bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B36: The role of dUTPase in ribonucleotide reductase-driven tumorigenesis and tumor progression
Authors: Chang Zee-Fen 
Published: August 2014

Abstract
Regulation of enzymes in nucleotide synthesis plays a critical role in DNA replication and repair. Ribonucleotide reductase (RNR) is the key enzyme that controls the de novo synthesis of all four dNTPs, and the expression of RRM2 subunit of RNR is often elevated in malignant tumor cells. Our previous study has demonstrated that RNR contributes to dUTP mis-incorporation in DNA repair when dTTP supply is deficient. In this study, we investigated the relationship between the expression level of RRM2 and dUTP pyrophosphatase(dUTPase) and tumor progression. Immunohistochemistry staining of surgical tumors from colorectal cancer (CRC) patients showed that high RRM2/low dUTPase correlates with poorer overall survival. We further analyzed the interplay of RRM2 and dUTPase in genome stress and cellular transformation. Our results revealed that constitutive elevation of RRM2 in normal fibroblasts promotes replication stress, as indicated by 53BP foci, and cellular transformation, both of which are prevented by co-expression of dUTPase. Knockdown of dUTPase in cancer cells containing high levels of RRM2 and dUTPase also increased replication stress. We proposed that the context of high RRM2/low dUTPase confers cancer cells replication stress to drive tumorigenesis and might serve as a prognostic indicator.
Citation Format: Zee-Fen Chang. The role of dUTPase in ribonucleotide reductase-driven tumorigenesis and tumor progression. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr B36.
Abstract IA11: Identification of therapeutic targets for MYC-driven cancers by functional genomics
Authors: Toyoshima Masafumi , Jang In Sock , Cermelli Silvia , Bernard Brady , Grandori Carla 
Published: August 2014

Abstract
The development of small molecules targeting MYC oncoproteins specifically in cancer cells has been a challenge, as MYC are DNA binding proteins required for proliferation of normal tissues. To circumvent these difficulties, we identified synthetic lethal interactions with MYC over-expression by high throughput siRNA screening (Toyoshima et al, 2012).
Here, we will present validation of specific MYC-synthetic lethal genes (MYC-SL) in MYCN amplified neuroblastoma and ovarian cancer with high level of MYC using both RNAi approaches as well as small molecule inhibitors. To prioritize genes for future drug development, we carried out meta-analysis of genomic tumor data and obtained statistical significant associations between MYC alterations (i.e. gene amplification or overexpression) for selected MYC-SL genes. We also addressed the need of identifying biomarkers to stratify patients with solid tumors for activation of MYC and we will discuss the challenges and potential strategies, with particular focus on ovarian and breast cancers.
Finally, to obtain a more global view of critical pathways that MYC-SL genes we performed network analysis of our targets. This analysis revealed that major points of vulnerabilities are linked to transcription and chromatin remodeling processes, DNA repair and cell-cycle checkpoints and metabolic functions. In addition, developmental, signaling and differentiation pathways represent unforeseen dependencies of MYC overexpressing cells. Altogether, these results provide a broad menu for therapeutic interventions to target MYC-driven cancers.
*Current affiliation: Tohoku University School of Medicine, Sendai, Japan.
Citation Format: Masafumi Toyoshima, In Sock Jang, Silvia Cermelli, Brady Bernard, Carla Grandori. Identification of therapeutic targets for MYC-driven cancers by functional genomics. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr IA11.
Abstract IA14: Harnessing genetic dependencies in cancer therapy
Authors: Ashworth Alan 
Published: August 2014

Abstract
The design of targeted therapeutic strategies for cancer has largely been driven by the identification of tumor-specific genetic changes. However, the large number of genetic alterations present in tumor cells means that it is difficult to discriminate between genes that are critical for maintaining the disease state and those that are merely coincidental. Even when critical genes can be identified, directly targeting these is often challenging. We have exploited principles utilized for many years in model organisms to address these issues. Here I will describe particular examples of the use of synthetic lethality in cancer therapy. In addition, I will discuss high-throughput screening strategies to identify genetic dependencies in tumors.
Citation Format: Alan Ashworth. Harnessing genetic dependencies in cancer therapy. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr IA14.
Abstract IA16: Large-scale systematic explorations of single and combined drug responses to suggest anticancer drugs and overcome resistance
Authors: Lehar Joseph 
Published: August 2014

