bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract LB-C23: A haploid genetic screen identifies the G1/S regulatory machinery as a determinant of Wee1 inhibitor sensitivity
Authors: Heijink Anne Margriet , Blomen Vincent , Degener Fabian , Matsushita Felipe Yu , Foijer Floris , Van Vugt Marcel A.
Published: May 2016

The Wee1 cell cycle checkpoint kinase prevents premature mitotic entry by inhibiting cyclin-dependent kinases. Chemical inhibitors of Wee1 are currently being tested clinically as targeted anti-cancer drugs. Wee1 inhibition is thought to be preferentially cytotoxic in p53-defective cancer cells. However, TP53 mutant cancers do not respond consistently to Wee1 inhibitor treatment, indicating the existence of genetic determinants of Wee1 inhibitor sensitivity other than TP53 status. To optimally facilitate patient selection for Wee1 inhibitor treatment and undercover potential resistance mechanisms, identification of these currently unknown genes and underappreciated functions of Wee1 is necessary. The aim of this study was to identify gene mutations that determine Wee1 inhibitor sensitivity.

We performed a genome-wide unbiased functional genetic screen in TP53 mutant near-haploid KBM-7 cells using gene-trap insertional mutagenesis. Insertion site mapping of cells that survived long-term Wee1 inhibition revealed enrichment of G1/S regulatory genes, including SKP2, CUL1 and CDK2. Stable depletion of SKP2, CUL1 and CDK2 or chemical Cdk2 inhibition rescued the γ-H2AX induction and abrogation of G2 phase as induced by Wee1 inhibition in breast and ovarian cancer cell lines. Remarkably, live cell imaging showed that depletion of SKP2, CUL1 and CDK2 did not rescue the Wee1 inhibition-induced karyokinesis and cytokinesis defects. These data indicate that the activity of the DNA replication machinery, beyond TP53 mutation status, determines Wee1 inhibitor sensitivity, and could serve as a selection criterion for Wee1-inhibitor eligible patient. Conversely, loss of the identified S-phase genes could serve as a resistance mechanism and coincides with development of severe genomic instability.

Citation Format: Anne Margriet Heijink, Vincent Blomen, Fabian Degener, Felipe Yu Matsushita, Floris Foijer, Marcel A. Van Vugt. A haploid genetic screen identifies the G1/S regulatory machinery as a determinant of Wee1 inhibitor sensitivity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-C23.
Abstract PL04-03: Basket studies: Lessons learned and future directions
Authors: Hyman David
Published: May 2016

Dramatic improvements in the ability to test for all classes of potentially actionable alterations in hundreds or even thousands of genes simultaneously, along with the rapidly expanding portfolio of therapeutic agents targeting a variety of cell signaling networks, have converged to create an unparalleled opportunity to pursue precision medicine in oncology. One obstacle to realizing the full potential of precision medicine in the clinic is the low prevalence of many potentially actionable genomic alterations as well as the diverse range of cancer types potentially implicated. To address this emerging challenge, multi-histology, genomically selected, basket studies have been developed. These studies represent a potentially transformative approach to genomically targeted drug development. In basket studies, patients with tumors known to harbor a qualifying genomic alteration are enrolled irrespective of tumor histology. Tumor types most likely to harbor the genomic biomarker are enrolled to their own cohort. Notably, in these tumor types that enroll to sufficient quantities, efficacy assessments are independently undertaken, therefore accounting for the possibility that tumor lineage may influence drug sensitivity. While the first generation of basket studies were designed mainly to detect early signals of activity across multiple tumor types simultaneously, newer basket studies are now being designed to collect the data required to seek health authority approval. Here we review the current landscape of precision medicine basket studies, with a focus on how to maximize their potential for advancing the standard of care.

Citation Format: David Hyman. Basket studies: Lessons learned and future directions. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PL04-03.
Abstract PL05-02: Synthetic Lethal Interaction between Homologous Recombination Repair and POLQ-mediated Alternative End-Joining
Authors: D'Andrea Alan D.
Published: May 2016

Large-scale genomic studies have shown that half of epithelial ovarian cancers (EOCs) have alterations in genes regulating homologous recombination (HR) repair. Loss of HR accounts for the genomic instability and replicative stress of EOCs and for their cellular hyperdependence on alternative poly-ADP ribose polymerase (PARP)-mediated DNA repair mechanisms. Previous studies have implicated the DNA polymerase POLQ in an error-prone pathway required for the repair of DNA double-strand breaks, referred to as alternative endjoining (alt-EJ). In Drosophila melanogaster and Caenorhabditis elegans, POLQ functions in alt-EJ and in the maintenance of genome stability at sites of G-quadruplex structures. Whether POLQ interacts with canonical DNA repair pathways to prevent genomic instability at stalled replication forks remains unknown. We have recently demonstrated an inverse correlation between HR activity and POLQ expression in EOCs (Ceccaldi R. et al, Nature, 518: 258-262, 2015). While knockdown of POLQ in HR-proficient cells upregulates HR activity and RAD51 nucleofilament assembly, knockdown of POLQ in HR-deficient EOCs results in enhanced cell death. Consistent with these results, genetic inactivation of an HR gene (Fancd2) and Polq in mice results in embryonic lethality. Moreover, POLQ contains a repeat of RAD51 binding motifs, and it blocks D-loop formation and recombination. Taken together, these results reveal a synthetic lethal relationship between the HR pathway and POLQ-mediated alternative end-joining in EOCs, and identify POLQ as a novel druggable target for ovarian cancer therapy.

