cancer therapeutics response portal

The latter is a phenomenon known as non-oncogene addiction or oncogene-induced dependency. array of cell processes. Calvin J. Kuo, M.D., Ph.D. TheCancer Cell Line Encyclopediaprovides public access to genomic data, analysis and visualization for about 1000 cell lines. Hepatocellular carcinoma (HCC) is the most common form of primary adult liver cancer and the fourth leading cause of cancer-related death worldwide in 2018 (REF. rDriver predicts driver mutations by integrating genome-wide mRNA/protein expression levels,evolutionary and structural properties of mutations characterized by functional impact scores. The Cancer Therapeutics Response Portal (CTRP) links genetic, lineage, and other cellular features of cancer cell lines to small-molecule sensitivity with the goal of accelerating discovery of patient-matched cancer therapeutics. Access EDDY-CTRP:http://biocomputing.tgen.org/software/EDDY/CTRP/home.html, Functional Annotation of Somatic Mutations in Cancer (FASMIC)(University of Texas MD Anderson Cancer Center). Finally, the statistical significance of this divergence is computed. The OncoPPi Portal is a resource of cancer-relevant protein-protein interactions (PPI) that allows users to access, explore, and prioritize cancer-relevant PPIs for target discovery. Furthermore, Cancer Therapeutics Response Portal (CTRP) 13, and Genomics of Drug Sensitivity in Cancer (GDSC) 14 provided pharmacogenomics data from ~ 500 anticancer compounds across > 1000 cancer . These portals provide collections of tools for analyzing and visualizing genomic data. other cancer drugs yield similarly high response rates For example, a user might enter through the Compounds link then search for a molecule of interest, like navitoclax. Pathway Commons is a network biology resource that serves as a convenient access point to biological pathway information collected from public pathway databases, which users can search, visualize, and download. Access MAGNETIC:https://github.com/BandyopadhyayLab/MAGNETIC, For questions, please contact Sourav Bandyopadhyay: (Sourav.Bandyopadhyay@ucsf.edu), Modulator Inference by Network Dynamics (MINDy2)/ Conditional Inference of Network Dynamics (CINDy)(Columbia University). at the National Cancer Institute, An official website of the United States government, https://califano.c2b2.columbia.edu/aracne, https://www.broadinstitute.org/cancer/ataris, https://califano.c2b2.columbia.edu/demand, https://www.bioconductor.org/packages/release/bioc/html/diggit.html, http://biocomputing.tgen.org/software/EDDY/, http://biocomputing.tgen.org/software/EDDY/CTRP/home.html, https://software.broadinstitute.org/GENE-E/, http://wiki.c2b2.columbia.edu/workbench/index.php/Home, https://califano.c2b2.columbia.edu/marina, https://bioconductor.org/packages/3.1/bioc/html/MethylMix.html, https://github.com/BandyopadhyayLab/MAGNETIC, https://califano.c2b2.columbia.edu/mindy2-cindy, https://bioinformatics.mdanderson.org/main/RDriver, http://genomeportal.stanford.edu/pan-tcga, Systems Biology Lab from Columbia University Medical Center, Data Portal from Memorial Sloan Kettering Cancer Center, U.S. Department of Health and Human Services, mines data to find alterations that potentially influence tumor biology, characterizes the functional roles of candidate alterations in cancers, identifies novel approaches that target causative alterations either directly or indirectly. Our hope is that the insights mined from the resource, first based on cell-line models of cancer and then substantiated in more complex environments, will yield clinically relevant predictions of how patients will respond to novel types of targeted therapies and accelerate the discovery of new genetically matched. These analyses, and links to the underlying data, are provided openly on the CTRP. A computational method, CERES was developed for inferring gene essentiality from genome-wide CRISPR-Cas9 screens in cancer cell lines to correct the copy number effect. CCLE mutation source, confounding factors, correlations to copy-number and gene-expression data, mutation data integrate CCLE and Sanger/MGH calls, correlation and enrichment analysis on-the-fly, box-whisker visualization in addition to enrichment heatmaps, drill-down to scatter plots and concentration-response curves. Currently our programs serve ages 18 and older. The Gerstner Center is developing next-generation diagnostic technology for cancer detection and tracking disease progression. ScreenBEAM analyzes gene-level activity