bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1281: Genomic structure variation in large screening for pediatric sarcoma therapy
Authors: Cheng Lijun , Chandra Pooja , Wang Limei , Pollok Karen , Pandya Pankita , Murray Mary , Carter Jacquelyn , Ferguson Michael , Reza Mohammad , Mark Mashall , Li Lang , Renbarger Jamie 
Published: August 2018

Abstract
Complex chromosomal aberrations such as amplification and deletion of DNA copy number are frequently seen in sarcoma. Fifty-five DNA structure variation has been listed as standard clinical diagnosis for sarcoma by standard of National Comprehensive Cancer Network (NCCN). However, copy number variation (CNV) as a biomarker of drug treatment for pediatrics sarcoma is still unclear, especially for relapsed and high recurrent patients of pediatric sarcoma. The paper aims to detect the prognosis biomarkers for rhabdomyosarcoma, Ewing's sarcoma (ES), and osteosarcoma based on copy number variation for 128 FDA-approved cancer drugs systematically. The 182 copy number variation (CNV) profiles from clinical sarcoma patients across three types of sarcoma, including osteosarcoma, rhabdomyosarcoma and ES, are observed. Cox survival regression model is used to select significant cancer-related CNVs systematically by correlation with overall survival analysis. 532 significant common CNVs and 782 specific CNVs for different types of sarcoma are observed by p-value &lt;0.01. By comparing with healthy persons, COSMIC database, 947 cancer cells and our INHOUSE tumor datasets, 32 out of 532 CNVs for specific sarcoma types are validated. This systematic CNV comparison makes it possible to map DNA copy number changes and identify chromosomal regions containing “target genes” responsible for tumor development and/or progression. Integrating large-scale drug screening with copy number variation analysis on 38 sarcoma cancer cells, 95 out of 532 are confirmed as drugs resistance and sensitive biomarkers for different types of sarcoma. 15 chemotherapies show strong signals connecting with 42 biomarkers, including genes MYC, RAD21, and RB1 amplification. By bridging molecular biomarkers between tumors and sarcoma cell lines, 5 optimum drugs associated with 14 enzyme biomarkers are recommended for pediatric rhabdomyosarcoma, ES, and osteosarcoma treatment respectively. The research not only detects copy number variations both of sarcoma cell lines and tumors, but also provides novel insights into drug biomarkers based on copy number amplification or deletion for bone sarcoma and soft tissue sarcoma, respectively.
Citation Format: Lijun Cheng, Pooja Chandra, Limei Wang, Karen Pollok, Pankita Pandya, Mary Murray, Jacquelyn Carter, Michael Ferguson, Mohammad Reza, Mashall Mark, Lang Li, Jamie Renbarger. Genomic structure variation in large screening for pediatric sarcoma 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 1281.
Abstract 1307: Effect of tumor purity on somatic mutation detection using next-generation sequencing technology: A benchmarking study
Authors: Jones Wendell , Xiao Wenming ,   Somatic Mutation Working Group, SEQC2 Consortium
Published: August 2018

Abstract
Next generation sequencing (NGS) is becoming an essential tool for clinical cancer care. Whole genome sequencing (WGS), whole exome sequencing (WES), and targeted gene sequencing (TGS) have emerged as important tools and are critical for advancing precision oncology to meaningfully impact patient lives. To enable this goal, we must first thoroughly characterize the complexities of using NGS to identify somatic mutations in samples with tumor heterogeneity and variable tissue sample purity.
Here, we applied both experiment and in silico approaches to determine the effects of tumor heterogeneity on somatic mutation detection. First, we systematically investigated somatic mutation events in paired cell lines (breast carcinoma and matched normal) using a myriad of NGS platforms and protocols. Then, we applied machine learning algorithms to define high confidence mutation calls with datasets from the combination of all platforms and pipelines. Finally, we performed whole genome sequencing from tumor DNA samples titrated with matched normal cells to create a gradient of tumor purities from 100%, 75%, 50%, 20%, 10%, 5%, and 0%. We also created a series of in silico mixes by pooling reads from tumor and normal cell lines at respective ratios.