Citation Format: Alan D. D'Andrea. Synthetic Lethal Interaction between Homologous Recombination Repair and POLQ-mediated Alternative End-Joining. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PL05-02.
Abstract A19: Role of NF-κB and gene targets of NF-κB in glioma cell plasticity
Authors: Friedmann-Morvinski Dinorah , Narasimamurthy Rajesh , Xia Yifeng , Myskiw Chad , Soda Yasushi , Verma Inder M.
Published: May 2016

Glioblastoma (GBM) is the most common and lethal form of intracranial tumor. In the last century we have accumulated tremendous amounts of data on this type of cancer, but despite extensive study, few therapeutic targets have been identified for GBM. We have established a lentiviral-induced mouse model of malignant gliomas, which faithfully captures the pathophysiology and molecular signatures of human GBM. RNAseq analysis of these tumors revealed high NFκB activation showing enrichment of known NFκB target genes. Depletion of IKK2 in tumor derived cell lines attenuated tumor proliferation and prolonged mouse survival. We have previously shown that gliomas can originate by reprograming/dedifferentiation of terminally differentiated astrocytes and neurons following oncogenic insult. This tumor cell plasticity seems to be impaired when either cortical astrocytes or neurons derived from floxed-IKK2 mice are infected with a lentivirus expressing HRAS-iresCREerT2-shp53. The addition of tamoxifen to the infected cells induces IKK2 depletion and blocks the reprogramming process, manifested by inhibition of tumorspheres formation and retention of differentiation makers. When these cells are transplanted into mice, the control group (vehicle treated) succumbs to the disease, while induction of IKK2 depletion in the tamoxifen treated group (20 days post-transplantation) significantly prolonged the mice survival. Activation of NFκB requires the activity of IκB kinase (IKK) complex containing IKKα and IKKβ, and the regulatory protein NFκB essential modifier (NEMO). We tested a peptide corresponding to the NEMO-binding domain (NBD) of IKKα(IKK1) or IKKβ(IKK2), to specifically inhibit the induction of NFκB activation, and the mice treated with NBDwt peptide showed long-term survival compared to NBDmut control. We propose targeting the NFκB pathway as an attractive therapeutic strategy to treat GBM.

Citation Format: Dinorah Friedmann-Morvinski, Rajesh Narasimamurthy, Yifeng Xia, Chad Myskiw, Yasushi Soda, Inder M. Verma. Role of NF-κB and gene targets of NF-κB in glioma cell plasticity. [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 A19.
Abstract B26: MAPK-interacting kinase inhibition sensitizes glioblastoma and glioma stem cells to arsenic trioxide
Authors: Bell Jonathan B. , Eckerdt Frank , Arslan Ahmet Dirim , Iqbal Asneha , Alvarez Angel A. , Cheng Shi-Yuan , Nakano Ichiro , Platanias Leonidas C.
Published: May 2016

Glioblastoma (GBM) is the deadliest primary brain tumor with a median survival of around one year. Arsenic trioxide (ATO) is an emerging therapy for the treatment of GBM and other malignant brain tumors. The cytotoxic effects of ATO are mainly mediated by the production of reactive oxygen species and induction of cell death pathways. However, glioma stem cells in heterogeneous GBM tumors impart resistance by activation of survival pathways, thereby preventing therapeutic responses to cytotoxic agents such as ATO. We have previously shown that ATO responses in leukemia are antagonized by the MAPK-interacting kinases (MNKs), which activate protein translation and survival pathways including the eukaryotic translation initiation factor 4E (eIF4E) in response to ATO treatment. Yet, the role of MNK signaling in GBM and glioma stem cells and the potential of using MNK inhibitors to sensitize GBM to ATO has not been explored. In this study, we sought to determine the mechanisms by which MNK signaling regulates arsenic trioxide responses in GBM and glioma stem cells.

GBM cell lines were treated with ATO in the presence or absence of MNK inhibitors or siRNA against MNK isoforms. Western blots of treated samples were analyzed with antibodies against phosphorylated eIF4E, the key downstream effector of the MNKs. Following treatment with ATO and MNK inhibitors, proliferation rate and apoptosis were determined by WST-1 assay and Annexin V-FITC/PI staining. GBM cell lines were grown under stem cell conditions and subjected to qPCR and flow cytometry to monitor CD44 expression and aldehyde dehydrogenase (ALDH) activity, both markers of stemness. Patient-derived glioma stem cell lines displaying mesenchymal-like phenotype were treated with ATO and MNK inhibitors and analyzed by neurosphere formation assay.

