Primary cell models were established and cultured on collagencoated tissue culture plates in supplemented ksf media. Writing the book of cancer knowledge harvard gazette. Nonetheless, controversy remains whether cell lines provide an. Cells were passaged by trypsinization and used at early passage p 20 for the analysis of drug sensitivity. Graphic concept by francesco iorio, illustration by spencer phillips, emblebi cancer cell lines predict drug response 5 jul 2016 15. As the nci60 only involves five breast cancer cell lines, which only partially reflect the distinct subtypes, we performed the same analysis on the more comprehensive cancer cell line encyclopedia ccle. Predictive modeling of drug sensitivity gives an overview of drug sensitivity modeling for personalized medicine that includes data characterizations, modeling techniques, applications, and research challenges. The gi50 represents the negative log of the concentration that is required to inhibit the growth of a cell line by 50%. Ccle cancer cell line encyclopedia provides a compilation of gene expression, chromosomal copy number, and massively parallel sequencing data from human cancer cell lines.
The analysis of anticancer drug sensitivity of lung cancer cell lines by using machine learning clustering techniques chandi s. Predict drug sensitivity of cancer cells with pathway. In the first systematic, largescale study to combine molecular data from patients, laboratory cancer cell lines and drug sensitivity, the researchers looked at genetic mutations known to cause. On this website, you will find drug response data and genomic markers of sensitivity. More recently, the scale of cancer cell line drug screens has expanded dramatically e. Barretina j, caponigro g, stransky n et al 2012 the cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity. This large collection of cell lines enabled us to capture much of the genomic heterogeneity that underlies human cancer, and which appears to play a critical role in determining the variable response of patients to treatment with specific agents. The ccle provides public access analysis and visualization of dna copy number, mrna expression, mutation data and more, for cancer cell lines. Measuring cancer drug sensitivity and resistance in cultured cells. Hcc827 is an egfr exon19del mutant lung cancer cell line sensitive to.
Pancancer convergence to a smallcell neuroendocrine. The cancer cell line encyclopedia ccle project is an effort to conduct a detailed genetic characterization of a large panel of human cancer cell lines. Cancer cell line drug sensitivity data are generated from ongoing highthroughput screening performed by the cancer genome project at the wellcome trust sanger institute wtsi and the center for molecular therapeutics at massachusetts general hospital using a collection of cell lines. This sample is limited in amount and the genetic manipulation is almost impossible 3. Pharmacogenomic agreement between two cancer cell line. Drug combinations to overcome treatment resistance national. Halgamuge, azeem mohammad school of computing and mathematics charles sturt university melbourne, victoria 3000, australia abstractlung cancer is the commonest type of cancer with. Resistant populations were obtained for the four cell lines through lifetime exposure to the drug for a minimum of 3 months in the case of the line skbr3, 7 months in the case of the au565 and efm192a lines, and 8 months in the case of the bt474 line. First, the researchers engineered a mouse cell line to be sensitive or resistant to the targeted drug imatinib gleevec. The resulting collection, which we termed the cancer cell line encyclopedia ccle, encompasses 36 tumour types fig. A sensitivity of cancer specific drugs intended for breast cancer 41, colorectal cancer 24 and prostate cancer 38 across the nci60 panel covering 59 cancer cell lines derived from nine cancer tissues.
Robustness of our model was validated by crossvalidation and an independent dataset, the cancer genome project cgp. The importance of cancer cell lines as in vitro models in cancer methylome analysis and anticancer drugs testing 143 tumour. Cancer cell lines for drug discovery and development. Large cancer cell line based projects, such as nci60, 7 cancer cell line encyclopedia ccle, 2 and genomics of drug sensitivity in cancer gdsc, 3 have used molecularly heterogeneous cancer cell lines to identify stratification biomarkers and signatures for precision medicine. Here we describe the cancer cell line encyclopedia ccle. We have characterised human cancer cell lines and screened them with 100s of compounds. A biomarker harvest from one thousand cancer cell lines. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage. Anticancer drug sensitivity prediction in cell lines from. Quantification of sensitivity and resistance of breast. Drug sensitivity in cancer cell lines is not tissuespecific.
The importance of cancer cell lines as in vitro models in cancer methylome analysis and anticancer drugs testing 141 tissues 8. We find that cancer specific drugs do not show higher efficacies in cell lines representing the. The cancer cell line encyclopedia enables predictive. Here we show substantial agreement and biological consilience between drug sensitivity measurements and their associated genomic predictors from two publicly available largescale pharmacogenomics resources. Red cells indicate high activity while green cells indicate inactivity. The genomics of drug sensitivity in cancer provides public access to data on the sensitivity of genomically characterized cancer cell lines to. The genomics of drug sensitivity in cancer project is a collaboration between the cancer genome project at the wellcome sanger institute uk and the center for molecular therapeutics, massachusetts general hospital cancer center usa. Trastuzumab was dissolved in sterile water at a stock concentration of 20 mgml. To this aim, we here used gene expression features and drug sensitivity data in cancer cell line encyclopedia ccle to build a predictor based on support vector machine svm and a recursive feature selection tool. The cancer cell line encyclopedia and the genomics of drug sensitivity in cancer databases.
