bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1421: Evaluation of DDR-targeting strategy using ATR inhibitor in biliary tract cancer
Authors: Nam Ah Rong , Park Ji Eun , Bang Ju Hee , Jin Mei Hua , Oh Do Youn , Bang Yung Jue 
Published: July 2017

Abstract
Background: The DNA damage response (DDR) is a multicomplex network of signaling pathways involved in DNA damage repair, cell cycle checkpoints and apoptosis. The ataxia telangiectasia and Rad3-related (ATR) protein kinase is a key enzyme in the DDR that activates checkpoint kinase 1 (Chk1), resulting in cell cycle arrest. Tumor types with loss of ATM function and/or high replication stress are expected to be more susceptible to DDR targeting. In biliary tract cancer (BTC), DNA repair pathway, which includes BAP1, MSH6, BRCA1, ATM, MLH1, MSH2, is altered in about 20 % of cases. TP53 module is observed in 33.9% of BTC cases (Nat Genet 2015). The purpose of this study is to test DDR targeting strategy using ATR inhibitor in biliary tract cancer.
Methods: Using 9 kinds of BTC cells, MTT assay and colony formation assay were done for determining growth inhibitory effect of AZD6738, an ATR inhibitor. Cell cycle analysis was done by FACS Calibur flow cytometer and the methods described by Chou and Talalay were used to determine whether a synergistic effect existed between AZD6738 and cytotoxic chemotherapeutic agents (cisplatin, 5-FU, gemcitabine). The alkaline comet assay was done to measure of DNA damage in individual cells. Tumor xenografts model was used for in vivo test of AZD6738.
Results: Among 9 BTC cells, SNU478 and SNU869 were most sensitive to AZD6738, which showed low expression of both ATM and p53. AZD6738 blocked ATR-mediated Chk1 phosphorylation and increased rH2AX, a marker of DNA damage, in sensitive cells. AZD6738 significantly increased apoptosis (cleavage of PARP and caspase-7) and G2/M arrest, increased level of p21, and decreased cdc2. In addition, combination of AZD6738 and cytotoxic chemotherapeutic agents demonstrated synergistic effects in colony formation assay, cell cycle analysis and comet assay. In xenograft model of SNU478, AZD6738 monotherapy decreased tumor growth. The combination of AZD6738 and cisplatin showed more potent growth inhibitory effects, decreased Ki67, increased Tunel than monotherapy of each drug.
Conclusion: In BTC, DDR targeting strategy using ATR inhibitor demonstrated promising antitumor activity alone or in combination with cytotoxic chemotherapeutic agents. This supports further clinical development of DDR targeting strategy in BTC.
Citation Format: Ah Rong Nam, Ji Eun Park, Ju Hee Bang, Mei Hua Jin, Do Youn Oh, Yung Jue Bang. Evaluation of DDR-targeting strategy using ATR inhibitor in biliary tract 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 1421. doi:10.1158/1538-7445.AM2017-1421
Abstract 1426: Blinding the CYCLOPS - Cancer vulnerabilities unveiled by genomic loss
Authors: Torkov Alica , Henrich Kai-Oliver , Shao Chunxuan , Gartlgruber Moritz , Westermann Frank 
Published: July 2017

Abstract
Background:
Heterozygous deletions within distal 1p are observed in 30% of neuroblastomas. So far, several potential 1p tumor suppressor genes have been identified. However, in this study we are focussing on 1p genes whose inactivation is not necessarily linked to tumor development but which mediate cell-essential functions, rendering cells with copy number loss vulnerable to further impairment. These genes are candidate therapeutic targets according to the concept of CYCLOPS (copy number alterations yielding cancer liabilities owing to partial loss).
Methods:
To identify a subset of 1p genes for which heterozygous loss may be tolerated but further reduction leads to cell death, we performed siRNA screens mediating the systematic knock-down of distal 1p genes in five 1p-deleted versus five non-1p-deleted neuroblastoma cell lines. We used 3 different siRNAs per gene in a liquid forward approach. After 96h Hoechst stained nuclei were count. Among others, a neuron-related candidate gene has been identified as a potential CYCLOPS. The candidate gene was validated by viability assays, immunocytochemistry and cell cycle analysis via FACS.
