bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1220: Coordinated chemical-genetics approach identifies PTP4A3-mediated regulation of colon cancer cell migration and extracellular matrix interactions
Authors: McQueeney Kelley E. , Salamoun Joseph M. , Blanco Isabella K. , Pekic Paula , Ahn Jennifer , Sharlow Elizabeth R. , Wipf Peter , Lazo John S. 
Published: July 2017

Abstract
Aberrant regulation of protein phosphorylation is an exceedingly common driver of human cancers. It is notable that we understand much less about the role of protein tyrosine phosphatases in human malignancies compared to tyrosine kinases. The membrane-associated, intracellular, protein tyrosine PTP4A3 is highly overexpressed in multiple tumor types including colorectal cancer and has been associated with tumor metastases. We have, therefore, investigated the role of PTP4A3 in colon cancer migration and invasion. The Ptp4a3 gene was expunged from colon tumor cells derived from Ptp4a3flox/flox mice and the resulting cells exhibited impaired migration, invasion, and colony formation compared to the wildtype isogenic cells. We characterized a potent, selective, and noncompetitive small molecule inhibitor of PTP4A3, JMS-631-053, which also disrupted colon cancer cell migration, invasion, and colony formation. PTP4A3 deletion increased the expression of extracellular matrix and adhesion genes, including the tumor suppressor Emilin 1. Expression of these extracellular matrix genes is mutually exclusive with PTP4A3 expression in tumors derived from patients with colorectal cancer. These chemical and biological reagents reveal a previously unknown communication between the intracellular PTP4A3 phosphatase and the extracellular matrix and support continued efforts to pharmacologically target PTP4A3 for cancer therapy.
Citation Format: Kelley E. McQueeney, Joseph M. Salamoun, Isabella K. Blanco, Paula Pekic, Jennifer Ahn, Elizabeth R. Sharlow, Peter Wipf, John S. Lazo. Coordinated chemical-genetics approach identifies PTP4A3-mediated regulation of colon cancer cell migration and extracellular matrix interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1220. doi:10.1158/1538-7445.AM2017-1220
Abstract 1222: Developing kinase inhibitors with polypharmacological profiles for the treatment of resistant cancers
Authors: Rao Suman , Li Tan , Everley Robert , Du Guangyan , Sorger Peter , Gray Nathanael 
Published: July 2017

Abstract
Small molecule kinase inhibitors targeting a specific oncoprotein driving cancer cells have shown great clinical success in the past (e.g. imatinib against leukemia). However, resistance to targeted therapies quickly arises due to plasticity associated with cancer cell signaling and tumor heterogeneity. One way to overcome this problem is to rationally design drugs with polypharmacology that can target multiple signaling pathways engaging in cancer cell proliferation and survival. To this end, we have developed a strategy based on combining phenotypic screens of small molecule inhibitors and affinity-based mass spectrometry to identify drugs with multi-targeted properties and piloted this approach using the highly resistant KRAS mutant non-small cell lung cancer cell lines. We began this study by screening kinase inhibitors targeting MEK, ERK, PI3K, Akt and mTOR and found that the lung cancer cells were largely resistant to single drugs but showed enhanced sensitivity towards triple inhibition of MEK, ERK and PI3K. These cell lines were then screened with a library of covalent and non-covalent kinase inhibitors in an attempt to identify a small molecule inhibitor that could mimic the activity of the triple drug combination. This led to the discovery of SM1-71 that not only recapitulated the growth inhibitory activity of MEK+ERK+PI3K inhibition, but also blocked phosphorylation of ERK, Akt, mTOR and S6K in cells. Target profiling of the drug was carried out using chemoproteomics, which revealed that SM1-71 inhibited 55 kinases at a 1μM concentration. Dose-dependent evaluation further determined the IC50 of inhibition across the 55 kinases and rank ordered them based on binding affinity. Top hits including MEK1, MEK2, ERK1, ERK2, AURKA, SRC and RPS6KA3 were confirmed using alternate kinase screens and cellular assays. Growth factor receptors such as IGF1R, MET and EGFR were also identified and further validated using cell-based assays. Taken together, these results elucidated the polypharmacology associated with SM1-71 and uncovered key targets responsible for inducing strong cytotoxicity in KRAS mutant lung cancer cells. Through the combination of phenotypic screens and mass spectrometry-based target identification, we have demonstrated the proof of principle for developing kinase inhibitors with polypharmacology targeting resistant cancers.
