bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3421: Serial whole exome sequencing showed the genetic aggravation of refractory osteosarcoma
Authors: Heo Su Jin , Kim Ji Woong , Kwon Woo Sun , Kim Hyo K. , Hong Min Hee , Yang Woo Ick , Kim Se-Kyu , Kim Hyo Song , Chung Hyun Cheol , Hwang Tae Hyun , Rha Sun Young 
Published: May 2015

Abstract
Osteosarcoma is the most common malignant bone tumor in children and adolescents with frequent lung metastasis. As the survival has not been improved with chemotherapy for the last two decades, novel therapeutic approaches are required to efficiently treat osteosarcoma. Genomic analyses have revealed biologically useful information and genetically altered therapeutic targets. The subject of this study was a 25 year old patient with conventional high-grade osteosarcoma with multiple metastasis of lung, lymph nodes and chest wall, who had failed from several palliative systemic chemotherapies and radiotherapy. We performed whole exome sequencing of the gDNA from peripheral blood mononucleated cells (PBMC) and formalin fixed paraffin embedded (FFPE) tissues of primary tumor, secondary (recurrence 1) and tertiary (recurrence 2) metastatic tumors. Samples were sequenced using one lane of paired-end, 100 bp reads on Illumina Hiseq for each sample. Here, we present an analysis result using VarScan and custom-made programs for the detection of somatic mutations and loss of heterozygosity (LOHs) in exome data from changes of genetic variations throughout the disease progression compared to blood germ-line sequencing data. As a result, we observed the 36 common somatic mutated genes, including p73 and TSHR, in three tumor types. And we indentified the somatic mutations affecting the functions of known cancer genes, RBM15, SYNE1, GNAQ and XPA, which were only present in the secondary and/or tertiary metastatic tumors but not in the primary tumor. Especially, GNAQ mutations which is found in the metastatic tumors, is known to be mutated in 50% of melanoma and driven constitutive activity of the MAPK pathway. Therefore, GNAQ mutation in recurrent osteosarcoma patient might be a potential marker for new therapeutic strategies of inhibiting MAPK pathway. In conclusion, the ability to track clonal evolution in cancers may provide new strategies and opportunities for drug development, especially in refractory and rare diseases.
Citation Format: Su Jin Heo, Ji Woong Kim, Woo Sun Kwon, Hyo Ki Kim, Min Hee Hong, Woo Ick Yang, Se-Kyu Kim, Hyo Song Kim, Hyun Cheol Chung, Tae Hyun Hwang, Sun Young Rha. Serial whole exome sequencing showed the genetic aggravation of refractory osteosarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3421. doi:10.1158/1538-7445.AM2014-3421
Abstract 3422: RNAi screening identifies FGFR4 as a modulator of growth and survival in Ewing sarcoma
Authors: Azorsa David O. , Gonzales Irma M. , Arora Shilpi , Hagelstrom R. Tanner , Little Tanya H. , Arceci Robert J. , Mousses Spyro 
Published: May 2015

