch Uwe , Fucek Ivica , Weichel Michael , Rajkovic Erich , Treder Martin 
Published: July 2016

Abstract
Constitutive EGFR activation through amplification or dysregulation plays an important role in the pathophysiology of numerous solid cancers, such as colorectal cancer (CRC), non-small cell lung cancer (NSCLC) or squamous cell carcinomas of the head and neck (SCCHN), thus providing a strong rationale for the development of therapeutic strategies targeting EGFR. Different therapeutic approaches have been approved for treatment of such cancers, including tyrosine kinase inhibitors that interfere with signal transduction by blocking the kinase domain or monoclonal antibodies (mAbs) that prevent EGFR ligand binding, dimerization and activation. However, despite demonstrated clinical efficacy, intrinsic or acquired resistance to such treatments has been described for a larger number of patients.
Natural killer cells (NK-cells) play a central role in the innate immune system and have the capacity to destroy virally-infected or neoplastic cells. To specifically utilize the cytotoxic potential of NK-cells for the elimination of EGFR+ cancer cells, we developed tetravalent bispecific EGFR/CD16A NK-cell TandAbs, with two binding sites for EGFR being expressed on tumor cells, and two binding sites for CD16A expressed on NK-cells.
Using antibody phage display technologies, we identified high affinity scFvs recognizing conformational epitopes in the extracellular domain of EGFR that were different to those targeted by other therapeutic antibodies. We engineered a set of bispecific EGFR/CD16A TandAbs and analysed their binding, thermostability and cytotoxic properties in a panel of in vitro assays. TandAbs containing our EGFR-specific domain 21 were highly potent in cytotoxicity assays towards endogenously EGFR-expressing tumor cell lines or transfected CHO cells with single digit picomolar or subpicomolar EC50 values. In contrast to comparator NK-cell recruiting TandAbs containing the Fv sequences from cetuximab, the TandAbs containing our EGFR-binding domain 21 did not exhibit any signs of temperature-induced instability or aggregation in thermostability studies.
Taken together, our data suggest that EGFR/CD16A TandAbs are novel, highly potent drug candidates suitable for the treatment of EGFR-overexpressing malignancies and overcoming resistance to other therapeutic agents.
Citation Format: Kristina Ellwanger, Uwe Reusch, Ivica Fucek, Michael Weichel, Erich Rajkovic, Martin Treder. Highly cytotoxic EGFR/CD16A TandAbs specifically recruit NK cells to potently kill various types of solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 593.
Abstract 594: Antibodies targeting LAG-3, TIM-3, KIR cloned from healthy human donors
Authors: Estelles Angeles , Stephenson Robert , Liu Keyi , Lomongsod Evelene , Ngyen Da , Zhzng Jianzhong , Yang Yifan , Heideker Manfred , Kauvar Lawrence , Ryser Stefan , Gishizky Mikhail L. 
Published: July 2016

Abstract
The immunosurveillance/immunoediting theory postulates that tumor growth is repressed in healthy individuals through the activation of adaptive and innate immune mechanisms. The clinical success of antibodies that target inhibitory checkpoint pathways of the immune system (i.e. CTLA-4, PD-1) has provided compelling evidence in support of this theory and raises the question of whether antibodies targeting these, or other inhibitory immune cell modulators (ICM), are present in apparently healthy individuals. The present studies were designed to answer this question by probing the circulating memory B-cell compartment that represents a historic record of an individual's lifelong adaptive immune response.
Methods: Blood from donors, with no known cancer history, was screened for the presence of anti-ICM binding memory B-cells targeting LAG-3, TIM-3, B7-H3, KIR, and VISTA, using Trellis's established CellSpotTM technology that can detect the presence of antigen specific memory B-cells at a frequency of 0.1 per 100,000 memory B-cells.
Results: Circulating memory B-cells targeting ICM's were present in all apparently healthy individuals tested (20 total). There was substantial variation as to which ICM's were recognized within each individual across this sample population. Antibodies cloned from these rare B-cells were of IgG class and exhibited low to sub-nM affinity toward the specific ICM. These high affinity antibodies bound their respective antigens on activated T-cells and were able to augment immune stimulatory cytokine release in cellular assays. Data from ongoing studies will be presented.
Conclusion: These studies demonstrate that apparently healthy individuals produce high affinity, pharmacologically active anti-ICM antibodies. Thus, healthy individuals represent a previously unrecognized source of antibodies that have undergone natural selection and hold particular promise as potential therapeutic agents for the treatment of cancer.
Citation Format: Angeles Estelles, Robert Stephenson, Keyi Liu, Evelene Lomongsod, Da Ngyen, Jianzhong Zhzng, Yifan Yang, Manfred Heideker, Lawrence Kauvar, Stefan Ryser, Mikhail L. Gishizky. Antibodies targeting LAG-3, TIM-3, KIR cloned from healthy human donors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 594.
Abstract 596: Optimization of lead antibody selection for XMT-1522, a novel, highly potent HER2-targeted antibody-drug conjugate (ADC)
Authors: Bodyak Natasha , Yurkovetskiy Alex , Gumerov Dmitry R. , Xiao Dongmei , Thomas Joshua D. Thomas D. , Poling Laura L. , Qin LiuLiang , Yin Mao , DeVit Michael J. , Park Peter U. , Lee Winnie , Prinz Bianka , Bergstrom Donald A. , Lowinger Timothy B. 
Published: July 2016

Abstract
XMT-1522 is an anti-HER2 ADC that incorporates HT-19, a novel, human anti-HER2 antibody optimized for cytotoxic payload delivery. Several parameters such as cell binding, internalization rate, cytotoxicity, antibody-dependent cell-mediated cytotoxicity (ADCC) downstream signaling, affinity maturation, NHP cross-reactivity, normal human tissue cross-reactivity and in vivo efficacy were used to screen a wide range of antibodies to select a lead candidate optimized for use in ADC applications. In addition HT-19 was selected to be non-competitive for HER2 binding with existing therapies - trastuzumab or pertuzumab, to allow for potential combinability. In vivo efficacy as an ADC did not directly correlate with typical parameters used in antibody screening cascade such as in vitro cytotoxicity, internalization or binding affinity. The lead antibody underwent affinity maturation, and despite increases in affinity, affinity maturation significantly decreased the in vivo efficacy of the ADC in vivo xenograft models. This phenomenon was observed in all the antibody hits. HT-19 showed antibody-dependent cell-mediated cytotoxicity (ADCC) activity. When administered as a single agent in NCI-N87 gastric cancer xenograft model it had biological activity at 20 mg/kg as well as at 3 mg/kg. Consistent with the hypothesis that a non-competitive ADC is combinable with current anti-HER2 regimens, the combination of XMT-1522 with trastuzumab and/or pertuzumab showed more rapid internalization, more complete HER2 degradation, and significantly great anti-tumor activity in the NCI-N87 gastric cancer xenograft model relative to XMT-1522 alone or the combination of pertuzumab + trastuzumab.
Citation Format: Natasha Bodyak, Alex Yurkovetskiy, Dmitry R. Gumerov, Dongmei Xiao, Joshua D. Thomas D. Thomas, Laura L. Poling, LiuLiang Qin, Mao Yin, Michael J. DeVit, Peter U. Park, Winnie Lee, Bianka Prinz, Donald A. Bergstrom, Timothy B. Lowinger. Optimization of lead antibody selection for XMT-1522, a novel, highly potent HER2-targeted antibody-drug conjugate (ADC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 596.