bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1533: Transcriptional inhibition of brachyury in chordoma is associated with adoption of quiescent phenotype
Authors: Seldomridge Ashlee N. , Jung Jinkyu , Sonnemann Heather M. , Giles Amber , Meetze Kristan , Gilbert Mark R. , Palena Claudia M. , Park Deric M. 
Published: July 2017

Abstract
BACKGROUND: Brachyury is a mesoderm specification transcription factor involved in notochord development and overexpressed in a variety of cancers, including chordoma. High levels of brachyury protein expression in cancers is associated with a poor prognosis in part due to its role in mediating epithelial-mesenchymal transition (EMT). TG02 is a multikinase inhibitor that targets transcriptional regulation of cyclin-dependent kinases (CDKs). Because chordoma is characterized by a relative paucity of genomic mutations and largely driven by the super-enhancer activity of brachyury expression, we investigated the downstream effect of a transcriptional inhibitor, TG02, in chordomas.
METHODS: Established chordoma cell lines, UCH-1 and UM-Chor1, were exposed to increasing concentrations of TG02 to determine effect on brachyury protein expression. qPCR was used to analyze brachyury mRNA expression as well as the mesenchymal proteins, vimentin and fibronectin, typically associated with brachyury expression in tumor cells. Cell migration was
evaluated using wound healing assay. CellTiterGlo Luminescence Assay was used to quantify cell viability.
RESULTS: TG02 down-regulated protein expression of brachyury in a dose-dependent manner. Attenuation of brachyury expression was seen within 4 hours and persisted for 5 days upon single exposure to a clinically relevant concentration of TG02. Brachyury downregulation did not affect cell count or viability, and was associated with a quiescent phenotype, including impaired migration. Expression of vimentin and fibronectin, both associated with EMT, was also suppressed within 4 hours of TG02 treatment and persisted for 24 hours.
CONCLUSIONS: Inhibition of brachyury expression and its downstream signaling is associated with quiescent behavior of chordoma cells. Pharmacologically induced transcriptional targeting of brachyury using TG02, a potent CDK9 inhibitor, represents a potential therapeutic strategy.
Citation Format: Ashlee N. Seldomridge, Jinkyu Jung, Heather M. Sonnemann, Amber Giles, Kristan Meetze, Mark R. Gilbert, Claudia M. Palena, Deric M. Park. Transcriptional inhibition of brachyury in chordoma is associated with adoption of quiescent phenotype [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 1533. doi:10.1158/1538-7445.AM2017-1533
Abstract 1534: The significance of a p53 gain-of-function mutation in the acquisition of metastatic traits in the SW13 cell line
Authors: Montgomery McKale , Hull Elizabeth 
Published: July 2017

Abstract
The therapeutic potential of histone deacetylase inhibitors (HDACi), shown to epigenetically regulate a variety of genes, has yet to be fully realized due to their documented pleiotropic effects in vivo. Currently, four HDACi are FDA-approved for the treatment of hematological malignancies, but their effectiveness against other types of cancers have been shown to be limited at best and, as a result, most of these clinical trials have failed. A comprehensive review of the recent literature has identified that approximately 50% of all cell lines treated with an HDACi demonstrate an increase in metastatic potential as measured by increases in migration and invasion. Of these cell lines that respond with increased metastatic potential to HDACi treatment, 60% have a gain-of-function mutation within p53 (p=0.03). As HDACi have been shown to destabilize mutant p53, they have been used in studies to examine the effects of HDACi treatment on cancers with an identified p53 mutation. This is concerning as the specific p53 mutation in these cancers is not always known, and thus treatment could potentially result in an increase in cancer cell growth. Previous work in our lab demonstrates that the human SW13 adrenal adenocarcinoma cell line, which harbors a homozygous H193Y gain-of-function mutation, does have an HDACi-induced metastatic phenotype; treated cells demonstrate significant increases in MMP activity and ~50% reduction in p53 protein expression compared to untreated cells. To investigate the role that a decrease in mutant p53 expression plays in the acquisition of metastatic characteristics we utilized stable shRNA plasmids to knock-down p53 expression in the SW13 cell line. HeLa cells, which possess a wild-type p53 gene, were used as a positive control. We found that a decrease in p53 expression alone was not sufficient to induce changes in SW13 growth or invasiveness. In fact, even though p53 expression was knocked down by ~70% in the shRNA lines, HDAC inhibition still induced the acquisition of metastatic properties in these cells. Intriguingly, while the DNA binding activity of mutant p53 was correlated with protein expression and was significantly decreased following HDAC inhibition, the same response was not observed in HeLa cells. These findings suggest that p53 status may be an important determinant of therapeutic response to HDAC inhibition.
Note: This abstract was not presented at the meeting.
Citation Format: McKale Montgomery, Elizabeth Hull. The significance of a p53 gain-of-function mutation in the acquisition of metastatic traits in the SW13 cell line [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 1534. doi:10.1158/1538-7445.AM2017-1534
Abstract 155: Addition of RP6530, a dual PI3Kδ/γ inhibitor, accentuates Romidepsin activity in NHL cells in vitro
Authors: Viswanadha Srikant , Eleswarapu Satyanarayana , Nyayapathy Seeta , Vakkalanka Swaroop 
Published: July 2017