With somatic variation “ground truth” established by multiple orthogonal sequencing platforms and multiple analysis tools, we evaluated performance of individual software tools for tumor purity assessment and for mutation detection. Our experimental design allowed us to systematically evaluate accuracy, specificity and sensitivity of mutation detection across a range of tumor purities, as well as conduct a head-to-head comparison of in silico approaches versus experimental approaches.
This comprehensive study will help to clarify our understanding of experimental and analytical challenges that arise when confronted with tumor heterogeneity in patient care clinical decisions. In addition, data generated in this study will be used as a benchmark resource for the community to develop and improve tools to meet clinical challenges.
Citation Format: Wendell Jones, Wenming Xiao, Somatic Mutation Working Group, SEQC2 Consortium. Effect of tumor purity on somatic mutation detection using next-generation sequencing technology: A benchmarking study [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 1307.
Abstract 1369: Analysis of association between homologous recombination deficiency and tumor mutational burden in solid tumors
Authors: Li Hua , Wu Liqun , Shou Tao , Jiang Bo , Zhuang Li , Li Kunsong , Tan Xiang , Guo Chao , Guo Weidong , Guan Yan , Chen Zheng , Ding Xiao , Guo Jun , Du Zhenfang , Cui Qiang , Che Yue , Yao Ming 
Published: August 2018

Abstract
Background: Multiple types of tumors exhibit DNA repair dysfunction via homologous recombination deficiency (HRD) due to genetic and epigenetic alterations of HR pathway genes, including BRCA1/2, PALB2, ATM, ATR, CHK1/2, BARD1, BIRP1, MRE11A, RAD51 family and FANC family. Some studies showed that tumors with homologous recombination deficiency might result in more mutations than tumors with non-deficient HR. Accumulating evidence suggests that tumor mutational burden (TMB) evaluated by comprehensive genomic profiling was associated with the responses of immune checkpoint inhibitors in solid tumors.
Methods: FFPE tumor samples of 777 Chinese patients were collected for next-generation sequencing (NGS)-based targeted panel assay across multiple types of tumors, including lung, breast, soft tissue, gastrointestinal and gynecology cancers. There were 471 males (60.6%) and 306 females (39.4%) with a median age of 58 years old. Genomic alterations of HR-related genes and TMB values were assessed by next-generation sequencing assay, including single base substitution, short and long insertions/deletions, copy number variations, gene fusions and rearrangements.
Results: In total, 25% of the 777 solid tumor patients had at least one genomic alteration of the HR genes (N=197, HRD group). The top mutant HR genes included BRCA1/2 (28.8%), FANC family (27.6%), ATM (27.4%), ATR (11.2%), RAD51 family (8%), BARD1 (7.6%), PALB2 (7.1%), BIRP1 (5.6%), CHK1/2 (5.0%) and MRE11A (4.6%). TMB was 10.4 muts/Mb in the HRD group compared to 6.4 muts/Mb in the rest of the patients (p&lt;0.01). In addition, 43.2% of the patients in the HRD group had TMB-high values, which was higher than in the non-HRD group at 22.8% (P&lt;0.01). High TMB values were more commonly detected in the colorectal cancer patients.
Conclusions: Our study revealed that the solid tumors harboring HR gene mutation were more likely to have higher TMB values. BRCA1/2, FANC family and ATM were the most common mutant genes. CRC was the dominant cancer type showing high TMB values associated with HRD. Further analysis is warranted to investigate the association.
Citation Format: Hua Li, Liqun Wu, Tao Shou, Bo Jiang, Li Zhuang, Kunsong Li, Xiang Tan, Chao Guo, Weidong Guo, Yan Guan, Zheng Chen, Xiao Ding, Jun Guo, Zhenfang Du, Qiang Cui, Yue Che, Ming Yao. Analysis of association between homologous recombination deficiency and tumor mutational burden in solid tumors [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 1369.