Abstract
Novartis is undertaking a large-scale effort to comprehensively describe cancer through the lens of cell cultures and tissue samples. In collaboration with academic and industrial partners, we have generated mutation status, gene copy number, and gene expression data for a library of 1,000 cancer cell lines, representing most cancer lineages and common genetic backgrounds. Most of these cell lines have been tested for chemosensitivity against ~1,200 cancer-relevant compounds, and we are systematically exploring drug combinations for synergy against ~100 prioritized CCLE lines. We expect this large-scale campaign to enable efficient patient selection for clinical trials on existing cancer drugs, reveal many therapeutically promising drug synergies or anti-resistance combinations, and provide unprecedented detail on functional interactions between cancer signaling pathways. I will discuss early highlights of this work and describe our plans to make use of this resource.
Citation Format: Joseph Lehar. Large-scale systematic explorations of single and combined drug responses to suggest anticancer drugs and overcome resistance. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr IA16.
Abstract PR02: Targeting altered SWI/SNF function through synthetic lethal RNAi screening
Authors: Conery Andrew R. , Neiss Adrianne , Hatton Charlie , Bryant Barbara M. , Sims Robert J. 
Published: August 2014

Abstract
The SWI/SNF family of chromatin remodeling complexes is critical for the mobilization of nucleosomes during transcription, DNA replication and repair, and cell division. SWI/SNF consists of a central ATPase subunit (BRG1 or BRM) and 10-12 additional subunits whose identity lends specificity to the complex. Abundant genomic data indicates that SWI/SNF components are frequent targets of homozygous loss of function mutations in a variety of tumor types. These loss of function mutations alter the composition and activity of the SWI/SNF complex, resulting in a tumor-specific chromatin state. In this work we describe a strategy for targeting this tumor-specific chromatin state using synthetic lethal RNAi screening. We have assembled and validated a focused shRNA library targeting 120 factors that act on chromatin, including histone methyltransferases, histone demethylases, and bromodomain-containing proteins. The Constellation shRNA library was transduced into several cell lines containing mutations in SWI/SNF components in addition to a panel of reference cell lines in order to identify factors that are specifically essential in those cell lines with altered SWI/SNF activity. Primary screening generated a list of genes that are potentially synthetically lethal with loss of function mutations in SWI/SNF components. Experiments are underway to confirm these genetic relationships and to obtain mechanistic insight into the role of these relationships in the context of chromatin biology. Most importantly, we will evaluate these genes as novel therapeutic targets in cancers with altered SWI/SNF function.
This abstract is also presented as Poster A19.
Citation Format: Andrew R. Conery, Adrianne Neiss, Charlie Hatton, Barbara M. Bryant, Robert J. Sims, III. Targeting altered SWI/SNF function through synthetic lethal RNAi screening. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr PR02.
Abstract PR07: Synthetic lethal screens in zebrafish
Authors: Sidi Samuel 
Published: August 2014