Abstract
Background: Relapsed or refractory Non-Hodgkin’s Lymphoma (NHL) represents a significant unmet medical need. Novel treatment options currently being explored include Romidepsin, a histone deacetylase inhibitor, which has demonstrated significant preclinical and clinical activity. Because the PI3K pathway is often activated in NHL, combining Romidepsin with a PI3K δ/γ inhibitor may be a viable alternative to chemotherapy. RP6530 is a novel, potent, and selective PI3K δ/γ inhibitor that demonstrated high potency against PI3Kδ (IC50=25 nM) and γ (IC50=33 nM) enzymes with selectivity over α (&gt;300-fold) and β (&gt;100-fold) isoforms. Dose-escalation trials to evaluate the safety and efficacy of RP6530 in patients with hematological malignancies are currently underway at several sites in US and Europe. The objective of this study was to evaluate the effect of a combination of Romidepsin and RP6530 in NHL cells.
Methods: Combination of Romidepsin and RPRP6530 was evaluated in the following NHL cell lines: OCI-LY-1, OCI-LY-10, RAJI, DAUDI, TOLEDO, JEKO, MAVER, and SU-DHL-1. Synergism or additivity between Romidepsin and RP6530 was determined using different concentrations of the compounds in a 5 x 5 grid and calculated based on the BLISS score. Effect on apoptosis and cell cycle were estimated by flow cytometry. Phosphorylated AKT and PARP were determined by Western Blotting.
Results: Synergism or additivity between Romidepsin and RP6530 for anti-proliferative activity was noticed in all the cell lines tested with effect being most pronounced in OCI-LY-1, OCI-LY-10, JEKO, and SU-DHL-1. Incubating cells with 3-5 nM Romidepsin and 3 or 5 μM RP6530 resulted in a 2 to 5-fold increase in the total apoptotic population. Cell cycle analysis indicated that the combination of Romidepsin (1-5 nM) and RP6530 (1-5 μM) caused a G0/G1 arrest (2 to 3-fold) with a corresponding increase in percent of apoptotic cells. While Romidepsin had minimal effect of pAKT, treatment with RP6530 reduced expression by 40-90% across cell lines. Further, Romidepsin + RP6530 enhanced expression of cleaved PARP (8 to 60-fold) compared to either agent alone
Conclusions: Addition of RP6530, a potent and selective dual PI3Kδ/γ inhibitor, potentiated Romidepsin activity in NHL cells. Findings provide a rationale for use of the combination in future clinical trials involving naïve or relapsed NHL patients thereby providing a safer alternative to currently available therapy.
Citation Format: Srikant Viswanadha, Satyanarayana Eleswarapu, Seeta Nyayapathy, Swaroop Vakkalanka. Addition of RP6530, a dual PI3Kδ/γ inhibitor, accentuates Romidepsin activity in NHL cells in vitro [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 155. doi:10.1158/1538-7445.AM2017-155
Abstract 1550: Epigenetic downregulation and growth inhibition of IGFBP7 in gastric cancer
Authors: Kim Jin , Kim Min A , Byeon Sun-Ju , Kim Woo Ho 
Published: July 2017