Abstract
Ewing sarcoma is the second most common cancer of bone and soft tissue arising in children and young adults. Standard treatment of Ewing sarcoma includes surgery, radiation, and chemotherapy largely consisting of combinations of non-targeted cytotoxic agents. Although the survival rate has improved for patients treated for localized disease, the survival rate of patients with metastatic tumor remains lower than 30%. In order to improve therapeutic options for Ewing Sarcoma, we employed a functional genomics approach based on RNA interference (RNAi) screening to identify genes whose silencing affected the proliferation and survival of Ewing sarcoma cells. Four Ewing sarcoma cell lines, TC-32, TC-71, SK-ES-1 and RD-ES, were transfected with a library of siRNA targeting 287 cancer-associated genes. The siRNA screening data were normalized and statistical cut-offs were determined for each cell line. From the list of siRNA ‘hits,’ we identified siRNAs targeting Fibroblast growth factor 4, FGFR4, to be among the most effective in inducing cytotoxicity in Ewing sarcoma cells. Further validation was conducted showing that siRNAs to FGFR4, but not FGFR1, FGFR2, or FGFR3, were able to significantly reduce Ewing Sarcoma cell viability. Furthermore, siRNA targeting FGFR4 were able to induce Caspase 3 activity. FGFR4 protein was shown to be expressed in Ewing sarcoma by western blot analysis, with expression levels lower than FGFR4 expression on rhabdomyosarcoma cells. Targeting FGFR4 activity in Ewing sarcoma cells using a pan-FGFR inhibitor, PD-173074, demonstrated that Ewing sarcoma cells were sensitive to FGFR inhibition. Since FGFR4 in a potential therapeutic target in rhadomyosarcoma, we compared the response of the Ewing sarcoma cells to PD-173074 to that of the rhabdomyosarcoma cell lines, RH-30 and RD. The IC50s of the four Ewing sarcoma cells ranged from 3.8-4.7 µM and were slightly lower than the IC50 for the rhabdomyosarcoma cell lines RH-30 (5.6 µM) and RD (7.9 µM). These results indicate that FGFR4 is a potential therapeutic target in Ewing sarcoma and that FGFR4 targeted therapy should be tested in preclinical xenograft models of Ewing sarcoma.
Citation Format: David O. Azorsa, Irma M. Gonzales, Shilpi Arora, R. Tanner Hagelstrom, Tanya H. Little, Robert J. Arceci, Spyro Mousses. RNAi screening identifies FGFR4 as a modulator of growth and survival in Ewing sarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3422. doi:10.1158/1538-7445.AM2014-3422
Abstract 3429: Synthetic lethal RNAi screens to nominate potential therapeutic combinations for uveal melanoma
Authors: Place Chelsea S. , Cowley Glenn S. , Root David E. , Garraway Levi A. 
Published: May 2015

Abstract
Uveal melanoma (UM) is the most common form of ocular cancer in adults and metastatic disease currently has no effective therapy. Over 80% of UM tumors harbor activating mutations in the heterotrimeric G protein α subunits GNAQ or GNA11. These mutations induce protein kinase C (PKC) and the MAP kinase pathway, which signals through RAF, MEK, and ERK. Clinical trials of MEK and PKC inhibitors are underway to treat UM, however, novel therapeutic strategies may be required for effective treatment. To identify rational combination therapies in the context of MEK or PKC inhibition, we performed a pooled, genome-wide synthetic lethal RNA interference screen. Candidate genes whose silencing sensitizes GNAQ/11-mutant UM cells to MEK or PKC inhibition were nominated and further validated across a panel of cell lines using a custom pool of shRNAs. Several genes scored well across all cell lines. The top MEK inhibitor sensitizer was BRAF, thereby highlighting the importance of MAPK signaling in UM. Several non-MAPK pathway genes were also nominated and may represent novel pathways for the development of combination therapies.
Citation Format: Chelsea S. Place, Glenn S. Cowley, David E. Root, Levi A. Garraway. Synthetic lethal RNAi screens to nominate potential therapeutic combinations for uveal melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3429. doi:10.1158/1538-7445.AM2014-3429
Abstract 3433: ARHGAP30 and DEDD as potential genomic drivers of invasive urothelial carcinomas
Authors: Hong Andrew L. , Riester Markus , Schinzel Anna C. , Schlauch Amy , Adam Rosalyn M. , Kwiatkowski David J. , Rosenberg Jonathan E. , Hahn William C. 
Published: May 2015