Abstract 1553: Carcinoembryonic antigen (CEA) expression is regulated by mutant KAS in mucinous colon cancers
Authors: Kuracha Murali , Govindarajan Venkatesh , Loggie Brian W. , Thomas Peter 
Published: August 2018

Abstract
Purpose: Carcinoembryonic antigen (CEA/CEACAM5) is a marker and prognostic indicator for colorectal cancers (CRCs). CEA overexpression is also a major causative factor in the development of liver metastasis from a significant fraction of colorectal cancers (CRC) including mucinous adenocarcinomas (MCAs). Very little is known about the molecular mechanisms that regulate the expression of CEA in cancers in general and in CRCs in particular. This study tests the hypothesis that mutant KRAS, a frequently mutated gene in CRCs, regulates CEA expression in CRCs.
Methods: Mutant KRAS expression was reduced in two high CEA-expressing mucinous CRC cell lines, LS174T (KRAS G12D) and RW7213 (KRAS G12C), by short hairpin RNA (shRNA)-mediated knockdown using a lentiviral vector. Inducible and reversible knockdown of KRAS was achieved by addition or withdrawal of doxycycline. Alterations in activation of ERK-and PI3K-pathway effectors downstream of KRAS were assessed by Western blots. Two small-molecule inhibitors, pictilisib (GDC0941) and cobimetinib (GDC0973), were used to inhibit PI3K and MEK respectively.
Results: Knockdown of mutant KRAS in CRC cell lines reduced CEA expression. However, knockdown of wild-type RAS did not change CEA expression. Restoration of mutant KRAS reestablished CEA expression in both cell lines. This recovery of CEA expression was blocked by addition of the MEK inhibitor, cobimetinib or the PI3K inhibitor, picstilisib. Combined treatment with both inhibitors was more effective in reducing CEA expression than single-agent treatment.
Conclusions: Our results suggest that mutant KRAS, through engagement of MEK-ERK and PI3K-AKT signaling pathways, regulates CEA expression in CRCs. CEA has been implicated in the development of lung and liver metastasis from CRCs, by reacting with stromal cells and altering the tumor microenvironment. Our results therefore, suggest a potential vulnerability that could be exploited for antimetastatic therapy.
Citation Format: Murali Kuracha, Venkatesh Govindarajan, Brian W. Loggie, Peter Thomas. Carcinoembryonic antigen (CEA) expression is regulated by mutant KAS in mucinous colon cancers [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 1553.
Abstract 160: Novel strategy targeting breast cancer stem cells CD44+/CD24-low responsible for breast cancer progression
Authors: Abouelnazar Fatma A. , Sultan Ahmed S. 
Published: August 2018

Abstract
The present study has been designed to isolate the highly tumorigenic sub-population of cells from the breast cancer cell line (T47-D). The effect of Manuka honey (MH), Frankincense essential oil (F), Metformin (M) and combined treatment on eradicating breast cancer stem cells (BCSCs) that are responsible for cancer progression was investigated.
The isolated (BCSCs) were subjected to different concentrations of (MH), (F), (M) and combined treatment to visualize their effects on BCSCs viability, morphological changes, caspase-3 activity, apoptosis induction, clonogenic survival, β-catenin, ALDH6A1, Notch-1, Notch-4 and Nonog protein expression, using western blot analysis and protein localization by immunocytochemical technique.
Inhibited viability of isolated breast cancer stem cells, which showed apoptotic morphological changes were observed beside increased caspase-3 activity and inhibited clonogenic survival compared to control. At the protein level, our data showed that (MH), (F), (M) and combined synergistic treatment decreased the expression of β-catenin levels, ALDH6A1 and Notch-1 compared to control. In addition, (MH) showed no effect on Notch-4 expression, but significantly decreased the expression level of Nanog. In contrast, (F) treatment enhanced the protein expression of Nanog level in a dose dependent manner compared to control. Furthermore, (MH), (F), (M), and combined treatment showed conspicuously decrease in the nuclear and cytoplasmic level of β-catenin and ALDH6A1 of CD44+/CD24-low (BCSCs) compared to control.
Taken together, natural compounds of Manuka honey and Frankincense essential oils and their combination with Metformin have been emerged as a potential strategy to target and eradicate (BCSCs).
Citation Format: Fatma A. Abouelnazar, Ahmed S. Sultan. Novel strategy targeting breast cancer stem cells CD44+/CD24-low responsible for breast cancer progression [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 160.
