bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1531: The Polycomb repressor complex 1 promotes recruitment of myeloid-derived suppressor cells and immune evasion during bone colonization in castration-resistant prostate cancer
Authors: Su Wenjing , Zhang Boyu , Han Hyunho , Chakraborty Goutam , Zhou Bing , Su Jie , Yang Guangli , Ouerfelli Ouathek , Rosen Neal , Scher Howard I. , Giancotti Filippo G. 
Published: August 2019

Abstract
The mechanisms that enable immune evasion at metastatic sites are poorly understood. We show that the Polycomb Repressor Complex-1 (PRC1) drives colonization of the bones and visceral organs in Double Negative (AR- NE-) Prostate Cancer (DNPC). In vivo genetic screening identifies the cytokine CCL2 as the top pro-metastatic gene induced by PRC1. Mechanistic studies show that CCL2 not only controls self-renewal and metastatic initiation but also governs the recruitment of M2-like TAMs and Tregs, thus creating a profoundly immune suppressive and proangiogenic microenvironment. Inhibition of PRC1 reverses these processes and cooperates with checkpoint immunotherapy to suppress multi-organ site metastasis. These results reveal a link between epigenetic regulation of cancer stem cells and molding of the tumor microenvironment and identify PRC1 as a potential therapeutic target in M-CRPC.
Citation Format: Wenjing Su, Boyu Zhang, Hyunho Han, Goutam Chakraborty, Bing Zhou, Jie Su, Guangli Yang, Ouathek Ouerfelli, Neal Rosen, Howard I. Scher, Filippo G. Giancotti. The Polycomb repressor complex 1 promotes recruitment of myeloid-derived suppressor cells and immune evasion during bone colonization in castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1531.
Abstract 1539: Mechanisms of action of bispecific T cell engager-mediated immune response in a lymphoma tumor model
Authors: Coupet Tiffany A. , Godbersen-Palmer Claire , Sentman Charles L. 
Published: August 2019

Abstract
Bispecific T cell Engagers are molecules composed of two single chain variable fragments where one arm binds CD3 on T cells and redirects them to a tumor antigen with the other arm. This causes immune synapse formation between the T cell and tumor cell resulting in T cell activation and destruction of tumor cells. Bispecific T cell engagers have been used successfully in the clinic, however, it is unclear which activities of the host immune system are required for efficacy. This study investigates the mechanisms of action of a Bispecific protein specific for the B7H6 tumor antigen in an immune intact tumor model of lymphoma. In this lymphoma model the median survival for the B7H6xCD3 bispecific treated group was greater than 80 days while the median survival of the control bispecific treated group was 20 days. Monitoring of cellular changes in the bone marrow, blood, spleen and lymph nodes by flow cytometry 24h after bispecific protein treatment revealed that most cellular changes occurred in the inguinal lymph nodes were increases in CD8+ T cell and NK cells while CD4+ T cells decreased. Additionally, intracellular staining of cytokines IFNγ, Mip1α and TNFα in mouse T cells cultured in vitro with target tumor cells and bispecific protein showed that CD8+ T cells had greater polyfunctionality than CD4+ T cells. We have shown that IFNγ is essential for efficacy against lymphoma in vivo. To study the relative contribution of CD4 and CD8 T cells in vivo, lymphoma bearing mice that were depleted of CD4+ T cells or were deficient in CD8+ T cells were monitored for survival after bispecific protein treatment. While both CD4 or CD8 deficient mice had a greater survival when treated with B7H6xCD3 bispecific compared to control bispecific protein, the loss of either cell type resulted in much lower survival compared to WT mice treated with B7H6xCD3. All WT mice receiving B7H6xCD3 bispecific protein survived at least 65 days compared to CD4-depleted mice (median survival 20 days) and CD8-deficient mice (median survival 30 days) receiving the same treatment. In conclusion, both CD4+ and CD8+ T cells play a critical role in bispecific therapy. Understanding the mechanisms of action of bispecific proteins in vivo will help to develop more effective ways to use these powerful immune activating proteins to treat cancer.
Citation Format: Tiffany A. Coupet, Claire Godbersen-Palmer, Charles L. Sentman. Mechanisms of action of bispecific T cell engager-mediated immune response in a lymphoma tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1539.
Abstract 1550: Bruteforcing immune oncology discovery with computational immuno-engineering
Authors: Ives Sarah , Maurer David , Pettus Christina , Newland Raymond , Chiou Valerie , Daraeikia Shahrad , Jones Chelsea , Hervold Kieran , Day Giles , Smith Chris , Waddell Ian D. , Youssef Sawsan , Glanville Jacob 
Published: August 2019