for the whole set of shRNAs or sgRNAs targeting the same gene (multi-probe analysis) instead of analyzing the effect of each individual shRNA or sgRNA on a given gene. In the case of permitted digital reproduction, please credit the National Cancer Institute as the source and link to the original NCI product using the original product's title; e.g., The Broad Institute was originally published by the National Cancer Institute., Center for Cancer Genomics Stuart L. Schreiber, Ph.D.ContactPaul Clemons, Principal Investigator (2012) The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. In the process of malignancy, cells acquire multiple genetic alterations, such as focal mutations, translocations, amplifications, or deletions, which allow them to survive and divide uncontrollably. Finally, we evaluated the sensitivity and resistance to drugs targeting TRPV channel-related genes using the Cancer Therapeutics Response Portal (CTRP) and the Genomics of Drug Sensitivity in Cancer (GDSC) database. Master regulators (MR) are transcription factors that control the majority of genes differentially expressed between two molecular phenotypes. Gordon Mills, M.D., Ph.D.Contacts Gene expression based inference of cancer drug sensitivity Supporting Information accompanying the Resource paper contains all raw sensitivity and enrichment data. Screening for Dependencies in Cancer Cell Lines Using Small Molecules. This reduces false positive and negative rates of high-throughput RNAi or CRISPR screens. Stuart L. Schreiber, Ph.D. Through robust cross-Network collaborations, the CTD Network includes three goals: Methodologies include bioinformatics, genome-wide gain- and loss-of-function screening, and small molecule high-throughput screening, among others. CellMiner Cross-Database (CellMinerCDB) version 1.2: Exploration of This method creates an accurate, context-rich map of the datasets and enables biological interpretation of the data. Access TCPA:https://tcpaportal.org/tcpa/, Virtual Inference of Protein-activity by Enriched Regulon analysis (VIPER)(Columbia University). DEMETER2 is a computation method that estimates gene dependencies by integrating data from large-scale RNAi screens (targeting up to the whole transcriptome) with read-out of cell viabilities performed in cancer cell lines. Optimism. Using cancer cell-line profiling, we established an ongoing resource to identify, as comprehensively as possible, the drug-targetable dependencies that specific genomic alterations impart on human cancers. This could be used to identify differentially and transcriptionally predictive methylated genes within a disease by comparing with the normal DNA methylation state. Finally, we investigated pyroptosis-related genes in the level of single-cell and validated the expression levels of these genes between normal and CRC cell lines by RT-qPCR. The Cancer Genome Atlas (TCGA) Clinical Explorer is a web and mobile interface for identifying clinical genomic driver associations. Cracks in the armor of therapy-resistant cancer cells The data are then used to identify network dysregulation to determine both the interactions and the genes that are involved in the mechanism of action. Twenty-seven sarcoma cancer cell lines were included from CTRP. To determine the optimal density for profiling, each CCL underwent an assay-development step with a control compound (staurosporine or MG-132). Cancer Therapeutics Response Portal (CTRP v1, 2013) dataset: 355 small molecules; 242 cancer cell lines (CCLs). This approach uses the transcripts most directly affected by the activity of the proteinand ranks relative protein activity on a sample-by-sample basis by transforming a gene expression matrix into a protein activity matrix. TheGenomics of Drug Sensitivity in Cancerprovides public access to data on the sensitivity of genomically characterized cancer cell lines to select compounds. PiHelper integrates drug target and antibody target interactions from publicly available resources to facilitate research in systems pharmacology, perturbation biology, and proteomics. Heiser LM, Sadanandam A, Kuo WL, Benz SC, Goldstein TC, Ng S, et al. Under the General tab, the navitoclax entry shows the chemical structure of the compound and provides other general information (top right). Drug efficacy estimation of AUC values, a . Responsiveness. Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH . Chan School of Public Health to study the genetics of severe mental illness, has recruited more than 42,000 participants in Ethiopia, Kenya, Uganda, and South Africa. In 2021, our sustainability efforts sent more than 80 percent of waste from the Genomics Platform to either a recycling facility or to an incineration plant that generates electricity. The DIGGIT package integrates patient-matched genomic mutation and gene expression data with corresponding gene regulatory networks to identify candidate driver mutations that are upstream of master regulators and drive cellular phenotypes. This tool could be used by researchers to determine novel driver genes and drug mechanisms of action. comprehensively relationships between genetic and lineage DecoRNAi is a computational approach that could be used for identification and correction of the off-target effects in the primary RNAi screening data sets. To accelerate discovery of patient-matched therapies, systematic approaches are needed to identify oncogene-induced dependencies that cancers acquire as a result of specific cellular or genetic features and small-molecule drugs that target them. We assessed the sensitivities of drugs targeting COVID-19 receptor-related regulators, using information from the Cancer Therapeutics Response Portal database. For CTRP v2 data, we evaluated whether small-molecule sensitivity could be correlated with basal gene-expression levels or copy-number variation to identify new biomarkers of sensitivity, candidate protein targets, or other biological determinants of small-molecule sensitivity. In the Project Achilles portal, genes can be queried for essentiality across all cell lines. Please cite our cancer cell-line profiling Resource by referencing: Access DepMap:https://depmap.org/portal/depmap/, For questions, please contact this email: (depmap@broadinstitute.org), Detecting Mechanism of Action based Network Dysregulation (DeMAND)(Columbia University). Massachusetts General Hospital and the Wellcome Trust Sanger Institute profiled 350 cancer cell lines against 130 pre-clinical or clinical anti-cancer agents, though the set of genomic alterations correlated to sensitivity was limited to ~70 genes4. The Cancer Therapeutics Response Portal (CTRP; http://portals.broadinstitute.org/ctrp/ ) homepage (top left) allows users to access data through three entry points: small molecules, enriched features, or targets. Thirty-one patients at four different states, including health, hepatitis, cirrhosis, and cancer, were enrolled in this study. We input the resulting data as well as previously determined molecular characterizations/annotations into one database and created the CTRP for access, query, and visualization. Our Core Values. Dependencies can be represented and assessed graphically for the expression of a gene set within a particular cellular context. ScreenBEAM is an algorithm that measures gene-level activity to assess the effect of high-throughput RNAi or CRISPR screens through Bayesian hierarchical modeling. Scientific Applications of Next-Generation Cancer Models The CTDis a community resource project and network where members release their data to this Data Portal and our Dashboard for other investigators to maximize the impact of the findings. https:// portals.broadinstitute.org /ctrp/ 10840Bliss-based . Using data from two large-scale studies, The Genomics of Drug Sensitivity of Cancer (GDSC) and The Cancer Therapeutics Response Portal (CTRP), we investigated the relationship between the sensitivity of hundreds of cell lines to hundreds of drugs, and the relative expression levels of the targets these drugs are directed against. Cancer Response Team, Inc. is a 501 (c) (3) nonprofit organization dedicated to helping children get supportive cancer care. collection on a panel of cancer cell lines for which More than 11,000 individuals living with cancer in the United States and Canada have partnered with Count Me In to share their experiences and help accelerate cancer research. Mice were . with specific genomic alterations in their cancers. Identification of inhibitory immune checkpoints and relevant regulatory However, this list gives researchers a gateway to access many tools that are useful for analyzing and visualizing large-scale genomic and complex datasets generated through high-throughput screens and other assays. Where multiple probes existed for a target, we prioritized those in clinical development, with stronger selectivity data, or with pharmacokinetic metadata that should enable more rapid drug development. This method uses microarray expression profiles to reconstruct tissue-specific gene