bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B34: Inhibitor of DNA binding (Id) regulates glioma infiltration on myelin tracts by suppressing Nogo receptor 1
Authors: Hong JunHee , Oh Young Taek , Kim Tae Hoon , Park Jong Bae 
Published: May 2017

Abstract
Myelin-associated infiltration is mostly attributed to clinical failure of glioma. Identifying molecular mechanisms and identity of infiltrating cells are major concern in glioma research. Here, we show that stem cell properties of glioma contribute to myelin-associated infiltration by the down-regulation of NgR1, a receptor for myelin-associated inhibitors (MAIs). Inhibitors of DNA binding (Id) proteins, regulators of early neural development, are responsible for down-regulation of NgR1. During differentiation and dedifferentiation of glioma stem cells (GSCs) Id/NgR1 regulation was reversible, and correlated to the infiltrative capacity of GSCs. Remarkably, NgR1 overexpression in mouse xenograft blocks infiltration of GSCs on myelin and significantly increased survival. NgR1 and Id1/4 levels are inversely correlated and low expression of NgR1 portends poor prognosis in glioma patients. Our findings clarify that functional significance of NgR1 regulation and provide first molecular evidence for myelin-associated infiltration. Our work suggests Id-NgR1 axis as a novel prognostic marker and proposes this axis as a potential targets for future therapeutic intervention for the myelin-associated glioma infiltration.
Citation Format: JunHee Hong, Young Taek Oh, Tae Hoon Kim, Jong Bae Park. Inhibitor of DNA binding (Id) regulates glioma infiltration on myelin tracts by suppressing Nogo receptor 1. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B34.
Abstract B46: Activation of TWIST1 by COL11A1 decreases cell sensitivity to paclitaxel by modulating NFκB -mediated Iκκβ expression
Authors: Wu Yi-Hui , Chou Cheng-Yang 
Published: May 2017

Abstract
Background: We have shown that collagen type XI alpha 1 (COL11A1) promotes ovarian tumorigenesis via upregulating the Transforming growth factor beta 1 (TGF-β)/ Matrix metalloproteinases 3 (MMP3) axis and upregulated COL11A1 expression enhanced metastatic potential to the lungs. COL11A1 expression is also associated with chemoresistance to cisplatin and paclitaxel in ovarian cancer cells. In this study, we verified how COL11A1 to regulate twist-related protein 1 (TWIST1) in ovarian cancer cells.
Methods: ES2 and TOV-21G cells transfected with a small interference RNA of COL11A1 (shCOL11A1) and OVCAR3 and OVCAR4 cells transfected with a COL11A1 expression plasmid. Site-directed mutagenesis assay, luciferase assay, chromatin immunoprecipitation assay, immunofluorescence assay, anchorage-independent soft-agar assay, invasion assay and xenograft animal study were performed in this study. COL11A1 and TWIST1 mRNA expression levels of 104 ovarian tumors were determined by real-time RT-PCR.
Results: We found that the level of COL11A1 expression in a panel of ovarian cancer cells was positively correlated with the expressions of TWIST1 and Iκκβ. Mechanistic studies indicated that a decrease in TWIST1 caused by COL11A1-suppressed Iκκβ transcription was achieved by derepression of binding of Sp1 to the Iκκβ promoter. COL11A1-mediated nuclear factor-kappaB (NF-κB) activation, via the activation of Iκκβ transcription, promoted anchorage-independent soft-agar growth, invasion and xenograft tumor formation, which was associated with epithelial-to-mesenchymal transition. In addition, TWIST1 messenger RNA level was positively associated with COL11A1 messenger RNA expression level in ovarian tumors.
Conclusions: COL11A1 activates NF-κB signaling by increasing Iκκβ transcription, which results in progression of ovarian cancer and poorer patient outcomes. We suggest that Iκκβ may potentially be targeted in patients with COL11A1-positive tumors.
Citation Format: Yi-Hui Wu, Cheng-Yang Chou. Activation of TWIST1 by COL11A1 decreases cell sensitivity to paclitaxel by modulating NFκB -mediated Iκκβ expression. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B46.
Abstract IA03: mTORC1/S6K1: Regulation of RNA biogenesis, protein synthesis, and cell metabolism
Authors: Blenis John , Lee Gina , Dempsey Jamie , England Christina 
Published: May 2017