The diagonal of the heatmap shows the pearson correlation between corresponding sample types. What are the model cell lines for studying an anticancer. T wo things are required for the generation of reproducible and useful drug. Current trends in drug sensitivity prediction bentham science.
As an example, tomlinson and colleagues 1998 compared a breast primary tumour and a cell line originated from that tumour. The us national cancer institute nci 60 human tumour cell line anticancer drug screen nci60 was developed in the late 1980s as an in vitro drug discovery tool intended to supplant the use of. Pdf measuring cancer drug sensitivity and resistance in. A pancancer analysis of progression mechanisms and drug. Later, studies like cancer cell line encyclopedia ccle, genomic drug sensitivity of cancer gdsc and gsk panel have extended to largescale collection of cell lines with drug responses and more molecular data types. Cancer cell line panels have proved useful disease models to, among others, identify genomic markers of drug sensitivity and to develop new anticancer drugs. In the first systematic, largescale study to combine molecular data from patients, laboratory cancer cell lines and drug sensitivity, the researchers looked at genetic mutations known to cause cancer in more than 11,000 patient samples of 29 different tumour types. Distribution of cancer types in the ccle by lineage.
The first volume of a book of cancer knowledge has been published, which scientists say will speed up the search for new cancer drugs. Here we show substantial agreement and biological consilience between drug sensitivity measurements and their associated genomic predictors from two publicly available largescale pharmacogenomics. Device may predict cancer treatment response national. Drug sensitivity in cancer cell lines is not tissue. Assays in which immortalized cell lines are exposed to. In vitro cell viability and cytotoxicity assays with cultured cells are widely used for cytotoxicity tests of chemicals and for drug screening.
This is an increase of 70% compared to previous releases. The sensitivity patterns of the cell lines were correlated with extensive genomic and expression data to identify genetic features that are predictive of sensitivity. Cancerrxgene genomics of drug sensitivity in cancer. The team created a microfluidic cell culture device that allows the direct, realtime observation of the development of drug resistance in cancer cells. Characterization of human cancer cell lines by reverse. A cancer specific analysis correlates drug sensitivity for cancer cell lines of the specified cancer type with genomic features identified in patients from the designated cancer type. Machine learning prediction of cancer cell sensitivity to.
Established cell lines were from the atcc and cultured using published methodology. Clustering facility also allow users to identify promiscous drugs effectice against wide range of cell lines or cancer types. Cell line drug sensitivity was measured as the concentration at which the drug inhibited 50 % of the cellular growth ic 50. Pharmacogenomic agreement between two cancer cell line data sets. For each cell line, the researchers identified an average of 3. To study the relationship between biomarkers such as braf mutation status and drug sensitivity, the cell line panel was subjected to 109 different drugs, representing a wide range of substances targeting, among others, the mapk pathway, the pi3kakt pathway, as well as mitotic and metabolic processes. B comparison of crossvalidation model r 2 values cell line based with t test signed log p values of cell line sclc versus luad true drug sensitivities ic 50.
To address these challenges, we generated a largescale genomic data set for 947 human cancer cell lines, together with pharmacological profiling of 24 compounds across. The ubc40 urothelial bladder cancer cell line index. In order to determine the cell death caused by these mechanisms, there is a need for cheap, reliable and reproducible shortterm cytotoxicity and cell viability assays. Patientspecific cancer cell lines designed to predict. Tissue specificity displayed by canerspecific drugs. Combining molecular data from patients, laboratory cancer cell lines and drug sensitivity to improve precision medicine. Studies expand and update an encyclopedia of cancer cell.
For this analysis, we have determined the relative sensitivity z score of a cell line to a given drug compared to all other cell lines. Cancer cell lines predict drug response 5 jul 2016 15. This large collection of cell lines enabled us to capture much of the genomic heterogeneity that underlies human cancer, and which appears to play a critical role in determining. Writing the book of cancer knowledge here there be dependencies. We assess whether drug sensitivity in cancer cell lines. For this study, the research team wanted to determine if measuring mar following cancer treatment could rapidly and accurately predict cancer cell death or growth. Drug sensitivity assays of human cancer organoid cultures. From the available 19,000 gene expressions we use relieff to screen top 250 features.