regulatory transcriptional interactions in cellular networks. Insights into cancer genomes have led to novel clinical therapies that target oncogene proteins, and such targeted therapies have yielded high patient response rates. Asset Details - National Cancer Institute The multitask approach of this algorithm provides the ability to leverage similarities in the response profiles of drug groups, that are more likely to correspond to true biological effects. The Cancer Therapeutics Response Portal (CTRP) links genetic, lineage, and other cellular features of cancer cell lines to small-molecule sensitivity with the goal of accelerating discovery of patient-matched cancer therapeutics. Cancer Cell Line Encyclopedia (CCLE), 8 Genomics of Drug Sensitivity in Cancer (GDSC) 9, and Cancer Therapeutics Response Portal v2 (CTRPv2) 10 are noteworthy among these. Broad Genomics Platform sequences a whole human genome every four minutes. These maps link bioactive molecules to the proteins and biological processes that they engage in cells. cancer cells may become dependent, including but not limited to oncogenes/tumor suppressors, DNA-damage response, reactive-oxygen species metabolism, electrophile-stress response, protein degradation, hypoxic-stress response, mitotic-stress response, survival/apoptosis, nutrient metabolism, nutrient-stress response, chromatin modification, and other major signaling pathways (e.g., PI3K/mTOR; NFkB; others). As part of the National Cancer Institutes Cancer Target Discovery and Development (CTD2) Network, we profiled a large number of human cancer cell lines using a novel Informer Set of more than 350 small molecules to reveal such dependencies and their inhibitors. The Cancer Therapeutics Response Portal v1 provides open access to the results obtained through quantitatively measuring the sensitivity of 242 genetically characterized cancer-cell lines to a 354-member Informer Set of small-molecule probes and drugs. node in cell circuitry and that collectively modulate a broad These clinical successes Researchers anywhere can explore more than 6,000 drugs in the hub and search for possible new uses for them to jump-start new drug discovery. These data are being analyzed by our Center using a number of computational approaches to relate patterns of sensitivity to cellular and genetic features of CCLs. PiHelper can (1) import drug and antibody target information; (2) search the interactions; (3) visualize data interactively in a network; and (4) export interaction data for use in publications or other analysis tools. In 2015, there were 854,000 incident liver cancers and 810,000 deaths globally 2. Vizome, Beat AML data viewer allows easy access to clinical, genomic, transcriptomic and functional analyses of AML samples. Thus, we anticipate the ability to match patients with potentially effective drugs and that improved patient outcomes will dramatically increase. geWorkbench is an open source bioinformatics application that provides access to an integrated suite of tools for the analysis and visualization of data from a wide range of genomic domains (gene expression, sequence, protein structure and systems biology). Joel S. Bader, Ph.D.ContactsJoel Bader Whenever possible, concentration ranges for each compound were defined by review of literature to ensure plating at the optimal concentration for sensitivity measurements. . The queried gene is displayed in a tabular view with basic information for each mutation and details like summary (gene name, mutation, etc. Gordon B. In addition, by leveraging the Cancer Therapeutics Response Portal (CTRP) and PRISM Repurposing datasets, we determined the potential therapeutic agents for high IGS-risk patients. Cells were plated at the optimal density, compounds were pinned in 8-point (CTRP v1) or 16-point (CTRP v2), 2-fold concentration series, and sensitivity was assayed using CellTiter-Glo, which measures cellular ATP levels as a surrogate for cell number and growth. Shoemaker RH (2006) The NCI60 human tumour cell line anticancer drug screen. Once inside the portal, users can mine this resource for novel and therapeutically exploitable vulnerabilities in different cancer types across ~185 small molecules. Unlike previous methods, which aim to identify response biomarkers with compounds individually, ACME analysis detects multiple small molecules sharing a common protein target that perform similarly across CCLs. Due to inter-tumor genetic heterogeneity, many driver mutations occur at low frequencies, which make