Abstract
The zebrafish embryo enables high-content screens in the intact, whole vertebrate. The system is particularly amenable to drug screening (up to 96-well format), and the mechanism of action of identified compounds can be readily dissected via morpholino or mRNA microinjections in live embryos (Sidi et al., Cell 133:864-77, 2008). We are exploiting zebrafish lines bearing cancer-relevant mutations (e.g., p53, pten, brca2 mutants) as platforms for synthetic lethal screens, focusing mainly on libraries of kinase inhibitors or FDA-approved compounds. Drugs that selectively induce cell lethality in mutant but not wild-type embryos are rescreened against panels of genetically annotated human cancer cell lines. A key advantage of the whole-embryo approach is the ability to identify those cell- or tissue-types in which the synthetic interaction occurs, thus guiding our human cancer cell-based validation screens. We will discuss the results of our large-scale screens targeted to p53, performed in the presence or absence of ionizing radiation-induced DNA damage.
This abstract is also presented as Poster A11.
Citation Format: Samuel Sidi. Synthetic lethal screens in zebrafish. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr PR07.
Abstract PR08: Identifying effectors of WT1 that regulate KRAS-induced senescence and chemoresistance in non-small cell lung cancer
Authors: Chen Ron , Simpson David R. , Zheng Yanyan , Vaka Dedeepya , Vicent Silvestre , Sweet-Cordero Alejandro 
Published: August 2014

Abstract
Activating KRAS mutations occur frequently in non-small cell lung cancer (NSCLC), and are associated with poor response to chemotherapy and overall survival. We previously used an oncogenic KRAS gene expression signature as the basis for a negative selection screen for synthetic lethal interactions with mutant KRAS. We identified WT1 as a transcription factor that bypasses oncogene-induced senescence caused by KRAS signaling. Based upon the success of this approach, we derived an improved oncogenic KRAS signature using a novel strategy that compares gene expression in sorted primary mouse tumor cells to human NSCLC gene expression datasets to predict transcription factors that are potential effectors of KRAS. Based on these bioinformatic predictions, we conducted a pooled shRNA negative selection screen in a panel of KRAS mutant and wild-type NSCLC cell lines, which validated known mutant KRAS synthetically lethal partners such as WT1 and TBK1, and identified novel candidates. We are evaluating these hits for their ability to regulate the KRAS gene expression signature and facilitate KRAS-driven tumorigenesis. In addition to its ability to bypass KRAS-induced senescence, we have shown that WT1 expression increases resistance to chemotherapy in non-small cell lung cancer cells. Using RNA-Seq to analyze differential gene expression and alternative splicing of transcripts, we have further identified key pathways and targets downstream of WT1 signaling that could play a role in regulating senescence and chemosensitivity in KRAS-driven tumors. We are using the results from these studies to define downstream effectors of WT1 in KRAS driven tumors that can be targeted to induce senescence and improve response to chemotherapy in NSCLC.
This abstract is also presented as Poster A29.
Citation Format: Ron Chen, David R. Simpson, Yanyan Zheng, Dedeepya Vaka, Silvestre Vicent, Alejandro Sweet-Cordero. Identifying effectors of WT1 that regulate KRAS-induced senescence and chemoresistance in non-small cell lung cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr PR08.
Abstract A125: Universal homogenous bioluminescent assay to monitor the effect of modulators on various classes of methyltransferases in vitro.
Authors: Goueli Said A. , Hsaio Kevin 
Published: August 2014

Abstract
Methylation/demethylation of DNA and proteins play major roles in modulation of the epigenome and has been implicated in a wide variety of human diseases. Recent biochemical and biological data suggest that the enzymatic activities of several of these enzymes have pathogenic roles in cancer, inflammation, and neurodegenerative diseases. Thus, pharmacological modulation of these enzymes by small molecules will be beneficial in developing novel therapeutics for multiple unmet medical needs. Towards this goal of searching for activators/inhibitors of these enzymes for the development of next generation of drugs, screening assays for these modulators are urgently needed. To address these unmet needs, we have developed a novel assay that monitors the activities of these enzymes and their modulation by small molecules. The assay is bioluminescent based, HTS formatted, and highly sensitive. The assay is universal since it is based on monitoring the formation of the universal product S-adenosylhomocysteine (SAH), i.e., capable of detecting changes in activity of a broad range of methyltransferases such as DNA, protein, and small molecules methyltransferases. In addition, the assay has been validated for all classes of protein methyltransferases (lysine and arginine), and with different types of substrates (small peptides, large proteins, or even nucleosomes). This enables determining the specificity of these enzymes and their substrate requirements. The assay has high signal to background and low C.V. The assay is robust (Z’ value&gt;0.7) and has been validated using various plate densities such as 96-, 384, and 1536-well plates. A strong feature of this assay is its utility with broad range of substrates with no limitations on the use of high concentrations of substrates or the composition of the substrates (short vs. long peptides), thus enabling the generation of kinetic data and determining the mechanism of action of various modulators of methyltransferases of interest.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A125.
Citation Format: Said A. Goueli, Kevin Hsaio. Universal homogenous bioluminescent assay to monitor the effect of modulators on various classes of methyltransferases in vitro. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A125.
Abstract A126: Change in status promoter of 5 panel gene during progression of atypical hyperplasia to breast cancer.
Authors: Joaquina Martínez-Galán , Delgado Juan Ramon , Torres-Torres Blanca , Del Moral Rosario , Ríos Sandra , Núñez M. Isabel 
Published: August 2014