Abstract 1736: The combination of CXCR4 and checkpoint receptor inhibition improves survival in an orthotopic murine glioma model
Authors: Wu Adela , Cardarelli Pina , Oyasu Miho , Menezes Daniel , Ponath Paul , Cogswell John , Maxwell Russell , Luksik Andrew , Hung Alice , Kim Eileen , Belcaid Zineb , Brem Henry , Pardoll Drew , Lim Michael 
Published: August 2018

Abstract
Introduction: Angiogenesis plays an important role in the malignancy of glioblastoma (GBM) as well as in cancer immunotherapy. In addition, PD-1 checkpoint receptors are upregulated in GBM. We investigate the treatment effects of combination immunotherapy with checkpoint inhibitor anti-PD-1 and anti-CXCR4, an antagonist of a chemokine receptor involved in immune cell homing as well as vasculature development, in a murine glioma model.
Methods: C57Bl/6 mice were implanted with GL261-Luc+ glioma cells and randomized into 4 treatment arms: 1) control, 2) anti-PD-1 monotherapy, 3) anti-CXCR4 monotherapy, and 4) combination anti-PD-1 and anti-CXCR4 therapy. Overall survival and median survival were assessed. Brain samples from untreated mice were stained for CXCR4 expression on plasma membrane, and immunohistochemistry studies were conducted on human glioblastoma specimens as well. Immune cell activation and cell population changes were assessed through flow cytometry analysis.
Results: Both murine and human glioma specimens demonstrated robust positive expression of CXCR4 on tumor-infiltrating immune cells and endothelial cells of vasculature specific to the tumor bed. Combination therapy with anti-PD-1 and anti-CXCR4 conferred survival benefit compared to control and both monotherapy arms. Long-term survivors that had received combination therapy demonstrate immune memory and decreased populations of immunosuppressive, tumor-promoting immune cells. For instance, the monocytic myeloid-derived suppressor cell population was decreased in the brain in mice treated with combination therapy. The pattern of change in microglia was similar in the brain compartment for the combination treatment group as well.
Conclusion: Anti-CXCR4 and anti-PD-1 synergistic immunotherapy not only modulates the immune cell make-up of the glioma microenvironment but also affects vasculature within the tumor region. Dual therapy targeting both checkpoint and chemokine receptors results in improved survival rates.
Citation Format: Adela Wu, Pina Cardarelli, Miho Oyasu, Daniel Menezes, Paul Ponath, John Cogswell, Russell Maxwell, Andrew Luksik, Alice Hung, Eileen Kim, Zineb Belcaid, Henry Brem, Drew Pardoll, Michael Lim. The combination of CXCR4 and checkpoint receptor inhibition improves survival in an orthotopic murine glioma model [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 1736.
Abstract 1770: Morab-202, a folate receptor alpha-targeted antibody-drug conjugate, shows a highly potent activity against a panel of FRA-expressing tumors
Authors: Mignard Caroline , DURIX Coralie , Rybinski Katherine , Cheng Xin , Furuuchi Keiji , Albone Earl , Uenaka Toshimitsu , Boisferon Marc Hillairet de 
Published: August 2018

Abstract
Folate receptor alpha (FRA) is a membrane protein with high affinity for binding and transporting folate into cells. Overexpression of FRA may confer a growth advantage to tumors by increasing folate uptake and affecting cell proliferation via alternative cell signaling pathways (1). FRA levels have been found to be elevated in tumors of epithelial origin compared to normal tissue as cancers of the breast (including TNBC (2)), colon, lungs and ovary (3).
In this study, we report the development of MORAb-202, an anti-FRA antibody-drug conjugate (ADC), consisting of a FRA-binding antibody (MORAb-003, farletuzumab) with a cathepsin-cleavable form of eribulin (eribulin mesylate, marketed as Halaven®), a highly potent anti-mitotic agent that induces cell-cycle arrest and cell death by targeting microtubules.
We first study expression of FRA on a large panel of tumors patient-derived xenograft (PDX) and Cancer Cell Line-derived Xenograft (CDX). Then, we performed in vitro and in vivo anti-proliferation assays and compare antitumor activity of MORAb-202 with free eribulin accordingly to the FRA expression level. FRA expression was found to be determinant in the sensitivity of tumor cells to the cytotoxic effect of the ADC. Moreover, in case of high expression of FRA, MORAb-202 showed a higher antitumor activity compared with free eribulin.
