bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B05: Mechanism for enhanced 5-aminolevulinic acid fluorescence in isocitrate dehydrogenase 1 mutant malignant gliomas
Authors: Eun Kim Ja , Cho Hye Rim , Xu Wen Jun , Kim Young-Hoon , Phi Ji Hoon , Choi Seung Hong , Park Sunghyouk , Park Chul-Kee
Published: May 2016

Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) and the discovery of IDH1 mutations are major recent advances in glioma management and research. However, the mechanism underlying the selective intracellular accumulation of the 5-ALA derivative protoporphyrinogen IX (PpIX) and the metabolic effect of IDH1 mutations in malignant glioma cells are still not fully understood. Based on clinical experience, we hypothesized an association between enhanced 5-ALA fluorescence and IDH1 mutations in WHO grade III gliomas. Using genetically engineered malignant glioma cells harboring wild type (U87MG-IDH1WT) or mutant (U87MG-IDH1R132H) versions of IDH1, we confirmed a lag in 5-ALA metabolism and a temporary accumulation of PpIX in U87MG-IDH1R132H cells. To investigate the metabolic aspects of the mechanism responsible, we used liquid chromatography–mass spectrometry (LC-MS) to screen for tricarboxylic acid (TCA) cycle-related metabolite changes resulting from 5-ALA exposure. We observed low baseline levels of NADPH, an essential cofactor for the rate-limiting step of heme degradation, in U87MG-IDH1R132H cells. Abundant levels of NADPH are required to metabolize excessive 5-ALA, giving a plausible reason for the temporary enhanced 5-ALA fluorescence in mutant IDH1 cells. This hypothesis was supported by the results of metabolic screening in human malignant glioma samples. We discovered a relationship between enhanced 5-ALA fluorescence and IDH1 mutations in malignant gliomas and investigated the metabolic aspects of the mechanism responsible, identifying significantly different levels of NADPH between wild type and mutant IDH1 malignant glioma cells.

Citation Format: Kim Ja Eun, Hye Rim Cho, Wen Jun Xu, Young-Hoon Kim, Ji Hoon Phi, Seung Hong Choi, Sunghyouk Park, Chul-Kee Park. Mechanism for enhanced 5-aminolevulinic acid fluorescence in isocitrate dehydrogenase 1 mutant malignant gliomas. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr B05.
Abstract B10: Clinical validation of targeted next-generation sequencing for glioblastoma patients
Authors: Trépant Anne-Laure , Mercier Marie Le , Maris Calliope , Nève Nancy De , Blanchard Oriane , D'Haene Nicky , Salmon Isabelle
Published: May 2016

Objective: Glioblastomas (GBMs) are the most common malignant primary brain tumours in adults. These tumours are resistant to conventional treatment approaches including surgical resection, radiotherapy and chemotherapy. International efforts to catalogue mutations for multiple forms of cancer coupled with the successes of targeted agents in patients with molecularly defined tumors and improvements in genomic technology have generated enthusiasm for incorporating genomic profiling into clinical cancer practice. The development of tyrosine kinase inhibitor treatments has made it important to test cancer patients for clinically significant gene mutations that influence the benefit of treatment. Therefore, the number of biomarkers that will need to be assessed is expected to increase rapidly. Recently, next generation sequencing (NGS) has begun to supplant other technologies for gene panel sequencing. However, few studies have validated the use of targeted NGS for GBM patients. In the present study we evaluate the clinical applicability of targeted NGS for patients with GBM.

Methods: DNA from 50 GBM samples (formalin-fixed paraffin-embedded tissue) was retrospectively subjected to targeted NGS with the Ampliseq Cancer Hotspot Panel, using the Ion Torrent Personal Genome Machine, which allowed us to analyze 2850 known cancer-related mutations in 50 genes. In addition, MGMT methylation status, EGFR amplification and 1p19q deletion were evaluated by Methylation Specific PCR (MSP), chromogenic in situ hybridisation (ISH) and fluorescence ISH, respectively.

Results: Preliminary results on 28 patients, all successfully sequenced, showed that the most frequent mutations were found in TP53 (25%) and EGFR (18%). Potentially actionable mutations were identified in 9 patients (32%), including 5 EGFR mutations, 2 PIK3CA mutations, 1 PTEN mutation, 1 PDGFRA mutation and 1 IDH1 mutation. The frequencies of these variants detected by NGS were consistent with frequencies reported in public databases. Moreover, PDGFRA and EGFR amplifications were detected by coverage analysis for 10 (36%) and 2 (7%) patients respectively.

Conclusions: Overall, the AmpliSeq Cancer Hotspot Panel can be applied in daily practice for GBM samples. Moreover, it can provide clinically relevant information for GBM patients.