Citation Format: Suman Rao, Tan Li, Robert Everley, Guangyan Du, Peter Sorger, Nathanael Gray. Developing kinase inhibitors with polypharmacological profiles for the treatment of resistant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1222. doi:10.1158/1538-7445.AM2017-1222
Abstract 1228: Nintedanib selectively inhibits the activation and tumor-promoting effects of fibroblasts from lung adenocarcinoma patients
Authors: Alcaraz Jordi , Gabasa Marta , Ikemori Rafael , Reguart Noemí 
Published: July 2017

Abstract
Nintedanib (BIBF 1120) is a multikinase inhibitor recently approved to treat lung adenocarcinoma (ADC) patients based on the therapeutic benefits reported in clinical trials on ADC but not on squamous cell carcinoma (SCC), which are the two most common lung cancer subtypes. However, the biological processes underlying the selective anticancer function of nintedanib in ADC remain obscure. To shed light on this gap of knowledge, we examined the role of tumor-associated fibroblasts (TAFs) in the differential effects of nintedanib in ADC and SCC. Because TAFs are largely quiescent and activated in vivo, we focused on the antifibrotic effects of nintedanib on TAFs stimulated with TGF-β1, which is a potent fibroblast activator frequently upregulated in lung cancer. Nintedanib dose-dependently inhibited the TGF-β1-induced expression of activation markers in both ADC-TAFs and control fibroblasts derived from uninvolved parenchyma, whereas such inhibiton was very modest in SCC-TAFs, thereby suggesting that TAF activation is regulated by different mechanisms in ADC and SCC. Remarkably, nintedanib abrogated the stimulation of growth and invasion in a panel of carcinoma cell lines induced by secreted factors from activated TAFs in ADC but not SCC. These results reveal that nintedanib is a potent inhibitor of fibrosis and its associated tumor-promoting effects in ADC, and strongly suggest that the subnormal antifibrotic response of SCC-TAFs to nintedanib may underlie the lack of therapeutic benefits of this drug in SCC. Our findings also support that preclinical models based on carcinoma-TAF interactions may help unraveling the resistance mechanisms of SCC-TAFs to nintedanib and testing new combined therapies to further expand the therapeutic effects of this drug.
Citation Format: Jordi Alcaraz, Marta Gabasa, Rafael Ikemori, Noemí Reguart. Nintedanib selectively inhibits the activation and tumor-promoting effects of fibroblasts from lung adenocarcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1228. doi:10.1158/1538-7445.AM2017-1228
Abstract 1256: Non-steroidal anti-inflammatory drugs induce ER stress and have an immunomodulatory role in the suppression of colorectal tumorigenesis
Authors: Fletcher Rochelle E. , Zhang Lin , Leibowitz Brian , Yu Jian 
Published: July 2017

Abstract
Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths in the United States. A number of epidemiological studies, clinical trials, and animal studies have demonstrated the chemopreventive effect of non-steroidal anti-inflammatory drugs (NSAIDs) on CRC. However, the exact mechanism by which NSAIDs suppress colorectal tumorigenesis has remained unclear. Our previous study showed that NSAID-induced death receptor signaling, along with loss of the gatekeeper APC tumor suppressor, triggers a synthetic lethal interaction and apoptotic death in an otherwise normal cell. In this study, we determined how NSAIDs induce death receptor signaling, and found a critical role of the endoplasmic reticulum (ER) stress response. Treating CRC cells with the NSAIDs sulindac or indomethacin upregulated C/EBP homologous transcription factor (CHOP), a key mediator of the ER stress response that is required for the induction of death receptor 5 (DR5) by NSAIDs. Blocking ER stress abolished the apoptotic effect of NSAIDs in CRC cells and in normal colonic epithelial cells with knockdown of APC, and also suppressed the chemopreventive activity of NSAIDs in APCMin/+ mice. Furthermore, we identified plasma membrane translocation of calreticulin in cells undergoing NSAID-induced apoptosis, suggesting the involvement of immunomodulation in this tumor suppression. Our results provide novel insight into the chemopreventive mechanism of NSAIDs, which may help design more effective chemopreventive strategies and agents.