Abstract
Recent Nobel awards in immune checkpoint inhibitor biology, phage display discovery and protein evolution highlight our current golden age of immune oncology research. While it took 15 years to bring anti-CTLA4 and anti-PD1 therapeutics from conception to global patient populations, new advances in synthetic and data driven immune engineering are enabling new therapeutics to be discovered and engineered in weeks rather than years. Here we review ten years of progress in computational optimization of antibody discovery libraries through the lens of high-throughput data collection technologies, with specific case studies of modern repertoire design principles applied to a panel of immune checkpoint targets. We emphasize the case study of PD1, where a computationally optimized library generated over 6500 unique anti-PD1 antibodies in two weeks, including picomolar binders, mouse/cyno/human triple cross-reactive epitopes, antagonists, agonists, and saturated epitope coverage of the target.
Citation Format: Sarah Ives, David Maurer, Christina Pettus, Raymond Newland, Valerie Chiou, Shahrad Daraeikia, Chelsea Jones, Kieran Hervold, Giles Day, Chris Smith, Ian D. Waddell, Sawsan Youssef, Jacob Glanville. Bruteforcing immune oncology discovery with computational immuno-engineering [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1550.
Abstract 1556: Preclinical development of antibody drug conjugates targetting EGFRvIII
Authors: Jaramillo Maria Luz , Marcil Anne , Robert Alma , Jolicoeur Normand , Wu Cunle , Fortin Yves , Donates Yuneivy Cepero , Acchione Mauro , Slinn Jacqueline , Ling Binbing , Moreno Maria 
Published: August 2019

Abstract
EGFRvIII is a naturally occurring variant of epidermal growth factor receptor (EGFR) that results from an in-frame deletion that removes 267 amino acids from the extracellular domain. EGFRvIII is a tumor-specific receptor that is amplified and present in 25-64% of glioblastoma multiforme and in 20-36% of breast cancers. Numerous studies show that normal tissues are devoid of EGFRvIII, thus making this target ideal for development as an antibody drug conjugate (ADC) for the treatment of cancer,including glioblastoma.
At the National Research Council (NRC) of Canada, we have selected mouse monoclonal mAbs that are selective for the extracellular domain of EGFRvIII and which have been shown to be internalized into EGFRvIII expressing cells for ADC development . A panel of EGFRvIII internalizing antibodies was directly conjugated to maytansine, the microtubule disrupting agent through a noncleavable linker. EGFRvIII -DM1 ADCs were shown to efficiently induce growth inhibition in vitro, in EGFRvIII expressing U87MG and DKMG glioblastoma cells. When tested in vivo, EGFRvIII -DM1 ADCs were shown to have potent anti-tumor activity in the U87MG-EGFRIII expressing tumor xenograft model.
Citation Format: Maria Luz Jaramillo, Anne Marcil, Alma Robert, Normand Jolicoeur, Cunle Wu, Yves Fortin, Yuneivy Cepero Donates, Mauro Acchione, Jacqueline Slinn, Binbing Ling, Maria Moreno. Preclinical development of antibody drug conjugates targetting EGFRvIII [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1556.
Abstract 157: APE1 upregulates MMP-14 to promote invasion of esophageal adenocarcinoma via redox-sensitive ARF6-mediated recycling
Authors: Lu Heng , Bhat Ajaz A. , Peng Dunfa , Chen Zheng , Zhu Shoumin , Hong Jun , Maacha Selma , Robbins David , Belkhiri Abbes , El-Rifai Wael 
Published: August 2019