Abstract
Background: Urothelial carcinoma (UC) is diagnosed in 72,570 patients annually. 20-30% of these patients have high grade advanced disease. These patients have had historically poor prognosis with 5-year survival rates of 33% and 6% in patients with regional and distant staged disease, respectively. Recent genomic analysis suggests that amplification of 1q23.3 may be associated with poor survival in patients with advanced UC. Using functional genomic screens, we aim to identify the genomic driver(s) of this association.
Methods: First, we created an arrayed shRNA screen with 79 shRNAs targeting 15 genes within this amplification. We studied these effects across 4 and 6 bladder cell lines with and without amplification of 1q23.3, respectively. We then performed secondary screens through the overexpression of these genes. This was performed in 2 UC cells lines without amplification of 1q23.3, RT-4 (grade 1 UC) and RT-112 (grade 2 UC) along with an immortalized bladder cell line, TRT-HU1. These secondary screens include assessment of morphology, proliferation, clonogenicity, anchorage independence by soft agar colony formation, migration and invasion by Boyden chambers, and in-vivo tumor growth.
Results: RIGER analysis of the arrayed shRNA screen identifies DEDD, F11R, ARHGAP30 and PVRL4 knockdown as inducing decreased proliferation (FDR &lt;0.25) when comparing 1q23.3 amplified to non-amplified lines. Overexpression of those genes preliminarily shows: 1) ARHGAP30 overexpression changes the morphology from an epithelial to an amoeboid state in a subpopulation of both cancer cell lines. 2) DEDD overexpression confers a modest proliferative advantage in both UC cell lines. 3) No increased clonogenic potential or invasion/migration is observed when these genes are overexpressed. 4) DEDD and ARHGAP30 confer anchorage independence in RT-112 although this is not seen in RT-4 or TRT-HU1.
Conclusions: ARHGAP30 and DEDD are potential drivers within the amplification of 1q23.3 and possibly mediators of advanced urothelial carcinoma. Detailed biological mechanisms and cooperativity of these genes requires further investigation.
Citation Format: Andrew L. Hong, Markus Riester, Anna C. Schinzel, Amy Schlauch, Rosalyn M. Adam, David J. Kwiatkowski, Jonathan E. Rosenberg, William C. Hahn. ARHGAP30 and DEDD as potential genomic drivers of invasive urothelial carcinomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3433. doi:10.1158/1538-7445.AM2014-3433
Abstract 3437: Differential transcript expression in nasopharyngeal carcinoma by cDNA microarray analysis
Authors: Yip Timothy T.C. , Kwong Dora L.W. , Ngan Roger K.C. , Lim Cadmon K.P. , Cheng Wai Wai , Ma Victor W.S. , Law Stephen C.K. , Tse Loretta 
Published: May 2015

Abstract
By cDNA microarray, expression profiling was carried out in 360 paired tumor & normal biopsies from 60 nasopharyngeal cancer (NPC) patients at 3 time points, namely, at diagnosis of NPC, on treatment with an anti-inflammatory drug, Celecoxib (Celec) and on radiotherapy (RT). We found 1 cluster of 82 transcripts with statistically significant difference in expression between tumor & normal tissues at diagnosis, a second cluster of 214 tumor versus normal transcripts on Celec treatment and finally a third cluster of 202 tumor versus normal transcripts on RT. Differential expression of selected tumor associated transcripts was confirmed by RT-PCR. These include 8 tumor up-regulated transcripts with 3 encoding for immunological/inflammatory molecules, IL8, CXCL9 & CXCL10, 1 matrix metallopeptidase, MMP12, which break down extracellular matrix and thus is associated with cancer metastasis, 1 osteonectin protein which is involved in cell shape changes and thus related to cancer invasion, SPARC, 1 bone morphogenic protein with a role in tissue differentiation, GREM1, 1 GTPase-activating protein for phorbol ester receptor, CHN1 and a sorting nexin family member with a role in intracellular trafficking, SNX10. Genes which were prominently down-regulated in tumor were a variety of polymorphic xenobiotic detoxification enzyme genes or genes with antioxidant function (e.g. GSTA1, GSTA2, GSTA3, CYP4B1, ALDH1A1, ADHFE1, MAOB, NQO1 & OAT) which can detoxify carcinogens or other harmful chemicals or have anti-oxidant effects. Many genes were also down-regulated by RT in tumor tissues and one notable example was TOP2A which encodes topoisomerase 2A involving in chromosome condensation & chromatid separation during DNA replication, CLDN1 which has tight junction adhesion function, ANLN which is required for cytokinesis, and STMN1 which can regulate microtubule filament. These genes had good potential in applying for clinical applications in diagnosis or treatment of NPC in the future. Further exploration of the clinical applications of these genes is underway.
Citation Format: Timothy T.C. Yip, Dora L.W. Kwong, Roger K.C. Ngan, Cadmon K.P. Lim, Wai Wai Cheng, Victor W.S. Ma, Stephen C.K. Law, Loretta Tse. Differential transcript expression in nasopharyngeal carcinoma by cDNA microarray analysis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3437. doi:10.1158/1538-7445.AM2014-3437
Abstract 3438: Integrated analysis of germline and somatic variants in renal clear cell carcinoma
Authors: Wang Jiayin , Lu Charles , Xie Mingchao , Tripathi Piyush , McLellan Michael , Chen Feng , Johnson Kimberly J. , Ding Li 
Published: May 2015