Results:
We identified many potential CYCLOPS genes mapping on the distal end of chromosome arm 1p. One of these genes is involved in neuronal and embryonic development and has been further validated. Knock-down of the gene impaired cell viability in 1p-deleted cell lines but did not in 1p-non-deleted cells. G1/G0 phase arrest with corresponding S phase decrease was observed in both 1p-deleted and 1p-non-deleted cells. Additionally, neurite-like outgrowth could be observed in 1p-non-deleted cells indicating an induction of differentiation.
Conclusion:
This study identified a candidate CYCLOPS gene in neuroblastoma. Heterozygous deletions of chromosome arm 1p are also frequently observed in other cancers including melanoma, colorectal and breast cancer. We hypothesize that this proof-of-principle opens a new therapeutic window for tumors harbouring a heterozygous deletion of our candidate gene or other cell essential genes on chromosome arm 1p.
Citation Format: Alica Torkov, Kai-Oliver Henrich, Chunxuan Shao, Moritz Gartlgruber, Frank Westermann. Blinding the CYCLOPS - Cancer vulnerabilities unveiled by genomic loss [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 1426. doi:10.1158/1538-7445.AM2017-1426
Abstract 1430: The spliceosome U2 snRNP factors promote genome stability through distinct mechanisms; transcription of repair factors and R-loop processing
Authors: Tanikawa Michihiro 
Published: July 2017

Abstract
(Objective)Recent whole-exome sequencing studies of malignancies have detected recurrent somatic mutations in U2 snRNP components of the spliceosome. These factors have also been listed as novel players of DNA damage response in several genome wide screens and proteome analysis for DDR genes. Although accumulating evidences have implied that the spliceosome plays an important role in genome stability and is an emerging hallmark of carcinogenic pathways, its precise role in genome stability still remains ambiguous. The aim of this study is to clarify the functions of U2 snRNP splicing factors, especially SNRPA1 (Small Nuclear Ribonucleoprotein Polypeptide A1) in DDR pathway.
(Methods)SNAPA1 and other U2 snRNP splicing factors were identified as HR repair genes by genome-wide screens based on homologous recombination and RAD51 immunofoci formation. Each splicing factor was depleted by siRNA knockdown in USOS cells. The functions of SNRPA1 in DNA repair were analyzed by HR assay (DR-GFP assay), immunofluorescence, real-time laser micro-irradiation and comet assay (single cell gel electrophoresis).
(Results)HR assay showed strong HR deficiencies in splicing factor's depleted cells. In these cells, accumulation of BRCA1 and Rad51, major HR factors, to DNA damage sites were severely impaired. Especially, live cell imaging showed recruitment of SNRPA1 to laser induced DNA damage sites and unveiled its direct involvement to DNA damage repair. Comet assay also showed that depletion of SNRPA1 markedly caused DNA damage with the tail of broken DNA fragments. This DNA damage was R-loop (DNA-RNA hybrid) mediated DNA damage and rescued by overexpression of RNAseH1.
(Conclusion) Here we unveiled two distinct pathways how spliceosome U2 snRNP factors contribute to genome stability. The main function is indirect, through transcription, to maintain the protein levels of essential repair factors and contribute to homologous recombination repair. Our data suggest that depletion of splicing factors can be one mechanism for HR deficiency (i.e. BRCAness). In addition real-time laser microirradiation analysis identified the rapid recruitment of SNRPA1 to DNA damage sites. Intensive functional analysis of SNRPA1 unveiled the other, more immediate and direct effect to process R-loop structure, deleterious transcriptional by-products for the genome, at sites of on-going transcription.
Citation Format: Michihiro Tanikawa. The spliceosome U2 snRNP factors promote genome stability through distinct mechanisms; transcription of repair factors and R-loop processing [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 1430. doi:10.1158/1538-7445.AM2017-1430
Abstract 1435: Immune/inflammatory polymorphisms predict lung cancer survival
Authors: Watza Donovan , Lusk Chrissy , Wenzlaff Angie , Neslund-Dudas Christine , Dyson Gregory , Soubani Ayman , Gadgeel Shirish , Schwartz Ann G. 