Citation Format: Anne-Laure Trépant, Marie Le Mercier, Calliope Maris, Nancy De Nève, Oriane Blanchard, Nicky D'Haene, Isabelle Salmon. Clinical validation of targeted next-generation sequencing for glioblastoma patients. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr B10.
Abstract B35: BMP regulation of cancer stem cell quiescence is responsible for chemotherapeutic resistance in glioblastoma
Authors: Wu Megan YiJun , Celebre Angela , Chan Jeffrey , Guan Jennifer , Dhand Karan , Loukides James , Karamchandani Jason , Das Sunit
Published: May 2016

Introduction: Cancer stem cells (CSCs) represent a distinct cellular population that has been implicated in tumor recurrence following chemotherapy. Accumulating evidence indicates that BMP signaling plays an important role in the regulation of CSCs, and may be involved in the resistance of CSCs to cytotoxic drugs. The role of BMP pathway regulation of the CSC phenotype responsible for treatment resistance in glioblastoma (GBM) has not been explored.

Methods: Paraffin-embedded (FFPE) samples from GBM patients were used to evaluate the expression of markers for BMP signaling (pSMAD1/5/8), proliferation (PCNA), and stemness (SOX2) by immunostaining. We tested the self-renewal capacity of primary patient-derived glioma stem cell (GSC) lines using a sphere formation assay. Expression of stemness markers SOX2 and Bmi-1 in BMP4 treated and untreated GSCs, was analyzed by Western blotting. We also performed xenograft transplantation, whereby GSCs were injected intracranially into immunedeficient mice. When tumor formation was confirmed post-injection, mice were administrated EdU and sacrificed at successive time points thereafter. The frequency of all EdU positive cells as well as ID-1positive/ EdU positive cells was quantified from the primary tumor sections throughout the labeling and chase. To study chemoresistance in glioblastoma, GSC lines were treated with graded concentrations of temozolomide (TMZ).

Results: We found that pSMAD1/5/8 positive cells in primary patient tumors were largely PCNA-negative. BMP4 treatment inhibited GSC proliferation and self-renewal (sphere-formation), but did not abolish expression of markers of stemness, such as Sox2 and Bmi-1, or tumorigenicity. In our in vivo model, we found ID-1 positive cells retain EdU following a long-term chase. Taken together, these results demonstrate that BMP4-enriched cells possess the characteristics of a quiescent stem cell population. BMP4 treatment protects GSCs against TMZ-induced growth inhibition. Furthermore, pSMAD1/5/8-expressing cells do not possess the DNA damage marker gamma-H2AX following TMZ treatment, suggesting that activation of the BMP pathway protects GSCs against TMZ-induced DNA damage.

Conclusion: This study establishes that the BMP signaling pathway is involved in the maintenance of GSC quiescence and may play a role in glioblastoma chemoresistance.

Citation Format: Megan YiJun Wu, Angela Celebre, Jeffrey Chan, Jennifer Guan, Karan Dhand, James Loukides, Jason Karamchandani, Sunit Das. BMP regulation of cancer stem cell quiescence is responsible for chemotherapeutic resistance in glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr B35.
Abstract B36: NF-kappaB-dependent and -independent roles for NIK in regulating GBM cell invasion
Authors: Duran Camille L. , Lechuga Linda Herrera de , Lee Dong W. , Bayless Kayla J. , Sitcheran Raquel
Published: May 2016

The aggressive invasion of GBM cells into healthy brain tissue is a major factor contributing to the therapy resistance and poor prognosis of this malignancy. Our recent results demonstrated that the alternative, or noncanonical, NF-kappaB signaling pathway, predominates in the aggressive mesenchymal subtype of GBM. Additionally, NF-kappaB-inducing kinase (NIK), a key upstream activator of noncanonical NF-kappaB signaling, robustly promotes GBM cell invasion and pathogenesis. We demonstrate that expression of NIK is increased in response to exposure to collagen, a major extracellular matrix (ECM) protein present in GBM tumors, with NIK protein levels continuing to increase during invasion in 3D collagen matrices. Interestingly, NIK expression levels correlates with induction of membrane type-1 matrix metalloproteinase (MT1-MMP), a critical enzyme in many invasive tumors, functioning to degrade the basement membrane and ECM during cell migration and invasion. We provide evidence that NIK promotes MT1-MMP activation through increased phosphorylation at membrane protrusions and elevated enzymatic activity. Notably, the activation of MT1-MMP and the pro-invasive effects of NIK persist in the absence of the downstream NF-kappaB transcription factors RelA/p65 and RelB. Together, these data demonstrate a novel ability of NIK to promote GBM cell migration and invasion that is independent of NF-kappaB transcriptional activation functions. The results underscore the therapeutic potential of targeting noncanonical NF-kappaB signaling in these highly invasive tumors.