Abstract
Each year in the United States, there are approximately 54,000 new cases of kidney and upper urinary tract cancers and 13,000 deaths. Renal clear cell carcinoma (RCC) is the most common type of kidney cancer comprising more than 75% of cases. It is known that certain genetic syndromes strongly increase risk for renal cell carcinoma including Von Hippel Lindau disease (VHL) that is caused by germline mutations in the VHL tumor suppressor gene. However, there are a large number of cases with familial RCC that are not explained by germline VHL mutations. Publically available data generated through large scale genomic sequencing projects such as The Cancer Genome Atlas (TCGA) provides new opportunities for identifying both known and novel germline cancer susceptibility variants. Moreover, the availability of matched tumor and normal genomic sequencing data from cancer patients (including RCCC) through TCGA allows for integrated analyses of germline and somatic interactions. Toward this end, we analyzed the TCGA exome sequencing data from 499 RCC cases. We employed GATK, VarScan, and Pindel tools to identify germline single nucleotide variants and indels and identified 10,492 candidate germline rare truncation variants (X truncation variants were in cancer genes). All the truncation candidates in commonly mutated cancer driver genes were manually reviewed, resulting in a total of 119 high confidence germline truncation variants in cancer genes. To date, we have identified one nonsense mutation in the VHL gene. In addition, there was one nonsense mutation and a frame-shift deletion in WRN and a nonsense and a splice-site mutation in BAP1, a recently identified RCC predisposition gene. Moreover, we also identified 6,079 candidate missense variants in known cancer driver genes, among a total of 179,066 rare missense variants. Future directions for this project will be to use the burden analysis to determine genes with significant enrichment for deleterious variants. We will also examine loss of heterozygosity patterns to evaluate germline somatic interactions.
Citation Format: Jiayin Wang, Charles Lu, Mingchao Xie, Piyush Tripathi, Michael McLellan, Feng Chen, Kimberly J. Johnson, Li Ding. Integrated analysis of germline and somatic variants in renal clear cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3438. doi:10.1158/1538-7445.AM2014-3438
Abstract 3440: Cell-based screening identify gene expression signature correlated with sensitivity to an MEK1/2 inhibitor
Authors: Zhang Jing 
Published: May 2015

Abstract
The mitogen-activated extracellular signal-regulated kinase (MEK) family is one of the key kinase regulators involved in tumor oncogenic growth and progression. Multiple MEK inhibitors are currently under clinical investigation for cancer treatment and more agents targeting MEK are under preclinical development. The mechanisms underlying resistance to MEK inhibitor are unclear. Here we examined the anti-proliferation activity of a new small molecule MEK inhibitor in a panel of cell lines harboring either ras or raf mutation. We found 23 lines that are sensitive to the inhibitor and 24 lines are resistant. We compared gene expression by Affymetrix U219 arrays and gene copy number by Affymetrix SNP6.0 arrays in these two cell line groups. With a p-value cutoff set at0.01, we identified 549 genes differentially expressed and 328 genes demonstrated different copy numbers between the two groups. 23 genes were both detected by gene expression profiling and gene copy number data. These genes include MEK family members MAP2K3 and MAP2K7, as well as other important molecule markers in cancer biology, including PIK3R2 and BRCA2. The results suggested a potential genomic signature that could be predictive of response to the MEK inhibitor in vitro. Further investigation and validation in patient-derived xenograft (PDX) models will undoubtfully provide valuable information for selecting patients that are likely to receive clinical benefit.
Citation Format: Jing Zhang. Cell-based screening identify gene expression signature correlated with sensitivity to an MEK1/2 inhibitor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3440. doi:10.1158/1538-7445.AM2014-3440
Abstract 3454: Integrin-linked kinase and proximal signaling contributes to the cisplatin resistance of ovarian cancer cells
Authors: Soto Daniel , Valiyeva Fatima , Echevarria Ileabett , Reyes Jeyshka , Vivas-Mejia Pablo E. 
Published: May 2015