Published: July 2017

Abstract
Lung cancer is the leading cause of cancer related mortality in the United States, with a median five year survival of ~16%. Recent advancements in the treatment of lung cancer focus on modulating the immune system to improve patient outcomes with markedly reduced toxicity profiles. This study aims to investigate single nucleotide polymorphisms (SNPs) within functional units of the immune system genome to identify genetic markers indicative of overall survival in a cohort of metropolitan Detroit lung cancer patients. This cohort presents a unique population of lung cancer patients for analysis, consisting of 40% African Americans, whom are known to have worse outcomes than their Caucasian counterparts. To assess SNPs within functional units of the immune genome, a hierarchical immune system gene and pathway list was constructed, incorporating genes and pathway identifiers from the Reactome database as well as previous genetic and inflammatory specific cancer studies to generate a well curated gene and pathway dataset. Genomic locations for the genes, together with proximal regulatory regions, were obtained from the UCSC genome browser for cross-referencing with the Illumina MEGA SNP array to generate SNPs for inclusion. Preliminary analysis of 848 NSCLC patients in association with 29,126 immune specific SNPs identified six SNPs as significantly associated with survival (p-value &lt;10-4) in this lung cancer cohort, implicating the following six genes, PXN, GFRA3, HLA-DQA1, KSR2, BTBD1, and ATF2; although further gene/pathway analysis is necessary to elucidate how these associations interact in the context of genes and pathways of the immune system. PXN over expression has been previously implicated in both high risk lung epithelial dysplasia as well as in the development of lung adenocarcinoma in prior clinical studies. Additionally, GFRA3 has been identified as an activator of the RET kinase and increased GFRA3 activity in context of the Artemin pathway is a known promoter of NSCLC progression. As well, select polymorphisms in the HLA-DQA1 gene are known clinical modifiers of lung squamous cell carcinoma risk. Finally, ATF2 is a broadly active transcription factor and ATF2 upregulation has been associated with tumorigenesis and metastasis in both cell models and patient tumor samples in multiple cancer studies. The previous association of these genes in lung cancer is promising and further immune system gene/pathway analysis is warranted.
Citation Format: Donovan Watza, Chrissy Lusk, Angie Wenzlaff, Christine Neslund-Dudas, Gregory Dyson, Ayman Soubani, Shirish Gadgeel, Ann G. Schwartz. Immune/inflammatory polymorphisms predict lung cancer survival [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 1435. doi:10.1158/1538-7445.AM2017-1435
Abstract 144: Src leads to a novel mechanism of resistance to PI3K inhibitors through regulation of PI3K/p85 activation
Authors: Kim Gui Chul , Nam Hae Yun , Lee Hyang Ju , Kim Min Kyung , Lee Geun Hee , Han Myung Woul , KIM Seong Who , Kim Sang Yoon 
Published: July 2017

Abstract
Activation of the PI3K pathway is commonly observed and is correlated with tumor development, progression, poor prognosis, and resistance to cancer therapies, such as radiotherapy, in most cancers. As a central node of this pathway, PI3K is an attractive target for PI3K-addicted cancer therapy and PI3K inhibitors may thus restore sensitivity to other treatments when administered as part of combination regimens. Here, we found that PI3K/p85 was expressed predominantly in the radioresistant head and neck cancer cell line (HN31 cell line). And then, we investigated whether PI3K modulation was crucial for the development of novel treatment strategies for radioresistant cancer cell line. Interestingly, we found that head and neck cancer cell lines with PI3K/p85 activation showed the resistance to PI3K inhibitors and the resistance mechanism was associated with Src activation which is a member of a superfamily of membrane-associated nonreceptor protein tyrosine kinases. Src inhibitor improves the efficacy of PI3K inhibitor treatment through suppression of Src and PI3K/p85 activation in HN31 cell line. Collectively, our study highlights the role of p85 and Src activation in the resistance for PI3K inhibition and the potential clinical application of combination regimens of Src and PI3K inhibitors in head and neck cancers. This is the first investigation to analyze the role of Src in resistance to the PI3K inhibitors of head and neck cancer. As a consequence, a greater understanding of resistance mechanisms through our results will enable the rational design of combination regimens and sequential treatment algorithms to improve clinical outcomes.