Treatment of GBM cell lines with ATO resulted in MNK activation and induction of eIF4E phosphorylation in a MNK1-depedent manner. Furthermore, MNK inhibition sensitized GBM cells to the anti-proliferative and pro-apoptotic effects of ATO. Knockdown of MNK1 in GBM cell lines grown under stem cell conditions decreased neurosphere formation. Finally, pharmacological MNK inhibition sensitized mesenchymal-like glioma stem cells to ATO. Our results suggest ATO in combination with MNK inhibition might represent a new approach for the treatment of GBM, in particular the therapy-resistant glioma stem cell subpopulation.

Citation Format: Jonathan B. Bell, Frank Eckerdt, Ahmet Dirim Arslan, Asneha Iqbal, Angel A. Alvarez, Shi-Yuan Cheng, Ichiro Nakano, Leonidas C. Platanias. MAPK-interacting kinase inhibition sensitizes glioblastoma and glioma stem cells to arsenic trioxide. [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 B26.
Abstract IA09: Imaging to guide genomics and epigenomics of glioma
Authors: Costello Joseph F.
Published: May 2016

Genomic analysis of cancer is typically conducted at a single time point and on a single piece of tumor tissue without knowledge of its original context within the heterogeneous tumor. Glioma tissue biopsies guided by distinct physiologic and metabolic imaging parameters can enrich for tumor regions with elevated levels of cycling cells, differences in blood vessels, and increased presence of hypoxic regions, and an increased probability of malignant transformation. An imaging guided approach to biopsy allows the tumor genomic and transcriptome evolution to be focused on malignant transformation. I will describe the use of novel quantitative imaging methods to guide biopsies to biologically distinct regions of brain tumors for targeted genomic, epigenomic and transcriptome analysis.

The clonal evolution of tumor cell populations can be reconstructed from patterns of genetic alterations. In contrast, tumor epigenetic states are reversible and sensitive to the tumor microenvironment, presumably precluding the use of epigenetics to discover the clonal and sub-clonal evolution of tumors. We recently used mutation patterns to learn how low grade brain tumors evolve over time, and also discovered that temozolomide treatment of LGG is associated with TMZ-induced hypermutation and malignant progression to GBM (BE Johnson et al, Science, 2014). I will present an update to these results, and our follow up analysis of the spatial and temporal dynamics of DNA methylation in this clinically and genetically characterized cohort and in imaging guided biopsies.

Citation Format: Joseph F. Costello. Imaging to guide genomics and epigenomics of 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 IA09.
Abstract IA14: The unique genomic landscape of pediatric high-grade glioma
Authors: Larson Jon D. , Silveira Andre B. , Kasper Lawryn H. , Russell Helen R. , Qu Chunxu , McKinnon Peter J. , Baker Suzanne J.
Published: May 2016

Diffuse high-grade gliomas (HGGs) of childhood are a devastating spectrum of disease with no effective cures. The two-year survival for pediatric HGG ranges from 30 percent, for tumors arising in the cerebral cortex, to less than 10 percent for diffuse intrinsic pontine gliomas (DIPGs), which arise in the brainstem. Frequent recurrent somatic mutations in histone H3 distinguish the genetic drivers among pediatric and adult HGG. Mutually exclusive somatic heterozygous H3F3A or HIST1H3B mutations encoding a K27M variant of histone H3.3 or H3.1, respectively, are found in nearly 80 percent of DIPGs and 22 percent of non-brainstem HGG, where they occur predominantly in thalamic and other midline tumors. Strikingly, heterozygous H3F3A mutations encoding histone H3.3 G34R or G34V occur in approximately 14 percent of non-brainstem HGG, and are associated predominantly with cortical tumors arising in older children through young adulthood, suggesting a distinct developmental origin compared to the majority of tumors harboring K27M mutations. Recurrent mutations of the BMP receptor ACVR1/ALK2 have not been reported outside the brainstem, and are further restricted to the youngest DIPG patients, highlighting critical connections between development and gliomagenesis. Experiments to model the connections between oncogenic activity and developmental context will be discussed.

Citation Format: Jon D. Larson, Andre B. Silveira, Lawryn H. Kasper, Helen R. Russell, Chunxu Qu, Peter J. McKinnon, Suzanne J. Baker. The unique genomic landscape of pediatric high-grade 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 IA14.
Abstract IA18: Epigenetic addiction in pediatric high-grade gliomas
Authors: Jabado Nada
Published: May 2016