Abstract
The mTOR Complex 1 (mTORC1) signaling pathway has evolved to sense and respond to cellular energy status, nutrient availability and surrounding oxygen concentrations. In addition, mTORC1 signaling can be further activated by mitogen- and hormone-stimulated kinases including Akt, ERK and RSK, and suppressed by mTORC1 and its effector S6K1, via a variety of negative feedback loops. This incredible integration of extracellular and intracellular cues translates into carefully regulated outputs that control cell growth, motility and survival. A major mechanism through which mTOR regulates downstream processes is via the regulation of gene expression, mRNA processing, protein synthesis and protein degradation. In an mTOR phosphoproteomic screen, we and others identified SR Protein Kinase 2 (SRPK2) as a potential downstream effector of mTORC1. I will discuss a novel mechanism by which SRPK2 is regulated and contributes to mTORC1-dependent regulation of lipid metabolism via the regulation of mRNA processing.
Citation Format: John Blenis, Gina Lee, Jamie Dempsey, Christina England. mTORC1/S6K1: Regulation of RNA biogenesis, protein synthesis, and cell metabolism. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA03.
Abstract IA08: Role of the RNA binding protein UNR/CSDE1 in cancer progression
Authors: Gebauer Fatima 
Published: May 2017

Abstract
RNA binding proteins (RBPs) are gaining great attention in cancer research for their potential to regulate essentially every hallmark of tumor development. Yet, the molecular mechanisms that underlie these capacities are unclear, particularly in aggressive cancers such as melanoma, where RBPs remain largely uncharacterized. Here we show that the conserved RBP UNR/CSDE1 is over-expressed in melanoma tumors and promotes invasion and metastasis. iCLIP-Seq, RNA-Seq and ribosome profiling combined with in silico studies unveiled sets of pro-metastatic factors coordinately regulated by UNR as part of RNA regulons. In addition to RNA steady state levels, UNR was found to control many of its targets at the level of translation elongation/ termination. Our results identify UNR as an oncogenic modulator of melanoma progression, unravel the underlying molecular mechanisms, and identify potential targets for this therapeutically challenging malignancy.
Citation Format: Fatima Gebauer. Role of the RNA binding protein UNR/CSDE1 in cancer progression. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA08.
Abstract IA13: Ribosome stalling and disease
Authors: Ackerman Susan L. 
Published: May 2017

Abstract
La Jolla, CA.
Protein synthesis is vital for cell function and disturbances in translation are associated with cancer, neurological disorders and other diseases. Although regulation of translation is thought to largely occur at initiation, elongation, the reiterative addition of amino acids by the ribosome, is emerging as a translational phase that is also highly regulated. Transfer RNAs, the adaptor molecules essential for elongation are encoded by several hundreds of nuclear genes in higher eukaryotes suggesting great functional redundancy. Our work has defined epistatic interactions between mutations in a mammalian tRNA gene and a novel ribosome rescue factor, defining the importance of individual tRNA genes in translation and the pathologies that can arise from disruptions in this process.
Citation Format: Susan L. Ackerman. Ribosome stalling and disease. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA13.
Abstract IA20: Monitoring translation in space and time with ribosome profiling
Authors: Weissman Jonathan 
Published: May 2017