Citation Format: Rochelle E. Fletcher, Lin Zhang, Brian Leibowitz, Jian Yu. Non-steroidal anti-inflammatory drugs induce ER stress and have an immunomodulatory role in the suppression of colorectal tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1256. doi:10.1158/1538-7445.AM2017-1256
Abstract 126: A chemogenomic approach reveals the action of splicing modulators at the branch point adenosine binding pocket defined by the PHF5A/SF3b complex
Authors: Teng Teng , Tsai Jennifer , Puyang Xiaoling , Seiler Michael , Peng Shouyong , Aird Daniel , Buonamici Silvia , Caleb Benjamin , Chan Betty , Corson Laura , Feala Jacob , Fekkes Peter , Karr Craig , Korpal Manav , Mizui Yoshiharu , Park Eunice , Palacino James , Smith Peter , Subramanian Vanitha , Wu Jeremy , Yu Lihua , Chicas Agustin , Warmuth Markus , Larsen Nicholas , Zhu Ping 
Published: July 2017

Abstract
Dysregulation of RNA splicing can cause various forms of cancer and neuromuscular disorders. Thus, developing compounds with splicing-modulating activity represents a promising therapeutic approach for these diseases. Natural products such as pladienolide, herboxidiene, and spliceostatin have been identified as potent splicing modulators that bind SF3B1, a member of the SF3b subcomplex that assembles into the U2 snRNP. Using integrated chemogenomic, structural and biochemical approaches, we show that PHF5A, another core component of the SF3b complex, is also targeted by these modulators. Whole exome sequencing of E7107 (pladienolide analogue) and herboxidiene resistant clones identified common mutations in either PHF5A-Y36, SF3B1-K1071, SF3B1-R1074, or SF3B1-V1078, which confers resistance to these modulators as assessed by splicing modulation and cell growth inhibition, suggesting a common site of interaction for these splicing modulators. We determine the crystal structure of human PHF5A and find that Y36 is located on the surface in a region of high sequence conservation. Analysis of the cryo-EM spliceosome Bact complex from yeast shows that these mutations cluster in a well-defined pocket surrounding the branch point adenosine suggesting a possible competitive mode of action for these modulators. Whole-transcriptome RNA-seq analysis reveals that PHF5A Y36C alters the profile of splicing modulators from inducing intron-retention events to exon-skipping events. Furthermore, the differential in GC content between adjacent introns and exons correlates with the relative intron strength, making some splicing events more susceptible to modulation. Collectively, we propose that PHF5A-SF3B1 is a central node for binding to these small-molecule splicing modulators offering novel approaches to modulate specific splicing events.