Citation Format: Camille L. Duran, Linda Herrera de Lechuga, Dong W. Lee, Kayla J. Bayless, Raquel Sitcheran. NF-kappaB-dependent and -independent roles for NIK in regulating GBM cell invasion. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr B36.
Abstract IA12: Investigating the functional consequences of ATRX deficiency in glioma
Authors: Huse Jason T.
Published: May 2016

Comprehensive genomic profiling in cancer continues to reveal frequent alterations in epigenetic regulators, firmly implicating chromatin biology in the oncogenic process. We and others recently found that inactivating mutations in the SWI/SNF family member ATRX represent defining molecular alterations in diffusely infiltrating gliomas, where they invariably pair with mutations in TP53 and IDH1/2. ATRX normally regulates the composition of histone monomers at a variety of sites across the genome, and may also affect the distribution of specific histone modifying complexes. A number of studies have linked ATRX deficiency to a wide spectrum of physiological dysfunction, including aberrant gene regulation, abnormal telomere maintenance, genomic instability, and aneuploidy. Nevertheless, the precise mechanisms by which ATRX deficiency promotes oncogenesis remain unknown.

To investigate the effects of ATRX deficiency on chromatin structure, gene expression, and transformation, we inactivated Atrx in murine neuroepithelial progenitor cells (NPCs) also lacking Tp53. We found that, in this context, Atrx deficiency induced widespread alterations in chromatin accessibility and organization, which in turn led to dramatic shifts in gene expression. Among the altered transcriptional networks were pathways implicated in cellular motility and invasion, an established feature of diffusely infiltrating gliomas. Intriguingly, Atrx-deficient NPCs also exhibited significantly increased transwell migration. Our findings demonstrate that ATRX deficiency promotes disease-relevant biological behavior by modulating chromatin accessibility and influencing gene expression. We are now performing detailed epigenetic and biochemical studies to identify the precise transcriptional events mediating these effects. We are also investigating how IDH mutations influence the genomic distribution of ATRX, thereby modulating its function and the consequences of its deficiency.

Citation Format: Jason T. Huse. Investigating the functional consequences of ATRX deficiency in glioma. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr IA12.
Abstract A32: The role of microRNA in the regulation of DUSP16 gene and JNK family in hepatocellular carcinoma patients
Authors: Tantawy Marwa , Hassan Nagwa , Kobaisi Mohamed , Wahab Abdel Hady Abdel
Published: May 2016

Introduction: Human hepatocellular carcinoma (HCC) is consider one of the most common and lethal tumors worldwide, HCC is currently the fifth most common solid tumor worldwide and the fourth important cause of cancer-related death. Eighty percent of new cases found in developing countries as Egypt, but the incidence is increasing in economically developed regions, including Japan, Western Europe, and the United States.

It has shown that expression level of different miRNAs was correlated with cellular liver processes such as inflammation, hepatocyte regeneration and apoptosis which indicate their important role in many liver diseases including hepatocellular carcinoma. The main objective of the present study is to correlate between the expression levels of liver specific miRNAs with different mitogen activated protein kinase (MAPK) pathway in primary HCC patients.

Patients and Methods: The expression level of miRNA targeting MAPK pathway, Dual-Specificity Phosphatase 16 (DUSP16), c-Jun N-terminal kinases (JNK) family (JNK1, JNK2 and JNK3) were detected in tissue biopsy of 38 primary HCC patients as well as 6 healthy controls using qRT-PCR technique. Detection of the protein levels for DUSP16, JNK1 and JNK2 was done using immunohistochemistry (IHC) assay.

Results: The correlation between different expressions was done using (statistical method). Significant correlation was observed between 10 miRNAs with mRNA for DUSP16, JNK1, JNK2 and JNK3 (miR-18b; miR-30c; miR-30e; miR-99a; miR-126; miR-194; miR-198; miR-215; miR-455 and miR-455-3p). Highly significant down regulation was detected in JNK2 and JNK3 gene expression in HCC patients as compared to controls with (P value = 0.016, 0.000) respectively. Using IHC assay, 34% (13 out 38) showed DUSP16 (P value <0.0001), 82% (31 out 38) for JNK1 (P value <0.0001) and 71% (27 out 38) for JNK2. All control samples didn't show any protein expression of genes analyzed.

Conclusion: Understanding the role of miRNA in MAPK pathway may open new avenue for development novel treatment strategy in primary hepatocellular carcinoma.

Citation Format: Marwa Tantawy, Nagwa Hassan, Mohamed Kobaisi, Abdel Hady Abdel Wahab. The role of microRNA in the regulation of DUSP16 gene and JNK family in hepatocellular carcinoma patients. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr A32.
Abstract B1-01: Whole genome expression based drug repurposing
Authors: Geeleher Paul , Bhutra Steven , Wang Jacqueline , Huang R. Stephanie
Published: May 2016