Citation Format: Gui Chul Kim, Hae Yun Nam, Hyang Ju Lee, Min Kyung Kim, Geun Hee Lee, Myung Woul Han, Seong Who KIM, Sang Yoon Kim. Src leads to a novel mechanism of resistance to PI3K inhibitors through regulation of PI3K/p85 activation [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 144. doi:10.1158/1538-7445.AM2017-144
Abstract 1446: Super-enhancer identification via Bru/BrUV-Seq and H3K27Ac ChIP-Seq
Authors: Tang Chunlao , Yadav Vipin , Qian Hui-Rong , Cunningham Jason B. , Gao Hong , Liu Yushi , Ting Jason C. , Bray Steven M. , Ebert Philip J. , Lin Yuhao , Aggarwal Amit , Calley John N. , Patel Bharvin K. 
Published: July 2017

Abstract
Transcriptional super-enhancers (SEs) are large clusters of active enhancers that drive expression of genes critical to cell identity and function. In cancer and other human diseases, SEs can be acquired through somatic aberrations. Importantly, SEs and their target genes are particularly sensitive to perturbation, making this mechanism a promising target for both diagnosis and therapy. Histone modification H3K27Ac is a good single predicative marker of active enhancers, though additional marks would help. Accordingly, a common approach to SE identification is using H3K27Ac ChIP-Seq. The non-TSS (transcription start site) histone binding sites (e.g., principally excluding TSS±2.5kb regions) are mapped to genome and then subject to near-neighbor stitching (e.g., within 12.5kb). From the resulted relatively broad regions, SEs are identified by exceptional binding enrichment. Another potentially powerful approach is to use Bru/BrUV-Seq in combination. By directional sequencing of bromouridine(Bru)-labeled nascent RNAs, Bru-Seq has been developed to study nascent transcription. In the derivative BrUV-Seq, UV irradiation is additionally conducted to stabilize transcripts prior to labeling, thereby allowing more sensitive detection of TSSs and unstable transcripts, including enhancer RNAs (eRNAs). It has been shown that eRNAs indicate enhancer activity better than H3K27Ac binding. In this study, both approaches were used to identify SEs for three colon cancer cell lines, HCT-116, SW48, and SW620. We have demonstrated that Bru/BrUV-Seq has advantages in differentiating between mRNAs and eRNAs, and between overlapping transcripts; the reduced complexity helps prevent false identifications, which inflated our results obtained from ChIP-Seq.
Citation Format: Chunlao Tang, Vipin Yadav, Hui-Rong Qian, Jason B. Cunningham, Hong Gao, Yushi Liu, Jason C. Ting, Steven M. Bray, Philip J. Ebert, Yuhao Lin, Amit Aggarwal, John N. Calley, Bharvin K. Patel. Super-enhancer identification via Bru/BrUV-Seq and H3K27Ac ChIP-Seq [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 1446. doi:10.1158/1538-7445.AM2017-1446
Abstract 1448: Unraveling the oncogenic pathway of serrated polyposis syndrome driven by RNF43 germline mutation
Authors: Yan Helen Hoi Ning , Lai Jeffrey C W , Ho Siu Lun , Chan Anthony K W , Tsui Wai Yin , Chan Annie S Y , Yuen Siu Tsan , Leung Suet Yi 
Published: July 2017

Abstract
Serrated polyps can arise in a sporadic or familial polyposis setting and predispose to colorectal cancer (CRC). Recently, we have identified RNF43 germline mutation in a family with Serrated Polyposis Syndrome (Yan et al, GUT 2016). The presence of second somatic hit in all serrated polyps examined from members of this family further confirmed the pathogenicity of RNF43 germline mutation. In an attempt to further delineate the global genomic alterations in these serrated polyps, so as to understand the RNF43 driven serrated neoplasia pathway for the development of colorectal cancer, we performed whole exome sequencing (WES) on two sessile serrated adenomas (SSAs) resected from an RNF43 germline mutation carrier, together with the paired blood DNA. Consistent with the results from our previous Sanger sequencing study, WES detected complete inactivation of RNF43 through a 2nd hit somatic mutation, c.461 C&gt;T P154L, or loss of heterozygosity (LOH) in the two SSAs, respectively. We also identified 51 and 58 somatic mutations in the two SSAs, respectively. BRAFV600E mutation was the only shared mutation between the two polyps. Interestingly, each of the SSAs carried a truncating mutation in a histone-methyltransferase gene, either PRDM9 or SETD1B, respectively. Other truncating or deleterious mutations included chromatin modifiers (CHD2, CHD4, TSPYL2) or other genes with methyltransferase activity (TRMT2B, METTL12, METTL14, ECE2). In addition, we found few instances of chromosomal aberration or LOH, apart from a region of LOH at chromosome 17 encompassing RNF43 in one of the SSAs.