Abstract
Background: DNA methylation is the main epigenetic modification in cancer. The pathological features of breast cancer follow a sequential progression from transition of a normal cell to benign proliferative hyperplasia, hyperplasia with atypia, in situ carcinoma and, eventually, to invasive and metastatic disease. Purpose: This study was designed to evaluate the changes in promoter CpG islands hypermethylation during breast cancer progression from pre-invasive lesions to invasive ductal carcinoma and different methylation patron with benign breast disease.
Material and Methods: We performed analysis for the methylation status of 5 promoter CpG island (ESR1, E-Cad, APC, RARB, and 14-3-3-; promoters) in a group with women with normal breast tissue n=74; other group with epithelial atypia/ atypical ductal hyperplasia (n=20), ductal carcinoma in situ (DCIS, n=14) and invasive ductal carcinoma (IDC, n=107).
Results: Relative serum levels of methylated gene promoters ESR1 and 14-3-3-; showed significant differences between IDC y normal breast tissue (were significantly higher in IDC than normal breast tissue) and between normal breast tissue and epithelial atypia/ atypical ductal hyperplasia/ ductal carcinoma in situ. There are no differences between IDC and epithelial atypia/ atypical ductal hyperplasia/ ductal carcinoma in situ when 14-3-3-; and ESR1 mean values are compared. In fact, the present findings showed a frequent presence of methylated 14-3-3-; in sera from women with breast benign disease, which could be considered the result of a proliferative alteration of epithelial and stromal components of the breast. Which may indicate presence of occult benign breast disease, although other possible sources of this DNA include normal tissues, which show higher methylation values with increasing age; which might undergo lysis during tumor growth; or premalignant lesion during tumor growth; or premalignant lesion.
Conclusions: These findings showed that promoter CpG island methylation changed significantly in pre-invasive lesions, and breast cancer, suggesting that CpG island methylation of tumor-related genes is an early event in breast cancer progression.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A126.
Citation Format: Martínez-Galán Joaquina, Juan Ramon Delgado, Blanca Torres-Torres, Rosario Del Moral, Sandra Ríos, M. Isabel Núñez. Change in status promoter of 5 panel gene during progression of atypical hyperplasia to breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A126.
Abstract A128: Zebularine, a DNA methyltransferase inhibitor, increases apoptosis and decreases cell proliferation, cell cycle arrest and clonogenic capacity on childhood medulloblastoma cell lines.
Authors: Andrade Augusto F. , Borges Kleiton S. , Suazo Veridiana K. , Castro-Gamero Angel Maurício , Queiroz Rosane G. P. , Scrideli Carlos A. , Tone Luiz Gonzaga 
Published: August 2014