Abstract
The incidence of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) has increased dramatically in the past three decades. The development of BE and its progression to EAC is highly correlated with exposure to acidic bile salts due to chronic gastroesophageal reflux disease (GERD). A stimulated overexpression of APE1 has been identified in response to bile acids for oxidative DNA repair and oncogenic signal transduction in BE and EAC, but function and mechanism of APE1 in BE and EAC development remains largely unknown. Here, we demonstrate a new function of APE1 in promoting invasion of dysplastic BE and EAC cells that is dependent on its redox function. We observed aberrant overexpression of APE1 in the cell lines and patients’ samples of dysplastic BE and EAC. In contrast to wild-type APE1, overexpression of redox-defective mutant, C65A, or treatment with APE1-redox-specific inhibitor, E3330, abrogated the pro-invasive phenotype of APE1. Mechanistically, we found that APE1 upregulated protein levels of the key matrix metalloproteinase MMP-14. Knockdown of APE1 decreased MMP-14 protein levels in dysplastic BE and EAC cells. Zymography assays indicated APE1 silencing reduced MMP-14 activity, subsequently impaired MMP-2 activation, and repressed extracellular matrix (ECM) degradation. Further, endocytosis and recycling assays revealed decreased endocytosis/recycling of MMP-14 protein in APE1-knockdown cells. Interestingly, our immunoprecipitation and proximity ligation assay (PLA) revealed a novel interaction between APE1 and ARF6, a key regulator of MMP-14 recycling. This interaction between APE1 and ARF6 activates ARF6 to regulate MMP-14 recycling through APE1-dependent redox function.
Conclusion: Our findings demonstrate, for the first time, the role of APE1 redox function in upregulating MMP-14 protein levels through activation of ARF6-mediated MMP-14 recycling. We propose APE1/ARF6/MMP-14 as a novel signaling axis in the invasion and progression of dysplastic BE and EAC.
Citation Format: Heng Lu, Ajaz A. Bhat, Dunfa Peng, Zheng Chen, Shoumin Zhu, Jun Hong, Selma Maacha, David Robbins, Abbes Belkhiri, Wael El-Rifai. APE1 upregulates MMP-14 to promote invasion of esophageal adenocarcinoma via redox-sensitive ARF6-mediated recycling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 157.
Abstract 1578: Cohesin complex-related genes in colorectal cancer
Authors: Sasaki Masaru , Miyoshi Norikatsu , Saso Kazuhiro , Fujino Shiki , Takahashi Hidekazu , Haraguchi Naotsugu , Matsuda Chu , Hata Taishi , Yamamoto Hirofumi , Mizushima Tsunekazu , Mori Masaki , Doki Yuichiro 
Published: August 2019

Abstract
Backgrounds: One of the hallmarks of cancer is chromosomal instability and it leads to aneuploidy. Defective sister chromatid cohesion represents a major cause of chromosome instability in human cancers. Stromal antigen (STAG) encodes a subunit of the cohesin complex, which regulates cohesion and segregation of sister chromatids. STAG contains STAG1, STAG2 related to somatic division and STAG3 related to meiosis. We evaluated the relationship between STAG and colorectal cancer.
Materials and methods: We examined STAG mRNA expression in tumor tissues by real-time qPCR. The samples were obtained from 172 colorectal cancer patients who underwent curative resection from November 2009 to December 2013 at the Osaka International Cancer Institute, Japan. STAG mRNA expression was evaluated by comparing with clinicopathological features and patients’ survival. Patients were classified into a high STAG expression and low STAG expression groups. Kaplan-Meier survival curves were evaluated using the log-rank test. The association with STAG expression and prognosis was analyzed by the Cox proportional regression model. Then, we utilized siRNA to knock down the expression of STAG3 and examined whether this altered proliferation in colorectal cancer cell lines (HCT116, RKO, HT29 and SW480).
Results: STAG1 and STAG2 did not show no statistically significant differences in disease-free survival (DFS) and overall survival (OS). In contrast, DFS rate was significantly lower in the high STAG3 expression group than the low STAG3 expression group (P = 0.032). A multivariate analysis showed that the high STAG3 mRNA expression was a significant independent risk factor for the recurrence (P = 0.006). In patients with adjuvant chemotherapy, the high STAG3 expression group was significantly worse for DFS (P = 0.043) and OS (P = 0.020), compared to the low STAG3 expression group. However, the proliferation assays evaluating the knockdown of STAG3 did not show any significant differences.
Conclusions: Our study showed that STAG3 can be a novel prognostic biomarker and the high STAG3 mRNA expression was an independent risk factor for the recurrence, suggesting that it relates to the chemotherapy resistance in colorectal cancer. We perform some other assays to evaluate the biology (focusing on the cancer invasiveness, the drug sensitivity, etc.) which reveal the mechanism of STAG3 in colorectal cancer.
Citation Format: Masaru Sasaki, Norikatsu Miyoshi, Kazuhiro Saso, Shiki Fujino, Hidekazu Takahashi, Naotsugu Haraguchi, Chu Matsuda, Taishi Hata, Hirofumi Yamamoto, Tsunekazu Mizushima, Masaki Mori, Yuichiro Doki. Cohesin complex-related genes in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1578.
Abstract 1580: Genetic variability of H3K27me modifier genesEZH2,KDM6AandKDM6Bin association with pancreatic cancer risk
Authors: Lu Ye , Obazee Ofure , Canzian Federico 
Published: August 2019

