CellPress is showcasing a collection of CTD² Network’s articles which will help develop precision therapeutics in cancer. Register for the Cell-NCI Symposium: Beyond Cancer Genomics Toward Precision Oncology taking place from October 4-6, 2021.
The CTD2 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. Through robust cross-Network collaborations, CTD2 (1) mines data to find alterations that potentially influence tumor biology, (2) characterizes the functional roles of candidate alterations in cancers, and (3) identifies novel approaches that target causative alterations either directly or indirectly. Methodologies include bioinformatics, genome-wide gain- and loss-of-function screening, and small molecule high-throughput screening, among others.
Part of the CTD2 mission is to make data and tools available and accessible to the greater research community to accelerate the discovery process. Bioinformatics support is often required for analyses of the massive datasets used and generated through experimental pipelines employed by the Network Centers. To facilitate the processes of mining, visualizing, analyzing, and using such datasets, OCG has curated this collection of analytical tools. OCG/CTD2 does not endorse any specific tool. However, this list gives researchers a gateway to access many tools that are useful for analyzing and/or visualizing large-scale genomic and/or complex datasets generated through high-throughput screens and other assays.38 Analytical Tools
ARACNe is an algorithm for inferring direct regulatory relationships between transcriptional regulator proteins and target genes. This method uses microarray expression profiles to reconstruct tissue-specific gene regulatory transcriptional interactions in cellular networks. This tool could be used by researchers to determine novel driver genes and drug mechanisms of action.
ATARiS is a computational method designed to analyze the off-target effects in the data generated fromRNAi screens. RNAi reagents designed to target the same gene often induce different degrees of on-target and off-target gene suppression, resulting in inconsistent phenotypes. To address this, ATARiS tries to identify subsets of its RNAi reagents that produce a significantly similar phenotype across the screened samples. This approach also computes a consistency score for each reagent that represents the confidence that its observed phenotypic effects are the result of on-target gene suppression.
CTRP is a resource of compound sensitivity data (concentration-response curves) that can be mined to develop insights into small-molecule mechanisms of action and novel therapeutic hypotheses. CTRP hosts data that are generated by measuring cellular responses to an 'Informer Set' of small-molecule probes and drugs. Users can mine for lineages or mutations enriched among cell lines sensitive to small molecules. By connecting cellular features to small molecule sensitivities, CTRP identifies new potential therapeutic vulnerabilities for different cancer types.
The cBioPortal is a web resource for exploring, visualizing, and analyzing complex multidimensional cancer genomics datasets. Researchers can interactively explore genetic alterations across samples, genes, and pathways and link these to clinical outcomes, when available. The portal facilitates discoveries by making large and complex cancer genomics profiles accessible to researchers and clinicians without bioinformatics expertise.
Studies have shown that genome-wide CRISPR-Cas9 inactivation of genes that are amplified need different analytical approaches for interpretation of the results. The Cas9 induces double strand breaks which lead to false-positive results. 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. This approach decreases the false-positive results while taking into account the anti-proliferative copy-number effect.
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. CARMEN allows researchers to perform expression analysis using their own data and publicaly available data.
Cytoscape allows users to visualize networks and related information derived from complex datasets. Data in the CTD2 Data Portal can be downloaded and viewed with Cytoscape, which eliminates the need to install additional visualization software. The program is flexible about the format of input files.
A major challenge of the large-scale siRNA and shRNA loss-of function screens is off-target effects resulting from short regions (~6 nucleotides) of oligonucleotide complementary to many different mRNAs. 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.
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. This method infers gene dependency estimates and allows for corrections to eliminate batch effects and confounders due to gene amplifications.
DepMap is a comprehensive preclinical reference portal that connects tumor features with genetic and small molecule dependencies. This Portal could be used to understand the vulnerabilities of cancer, identify genetic targets for therapeutic development, and patient stratification.