Abstract
Medulloblastoma (MB) is the most common malignant brain tumors in childhood, accounting for 20 % of all primary pediatric intracranial tumors. Although conventional therapies can cure a large proportion of patients with medulloblastoma, the majority of survivors suffer from long-term side effects, including developmental and neurological deficits. Thus, new approaches and therapeutic drugs are needed. Epigenetic drugs such as inhibitors of DNA methyltransferases (iDNMTs) have shown antineoplastic effects in different tumors. Zebularine (ZB) is a potent inhibitor of DNA methylation and has been associated with induction of apoptosis and enhancing tumor chemo- and radiosensitivity. However, its effects on childhood MB have not been previously reported. Herein, this study shows the preliminary data from the effects of ZB on cell proliferation, cell cycle, clonogenic capacity and apoptosis of childhood MB cells.
DAOY, ONS-76, UW-402 and UW-473 MB cell lines were used in all functional studies. Cell proliferation by XTT® assay, clonogenic capacity, cell cycle and apoptosis by flow cytometry using propidium iodide and anexin-V staining were performed using different doses of ZB (50-800µM). Statistical analysis was performed by one or two-way ANOVA and Bonferoni post-hoc.
ZB decreased cell proliferation and clonogenic capacity in all cell lines in a time- and dose-dependent manner, respectively (P&lt; 0.05). ZB also caused apoptotic cell death in MB cells, where the percentage of apoptotic cells significantly increased after treatment compared control (P&lt;0.05), reaching 60% on DAOY cells. Since the dose of 200uM, the drug showed a cell cycle arrest in S-phase in UW-473 and UW-402 cell lines and in G2/M phase in ONS-76 and DAOY cells after 72h of exposure.
These results indicate that ZB may be a promising drug for MB treatment and it confirms the potential of demethylating drugs in cancer treatment. Others studies and novel assays are being conducted to better understand these findings.
Financial Support: FAPESP (process no. 2011/22440-7)
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A128.
Citation Format: Augusto F. Andrade, Kleiton S. Borges, Veridiana K. Suazo, Angel Maurício Castro-Gamero, Rosane G. P. Queiroz, Carlos A. Scrideli, Luiz Gonzaga Tone. Zebularine, a DNA methyltransferase inhibitor, increases apoptosis and decreases cell proliferation, cell cycle arrest and clonogenic capacity on childhood medulloblastoma cell lines. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A128.
Abstract A134: Functional perturbation of PARP6 affects centromeric proteins and is associated with increased multi-polar spindles in breast cancer cell lines.
Authors: GROSSKURTH SHAUN , Petteruti Philip , Wang Xin , Mikule Keith 
Published: August 2014

Abstract
Poly(ADP-ribose) polymerases (PARP) are a family of 17 enzymes that catalyze the transfer of the ADP-ribose from NADH to post-translationally modify (PTM) acceptor proteins. Currently, the PTM regulation of proteins by PARPs have been demonstrated to regulate numerous signaling cascades including but not limited to DNA damage response and tumor development for PARP1-3 as well as telomere maintenance, spindle assembly, vesicular movement, and regulation of beta-catenin destruction complex for PARP5a-5b. Although progress on the biological role and therapeutic potential for some PARPs has been made, the function of and possible therapeutic application for other PARPs are not fully understood. Using cell free enzyme and cell-base multi-polar spindle assays, semi-selective PARP6 inhibitors AZ482 and AZ108 were identified. From in vitro PARP6 knock-down and AZ108 pharmacological studies in breast cancer cell lines, PARP6 perturbation was demonstrated to disrupt spindle pole clustering. To identify PARP6 protein substrate that may contribute to the spindle pole clustering defect, an in vitro acceptor protein substrate screen was performed using high-density protein microarrays containing more than 8,000 unique proteins. From this screen, an enrichment for centromeric and microtubule organizing proteins was identified. Of these centromeric PARP6 protein substrate, CHEK1 and CENP were shown to be modulated by AZ108 treatment in breast cancer cell lines. These results implicate PARP6 in a role for stablization of the spindle assembly during mitosis.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A134.
Citation Format: SHAUN GROSSKURTH, Philip Petteruti, Xin Wang, Keith Mikule. Functional perturbation of PARP6 affects centromeric proteins and is associated with increased multi-polar spindles in breast cancer cell lines. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A134.