Abstract
The ability to sequence genomes has far outstripped approaches for deciphering the information they encode. We have developed a suite of techniques based on ribosome profiling (deep sequencing of ribosome protected fragments) that dramatically expand our ability to follow translation in vivo. I will present recent applications of our ribosome profiling approach including the following: (1) Development of ribosome profiling protocols for a wide variety of eukaryotic and prokaryotic organisms. (2) Uses of ribosome profiling to globally monitor when chaperones, targeting factors or processing enzymes engage nascent chains. (3) Application of ribosome profiling to define the protein coding potential of complex genomes. (4) The development of a proximity-specific ribosome profiling assay for monitoring subcellular localized translation and its use to follow translation on the surface of the endoplasmic reticulum and mitochondria.
Citation Format: Jonathan Weissman. Monitoring translation in space and time with ribosome profiling. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA20.
Abstract IA27: A kinase inhibitor targeted to mTORC1 drives regression in glioblastoma
Authors: Fan QiWen , Aksoy Ozlem , Wong Robyn , Ilkhanizadeh Shirin , Novotny Chris , Gustafson William , Tuong Albert , Cayanan Geraldine , Simonds Erin , Haas-Kogan Daphne , Phillips Joanna , Nicolaides Theo , Nicolaides Theo , Okaniwa Masanori , Shokat Kevan , Weiss William A. 
Published: May 2017

Abstract
San Francisco, San Francisco, CA.
Glioblastoma (GBM), the most common primary brain tumor, numbers among the most aggressive of cancers. Although signaling from PI3K and AKT to mTOR is dysregulated prominently, we show here that blockade of these upstream targets affects mTOR activity minimally in glioma. Direct targeting using allosteric inhibitors (rapamycin) blocked mTORC1 incompletely, while we also show here that mTOR active site inhibitors (TORKi) have short residence times, limiting their efficacy preclinically. We therefore tested the third-generation mTOR inhbitior RapaLink-1 a TORKi to the mTORC1-specific binding domain of rapamycin, for activity in GBM. RapaLink-1 interacted with FKBP12, an abundant mTOR interacting protein, enabling accumulation of RapaLink-1 in tumor cells. RapaLink-1 showed better efficacy and durability than rapamycin or a TORKi, potently blocking cancer-derived, activating mutants of mTOR. RapaLink-1 drove regression of intracranial xenografts in-vivo, improving survival compared with earlier-generation inhibitors. Our studies re-establish mTOR as a central target in glioma, trace the failure of existing drugs to incomplete/nondurable inhibition of mTORC1, and offer a new class of mTORC1 inhibitors with improved potency and durability.
Citation Format: QiWen Fan, Ozlem Aksoy, Robyn Wong, Shirin Ilkhanizadeh, Chris Novotny, William Gustafson, Albert Tuong, Geraldine Cayanan, Erin Simonds, Daphne Haas-Kogan, Joanna Phillips, Theo Nicolaides, Theo Nicolaides, Masanori Okaniwa, Kevan Shokat, William A. Weiss. A kinase inhibitor targeted to mTORC1 drives regression in glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA27.
Abstract PR04: Translational control of human colon tumor cell survival
Authors: Lemma Eyerusalem M. , McCall Jamie L. , Clymer Beth K. , Kelly David L. , White Michael A. , Lewis Robert E. 
Published: May 2017