Currently, personalizing cancer chemotherapy relies on pathology and more recently molecular biomarker-based approaches. However, as the driving biology is normally not fully understood, the majority of existing biomarkers do not capture a substantial proportion of variability in drug response. This partly explains the commonly observed lack of reproducibility of findings (e.g. from many conventional gene expression signatures) when these markers are applied to new datasets. We developed an approach to predict in vivo drug sensitivity that leverages whole-genome gene expression microarray data and allows the expression of every gene to influence the prediction by a small amount. Our approach builds statistical models from gene expression and drug sensitivity data in a very large panel of cell lines, then applies these models to gene expression data from primary tumor biopsies. In this study, we applied this approach to tumor samples collected in The Cancer Genome Atlas (TCGA). We derived predicted sensitivity for over one hundred drugs in each of the tumor samples. As a proof-of-concept, we demonstrated that a targeting agent (lapatinib) designed against a specific tumor marker (HER2 positive) is indeed predicted to be more sensitive in HER2 positive breast cancers when compared to the other type of cancers. Meanwhile, we identified other agents that exhibit similar or superior sensitivity when compared to commonly prescribed agents in different disease settings. These findings warrant further evaluation of these agents to be repurposed for possible new indications. Interestingly, some of our derived drug sensitivity predictive estimates are correlated with observed survival outcomes in certain cancer patients. When screening all tumor types based on their molecular profiles, we defined several classes of drugs that maybe differentially effective based on tumor molecular profiles. In conclusion, a genome-wide expression drug sensitivity model built in cell lines can be a powerful approach in repurposing drug in cancer treatment.

Citation Format: Paul Geeleher, Steven Bhutra, Jacqueline Wang, R. Stephanie Huang. Whole genome expression based drug repurposing. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-01.
Abstract B1-13: Phospho-proteomic analysis of MEK inhibition in mutant NRAS melanoma
Authors: Vu Ha Linh , Davies Michael A. , Aplin Andrew E.
Published: May 2016

Melanoma is a devastating form of skin cancer with limited therapeutic options. Fifteen to twenty percent of melanoma patients have an activating mutation in NRAS, a small GTPase. NRAS has several downstream effectors, the most well-characterized is RAF leading to activation of MEK/ERK. While there are no FDA-approved targeted therapies for melanoma patients with a primary mutation in NRAS, one form of targeted therapy that has been explored is MEK inhibition. Phase I to III studies of MEK inhibitors in mutant NRAS melanomas have shown disappointing clinical efficacy, the reasons for which are unclear. In 3D systems that mimic the dermal microenvironment, we found a heterogeneous response in our panel of mutant NRAS melanoma cells to the allosteric MEK inhibitor, trametinib. To explore the underlying basis of this heterogeneity, we utilized a high-throughput reverse-phase protein array (RPPA) platform to identify compensatory signaling alterations. The RPPA analysis of phospho-proteomic changes in NRAS mutant melanoma in response to trametinib indicated a compensatory increase in AKT signaling. Interestingly, we detected a decrease in mitogen inducible gene 6 (MIG6), a negative regulator of ERBB receptors. The overexpression of MIG6 led to a negative regulation of EGFR (ERBB1) and ERBB2, and subsequent decrease in AKT activation. Conversely, the depletion of MIG6 increased EGFR and ERBB2 signaling. Either depletion of MIG6 or addition of EGF increased migration of NRAS mutant cells treated with trametinib, an invasive phenotype that may mitigate the negative effects of trametinib on cell growth. Our results indicate a potential role for the combined inhibition of EGF/ERBB receptors and MEK in NRAS mutant melanoma patients.

Citation Format: Ha Linh Vu, Michael A. Davies, Andrew E. Aplin. Phospho-proteomic analysis of MEK inhibition in mutant NRAS melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-13.
Abstract B1-16: Attractor analysis of p53 gene network in colon cancer
Authors: Kim Man-Sun , Kim Jeong-Rae
Published: May 2016

Colon cancer is a heterogeneous and complex disease. Mutation of the p53 gene is most commonly observed in many people with colon cancer [1-2]. In this regard, to understand how the p53 network controls cell fate, it is important not only to identify the network components and their molecular interactions but also to study essential network properties at the system level [3]. However, the molecular mechanisms remain largely unexplored. Here, we used Boolean network modeling and attractor landscape analysis to analyze the state transition dynamics of a simplified p53 network.

We first constructed a simplified Boolean network model with multiple feedback loops through p53 for analyzing the p53 network. After building the simplified p53 regulatory network, we modeled the network dynamics using a Boolean network with a set of state transition logics defined on the basis of biological evidence.

Attractor landscape analysis of dynamics and its regulation can identify potential therapeutic strategies for treating cancer.

Citation Format: Man-Sun Kim, Jeong-Rae Kim. Attractor analysis of p53 gene network in colon cancer. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-16.
Abstract B1-30: Receptor-level feedback mechanisms distinguish frequency- and amplitude-modulated ERK activation
Authors: Sparta Breanne , Pargett Michael , Distor Kevin , Minguet Marta , Albeck John G.
Published: May 2016