Abstract
Insulin-like growth factor-binding protein 7 (IGFBP7) has been found to be a tumor suppressor in several human cancers, but the role of IGFBP7 in gastric cancer has not yet been fully investigated. In this study, we examined the epigenetic downregulation of IGFBP7 expression in gastric cancer. Analysis by qRT-PCR, western blot, and methylation specific-PCR revealed that DNA methylation was inversely correlated with IGFBP7 expression, and the expression of IGFBP7 was restored after treatment with 5-aza-2'-deoxycytidine. Immunohistochemistry showed that IGFBP7 expression was downregulated in 47.5% of advanced gastric cancer patients. Univariate and multivariate analysis showed that IGFBP7 expression and tumor stage were independent prognostic factors. In cell culture, IGFBP7 knockdown increased gastric cancer cell growth, invasion, and migration, whereas IGFBP7 overexpression in gastric cancer cells showed cell growth inhibition and apoptosis. Our data suggest that IGFBP7 functions as a tumor suppressor in gastric cancer via an epigenetic pathway.
Citation Format: Jin Kim, Min A Kim, Sun-Ju Byeon, Woo Ho Kim. Epigenetic downregulation and growth inhibition of IGFBP7 in gastric 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 1550. doi:10.1158/1538-7445.AM2017-1550
Abstract 1553: Delineating the role of multiple copies of RNA binding domains in human nucleolin and its homologs using a computational approach
Authors: Begum Kamrun , Steinberg Ruchama Chaya , Saxena Anjana , Singh Shaneen 
Published: July 2017

Abstract
All eukaryotes have nucleoli, the sub-nuclear compartments where ribosomes synthesis occur. Nucleolin (NCL), an abundant RNA binding phosphoprotein,constitutes 5-10% of total nucleolar proteins. This multifunctional protein plays defined role/s in many critical cellular processes e.g. chromatin remodeling, ribosome biogenesis, transcriptional and translational regulation of various non-coding as well as coding RNAs. NCL binds to its target RNAs via two or multiple RNA binding domains (RBDs) to control gene expression during normal cell cycle as well as during cellular response to stress. A variety of tumors express elevated levels of NCL where NCL plays a direct role/s in increasing expressions of genes involved in cell survival, angiogenesis and metastasis. A comparison of NCL in various organisms shows that it is highly conserved, especially in its RNA binding domains that can vary in number (2 to 4 consecutive domains). Interestingly, the individual NCL-RBDs are more conserved across different species rather than within the same protein. RBDs are known to interact in pairs with RNA via RNA recognition motifs called RNP motifs, and complementary nucleic acid motifs or elements in RNA allow interaction with NCL. Vertebrate NCL proteins contains four RBDs, however most studies have focused only on the role/s of RDB 1,2; none probing the possible functional redundancy of the additional RBDs nor identifying any target-specificity for the RBD 3,4 in human NCL and other homologs. Earlier data from our lab suggested RBD 3,4 can bind RNA in a structurally analogous manner to RBD1,2 albeit with altered affinity. Here, we continue this research by investigating various homologs of human NCL to better understand the conserved mechanism of its interaction with RNA and whether the additional RBDs, are in fact, redundant in function. To test this hypothesis, RBDs from various homologs were modeled using template based methods and analyzed by a combination of sequence and structure analysis tools. We show that there are key residue differences in individual RBDs from various homologs that potentially manifest as differences in binding affinities. This study reveals new insights into NCL RBD function and describes the evolution of RBD function with respect to nucleic acid binding.
Citation Format: Kamrun Begum, Ruchama Chaya Steinberg, Anjana Saxena, Shaneen Singh. Delineating the role of multiple copies of RNA binding domains in human nucleolin and its homologs using a computational approach [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 1553. doi:10.1158/1538-7445.AM2017-1553
Abstract 1555: Pan-cancer patterns of synthetic lethality: statistical modeling of gene dependency profiles
Authors: Yeerna Huwate , Rangan Ramya , Aguirre Andrew , Kim William , Vazquez Francisca , Weir Barbara , Ghandi Mahmoud , Tsherniak Aviad , Boehm Jesse , Hahn William , Mesirov Jill , Tamayo Pablo 
Published: July 2017