A remarkably rapidly expanding body of literature points to the epigenome as a new previously unsuspected mechanism of oncogenesis and another “hallmark of cancer.” Indeed, in a large number of cancers, aberrant epigenetic states occur through different mechanisms including altered DNA methylation, covalent histone modification, the reading of these histone modifications by protein regulation modules, histone exchange, chromatin remodelers, or via the effects of non-coding RNAs. Although mutations are also found in canonical signaling pathway genes, we and others identified chromatin-associated proteins to be more commonly altered by somatic alterations than any other class of oncoprotein in several subgroups of childhood high-grade brain tumors. Furthermore, as these childhood malignancies carry fewer non-synonymous somatic mutations per case in contrast to most adult cancers, these mutations are likely drivers in these tumors. Herein, we will use as examples of this novel hallmark of oncogenesis high-grade astrocytomas, including glioblastoma, and a subgroup of embryonal tumors, embryonal tumor with multilayered rosettes (ETMR) to describe the novel molecular defects uncovered in these deadly tumors. We will further discuss evidence for their profound effects on the epigenome and their links to brain development. Importantly, the type, timing and spatial clustering of these molecular alterations provide a better understanding of the pathogenesis of the respective brain tumor they target as well as critical markers for therapy that will help refine pathological grading.The relative genetic simplicity of these tumors promises general insights into how mutations in the chromatin machinery modify downstream epigenetic signatures to drive transformation, and how to target this plastic genetic/epigenetic interface.

Citation Format: Nada Jabado. Epigenetic addiction in pediatric high-grade 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 IA18.
Abstract PR10: A DNA hypomethylation signature predicts novel antitumor activity of LSD1 inhibition in SCLC
Authors: Mohammad Helai , Kruger Ryan
Published: May 2016

Epigenetic dysregulation has emerged as an important mechanism in cancer. Alterations in epigenetic machinery have become a major focus for new targeted therapies. The current report describes the discovery and biological activity of a cyclopropylamine containing inhibitor of Lysine Demethylase 1 (LSD1), GSK2879552. This small molecule is a potent, selective, orally bioavailable, mechanism-based irreversible inhibitor of LSD1. A proliferation screen of cell lines representing a number of tumor types indicated that small cell lung carcinoma (SCLC) is sensitive to LSD1 inhibition. The subset of SCLC lines that undergo growth inhibition in response to GSK2879552 exhibit DNA hypomethylation of a signature set of probes suggesting this may be used as a predictive biomarker of activity. This targeted mechanism coupled with a novel predictive biomarker make LSD1 inhibition an exciting potential therapy for SCLC, a highly prevalent, rarely cured, tumor type representing approximately 15% of all lung cancers.

Citation Format: Helai Mohammad, Ryan Kruger. A DNA hypomethylation signature predicts novel antitumor activity of LSD1 inhibition in SCLC. [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 PR10.
Abstract B1-38: PARADIGM-SHIFT: Predicts the functional impact of ‘driver modules’ in multiple cancers using pathway impact analysis
Authors: Ng Sam , Benz Christopher , Haussler David , Stuart Joshua M.
Published: May 2016

The major mechanism by which cancer arises is through genomic alterations. These alterations can lead to changes in gene regulation, protein structure, and function. Individual tumors can contain hundreds to thousands of alterations. It is critical to distinguish alterations that have an important role defining the cancer – drivers – from alterations that are unimportant to the tumor – passengers. Driver genes can lead to significant changes in their pathways; however, alterations in a single gene may not be sufficient to explain all the pathway perturbations across patients. Additional alterations could range from DNA copy number changes, gene-fusions, or even lesser understood non-coding mutations. Identifying these ‘driver modules’ is essential for understanding cancer disease mechanisms, which can help guide treatment decisions as well as identify novel targets for treatment.

We have developed a functional impact prediction method called PARADIGM-SHIFT based on integrated pathway analysis to discriminate loss-of-function, neutral, and gain-of-function alterations. Utilizing the set of regulatory interactions annotated for a given gene, we can detect a shift in the downstream effects of an altered gene compared to what is expected from its upstream influences. Additionally, since these shifts in pathway signal can be detected for all samples, PARADIGM-SHIFT can be used to identify additional genomic alterations that lead to similar changes to the altered pathway to form ‘driver modules.’ Application of our method to the TCGA Pan-Cancer cohort identifies many genes with significant alterations that lead to loss- and gain- of function. PARADIGM-SHIFT then identifies several additional genomic alterations, including non-coding mutations variants, which are significantly implicated in these pathway changes. This analysis offers insight into the mechanism of non-coding mutations orthogonal to sequence-based methods by interpreting the pathway consequences of these variants.

Citation Format: Sam Ng, Christopher Benz, David Haussler, Joshua M. Stuart. PARADIGM-SHIFT: Predicts the functional impact of ‘driver modules’ in multiple cancers using pathway impact analysis. [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 B1-38.
Abstract B1-43: Cancer drug response networks built for comparative cancer pharmacogenomics identifies combination therapies for repositioning
Authors: Brubaker Douglas , Svenson Elena , Kai Smith , Monroe Maya , Ryu Christopher , Narla Goutham , Chance Mark R. , Bebek Gurkan
Published: May 2016