it challenging to distinguish them from passenger mutations. Connections and visualizations based on these approaches are available via theCTRP website. Transcription Factor Activities Enhance Markers of Drug Sensitivity in This tool performs functional network analysis to identify gene networks (modules) that are preserved in both cancer patients and cell lines. Access OncoPPi Portal:http://oncoppi.emory.edu, For questions, please contact Andrey Ivanov: (andrey.ivanov@emory.edu). Cancer Therapeutics Response Portal (CTRP) | Broad Institute (2012) Systematic identification of genomic markers of drug sensitivity in cancer cells. Access free classroom materials and more for STEM educators, parents, students, tutors, and others. 5Cancer Therapeutics Response Portal (CTRP) Genomics of Drug Sensitivity in Cancer ( GDSC) Cancer Genome Project (CGP)138 anticancer drugs against 727 cell lines pRRophetic pRRophetic_0.5.tar.gz500M These results can be accessed using the following URL. Moreover, the Cancer Therapeutics Response Portal (CTRP) and PRISM Repurposing dataset (PRISM) were used to explore novel drug treatment strategies of CRC. The Stanley Center aims to reduce the burden of serious mental illness by contributing new insights into pathogenesis, identifying biomarkers, and paving the way toward new treatments. Kentucky Cancer Registry Multiple Contacts, Principal Investigator We used 242 of ~1000 cancer cell lines from the CCLE, which had been genomically characterized for gene expression, amplification/deletion, and somatic mutation in 1,645 cancer genes, and had lineage or histology annotations. Many of our compounds were accessed through synthetic organic chemistry, either externally or with collaborators in the probe-development community. Genomic alterations that contribute to aberrant MR activity must be upstream of the MR, although the specific pathways involved may not be known. We deposited the dataset into a publicly accessible data portal, called the Cancer Therapeutics Response Portal (CTRP; www.broadinstitute.org/ctrp; Figure 1), so that other researchers can make connections between the genetic and lineage features of cancer cell lines and small-molecule sensitivities. CINDy uses a more sophisticated algorithm: while both try to assess the effects of a modulator over a transcriptional network, CINDy uses the entire expression range of the modulator. TheCancer Cell Line Encyclopediaprovides public access to genomic data, analysis and visualization for about 1000 cell lines. Access EDDY:http://biocomputing.tgen.org/software/EDDY/, For questions, please contact Gil Speyer: (gspeyer@tgen.org), Evaluation of Differential DependencY-Cancer Therapeutic Response Portal (EDDY-CTRP)(Translational Genomics Research Institute). More recently, the Cancer Cell Line Encyclopedia (CCLE), a joint effort between the Broad Institute and Novartis Institutes for BioMedical Research, profiled 479 cancer cell lines with significant genomic characterization using 24 anti-cancer drugs3. The team drew on data from small-molecule screens described in the Cancer Therapeutics Response Portal, a database developed by researchers at Broad and sponsored in part by the National Cancer Institute. Pan-Cancer Analysis Reveals Genomic and Clinical Characteristics of CARMEN is a point-and-click application which permits discovery of significant relationships using gene expression data, generating gene pathway maps, and finding differential expression between two conditions. The area under the concentration-response curve was used to calculate compound (i.e., small-molecule) sensitivities. RNAi reagents designed to target the same gene often induce different degrees of on-target and off-target gene suppression, resulting in inconsistent phenotypes. Access Texomer:https://github.com/KChen-lab/Texomer, For questions, please contact Fang Wang: (fwang9@mdanderson.org), The Cancer Genome Atlas Clinical Explorer(Stanford University). Multiple Contacts, Principal Investigators This algorithm can handle both microarray and next generation sequencing data as input. We want to be a link to hope in Kentucky to make an impact on cancer incidence and mortality. For CTRP v2 data, we developed a new data-mining approach, annotated cluster multidimensional enrichment (ACME) analysis. Learn about breakthroughs from Broad scientists. Through programs spanning genetics, biology, and therapeutic development, Broad researchers are making discoveries that drive biomedical science forward. "Harnessing Connectivity in