Abstract
We present a methodology to fit statistical models of cell-viability profiles from RNAi-gene knockdowns. This method allows us to classify genes according to the degree of skewness in their viability distributions. The set of genes with the highest degree of skewness is highly enriched with many known oncogenes and tumor suppressors. We characterize many of these genes, compare them against the results of large sequencing efforts, and use them as inputs to a matrix-decomposition procedure that identifies the most salient cell viabilities shared by different cancer types. We catalog these pan-cancer patterns of synthetic lethality and characterize them by the genomic, transcriptional, and phenotypic features. This analysis provides a rich catalog of the most salient Achilles’ Heels of Pan-Cancer that can be helpful to identify new therapeutic strategies across cancers.
Citation Format: Huwate Yeerna, Ramya Rangan, Andrew Aguirre, William Kim, Francisca Vazquez, Barbara Weir, Mahmoud Ghandi, Aviad Tsherniak, Jesse Boehm, William Hahn, Jill Mesirov, Pablo Tamayo. Pan-cancer patterns of synthetic lethality: statistical modeling of gene dependency profiles [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 1555. doi:10.1158/1538-7445.AM2017-1555
Abstract 1563: A machine learning approach to predict platform specific gene essentiality in cancer
Authors: Gilvary Coryandar M. , Madhukar Neel S. , Gayvert Kaitlyn M. , Rickman David S. , Elemento Olivier 
Published: July 2017

Abstract
Loss-of-function (LOF) screenings across a set of diverse cancer cell lines has the potential to reveal novel synthetic lethal interactions, cancer-specific vulnerabilities, and guide treatment options. These were traditionally done using shRNAs, but with the recent emergence of CRISPR technology there has been a shift in methodology. The Achilles project is to date the largest cancer LOF screening effort undertaken, however we found a large amount of inconsistency between their shRNA and CRISPR-Cas9 essentiality results for the same set of cell lines. Here we characterize the differences between genes found to be essential in either CRISPR or shRNA screens. We found that certain features such as gene expression, network connectivity and conservation could accurately separate out essential genes that were found exclusively in either one of these screens. This information could be tremendously useful in understanding the differences in the CRISPR and shRNA screening results. Furthermore, one limitation with Project Achilles was that they conducted shRNA screens on 216 cell lines, but only 33 cell lines in CRISPR. Therefore we developed a model that integrates these genetic, network, and population features to predict CRISPR results from shRNA screenings, and found that our model can accurately identify CRISPR essential genes better than approaches just based on the shRNA results (p-value &lt; 10-5, d-statistic =~0.5 ). This potentially eliminates the need for a costly CRISPR screen, predicts essential genes that would be missed in the shRNA screen, and provides new data on thousands of genes in almost 200 cell lines. Additionally we integrated prior screening results to build a second set of models to predict gene essentiality for untested genes with no LOF screening needed. We found this accurately predicted whether a gene would be marked as essential as well as what type of platform (CRISPR or shRNA) was more likely to accurately identify essentiality. When predicting genes which were exclusively essential in CRISPR we observed an area under the receiver operating characteristic curve (AUC) of 0.82. Overall, these methods allow for a more comprehensive essentiality analysis of genes; which is not possible by single screening platforms.
Citation Format: Coryandar M. Gilvary, Neel S. Madhukar, Kaitlyn M. Gayvert, David S. Rickman, Olivier Elemento. A machine learning approach to predict platform specific gene essentiality in 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 1563. doi:10.1158/1538-7445.AM2017-1563
Abstract 1567: Oncogenesis may result from multiple different combinations of a small number of tumorigenic mutations
Authors: Anandakrishnan Ramu , Varghese Robin , Kinney Nick , Garner Harold R. 
Published: July 2017