We present an integrative framework for classifying drug response: CAncer Drug Response nEtworks (CADREs). We built CADREs for drugs with differential sensitivity profiles in cancer cell lines by integrating baseline copy number, gene expression, and drug sensitivity data for the cell lines. The nodes in the network are drugs and the edges are weighted according to the number of shared copy number variations, differentially expressed genes, and dysregulated pathways present in sensitive cell lines at baseline. These baseline features were mapped into pathways to generate a Pathway CADRE, and were also integrated into a differential gene expression and copy number Feature CADRE. CADREs were built for breast, ovarian, and endometrial cancers individually and combined to assess shared and unique features of drug sensitivity. Analyzing CADRE clusters associated multiple gene features and pathways with sensitivity to frontline therapies used in combination in these cancers. We identified four clusters of breast cancer drugs whose effectiveness is driven by a shared core of pathways. Compounds that were used in combination in clinical trials tended to not share an edge or are completely disconnected in networks. Specifically, ten such drug pairs in our breast CADREs have been found to work in combination in breast cancer and an additional five have been used in combination in other cancers, representing opportunities for repositioning these combinations in breast cancer. Examining highly interconnected CADRE nodes gave us an understanding for compounds that might work best together.

Citation Format: Douglas Brubaker, Elena Svenson, Smith Kai, Maya Monroe, Christopher Ryu, Goutham Narla, Mark R. Chance, Gurkan Bebek. Cancer drug response networks built for comparative cancer pharmacogenomics identifies combination therapies for repositioning. [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 B1-43.
Abstract B2-01: Integrated omic analysis of lung cancer reveals metabolism proteome signatures with prognostic impact
Authors: Moran Michael F. , Kislinger Thomas , Li Lei , Ignatchenko Vladimir , Wei Yuhong , To Christine , Taylor Paul , Tong Jiefei , Pham Nhu An , Pintilie Melania , Muthuswamy Lakshmi , Shepherd Frances A. , Tsao Ming Sound
Published: May 2016

Cancer results from processes prone to selective pressure and dysregulation acting along the sequence-to-phenotype continuum DNA→RNA→Protein→Disease. An Omics Array integrating DNA gene copy number, mRNA transcriptome, and quantified proteome was assembled into a genetic map representing non-small cell lung carcinoma (NSCLC). Data were collected from patient-matched normal lung, primary tumors, and patient tumor-derived xenograft (PDX) tumors. Dysregulated proteins not previously implicated as cancer drivers were found encoded throughout the genome including but not limited to regions of recurrent DNA amplification/deletion in NSCLC. Unsupervised clustering revealed signatures comprising metabolism proteins particularly highly recapitulated between matched primary and PDX tumors, and which distinguished between the major NSCLC histological subtypes adenocarcinoma (ADC) and squamous cell carcinoma (SCC). Interrogation of The Cancer Genome Atlas (TCGA) revealed sizeable cohorts of NSCLC patients with DNA alterations in genes encoding the metabolism proteome signatures, and accompanied by differences in survival. Similar to the proteome signatures from which they were extrapolated, the gene mutation signatures with prognostic impact discriminated between the lung ADC and SCC subtypes. Serine hydroxymethyltransferase 2 (SHMT2), a key enzyme in serine/glycine and folate-dependent one-carbon metabolism, is upregulated in the proteomes of NSCLC primary and PDX tumours, and is implicated as a driver of recurrent chromosome 12q14.1 amplification in NSCLC. SHMT2, along with other enzymes implicated as anti-folate targets, is also part of a metabolism signature associated with poor outcome in lung ADC. The interrogation of cancer genomes and proteomes for alterations that are related products of selective pressures driving the cancer phenotype may be a general approach to uncover and group together cryptic, polygenic cancer drivers, which might represent new anti-cancer therapeutic targets.

Note: This abstract was not presented at the conference.

Citation Format: Michael F. Moran, Thomas Kislinger, Lei Li, Vladimir Ignatchenko, Yuhong Wei, Christine To, Paul Taylor, Jiefei Tong, Nhu An Pham, Melania Pintilie, Lakshmi Muthuswamy, Frances A. Shepherd, Ming Sound Tsao. Integrated omic analysis of lung cancer reveals metabolism proteome signatures with prognostic impact. [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 B2-01.
Abstract B2-18: Mechanisms of GBM progression on bevacizumab: Model predictions
Authors: Scribner Elizabeth , Saut Olivier , Colin Thierry , Fathallah-Shaykh Hassan M.
Published: May 2016

Glioblastoma multiforme (GBM) causes significant neurological morbidity and short survival times. Brain invasion by GBM is associated with poor prognosis. Recent clinical trials of bevacizumab in newly-diagnosed GBM found no beneficial effects on overall survival times. We have reported a mathematical model of GBM growth and invasion, built at the scale of clinical magnetic resonance imaging. Here, we replicate the patterns of progression of GBM patients treated with bevacizumab. The model is interrogated to derive a mechanistic explanation for each type of recurrence.