Receptor tyrosine kinases transduce signals through ERK and drive distinct cellular behaviors, but it is not clear how dynamic patterns of ERK activity are generated. To approach this question quantitatively, we have generated an epithelial cell line expressing a tunable version of the canonical nerve growth factor (NGF) receptor TrkA. Upon NGF stimulation, we visualized the dynamics of ERK activity in live cells using an improved fluorescent reporter for ERK activity, EKAR3. Examination of the NGF receptor pathway in isolation revealed that stimulation with NGF promotes a prolonged ERK activity pulse that is amplitude-modulated by the concentration of the stimulus, in contrast to the frequency modulation observed in the epidermal growth factor (EGF)-RAS-ERK pathway. This result implies that the primary determinants of ERK kinetics are the unique set of signaling proteins recruited to the activating receptor. To dissect the context in which ERK is activated in respect to parallel signaling pathways, we have engineered mutant NGF receptors that cannot be phosphorylated at one or more of the three adaptor binding sites and characterized how each signaling pathway contributes to the pattern of dynamic ERK activity. Furthermore, because our NGF receptor expression system allows the tunable and quantifiable expression of receptor levels, we have evaluated the effect of receptor number on ERK kinetics in single cells. Our findings indicate that the dynamics of ERK activity are in fact decided at the receptor-level and may explain how different receptor tyrosine kinase profiles in cancer cells modulate distinct patterns of ERK activity.

Citation Format: Breanne Sparta, Michael Pargett, Kevin Distor, Marta Minguet, John G. Albeck. Receptor-level feedback mechanisms distinguish frequency- and amplitude-modulated ERK activation. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-30.
Abstract B1-35: Enrichr2: Next generation gene set enrichment analysis web-based tool
Authors: Jones Matthew R.
Published: May 2016

Background: System-wide profiling of genes and proteins in mammalian cells produces lists of differentially expressed genes/proteins needing to be further analyzed for their collective functions in order to extract new knowledge. Once lists of genes or proteins are generated from such experiments, they are compared to existing annotated lists created from prior knowledge organized into gene-set libraries. While many enrichment analysis tools and gene-set library databases have been developed, there is still room for improvement. Enrichr2 is a major update of the published popular tool Enrichr.

Methods: Enrichr2's architecture has been redesigned to be highly scalable. The new database centric design allows Enrichr2 to perform enrichment analysis within seconds while accommodating for the rapid growth of our gene-set library database. Recent additions to our gene-set library database include: disease signatures from GEO, drug perturbations from GEO, kinase perturbations from GEO and L1000, as well as tissue protein expression from two recent publications. Principal Angle Enrichment Analysis has been implemented and is one of the available enrichment analysis scoring methods. Enrichr2 can be restricted to only consider a subspace of the genome, and it accepts input formats that are crisp or fuzzy gene sets, probe IDs from microarrays, BED files and SOFT files. Gene synonyms are also recognized and automatically converted. Users can upload their own gene-set libraries as well as access the legacy versions of our libraries.

Results: Enrichr2 is an easy to use intuitive enrichment analysis web-based tool providing various visualization summaries of collective functions of gene lists. Enrichr2 includes many new gene-set libraries, alternative approaches to rank enriched terms, and various new interactive visualization approaches to display enrichment results. We applied Enrichr2 to analyze many of the gene expression datasets available at The Cancer Genome Atlas (TCGA). Global visualization of such enrichment analysis results provides a global view of the biological molecular mechanisms driving tumor behavior across cancers at the individual patient level.

Conclusions: Enrichr2 is emerging as a leading search engine for annotated gene lists, taking gene set enrichment analysis to a new level. Enrichr is an open source web-based tool available online at: http://amp.pharm.mssm.edu/Enrichr

Note: This abstract was not presented at the conference.

Citation Format: Matthew R. Jones. Enrichr2: Next generation gene set enrichment analysis web-based tool. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-35.
Abstract B1-44: G-DOC Plus: A cloud based next-generation systems medicine platform for precision medicine
Authors: Bhuvaneshwar Krithika , Belouali Anas , Singh Varun , Johnson Robert M. , Song Lei , Alaoui Adil , Harris Michael , Gusev Yuriy , Clarke Robert , Madhavan Subha
Published: May 2016

Systems medicine leverages complex computational tools and high dimensional data offering the potential for effective individualized diagnosis, prognosis and treatment options. Our flagship web platform, the Georgetown Database of Cancer (G-DOC), was deployed with the goal of enabling translational research by integrating patient characteristics and clinical outcome data with a variety of high-throughput research data in a unified environment. With the goal of improving health outcomes through genomics research, we present G-DOC Plus, our enhanced web platform offering precision medicine, translational research and population genetics workflows. This enhanced platform takes advantage of cloud computing to handle next generation sequencing (NGS) data so that they can be analyzed in the full context of other omics and clinical information.

G-DOC Plus uses cloud computing and other advanced computational tools to enable analysis of NGS and medical images in the full context of other omics and clinical information. It allows translational science researchers to explore data one sample at a time, as a sub-cohort of samples; or as a population as a whole, providing the user with a comprehensive view of the data. G-DOC Plus tools have been leveraged in cancer to support detection of prognostic markers for relapse in colorectal cancer samples, and to detect key metabolites related to disease severity; hypothesis generation; biomarker detection and multi-omic analysis, in-silico and population genetics analysis; and to explore somatic mutation and breast cancer MRI images. The long-term vision of G-DOC Plus is to extend this systems medicine platform to hospital networks to provide clinical decision support using multi-omics and relevant clinical information to support personalized patient care. G-DOC Plus was released in October 2014, and is available at: https://gdoc.georgetown.edu.