Citation Format: Teng Teng, Jennifer Tsai, Xiaoling Puyang, Michael Seiler, Shouyong Peng, Daniel Aird, Silvia Buonamici, Benjamin Caleb, Betty Chan, Laura Corson, Jacob Feala, Peter Fekkes, Craig Karr, Manav Korpal, Yoshiharu Mizui, Eunice Park, James Palacino, Peter Smith, Vanitha Subramanian, Jeremy Wu, Lihua Yu, Agustin Chicas, Markus Warmuth, Nicholas Larsen, Ping Zhu. A chemogenomic approach reveals the action of splicing modulators at the branch point adenosine binding pocket defined by the PHF5A/SF3b complex [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 126. doi:10.1158/1538-7445.AM2017-126
Abstract 1271: Genetic variants in the 16q24.3 region of melanocortin-1-receptor (MC1R) and prostate cancer risk: A Mendelian randomization analysis of 39,000 cases and 25,000 controls
Authors: Weinstein Stephanie J. , Layne Tracy M. , Huang Jiaqi , Karlins Eric , Chanock Stephen J. , Albanes Demetrius , Consortium the PRACTICAL 
Published: July 2017

Abstract
We previously reported that men with naturally red hair had a significantly lower risk of prostate cancer (HR=0.46, 95% CI 0.24-0.89) compared with the most prevalent hair color, light brown (Br J Cancer 2013;109(3):747-750). The red hair phenotype is encoded by variants in the melanocortin-1-receptor (MC1R) gene that controls expression of the eumelanin and pheomelanin pigments. In order to re-examine this association through the relatively unbiased Mendelian randomization approach, we examined single nucleotide polymorphisms (SNPs) in and near MC1R in relation to prostate cancer risk using data from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. The analysis includes 38,868 men diagnosed with prostate cancer and 25,210 controls from 35 studies participating in PRACTICAL Consortium (Nat Gen 2014;46(10)1103-1109). Logistic regression modeling was used to estimate the odds ratio (OR) and confidence interval (CI) for the per allele prostate risk associations with 148 genotyped SNPs and 164 imputed SNPs. Variants demonstrating nominal significance (alpha-error p&lt;0.05) as well as those reaching a stringent Bonferroni threshold of p&lt;0.0003 adjustment for multiple comparisons were examined. We identified prostate cancer risk associations with 30 genotyped and 36 imputed polymorphisms that were nominally significant, three of which achieved Bonferroni significance and were in a region of 16q24.3 that includes MC1R, GAS8 (growth arrest specific-8, an alleged tumor suppressor that is deleted in some prostate cancers), and transcription factor-25 (TCF25). These were rs4628973 and rs3743824 that were in high LD (r2=0.931; prostate cancer risk associations p=0.00029 and 0.00023, respectively), as well as rs6500461 that was independently associated with risk (r2=0.20 with rs4628973; p=0.00020). This large-scale Mendelian randomization analysis suggests genetic variants near MC1R, which directs melanocyte melanin synthesis, secretion and human pigmentation, may be associated with risk of prostate cancer.
Citation Format: Stephanie J. Weinstein, Tracy M. Layne, Jiaqi Huang, Eric Karlins, Stephen J. Chanock, Demetrius Albanes, the PRACTICAL Consortium. Genetic variants in the 16q24.3 region of melanocortin-1-receptor (MC1R) and prostate cancer risk: A Mendelian randomization analysis of 39,000 cases and 25,000 controls [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1271. doi:10.1158/1538-7445.AM2017-1271
Abstract 1273: Pathway analysis of insulin-like growth factor candidate genes and risk of pediatric rhabdomyosarcoma
Authors: Morimoto Libby , Shao XIaorong , Chokkalingam Anand , Wiemels Joseph , Ma Xiaomei , Metayer Catherine 
Published: July 2017

Abstract
Pediatric rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children under 15 years of age. Due largely to its rarity, the etiology of pediatric RMS is poorly understood. Patterns of fetal growth were previously shown to be independent risk factors for RMS among non-Hispanic white (NHW) children; however, the underlying biologic mechanisms remain unclear. Alterations in the insulin-like growth factor (IGF) system, the primary regulator of growth during the fetal and early life period, may provide clues. Using an innovative linkage between the California birth records and cancer registry information, we conducted a population-based case-control study (1982-2009) of candidate genes involved in IGF signaling and risk of pediatric RMS. Fifteen genes involved in the IGF pathway were selected: IGF1, IGF2, IGF1R, IGF2R, IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, IGFBP6, INS, INSR, IRS1, GH1, and GHRH. DNA extracted from the archived newborn blood spots of all available RMS cases (n=644) was genotyped on the Illumina OmniExpress Exome array (n=964,043 SNPs); after stringent quality control (QC), a total of 633 RMS cases (360 embryonal RMS [eRMS] and 197 alveolar RMS [aRMS]) were available for analysis. A total of 815 controls genotyped on the Illumina OmniExpress Exome array and 3,922 controls genotyped on the Affymetrix Axion LAT array (n=801,830 SNPs) from the same base population of California children, with no evidence of RMS, were included in this analysis. After imputation to increase coverage of the genome and post-imputation QC to identify and remove platform effects, a total of 5,556,335 SNPs were available for analysis. Among NHW children, SNPs in IGF1 (rs10860869, p=0.0031) and IGF1R (rs62023616, p=0.00074; rs62023648, p=0.00076) were significantly associated with RMS risk after adjustment for multiple comparisons. Analyses stratified by histologic subtype showed that these associations were limited to eRMS, and of stronger magnitude. Among Hispanic children, 12 SNPs in IGF1R (p-value range: 0.0007-0.0027) and 3 SNPs in IGFBP1 (p-values: 0.0016-0.0023) were significantly associated with eRMS risk. The SNPs found to be associated with RMS were located in intergenic and intronic areas of the genes, areas that may influence gene regulation. Our results support the hypothesis that genetic variation in IGF1 signaling pathway modulate the risk of RMS, especially eRMS, among NHW and Hispanic children.