Overall, we have revealed the genomic landscape of two sessile serrated adenomas resected from a germline RNF43 mutation carrier. The results confirmed somatic RNF43 2nd hit and BRAFV600E mutation as the key events, along with putative roles for histone methyltransferase, as well as other chromatin modifiers. These findings highlight the potentially important role of an altered chromatin in the oncogenic pathway of serrated neoplasia.
Citation Format: Helen Hoi Ning Yan, Jeffrey C W Lai, Siu Lun Ho, Anthony K W Chan, Wai Yin Tsui, Annie S Y Chan, Siu Tsan Yuen, Suet Yi Leung. Unraveling the oncogenic pathway of serrated polyposis syndrome driven by RNF43 germline mutation [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 1448. doi:10.1158/1538-7445.AM2017-1448
Abstract 145: PIK3CB inhibitors selectively block the survival of glioblastoma cells
Authors: Le Lamvy , Sheng Zhi 
Published: July 2017

Abstract
Objective: To explore the divergent role of PI3K isoforms in glioblastoma
Background: Glioblastoma multiforme is the most malignant brain tumor in adults. Despite aggressive treatments, the median survival and five-year overall survival of glioblastoma patients remains low (14.6 months and 4.7%, respectively). Nearly 90% of patients experience recurrence within two years, leaving patients with few treatment options. Recently, PI3K pan inhibitors have been used to treat recurrent glioblastoma and achieved modest effect in the clinic. PI3K has four catalytic isoforms (PIK3CA, B, D, and G); hence, it is possible that these isoforms may have different roles in glioblastoma and need to be selectively targeted. This idea is further supported by our recent results, in which we have shown that elevated expression of PIK3CB, but not other PI3K isoforms, significantly correlated with higher rate, risk, and poor prognosis of recurrent glioblastomas. Hence, we hypothesize that PIK3CB-selective inhibitors are more effective for glioblastoma.
Design/Methods: We used a panel of glioblastoma cells with different levels of PIK3CB, treated them with PI3K-isoform-selective inhibitors, and compared them to pan PI3K inhibitors. We measured cell viability using the MTS cell viability assay. Normal human astrocytes were used as controls to determine toxicity.
Results: We found that PIK3CB inhibitors TGX-221 and GSK2636771 significantly blocked the proliferation of PIK3CB-high U87MG and SF295 cells, while it had no effect on the viability of PIK3CB-low A172 and LN229 cells. In contrast, other PI3K inhibitors and pan inhibitors either non-selectively blocked or had no effect on these cells. Importantly, these compounds, but not PIK3CB inhibitors, blocked the growth of astrocytes.
Conclusions: Selective blockade of PIK3CB, but not other PI3K isoforms, is an effective therapy for glioblastoma with a low toxicity to normal tissues.
Citation Format: Lamvy Le, Zhi Sheng. PIK3CB inhibitors selectively block the survival of glioblastoma cells [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 145. doi:10.1158/1538-7445.AM2017-145