Abstract
Kinase Suppressor of Ras 1 (KSR1), a molecular scaffold for the Raf/MEK/ERK kinase cascade, is required for transformation and survival of cells bearing oncogenic Ras, but is not required for normal cell survival. KSR1 knockout mice are phenotypically normal, and depletion of KSR1 by RNAi does not kill immortalized, non-transformed human colon epithelial cells (HCECs), suggesting that KSR1 or KSR1-dependent effectors may serve as highly selective therapeutic targets. Our previous work showed that KSR1 regulates expression of the transcription factor peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1β), whose expression is critical to colon cancer cell survival. Using RNAi and pharmacological inhibition, we observed that KSR1 and ERK drive both cap-dependent and cap-independent translation of Myc in human colon tumor cell lines, which increases PGC1β mRNA expression (McCall et al. MCB, 2016). This effect is mediated through the KSR1 and ERK-dependent phosphorylation of 4E-PB1 and phosphorylation-dependent loss of PDCD4 that reverses their inhibitory effect on eIF4E and eIF4A, respectively. Treatment with ERK inhibitor SCH772984 showed that ERK regulates PDCD4 protein expression and 4EBP1 phosphorylation to promote Myc expression in four of the seven colon cancer cell lines. These observations suggest that KSR1-dependent regulation of translation may be a common mechanism used to support tumor cell survival. Using KSR1 as a reference standard, Functional Signature Ontology (FUSION, Potts et al. Sci. Signaling 2013) was used to identify genetic vulnerabilities in human colon tumor cells that are absent in HCECs. Comparison of results from this screen to genome-wide polysome profiling data from cells transformed with Ras and Myc (Truitt et al. Cell 2015) identified 25 candidate mRNAs with altered translational efficiency that are predicted to support the survival of human colon tumor cells. These data suggest that KSR1 and ERK-dependent alteration of the translational landscape is a common strategy used to support colon tumor cell survival. Identification of mRNAs preferentially translated in colon tumor cells may yield novel targets for therapeutic manipulation and may provide unique markers with which to classify colon tumors, predict patient outcome, and select effective treatment.
This abstract is also being presented as Poster B36.
Citation Format: Eyerusalem M. Lemma, Jamie L. McCall, Beth K. Clymer, David L. Kelly, Michael A. White, Robert E. Lewis. Translational control of human colon tumor cell survival. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr PR04.
Abstract IA02: Mcl-1 inhibitors for the treatment of cancer
Authors: Fesik Stephen W. 
Published: May 2017

Abstract
Myeloid cell leukemia 1 (Mcl-1) is a member of the Bcl-2 family of proteins that is overexpressed and amplified in a wide variety of cancers and causes resistance to many chemotherapies. Although a very promising cancer target, it exerts its activity through protein-protein interactions and is very challenging to drug with small molecules. In this presentation, I will describe the discovery of picomolar Mcl-1 inhibitors using fragment-based methods and structure-based design that show promise as therapeutic agents for the treatment of heme malignancies and solid tumors.
Citation Format: Stephen W. Fesik. Mcl-1 inhibitors for the treatment of cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA02.
Abstract IA05: Autophagy prevents fatal nucleotide pool depletion in Ras-driven cancer cells
Authors: White Eileen 
Published: May 2017

Abstract
Autophagy degrades and recycles proteins and organelles essential for quality control and survival in starvation. In genetically engineered mouse models (GEMMs) for Kras-driven lung cancer, autophagy prevents the accumulation of defective mitochondria and promotes tumor growth and malignancy. Autophagy-deficient tumor-derived cell lines (TDCLs) are respiration impaired, starvation sensitive, and glutamine-dependent. To survive starvation, autophagy may eliminate defective mitochondria or supply mitochondrial substrates. Here, we sequenced the mitochondrial genome from Kras-driven lung tumors and found higher mutant allele frequencies without autophagy-related-7 (Atg7). But the low pathogenic allele frequency was insufficient to account for metabolic defects. In starvation, Atg7 deficiency attenuated substrate supply for mitochondrial oxygen consumption and increased nucleotide degradation. The resulting nucleotide pool depletion and energy crisis in starvation was rescued by nucleoside supplementation. Thus the role for autophagy in Kras-driven tumor cells is to provide substrates to mitochondria to maintain nucleotide pools and energy homeostasis, which promotes survival to nutrient limitation.
Citation Format: Eileen White. Autophagy prevents fatal nucleotide pool depletion in Ras-driven cancer cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA05.
Abstract IA06: Genomic approaches to drug discovery
Authors: Golub Todd R. 
Published: May 2017