These results suggest that FRA expression could be used as a response-predictive biomarker for this targeted therapy. The ability to identify and treat patients with an effective therapy based on the known expression of the tumor marker is a key point in predictive medicine progress. These findings support the clinical development of MORAb-202 ADC as a novel targeted therapy for patients with FRA-expressing tumors.
The ADC described in this abstract is investigational, as efficacy and safety have not been established. There is no guarantee that this ADC will be available commercially.
1-Siu MK et al., PLoS One. 2012;7(11) 2-Nacela BM. et al., PLoS One. 2015, 10(3) 3-Cheung A. et al., Oncotarget. 2016 7(32), 52553-52574 4-Arrowsmith J. & Miller P. 2011-2012. Nat. Rev. Drug Discov. 12, 569 (2013). 5-Paul S.M. et al. Nat. Rev. Drug Discov. 9, 203-214 (2010). 6-Hidalgo, M. et al. Cancer Discov. 4, 998-1013 (2014).
Citation Format: Caroline Mignard, Coralie DURIX, Katherine Rybinski, Xin Cheng, Keiji Furuuchi, Earl Albone, Toshimitsu Uenaka, Marc Hillairet de Boisferon. Morab-202, a folate receptor alpha-targeted antibody-drug conjugate, shows a highly potent activity against a panel of FRA-expressing tumors [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 1770.
Abstract 1845: TP53 status determines the fate of cancer cells exposed to ionizing radiation and DNA-PK inhibitor, M3814
Authors: Sun Qing , Guo Yige , Liu Xiaohong , Czauderna Frank , Zenke Frank , Blaukat Andree , Vassilev Lyubomir T. 
Published: August 2018

Abstract
Inhibition of DNA double strand break repair in cancer cells has been proposed as a new therapeutic approach for potentiation of radiotherapy. M3814 is a potent and selective inhibitor of DNA-PK, a key component of non-homologous end joining repair pathway and is currently under clinical investigation in radiation combination trials. We studied the mechanism of cancer cell response to combined treatment with ionizing radiation and M3814 using cancer cell lines with different p53 status. M3814 blocked the repair of radiation-induced DSBs and suppressed a negative regulatory loop between DNA-PK and ATM causing enhanced phosphorylation and activation of ATM. In the p53 wild-type cells, ATM and its targets, CHK2 and p53, were activated more strongly by the combination treatment than by radiation alone, leading to a complete p53/CHK2-dependent cell cycle block and premature cell senescence. The p53-null or mutant cancer cells were unable to fully arrest the cell cycle and a substantial fraction entered S phase with unrepaired DNA, leading to mutations, chromosomal aberrations, aneuploidy, micronucleation and ultimately cell death, primarily due to mitotic catastrophe. Two isogenic pairs of p53 null/wt cells (A549 and HT-1080) were generated and used to demonstrate the critical role of p53 in the choice of M3814-modified radiation response. Time-lapse imaging of cell death kinetics using a small panel of p53 wild-type and p53 null/mutant cancer lines revealed clear differences in outcome dependent on p53 status. However, standard growth/viability assays failed to show a role of p53 in the response type, due to inability to discriminate between cell cycle arrest and cell killing. Similarly, screening results obtained from large cancer cell panels (&gt;100 lines) did not identify p53 as a marker of response. Our data revealed an important role of p53 in determining the mode of cancer cells' response to radiation in the presence of M3814 and suggest that p53 mutation status should be considered in the design of clinical trials. The failure of standard growth/viability screens with large cancer cell line panels to identify p53 status as a response indicator raises an alert for the utility of these screening platforms currently widely used in cancer drug discovery and development.
Citation Format: Qing Sun, Yige Guo, Xiaohong Liu, Frank Czauderna, Frank Zenke, Andree Blaukat, Lyubomir T. Vassilev. TP53 status determines the fate of cancer cells exposed to ionizing radiation and DNA-PK inhibitor, M3814 [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 1845.