Abstract
Cancer is known to result from genetic mutations, both inherited and somatic. Yet, decades of investigation and the availability of extensive genomic data, have failed to reveal the specific mutations that directly result in tumorigenesis for most cancers. One possible reason is that tumorigenesis may result from one or more of multiple different combinations of mutations, while investigators generally search for a single set of mutations. A mathematical model of the probability of “hitting” one of many possible combinations of a small number of mutations was compared to the actual distribution of accumulated mutations at diagnosis as reported on the cancer genome atlas (TCGA). This “multi-combination multi-hit” model reproduces the distribution of accumulated mutations from the TCGA database with surprising accuracy (RMSD = 1.5%) for a model where one or more of 100 different possible combinations of three mutations result in tumorigenesis. We speculate that each of the three mutations affects one of the several genes in three distinct cell proliferation control pathways, such as senescence, apoptosis, autophagy and necrosis, and different combinations of mutations affecting three of these pathways may result in tumorigenesis. We have identified several such combinations for further investigation.
Citation Format: Ramu Anandakrishnan, Robin Varghese, Nick Kinney, Harold R. Garner. Oncogenesis may result from multiple different combinations of a small number of tumorigenic mutations [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 1567. doi:10.1158/1538-7445.AM2017-1567
Abstract 1576: UGT2B17 promotes castration-resistant prostate cancer progression through enhancing ligand-independent AR signaling
Authors: Li Haolong , Xie Ning , Chen Ruiqi , Verreault Mélanie , Fazli Ladan , Gleave Martin E. , Barbier Olivier , Dong Xuesen 
Published: July 2017

Abstract
Background: Castration resistant prostate cancer (CRPC) is characterized by a shift of androgen receptor (AR) signaling from ligand-dependent to ligand-independent. Defining mechanisms that control AR signaling transformation is important to develop therapies for disease control. UDP-glucuronosyltransferase 2B17 (UGT2B17) is a key enzyme that maintains androgen homeostasis by catabolizing AR agonists into inactive forms. Although enhanced UGT2B17 expression by antiandrogens was reported in androgen-independent prostate cancers, its role in regulating AR signaling transformation and CRPC progression remain unknown.
Method and Results: We first evaluated the UGT2B17 protein expression levels by immunohistochemistry (IHC) on Vancouver Prostate Centre tissue microarrays. We show that higher UGT2B17 protein expression in prostate tumors is associated with higher Gleason score, metastasis and CRPC progression. The expression and activity of UGT2B17 are also higher in androgen-independent compared to androgen-dependent cell lines. Interestingly, enzalutamide-resistant MR49F cells expresses low UGT2B17 mRNA but strong protein expression, suggesting that posttranslational mechanisms may enhance UGT2B17 protein stability in these cells. We then constructed PCa cell lines with gain-of-function UGT2B17 by lentivirus. Functional analyses indicate that UGT2B17 stimulates cancer cell proliferation, invasion, and xenograft progression to CRPC after prolonged androgen deprivation. To further decipher the molecular mechanisms by which UGT2B17 enhance PCa cell growth independent of androgen, we performed gene microarray using LNCaP(mock) and LNCaP(UGT2B17) cells cultured under the regular serum condition or the prolonged androgen deprivation condition. Microarray analyses reveal that UGT2B17 suppresses androgen-dependent AR transcriptional activity, while enhancing androgen (ligand)-independent AR transcriptional activity. The latter targets genes associated with cell mitosis. These UGT2B17 actions in reprogramming androgen signaling are mainly mediated by activating the c-Src kinase. We confirmed that, in CRPC tumors, UGT2B17 expression is positively associated with c-Src activation.
Conclusion: These results indicate that UGT2B17 expedites CRPC progression by enhancing ligand-independent AR signaling that activates predominantly cell mitosis in cancer cells.
Citation Format: Haolong Li, Ning Xie, Ruiqi Chen, Mélanie Verreault, Ladan Fazli, Martin E. Gleave, Olivier Barbier, Xuesen Dong. UGT2B17 promotes castration-resistant prostate cancer progression through enhancing ligand-independent AR signaling [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 1576. doi:10.1158/1538-7445.AM2017-1576