Citation Format: Krithika Bhuvaneshwar, Anas Belouali, Varun Singh, Robert M. Johnson, Lei Song, Adil Alaoui, Michael Harris, Yuriy Gusev, Robert Clarke, Subha Madhavan. G-DOC Plus: A cloud based next-generation systems medicine platform for precision medicine. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-44.
Abstract B1-45: Chr3q26 amplification and associated pathways is the key driver in squamous cell carcinoma
Authors: Wu Song , Aggarwal Amit
Published: May 2016

The large scale characterization of molecular aberrations in cancer through efforts such as TCGA is resulting in better disease understanding as well as rational development of cancer therapies. Recently, in the pan-cancer analysis of TCGA data, Chr3q26 amplification was identified as the most frequent copy number amplification in over 5,000 samples across 12 cancer types (Ciriello et al. 2013). This aberration is more commonly seen in solid tumors of the squamous cells. In this study, we analyze three types of squamous cell carcinomas, Lung (N=494), Head&Neck (N=306) and Cervical (N=192), which have high prevalence of Chr3q26 amplification. We provide insights into core genetic aberration signals relating to Chr3q26 amplicon by integrating gene mutation, mRNA expression and DNA copy number data. These include concordant co-activation of multiple pathways relating to development biology, receptor tyrosine kinases and cell cycle. The co-activation of multiple key oncogenic signals in tumors with Chr3q26 may suggest that the need of combinational therapies. We also show lack of pre-clinical models that reflect similar molecular characteristics, there by suggesting challenge in translating such findings. Importantly, we then developed a Chr3q26 amplification gene expression signature, which may help to stratify patients into subgroups with different response to adjuvant chemotherapy

Citation Format: Song Wu, Amit Aggarwal. Chr3q26 amplification and associated pathways is the key driver in squamous cell carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-45.
Abstract B2-27: Systems biological identification of optimal drug targets for combination therapy of non-small cell lung cancer
Authors: Lee Jonghoon , Cho Kwang-Hyun
Published: May 2016

Non-small cell lung cancer (NSCLC) is the major subtype of lung cancer, accounting for about 85% of all lung patients. Recently, molecularly targeted inhibitors of receptor tyrosine kinase (RTK) such as epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor (FGFR) signalling pathways have been highlighted as promising anti-tumor drugs because of the prevalence of genetic alterations within EGFR and FGFR signalling pathways in NSCLC patients. However, their functional effects have been reported as varying over a wide range depending on the patient-specific mutational conditions. To understand the underlying mechanism of the heterogeneous responses to EGFR and FGFR inhibitors and to find the optimal strategy for combination therapy, we have developed an integrative Boolean network model of EGFR, FGFR and DNA damage signalling pathways by integrating previous experimental evidences from the literature. Systematic perturbation analysis revealed that the multiple feedback regulations embedded in the signalling pathways play important roles in determining the responses to EGFR and FGFR inhibitors. We further analyzed the mechanism for the heterogeneous responses of cells to the EGFR and FGFR inhibitors under various mutational conditions and identified key genetic alterations that can lead to undesirable responses. Finally, extensive combinatorial perturbation analysis and subsequent comparison of the attractor profiles in the presence and absence of targeted inhibitors identified novel candidate drug targets for combinatorial therapy. Our analysis provides a new insight into the underlying mechanism of the heterogeneous cellular responses to EGFR and FGFR inhibitors and the optimal combinatorial treatment strategies.

Acknowledgements: This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea Government, the Ministry of Science, ICT & Future Planning (2014R1A2A1A10052404, 2013M3A9A7046303, and 2010-0017662) and by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea. (HI13C2162).

Citation Format: Jonghoon Lee, Kwang-Hyun Cho. Systems biological identification of optimal drug targets for combination therapy of non-small cell lung cancer. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B2-27.
Abstract B2-43: Bioinformatics analysis of TCGA tumors to identify cancer associated epigenetic regulators
Authors: Gnad Florian , Zhang Zemin
Published: May 2016

Many cancer cells show distorted epigenetic landscapes. The Cancer Genome Atlas (TCGA) project profiles thousands of tumors, allowing the discovery of somatic alterations in the epigenetic machinery and the identification of potential cancer drivers among members of epigenetic protein families. We integrated mutation, expression, and copy number data from thousands of tumors from major cancer types to train a classification model that predicts the likelihood of being an oncogene (OG), tumor suppressor (TSG) or neutral gene (NG). Using classical driver genes to train an OG/TSG predictor, we determined mutation parameters as the most predictive features. We applied this predictor to epigenetic regulator genes (ERGs), and used differential expression and correlation network analysis to identify dysregulated ERGs along with co-expressed cancer genes. Mutation-based classifiers uncovered the TSG-like profiles for several ERGs, but did not detect any OG-like profile. Differential gene expression and correlation network analyses revealed that EZH2 is the most significantly over-expressed ERG in cancer and is co-regulated with a cell cycle network. Furthermore we quantified global proteomic changes by mass spectrometry after EZH2 inhibition. Proteomic analysis showed that EZH2 inhibition induced down-regulation of cell cycle regulators in lymphoma cells. We have now expanded our analysis to other types of proteins including kinases and secreted proteins.