Abstract
The principles of genomics (systematic, high throughput approaches to biology) can increasingly be brought to bear on drug discovery. Our group is developing two new approaches: Connectivity Map and PRISM.
The concept of the Connectivity Map (CMap) is that disease states, cellular states and the action of pharmacologic or genetic perturbation can be captured by gene expression profiling. In order to make large-scale perturbational profiling feasible, we developed a high-throughput, ultra-low cost profiling method (named L1000) whereby the abundance of 1000 transcripts are quantified by hybridization to Luminex microspheres. As part of the NIH LINCS program, we have now generated over 2 million such L1000 profiles representing knock-down and over-expression of over 3000 genes and perturbation with over 4000 small molecules in more than 15 cell types. Examples of discoveries emanating from this next generation Connectivity Map will be presented.
The PRISM method takes inspiration from recent large-scale drug sensitivity profiling studies demonstrating the value of determining the pattern of compound killing across a large panel of genetically characterized cancer cell lines. In order to increase the scale at which such studies can be performed, we inserted unique molecular barcodes (24-mer oligonucleotides) into the genomes of cancer cell lines, such that the lines could then be pooled and the pooled lines exposed to a compound of interest. Drug sensitivity is then quantified by changes in abundance of the molecular barcodes. We have demonstrated feasibility of pooling more than 500 cancer cell lines in a single pool, and have demonstrated feasibility of high throughput screening using the PRISM method. These experiments suggest that PRISM can be used as a starting point for oncology drug discovery and for the characterization of lead compounds for the genotype-specific patterns of cancer cell killing. Examples of recent PRISM discoveries will be presented.
Citation Format: Todd R. Golub. Genomic approaches to drug discovery. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA06.
Abstract IA23: Enhancing anti-tumor immunity through selective inhibition of IDO1
Authors: Huber Reid 
Published: May 2017

Abstract
Tryptophan catabolism serves as an important metabolic immunoregulatory checkpoint, functioning in anti-inflammatory, immunosuppressive and tolerance-inducing processes. Three distinct heme-containing enzymes—indoleamine 2,3-dioxygenase (IDO) 1, IDO2 and tryptophan 2,3-dioxygenase (TDO)—have the capacity to initiate the first and rate-limiting step in this metabolic process, catalyzing the conversion of tryptophan to kynurenine. A growing body of scientific evidence indicates that this pathway, and more specifically, the IDO1 enzyme, may be of fundamental importance to tumor immune evasion. Through the depletion of local tryptophan and the production of kynurenine and other downstream metabolites, IDO1 activity has been shown to have an anti-proliferative effect on T cells, to promote Treg differentiation and to bias dendritic cells and macrophages toward an immunosuppressive phenotype. Further, IDO1 expression is a negative prognostic factor across numerous cancer histologies. Therefore, the selective inhibition of IDO1 has emerged as an attractive therapeutic approach to enhance anti-tumor immunity. This presentation will review the immunologic basis for targeting tryptophan catabolism in cancer, describe the emerging preclinical and clinical data on epacadostat, a novel first-in-class selective IDO1 inhibitor, and discuss the therapeutic rationales for epacadostat-based combination immunotherapies.
Citation Format: Reid Huber. Enhancing anti-tumor immunity through selective inhibition of IDO1. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA23.
Abstract IA24: Transcriptional regulators as cancer dependencies
Authors: Vakoc Christopher 
Published: May 2017

Abstract
Broad alterations in the rate of gene transcription are necessary, and often sufficient, for cells to undergo malignant transformation. As a consequence, cancer cells are vulnerable to perturbations of individual transcription regulators, including DNA-binding transcription factors and general cofactors. Our laboratory has taken a functional-genomics approach to identify essential transcriptional regulators in cancer cells in an effort to expose opportunities for therapeutic intervention. Our initial efforts used shRNA screening to identify the BET bromodomain protein BRD4 as a targetable non-oncogene dependency in acute myeloid leukemia. More recently, we have pursued the use CRISPR-Cas9 genome editing as a tool for annotating essential transcriptional regulators in cancer. In my presentation, I will review our current understanding of BRD4 as a therapeutic target in leukemia, focusing on the upstream and downstream factors that support BRD4-dependent transcriptional activation. I will also present our use of CRISPR-Cas9 to identify and validate therapeutic targets in cancer, which exploits the heterogeneity of Cas9-induced indel mutations to infer structure-function relationships of individual protein domains.
Citation Format: Christopher Vakoc. Transcriptional regulators as cancer dependencies. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA24.