a Large-Scale Small-Molecule Sensitivity Dataset"Seashore-Ludlow et al.,Cancer Discovery,5, 1210-1223 (2015), and extensive genetic characterizations are publicly available, We measured the sensitivity of hundreds of genetically characterized cancer cell lines to hundreds of small-molecule probes and drugs that have highly selective interactions with their targets, and that collectively modulate many distinct nodes in cancer cell circuitry. Receive regular updates on Broad news, research and community. The Cancer Target Discovery and Development (CTD) Network develops new approaches to identify novel targets and functionally validate discoveries made from large-scale genomic initiatives, such as The Cancer Genome Atlas (TCGA), Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and the Cancer Genome Characterization Initiative (CGCI), and advance them toward precision medicine. CTRP can be mined to develop insights into small-molecule mechanisms of action and novel therapeutic hypotheses, and to support future discovery of drugs matched to patients based on predictive biomarkers. CTD Data from The Broad Institute - NCI Annotated Cluster Multidimensional Enrichment(ACME) Analysis. The PPIs are ranked based on their essentialityfor the survival and proliferation of cancer cells. We work closely with pharmaceutical, biotech, and technology partners to accelerate the translation of our discoveries. CARMEN allows researchers to perform expression analysis using their own data and publicaly available data. Cancer Therapeutics Response Portal Whenever possible, concentration ranges for each compound were defined by review of literature to ensure plating at the optimal concentration for sensitivity measurements. We generated concentration-response curves that determined each compounds potency and efficacy for each cell line. Under the Enrichment Analysis tab, users can select or exclude specific cell line subtypes and datasets. This approach decreases the false-positive results while taking into account the anti-proliferative copy-number effect. Patients partner with our scientists to accelerate the pace of discovery and find better treatments. An Interactive Resource to Identify Cancer Genetic and Lineage This approach combinesProject AchillesshRNA gene silencing data with network models of protein interaction pathways (NCI Pathway Interaction Database) in an analytic framework. We generated an 'Informer Set' of 481 small-molecule probes and drugs that selectively target distinct nodes in cell . for computational details. We quantitatively measured the sensitivity of 860 deeply characterized cancer-cell lines to Informer Set compounds, and have undertaken analyses connecting sensitivity to cancer features, including mutations, gene expression, copy-number variation, and lineage. Cancer Therapeutics Response Portal: A CTD Networ Basu A, Bodycombe NE, Cheah JH, Price EV, Liu K, Schaefer GI, et al. The program filters and sorts data by mutation status or other criteria chosen by the user and creates ranked links. Despite the availability of databases such as the Cancer Cell Line Encyclopedia (CCLE), the Cancer Therapeutics Response Portal (CTRP), and The Cancer Genome Atlas (TCGA), it is still challenging for biologists to explore the relationship between drug response and underlying genomic features due to the heterogeneity of the data. Access SWNE:https://github.com/yanwu2014/swne, For questions, please contact Yan Wu: (yauwning@gmail.com), Texomer(Oregon Health and Science University (2)), (University of Texas MD Anderson Cancer Center). One of the earliest profiling efforts, the NCI-602 probed a limited set of 59 cancer cell lines from various lineages with more than 100,000 diverse small molecules and identified mostly lineage-specific small-molecule sensitivities. For example, CTNNB1-mutant cancer cell lines are sensitive to navitoclax (bottom). Many of our compounds were accessed through synthetic organic chemistry, either externally or with collaborators in the probe-development community. Cheung HW, Cowley GS, Weir BA, Boehm JS, Rusin S, Scott JA, et al. For questions, please contact John MacMillan: (john.macmillan@utsouthwestern.edu). SWNE is a bioinformatic method for visualizing and analyzing high-throughput single-cell gene expression datasets. Haian Fu, Ph.D.ContactAndrey A. Ivanov, Systematic Discovery of Mutation-Directed Neo-Protein-Protein Interactions in Cancer, Principal Investigator Datasets | PharmacoDB
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