Note: This abstract was not presented at the conference.

Citation Format: Florian Gnad, Zemin Zhang. Bioinformatics analysis of TCGA tumors to identify cancer associated epigenetic regulators. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B2-43.
Abstract PR07: Functional analysis of diverse oncogenic driver mutations using an isogenic cell line library identifies novel drug responses and alterations in metabolism
Authors: Martins Maria M. , Zhou Alicia Y. , Corella Alexandra , Horiuchi Dai , Yau Christina , Rakshandehroo Taha , Gordan John D. , Levin Rebecca S. , Johnson Jeff , Jascur John , Shales Mike , Sorrentino Antonio , Cheah Jaime , Clemons Paul A. , Shamji Alykhan , Schreiber Stuart , Schreiber Stuart , Krogan Nevan J. , Shokat Kevan M. , Shokat Kevan M. , McCormick Frank , Nomura Daniel , Bandyopadhyay Sourav , Goga Andrei
Published: May 2016

There is an urgent need in oncology to link molecular aberrations in tumors with altered cellular behaviors, such as metabolic derangements, and to identify novel therapeutics for cancer treatment. We have sought to identify synthetic-lethal genetic interactions that cancer cells acquire in the presence of specific mutations. Using engineered isogenic cells, we generated an unbiased and quantitative chemical-genetic interaction map that measures the influence of 51 aberrant cancer genes on 90 drug responses. The dataset strongly predicts drug responses found in cancer cell line collections, indicating that isogenic cells can model more complex cellular contexts. Applied to triple-negative breast cancer, we report clinically actionable interactions with the MYC oncogene including resistance to PI3K/AKT pathway inhibitors and an unexpected sensitivity to dasatinib through LYN inhibition in a synthetic-lethal manner. These studies provide new drug and biomarker pairs for clinical investigation. We have also performed global metabolomics analysis in a subset of the isogenic cell lines demonstrating alterations in metabolic pathways that are shared across multiple oncogenes, as well as those that are distinct to specific oncogenic drivers. This scalable approach enables the prediction of drug responses from patient data and can be used to accelerate the development of new genotype-directed therapies.

This abstract is also presented as a poster at the Translation of the Cancer Genome conference.

Citation Format: Maria M. Martins, Alicia Y. Zhou, Alexandra Corella, Dai Horiuchi, Christina Yau, Taha Rakshandehroo, John D. Gordan, Rebecca S. Levin, Jeff Johnson, John Jascur, Mike Shales, Antonio Sorrentino, Jaime Cheah, Paul A. Clemons, Alykhan Shamji, Stuart Schreiber, Stuart Schreiber, Nevan J. Krogan, Kevan M. Shokat, Kevan M. Shokat, Frank McCormick, Daniel Nomura, Sourav Bandyopadhyay, Andrei Goga. Functional analysis of diverse oncogenic driver mutations using an isogenic cell line library identifies novel drug responses and alterations in metabolism. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr PR07.
Abstract PR15: Predicting the essentialities of protein-protein interactions in cancer
Authors: Cooper Lee AD , Moran Josue D. , Li Zenggang , Du Yuhong , Harati Sahar , Ivanov Andrey A. , Webber Phillip , Havel Jonathan J. , Johns Margaret A. , Fu Haian , Moreno Carlos S.
Published: May 2016

Many protein-protein interactions (PPIs) are essential to cellular proliferation and survival, and thus represent potential targets for novel compounds with high specificity and therapeutic potential in the treatment of cancer. Despite their therapeutic significance, there are currently no high-throughput experimental platforms to interrogate the essentiality of individual protein-protein interactions. The ability to computationally predict or infer PPI essentiality would help prioritize the development of therapeutic targets and advance understanding of cancer biology, and remains a significant barrier. We have developed a computational method to predict PPI essentiality by combining shRNA studies with network models of protein interaction pathways in an analytic framework. High-throughput single-gene shRNA silencing is a well-established experimental approach to study protein essentiality in genome-wide screens. The silencing of a single gene in an shRNA screen effectively disrupts multiple PPIs, masking their individual contributions to the observed protein essentiality. Our method uses a network model to infer cliques of PPIs that are disrupted as each gene is silenced, then uses these sets to formulate an additive model of how the unknown PPI essentialities combine to form the observed protein essentialities. This process is then deconvoluted to recover the unknown essentialities of each PPI using a regularized solver. We performed this analysis in 108 cell lines characterized for protein essentiality in Project Achilles [1, 2]. A superpathway of 2186 proteins and 11488 protein interactions was constructed from prior knowledge databases [3] and protein interaction screenings. We demonstrate the validity of our approach via prediction of essential PPIs such as TP53-MDM4 in cell lines sensitive to nutlin and CDK4-RB1 interactions in cell lines sensitive to CDK4 inhibitors.