Abstract
Background:
Several literature reports explain the critical role of epigenetic regulation in relation to different types of cancers, however this is still an emerging research area in pancreatic cancer. Methylation of lysine 27 on histone H3 (H3K27me) plays a critical role in regulating gene expression and this modification has been reported to have oncogenic effects. Specifically, in pancreatic cancer this mechanism has only been demonstrated in relation to patient outcome.
The demethylase KDM6A (UTX) or KDM6B (JMJD3, a paralog of KDM6A on a different chromosome), and methyltransferase EZH2 (KMT6A) specifically regulate the alteration level of H3K27me. Based on the hypothesis that genetic variants may influence overall gene function, it is plausible that single nucleotide polymorphisms (SNPs) in these genes may similarly affect the roles of these genes in H3K27me deregulation.
Materials and methods:
Using the SNPinfo tool, a total of 21 tag SNPs in EZH2, KDM6A and KDM6B were selected from European populations based on 1000 Genome project. SNPs below 80% linkage disequilibrium threshold or less than 5% frequency among Europeans were excluded.
These SNPs were analysed in relation to pancreatic cancer susceptibility using logistic regression among up to 8,741 pancreatic cancer cases and 6,957 controls from publically-available GWAS data (Pancreatic Cancer Cohort Consortium (PanScan) and Pancreatic Cancer Case-Control Consortium (PanC4)). Imputation of these data sets were performed according to standard protocol and used for subsequent analyses.
Results:
Following adjustment for age and gender, we observed promising associations between KDM6B rs12453250 C&gt;A and EZH2 rs2888566 T&gt;C ((OR=0.92 95% CI (0.85-0.99), P=0.018) and (OR=1.09 95% CI (1.03-1.17), P=0.007) respectively) and pancreatic cancer risk. Interestingly, rs12453250 results in an amino acid change from Phenylalanine (F) to Leucine (L) which is predicted to have a probably-damaging effect on the KDM6B protein.
Conclusions:
The extent to which epigenetic markers can be incorporated into pancreatic cancer risk prediction along with genetic information is unknown. Our novel findings suggest a plausible role of EZH2 and KDM6A SNPs in relation to pancreatic cancer risk among carriers of their minor alleles. These results warrant further validation in independent studies and may enhance systematic risk assessment among Europeans.
Citation Format: Ye Lu, Ofure Obazee, Federico Canzian. Genetic variability of H3K27me modifier genesEZH2,KDM6AandKDM6Bin association with pancreatic cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1580.
Abstract 1582: Catechol-O-methyltransferase (COMT) genotypes modify the effects of beta-carotene supplementation on cancer incidence in a controlled trial: findings from the ATBC Study
Authors: Weinstein Stephanie J. , Huang Jiaqi , Hall Kathryn Tayo , Sesso Howard D. , Albanes Demetrius 
Published: August 2019