Citation Format: Libby Morimoto, XIaorong Shao, Anand Chokkalingam, Joseph Wiemels, Xiaomei Ma, Catherine Metayer. Pathway analysis of insulin-like growth factor candidate genes and risk of pediatric rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1273. doi:10.1158/1538-7445.AM2017-1273
Abstract 1276: Gene-environment interaction relevant to estrogen and risk of breast cancer
Authors: Park JooYong , Choi Ji-Yeob , Chung Seokang , Song Nan , Park Sue K , Han Wonshik , Noh Dong-Young , Ahn Sei-Hyun , Kim Mi-Kyung , Yoo Keun-Young , Zheng Wei , Kang Daehee 
Published: July 2017

Abstract
Introduction:
Many established reproductive risk factors for breast cancer are mediated by hormonal mechanisms, and most parts are involved in estrogens. In addition, the estrogen level controlled by genetic factors might be a sort of determinants to breast cancer risk involving estrogen metabolism. This study aims to examine gene and environment interaction (GxE) between candidate genes which are involved in estrogen metabolism and environmental factors which are related to estrogen exposure.
Methods:
GxE analyses were conducted in the Korean 1,970 breast cancer cases and 2,052 controls which were recruited in the Seoul Breast Cancer Study (SEBCS), a multicenter case control study. 137 candidate genes involved in estrogen metabolism were searched from couple of databases and 11,555 SNPs (2,472 typed SNPs and 9,083 imputed SNPs) from the range of candidate genes were included in GxE analyses with 8 established environmental factors. Statistical analyses were performed by using GxEScan (ver. Beta 0.4.0; http://biostats.usc.edu/software) for GxE test.
Results:
There were three significant interaction between 11,555 SNPs and 8 environmental factors. Firstly, interaction rs851998 nearby ESR1 with height was shown in the GE|2df model (p-2df = 1.1x10-4) This SNP had protective effect marginally (ORG = 0.82, 95% CI: 0.75-0.90) and further protective effect for women whose height is smaller than 160cm (OR G | height ≥ 160cm = 0.78, 95% CI: 0.70-0.87, p = 1.09x10-5). Second interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2x10-3). This SNP also had protective effect marginally (ORG = 0.85, 95% CI: 0.77-0.97) and more protective effect when age at menarche is 14 years and over (OR G | age at menarche ≥ 14years = 0.82, 95% CI: 0.73-0.97, p=3.6x10-4). Lastly, there was marginally significant interaction between rs4140979 of FSHR and age at first full term pregnancy (FFTP) in the EDGxE model. Although this SNP had no marginal effect, qualitative interaction was shown with FFTP (OR G | FFTP &lt; 27years = 0.88, 95% CI: 0.78-1.00, p=0.0482; OR G | Nulliparity or FFTP ≥ 27 years = 1.30, 95% CI: 1.10-1.53, p=0.002).
Conclusion:
Three significant interactions were identified by focusing two step methods. Replication should be performed in the independent and larger population due to statistical limitation.
Citation Format: JooYong Park, Ji-Yeob Choi, Seokang Chung, Nan Song, Sue K Park, Wonshik Han, Dong-Young Noh, Sei-Hyun Ahn, Mi-Kyung Kim, Keun-Young Yoo, Wei Zheng, Daehee Kang. Gene-environment interaction relevant to estrogen and risk of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1276. doi:10.1158/1538-7445.AM2017-1276