[1] Cowley, Weir & Vazquez, et al. Nature Scientific Data 1, Article number: 140035. September 30, 2014

[2] Cheung HW, Cowley GS, Weir BA, et al. Proc Natl Acad Sci. 2011 Jul 26; 108(30):12372-7.

[3] Schaefer CF, Anthony K, Krupa S, et al. Nucleic Acids Research. Jan 2009. 37:674-9

Citation Format: Lee AD Cooper, Josue D. Moran, Zenggang Li, Yuhong Du, Sahar Harati, Andrey A. Ivanov, Phillip Webber, Jonathan J. Havel, Margaret A. Johns, Haian Fu, Carlos S. Moreno. Predicting the essentialities of protein-protein interactions in cancer. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr PR15.
Abstract A17: A lincRNA orchestrates glioma stem cell-mediated angiogenesis in glioblastoma
Authors: Wang Jenny J. , Wu Megan , Li Christopher , Shahzad Uswa , Karamchandani Jason , Marsden Phil , Das Sunit
Published: May 2016

Angiogenesis is a hallmark of glioblastoma. Recent data suggest that glioma stem cells (GSCs) contribute to pathologic angiogenesis through transdifferentiation into endothelial cells or vascular pericytes. Using an unbiased screen, we identified a lincRNA near the VEGFR1 gene, which we named LIVE (lincRNA-VEGFR1), that directs physiologic vascular network formation through global effects on gene expression. LIVE is highly expressed in glioblastoma and enriched in GSCs. Over-expression of LIVE results in specification of GSCs along a vascular lineage. LIVE associates with PARP1 in GSCs and RNA helicase A in endothelial cells to drive pericyte-specific and endothelial-associated gene expression, respectively. Depletion of LIVE in a xenograft model of glioblastoma results in decreased microvascular density, vascular perfusion and pericyte coverage, and depletion of GSCs within the vascular niche. Our findings demonstrate a novel role for lincRNAs in the orchestration of tumour angiogenesis and reveal a therapeutic potential for targeting LIVE in glioblastoma.

Citation Format: Jenny J. Wang, Megan Wu, Christopher Li, Uswa Shahzad, Jason Karamchandani, Phil Marsden, Sunit Das. A lincRNA orchestrates glioma stem cell-mediated angiogenesis in glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A17.
Abstract A20: Innovative drug discovery for bladder cancer by miR-130 family seed-targeting locked nucleic acid
Authors: Egawa Hiroshi , Jingushi Kentaro , Ueda Yuko , Kitae Kaori , Nakata Wataru , Fujita Kazutoshi , Uemura Motohide , Nonomura Norio , Tsujikawa Kazutake
Published: May 2016

Bladder cancer causes an estimated 150,000 deaths per year worldwide. Although 15% of the recurrent bladder cancer becomes an invasive type, targeted therapy for malignant bladder cancer does not make much progress. To investigate a novel therapeutic target, we focused on miRNA expression signatures obtained from bladder cancer clinical specimens, and found that the miR-130 family (miR-130b, miR-301a and miR-301b) was significantly up-regulated in bladder cancer specimens compared to adjacent normal urothelial specimens. Functional analyses revealed that the miR-130 family promoted bladder cancer cell migration and invasion by regulating both focal adhesion kinase (FAK) and Akt phosphorylation. Moreover, miR-130b directly targeted Phosphatase and Tensin Homolog Deleted from Chromosome 10 (PTEN), which suppresses FAK and Akt activation. Furthermore, Argonaute2-immunoprecipitation and the subsequent gene array analysis identified tyrosine-protein phosphatase non-receptor type 11 (PTPN11) as another target gene of both miR-130b and miR-301b. Thus, the miR-130 family promotes bladder cancer cell motility by regulating these target genes. We next designed miR-130 family-targeted LNA (Locked Nucleic Acid) that can inhibit entire miR-130 family through a common seed sequence. miR-130 family-targeted LNA suppressed bladder cancer cell proliferation, migration and invasion powerfully by targeting both PTEN and PTPN11. Furthermore, miR-130 family-targeted LNA significantly inhibits bladder tumor growth in a murine xenograft model. Taken together, the miR-130 family has a crucial role for malignant progression of bladder cancer and thus miR-130 family-targeted LNA could be a promising molecular-targeted drug for bladder cancer.

Citation Format: Hiroshi Egawa, Kentaro Jingushi, Yuko Ueda, Kaori Kitae, Wataru Nakata, Kazutoshi Fujita, Motohide Uemura, Norio Nonomura, Kazutake Tsujikawa. Innovative drug discovery for bladder cancer by miR-130 family seed-targeting locked nucleic acid. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A20.