Citation Format: Elizabeth Scribner, Olivier Saut, Thierry Colin, Hassan M. Fathallah-Shaykh. Mechanisms of GBM progression on bevacizumab: Model predictions. [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 B2-18.
Abstract B2-21: Identification of somatic RNA splicing alterations in human cancers
Authors: Brooks Angela N. , Ge Yawei , Chau Kevin , Freeman Samuel S. , Saksena Gordon , Pedamallu Chandra Sekhar , Meyerson Matthew
Published: May 2016

Recent whole-exome sequencing studies have found that somatic mutations frequently occur in splicing factors across multiple cancer types, supporting the need to systematically and globally characterize splicing alterations across human cancers. Somatic alterations that affect RNA processing of cancer genes may be caused by multiple mechanisms, including mutations in splicing factors, mutations in cis-acting splice sites and other regulatory sequences, alterations in methylation, or alterations in chromatin structure. For a global look at somatic RNA splicing alterations, we are applying the Cancer Outlier Profile Analysis (COPA) approach on ~7,000 cancer transcriptomes from 12 tumor types in The Cancer Genome Atlas (TCGA) and investigating the underlying somatic mutations that cause these splicing alterations using matched whole-exome, whole-genome, and methylation data from these samples.

To identify and quantify alternative splicing in RNA-Seq data, including unannotated splicing events, we have further developed a computational pipeline called JuncBASE. To distinguish between cancer-specific splicing alterations and normal transcriptome variation, we are utilizing ~700 RNA-Seq libraries from healthy individuals from the Genotype-Tissue Expression (GTEx) project.

COPA analysis of outlier splicing events in lung adenocarcinomas and glioblastomas successfully identified known altered splicing events in MET and EGFR, respectively, that are caused by DNA level somatic mutations. The genomic mechanisms for novel somatic splicing events in known cancer genes such as FGFR3, as well as genes previously uncharacterized in cancer genomes, are currently being investigated.

To identify splicing events that may be novel somatic driver alterations, these events have been profiled using RNA-Seq data from the Cancer Cell Line Encyclopedia and are being used as biomarkers to identify genetic vulnerabilities in high-throughput shRNA screens. This work will have a significant impact on the identification of somatic splicing events that contribute to cancer pathogenesis.

Citation Format: Angela N. Brooks, Yawei Ge, Kevin Chau, Samuel S. Freeman, Gordon Saksena, Chandra Sekhar Pedamallu, Matthew Meyerson. Identification of somatic RNA splicing alterations in human cancers. [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 B2-21.
Abstract B2-23: A Big Bang model of human colorectal tumor growth
Authors: Sottoriva Andrea , Kang Haeyoun , Ma Zhicheng , Graham Trevor A. , Salomon Matthew , Zhao Junsong , Marjoram Paul , Siegmund Kim , Press Michael F. , Shibata Darryl , Curtis Christina
Published: May 2016

What happens in the early and still undetectable human malignancy is unknown because direct observations are impractical. Here we present a “Big Bang” model, whereby a tumor grows predominantly as a single expansion producing numerous intermixed sub-clones, which are not subject to stringent clonal selection. In this model, both public and most detectable private mutations arise during the earliest phase of tumor growth. Multi-scale genomic profiling of 349 individual glands sampled from 15 colorectal tumors revealed the absence of selective sweeps, uniformly high intra-tumor heterogeneity, and sub-clone mixing in distant tumor regions, as postulated by the Big Bang. By integrating the data in a spatial model of tumor growth and statistical inference framework we also verified the most striking prediction of our model, namely that most detectable intra-tumor heterogeneity originates from private alterations acquired early during growth, and not from the later expansion of selected sub-clones. Hence, early sub-clones define the genomic profile of colorectal carcinomas and advanced adenomas, whereas potentially dangerous late-arising sub-clones will go undetected. Moreover, our results suggest that sub-clone mixing may be a biomarker of malignant potential. This new model provides a quantitative framework that explains the origins of intra-tumor heterogeneity and tumor growth dynamics with significant clinical implications.

Citation Format: Andrea Sottoriva, Haeyoun Kang, Zhicheng Ma, Trevor A. Graham, Matthew Salomon, Junsong Zhao, Paul Marjoram, Kim Siegmund, Michael F. Press, Darryl Shibata, Christina Curtis. A Big Bang model of human colorectal tumor growth. [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 B2-23.
Abstract B2-24: OVOL: A brake on EMT, driver of MET and expander of the hybrid E/M phenotype
Authors: Jia Dongya , Jolly Mohit Kumar , Boareto Marcelo , Parsana Princy , Mooney Steven , Pienta Kenneth J. , Levine Herbert , Ben-Jacob Eshel
Published: May 2016