Abstract
Platinum-based chemotherapy has been used for more than four decades for ovarian cancer patients. Although initially most ovarian tumors respond well to cisplatin treatment, many of the tumors become resistant to chemotherapy. Several drug resistant-associated genes have been identified by gene expression arrays in drug sensitive and drug resistant cells. Recent evidence indicates that posttranscriptional and posttranslational regulation of gene expression governs the function of several proteins associated with cancer initiation, progression and drug resistance. To reveal additional proteins associated with cisplatin resistance, we performed a proteomic analysis in cisplatin sensitive (A2780) and cisplatin resistant (A2780CP20) ovarian cancer cells. Forty-seven, out of 148 identified proteins, were differentially abundant in A2780CP20 compared with A2780 cancer cells. Western blot analysis was used to confirm the proteomic results. Particularly, the Integrin-Linked Kinase-Associated Serine/Threonine Phosphatase 2C (ILKAP) was decreased in A2780CP20 compared with A2780 cells. The phosphorylation levels of the Integrated-Linked Kinase ILK (the major ILKAP effector), protein kinase B (AKT), and glycogen synthase kinase 3β (GSK3β) (two ILK downstream effectors) were higher in A2780CP20 compared with A2780 cells. Small-interference RNA (siRNA)-targeted ILK, reduced the phosphorylation levels of AKT and GSK3β; and reduced cell proliferation and invasion of the A2780CP20 cells. Most important, combination of inactive ILK-targeted siRNA doses plus inactive cisplatin doses reduced cell growth in a synergistic-like way. These results indicate that protein phosphorylation of the ILK/AKT/GSK3β cascade play a vital role in cisplatin resistance, and propose ILK as a therapeutic target for advanced and drug resistant ovarian cancer.
Citation Format: Daniel Soto, Fatima Valiyeva, Ileabett Echevarria, Jeyshka Reyes, Pablo E. Vivas-Mejia. Integrin-linked kinase and proximal signaling contributes to the cisplatin resistance of ovarian cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3454. doi:10.1158/1538-7445.AM2014-3454
Abstract 3463: Identification and characterization of novel cancer cell derived factors that dictate vascular endothelial cell biology
Authors: Walshe Tony , Bourdelais Justin J. , Lee Arleide , Ouro-Djobo Rakib , Vishnudas Vivek , Kiebish Michael , Sarangarajan Rangaprasad , Narain Niven R. 
Published: May 2015

Abstract
Cell-cell communication in the tumor microenvironment drives tumor growth and facilitates neovessel recruitment from the adjacent vasculature. The aim of these experiments were to identify novel cancer derived factors that modulate the vascular endothelial response in a paracrine manner. An array of cancer cell lines from multiple tissue types (Panc1; Hep2G; LnCap; Skmel; Hep3B; PL45; SCC25; CaCo2; PaCa2; SKBR3) were grown under normoxic or hypoxic (1% oxygen) conditions for a total of 20 conditions. After 48 hours, conditioned media was collected and filtered prior to testing on endothelial cells. The effects of these media on endothelial apoptosis, proliferation and tube formation were investigated. In tandem with these endothelial cell fate assays, the proteomic and lipidomic profile of these 20 conditions were profiled and assessed using the Berg Interrogative Biology™ platform. Our results reveal that conditioned media from all cancer cells tested can alter endothelial cell apoptosis, proliferation rate and tube formation in 3D matrigel assays i.e. critical cell fate decisions that enable formation of nascent vessel formation. Interestingly, the predominant effect of tumor-derived conditioned media on endothelial apoptosis was a protective anti-apoptotic effect, with the discernable exception of normoxic Panc1 derived media. An unexpected finding was the general anti-proliferative effects of tumor-derived conditioned media on endothelial cell growth, with the exception of Hep2G, LnCap and PaCa2 cell derived media. Using a media fractionation strategy and the Berg Interrogative Biology™ platform, we identified several endothelial anti-apoptotic candidates from Panc1 cells within a unique molecular weight range. Upon application of ASO gene knockdown in Panc1 cells, these targets were verified for apoptotic and proliferation effects on vascular endothelial cells.Specific factors that determine paracrine cell-cell interaction in the tumor microenvironment have been identified and validated using the Berg Interrogative Biology™ platform.
Citation Format: Tony Walshe, Justin J. Bourdelais, Arleide Lee, Rakib Ouro-Djobo, Vivek Vishnudas, Michael Kiebish, Rangaprasad Sarangarajan, Niven R. Narain. Identification and characterization of novel cancer cell derived factors that dictate vascular endothelial cell biology. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3463. doi:10.1158/1538-7445.AM2014-3463