Abstract
Large cancer prevention trials of vitamin supplementation have yielded mixed results over the past three decades. Whether and how genetic variation that influences oxidative stress or vitamin absorption, transport, and metabolism can modify responses to supplementation remains to be elucidated. Catechol-O-methyltransferase (COMT) genotypes have been shown to impact the effects of vitamin E (i.e., alpha-tocopherol) supplementation on cancer, and the present pharmacogenetic analysis examines interactions among COMT, beta-carotene supplements, and risk of cancer. In a case-control study nested within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study of 29,133 Finnish men, we examined overall cancer risk based on the randomized assignment to beta-carotene supplementation (BC; 20 mg daily for 5-8 years) and two common genetic variants in COMT, rs4680 and rs4818 (genotyped by Illumina scans). Based on 2396 cases and 2235 non-cases, Cox proportional hazards models that adjusted for age, smoking intensity and duration, and randomized assignment to the trial vitamin E supplement were conducted to estimate overall cancer risk for the trial and 10-year post-trial periods combined. For rs4680, BC supplementation (versus no BC) was associated with higher cancer risk only in men with the AA (met/met) genotype (HR 1.29, 95% CI 1.08-1.53, P=0.004) as compared with the AG (met/val) and GG (val/val) genotypes (respectively, HR 1.04, 95% CI 0.93-1.16, P=0.52; and, HR 0.99, 95% CI 0.86-1.15, P=0.94). We observed a somewhat similar pattern for rs4818, with the BC supplement being associated with higher cancer risk in men with the GG and GC genotypes (respectively, HR 1.21, 95% CI 0.94-1.55, P=0.14; and, HR 1.15, 95% CI 1.01-1.30, P=0.03), but not the CC genotype (HR 0.99, 95% CI 0.88-1.11, P=0.80). Our findings indicate that the AA (met/met) genotype of COMT rs4680 and the G allele of rs4818 potentiate the increased cancer risk resulting from BC supplementation.
Citation Format: Stephanie J. Weinstein, Jiaqi Huang, Kathryn Tayo Hall, Howard D. Sesso, Demetrius Albanes. Catechol-O-methyltransferase (COMT) genotypes modify the effects of beta-carotene supplementation on cancer incidence in a controlled trial: findings from the ATBC Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1582.
Abstract 1599: Determining patient ancestry based on targeted tumor comprehensive genomic profiling
Authors: Newberg Justin , Connelly Caitlin , Frampton Garrett 
Published: August 2019

Abstract
Background. Cancer gene mutations exhibit mutation patterns of prevalence that vary across different ancestry groups. For example, EGFR variants are more frequent in non-small cell lung cancer among people with Asian ancestry, and KRAS variants are observed more frequently in colorectal cancer among patients with African American ancestry. Additionally, many histological subtypes of cancers demonstrate differences in prevalence between people of different ancestry. However, many cancer studies lack the statistical power to identify such nuances. The large cohort of patients who have undergone comprehensive cancer genomic profiling at Foundation Medicine may provide a useful starting point for characterizing these mutation patterns across ancestry groups.
Methods. To establish the ancestry on de-identified samples, we superimposed SNPs targeted by each of our comprehensive genomic profiling tests (FoundationOne, FoundationOne CDx, FoundationOne Heme) with Phase 3 1000 Genomes data. Using an established approach, we projected the SNPs down to the top five principal components and used random forest ensemble learning to train a classifier on each bait set. 10-fold cross-validation indicates this approach performs with 98-99% precision and recall for the different genomic profiling tests.
Results. Ancestry calls were made on over 170,000 de-identified samples consented for research. Initial analyses indicated that classification of American samples was not as robust as other groups. To address this, we trained classifiers on a per-chromosome basis, and re-assigned samples which exhibited less than 80% consensus across chromosomes to an admixture group. Overall prevalence of patient ancestry in the dataset is 75.9% European, 8.3% African, 4.7% East Asian, 0.8% South Asian, and 0.8% American, and 9.5% admixed. From the resulting data, we summarize cancer types that are well-represented across populations, identifying at least 28 tumor types for which we likely have power to identify ancestry-dependent somatic mutations.
Discussion. The dataset described contains a previously unavailable set of cancer types to be mined for ancestry-dependent cancer-driving alterations. Those results will be presented. The ancestry classification approach described in this work can be applied to a range of genomic profiling tests, and refinements on this approach can be integrated into clinical trials and ultimately clinical care to better elucidate varied biologic behavior across advanced cancer.
Citation Format: Justin Newberg, Caitlin Connelly, Garrett Frampton. Determining patient ancestry based on targeted tumor comprehensive genomic profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1599.