Aberrant activation of Epithelial to Mesenchymal Transition (EMT) and its reverse MET is a hallmark of cancer metastasis. Also, the carcinoma cells can undergo partial transitions to attain a hybrid epithelial/mesenchymal (E/M) phenotype, which can allow them to migrate collectively and form clusters of Circulating Tumor Cells (CTCs). These clusters can be up to 50 times more metastatic compared to cells that undergo complete EMT or individually migrating CTCs. Here, using experimental data and bioinformatics, we devised a dedicated model to study the role of transcription factor OVOL in regulating these bidirectional epithelial-hybrid-mesenchymal transitions. The new model incorporates the coupling between OVOL and miR-200/ZEB - the three-way EMT/MET decision-making switch that allows for three phenotypes (E, M and E/M). We found that OVOL operates as a brake holder of complete EMT and as an expander of the hybrid E/M phenotype (it extends the range of physiological parameters for which the cells can attain the hybrid E/M phenotype). Inhibition of OVOL, for example by Wg signaling, removes that brake and supports a complete EMT. Conversely, overexpression of OVOL, for example by BMP7/Smad4, leads to the reverse of EMT, i.e. MET. In addition, OVOL elevates the phenotypic plasticity of cells by turning both EMT and MET into a two-step process (E to E/M to M, and M to E/M to E). We show that depending on the context-specific coupling manner of OVOL with miR-200/ZEB, OVOL can shepherd cellular plasticity in multiple ways - by driving MET, by restricting EMT, and by expanding the existence of the hybrid E/M phenotype. In particular, we explain how the differences between the observed effects of OVOL in breast and prostate cancer are associated with the results of different miR-200/ZEB/OVOL couplings. Our computational framework can be tailored to include other signals such as p53, TGF-beta, inflammation and hypoxia that affect the cellular plasticity during metastasis, thus providing a platform to design novel anti-metastasis therapies.

Citation Format: Dongya Jia, Mohit Kumar Jolly, Marcelo Boareto, Princy Parsana, Steven Mooney, Kenneth J. Pienta, Herbert Levine, Eshel Ben-Jacob. OVOL: A brake on EMT, driver of MET and expander of the hybrid E/M phenotype. [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 B2-24.
Abstract B2-37: Understanding the variability in drug response in a panel of breast cancer cell lines using computational models
Authors: Thijssen Bram , Jastrzebski Katarzyna , Beijersbergen Roderick L. , Wessels Lodewyk FA
Published: May 2016

Cancer cell lines differ widely in their sensitivity to anticancer drugs. While many oncogenic drivers and drug resistance mechanisms have been discovered, it is generally unclear how these mechanisms interact in each cell line to make the cell line sensitive or resistant to a particular drug.

We set out to explain this variability in drug sensitivity in a panel of 30 breast cancer cell lines. We characterized these cell lines at the DNA, RNA and protein level, and accurately measured the proliferation under treatment with various different kinase inhibitors. We then constructed computational models encompassing several of the important driver pathways and sensitivity mechanisms, and tested how well these models describe the available data. After selecting the well-fitting models, we could use these models to estimate the relative contribution of each of the interacting mechanisms to the proliferation of the cells under drug treatment. For example, the models indicated that FGF2 autocrine signaling contributes to fast proliferation in some cell lines; that SGK1 expression provides a bypass for Akt signaling in some cell lines; or that the expression level of 4E-BP1 is a key determinant of mTOR-inhibitor sensitivity on top of other genetic alterations in the PI3K-pathway. Additionally, we could use these models to thoroughly analyze which parts of the data cannot be explained. This greatly narrows down which follow-up studies are necessary to advance our understanding of drug response.

These results show that knowledge-based computational models can be used to systematically study drug response in cell line panels. Such systematic, quantitative understanding of drug response will be useful in working towards precision medicine for individual cancer patients.

Citation Format: Bram Thijssen, Katarzyna Jastrzebski, Roderick L. Beijersbergen, Lodewyk FA Wessels. Understanding the variability in drug response in a panel of breast cancer cell lines using computational models. [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 B2-37.
Abstract B2-48: Biological profile in invasive lobular carcinoma in medical oncology department, Algeria
Authors: Sakhri Selma
Published: May 2016

Background: Invasive lobular cancers(ILC) constitute 5% - 15% of all invasive breast tumors, less common than invasive ductal carcinoma(IDC), and appear to have a distinct biology. The aim of our study is to determine the ILC biological profile collected in the department ofoncology medical Tizi Ouzou hospital Algeria

Materials and Methods: We recorded the cases of 73 patients with ILC between January 2010 and January 2012. .the aim of this study is to evaluate the clinical and pathological response, molecular profiling using RE, RP, KI67, HER2, and the follow up between (2012 – 2014).

Result: The average age of patients with ILC is 52 years, 40% women have postmenopausal status, all patients underwent mammography, diagnosed by a core needle biopsy, the commonest stage at presentation was stage III (42%).10 patients (13%) underwent a breast conserving surgery, and 87 % a mastectomy

The majority of cases were histologic grade II (SBR II), 50% of the tumors were estrogen and progesterone receptor positive, Her2 neu was reported to be negative in 60 %. the treatment consisted on : neoadjuvant chemotherapy in 28 cases ( 38%) ,adjuvant chemotherapy in 42 cases (57%) , following by radiotherapy , and hormonal therapy ( HT) was given to 47 patients ( 64%) , and target therapy to 40% the follow up after 2 years , 12 % had metastatic or loco regional recurrence : bone ( 60%) , lung ( 30 %) , and liver in ( 10 %) , 88 % of the cases remain in complete remission.

Conclusion: ILC are a heterogeneous group of tumors and the management decisions should be based on individual patient and biologic characteristic of the tumor.

Citation Format: Selma Sakhri, Sr. Biological profile in invasive lobular carcinoma in medical oncology department, Algeria. [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 B2-48.
Abstract B2-49: Coupled cellular decision-making of EMT and stemness: A bottom-up regulatory model
Authors: Jolly Mohit Kumar , Huang Bin , Lu Mingyang , Mani Sendurai A , Levine Herbert , Ben-Jacob Eshel
Published: May 2016

Epithelial cells undergoing epithelial-to-mesenchymal transitions (EMT) have often been shown to behave as cancer stem cells (CSCs) but the precise molecular connection remains elusive. At the genetic level, stemness is governed by LIN28/let-7 double inhibition switch, whereas EMT/MET is controlled by miR-200/ZEB double inhibition circuit. The two switches are coupled by LIN28 being inhibited by miR-200, and ZEB being inhibited by let-7. Here, we devise a specific theoretical framework to investigate the dynamics of the LIN28/let-7 system, and show that it can operate as a three-way switch (between low, high and intermediate LIN28 levels termed the D, U and the hybrid D/U states) similar to the three-way operation of the miR-200/ZEB circuit that allows for the existence of a hybrid epithelial/mesenchymal (E/M) or partial EMT phenotype, in addition to epithelial and mesenchymal ones. We find significant correspondence between the existence of the three states of the two circuits: E-D; M-U; E/M-D/U. Incorporating the activation of OCT4 by LIN28, we find that the hybrid E/M phenotype has high likelihood (as compared to either the pure E or M states) to gain stemness. Combining the LIN28/let-7 regulation by NF-kB and c-MYC, we find that NF-kB, but not c-MYC, elevates the likelihood of E/M to gain stemness. Our results are consistent with emerging concept that cells undergoing partial EMT can gain stemness.

Citation Format: Mohit Kumar Jolly, Bin Huang, Mingyang Lu, Sendurai A Mani, Herbert Levine, Eshel Ben-Jacob. Coupled cellular decision-making of EMT and stemness: A bottom-up regulatory model. [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 B2-49.
Abstract IA02: The application of integrative sequencing for precision oncology
Authors: Chinnaiyan Arul
Published: May 2016

Studies of the genomic landscape of human cancers have demonstrated that most solid cancers have a multitude of mutations, a subset of which may be “actionable” with current drugs. Thus, the personalization of therapy for cancer will require molecular characterization of unique and shared genetic aberrations. Patients who have advanced/refractory cancer and are candidates for clinical trials could potentially benefit by identifying eligibility for “targeted” drugs based on the “actionable” genes in their specific tumor. Growing technological advances in genomic sequencing has now made it possible to consider the use of sequence data in a clinical setting. MI-ONCOSEQ initiative brings together expertise at the University of Michigan including clinical oncology, cancer genetics, bioinformatics, clinical pathology, social and behavioral sciences, and bioethics in order to implement clinical cancer sequencing. Our study identifies patients with advanced or refractory cancers that are eligible for clinical trials, consent them to the study, obtain biospecimens (tumor tissue, germline tissue) and store clinical data. The clinical sequencing team processes biospecimens, performs comprehensive sequencing and analysis of tumors to identify point mutations, copy number changes, rearrangements/gene fusions, and aberrant gene expression. Finally, a multi-disciplinary Sequencing Tumor Board deliberates on return of actionable or incidental genomic results.

Citation Format: Arul Chinnaiyan. The application of integrative sequencing for precision oncology. [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 IA02.
Abstract IA11: Differential networks and drug networks: A computational approach to drug discovery
Authors: Bernardo Diego di
Published: May 2016

Genome scale expression profiles (GEPs) of tumor samples versus non-tumor sampls can be analysed via innovative computational approaches to identify altered pathways and driver genes. These results can then be used to make identify appropriate small molecule therapies.

We developed and validated computational strategy, called Differential Co-expression Analysis (DiCA), to infer metabolic, signaling and regulatory pathways which are altered across two conditions (i.e. tumor vs non-tumor). DiCA is built on the hypothesis that genes in an active pathway are more likely to be regulated and hence co-expressed. On the contrary, inactive pathways will results in uncoordinated gene expression. DiCA measures how much a set of genes is co-expressed using a multidimensional information metrics. We apply DiCA to 100 Human HepatoCarcinoma samples collected within the MODHEP European Project. We demonstrate how DMI is able to correctly identify altered pathways known to be affected by HCC and to propose new hypothesis on HCC pathogenesis, which would be missed by conventional Differential Expression. We then show how GEPs from cancer samples can be used also to query a “drug network” by comparing them to transcriptional responses induced by drug treatment. The end result is a list of drugs which induce a transcriptional response similar to that of cancer samples thus hinting at which pathways are perturbed. Analogously, drugs inducing an “anti-similar” response, i.e. up regulating genes down regulated in cancer and vice-versa, could be investigated as potentially therapeutic. We tested these hypotheses on HCC samples demonstrating their potential usefulness.

Citation Format: Diego di Bernardo. Differential networks and drug networks: A computational approach to drug discovery. [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 IA11.