Furthermore, analysis of molecular correlates of drug sensitivity in the cell lines identified multiple known features, including tissue type lineage, as top predictors of sensitivity to several agents. Overcoming cancer evolution with collateral sensitivity and. May 01, 2017 this detailed growing understanding of the dynamics of cancer cell reaction to drug treatment regimes joins a growing school of potential cancer therapies guided by an understanding of cancer evolution, such as the approach by bob gatenby and colleagues at the moffitt, which suggests that the careful titration of low dose cancer therapy so. In each study, aucs are provided, measuring the relationship between drug concentration and cell viability. We integrated both genomic features of cell lines and chemical information of compounds to predict the half maximal inhibitory concentrations ic50 on the cancer cell line encyclopedia ccle and the genomics of drug sensitivity in cancer gdsc datasets using a deep neural network, which we called deepdsc. It covers the major mathematical techniques used for modeling drug sensitivity, and includes the requisite biological knowledge to. How to determine the cancer cells sensitivity to certain drugs. The xenografts models nude mice are used for testing the tumorigenicity and metastatic ability of cancer cell lines. The gi50 represents the negative log of the concentration that is required to inhibit the growth of a cell line. Drug sensitivity in cancer cell lines is not tissuespecific samira jaeger1, miquel duranfrigola1 and patrick aloy1,2 abstract background.
Our integrative proteogenomic analysis highlights the potential of proteome profiling to inform personalized cancer medicine. With many recent advances, cancer cell culture research is more important than ever before. Cancer cell lines are the most commonly utilized model systems in tumor biology and therapy development. Expression levels of therapeutic targets as indicators of. Methods and protocols covers the basic concepts of cancer cell biology and culture while expanding upon the recent shift in cell culture methods from the generation of new cell lines to the use of primary cells. The genomics of drug sensitivity of cancer gdsc database now contains data for an extra 187 drugs and more than 160,000 new unique compound cell line pairs. Predictive modeling of drug sensitivity sciencedirect. The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity article pdf available in nature 4837391. Exploiting evolutionary steering to induce collateral drug sensitivity in cancer. Sokilde r, kaczkowski b, podolska a, cirera s, gorodkin j, moller s, and litman t. Garraway, a senior associate member of the broad institute, an associate professor at harvard medical school and danafarber cancer institute, and a co. Measuring cancer drug sensitivity and resistance in. Comparison of dna copynumber profiles gistic gscores between cell lines and primary tumors. Drug sensitivity screening of cancer cell lines is routinely performed and largescale datasets are publically available 3, 4, 5, 6.
For many of the effective drug pairs, they realized that the second drug inhibited a signaling pathway that was able to bypass the effect of the original drug. Quantification of sensitivity and resistance of breast cancer cell lines to anti cancer drugs using gr metrics skip to main content thank you for visiting. However, their clinical relevance remains controversial. These large cell line datasets provide a more comprehensive representation of the genomics variability observed in tumors providing new means to identify novel drug targets or drug response.
The analysis of anticancer drug sensitivity of lung cancer. Drug sensitivity prediction by cpg island methylation profile in the nci60 cancer cell line panel. By integrating somatic mutation and gene expression data from hundreds of heterogeneous cell lines from the cancer cell line encyclopedia ccle, we identify sequences of genetic events that may help explain common patterns of oncogenesis across 22 tumor types, and evaluate the general effect of latestage mutations on drug sensitivity and. They also demonstrated that treatment with only one drug of. Faq cancerrxgene genomics of drug sensitivity in cancer. Putting cancers vulnerabilities on the map cancer cell lines evolve in ways that affect how they respond to drugs loss of a dna repair system creates a unique vulnerability in many cancer types. The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity. Genomics of drug sensitivity in cancer cancerrxgene. Conversely, midostaurin, a targeted drug against hrpositive tumors, only shows activity in triplenegative cell lines. These proteins can recapitulate mutational patterns seen in patients and show ability to predict drug sensitivity. These large cell line datasets provide a more comprehensive representation of the genomics variability observed in tumors. Datasets cell line numbers i the genomics of drug sensitivity in cancer project is a collaboration between the cancer genome project at the wellcome sanger institute uk and the center for molecular therapeutics, massachusetts general hospital cancer center usa.
When coupled with pharmacologic profiles for 24 anticancer drugs across 479 of the lines, this collection allowed identification of genetic, lineage, and gene expressionbased predictors of drug sensitivity. Clustering of cell lines based on their drug sensitivity allow users to identify group of cell lines, which are resistance for a particular anticancer drug. The cancer cell proteome and transcriptome predicts. What is the name of an article which is against the the. The growing of cancer cells in the laboratory has been a powerful tool for studying and understanding the biology of cancer and the effects of drugs on cancer cells. The cancer cell line encyclopedia provides public access to genomic data, analysis and visualization for about cell lines. Proteomes of established crc cell line are representative of primary tumors.
Mar 29, 2012 the cancer cell line encyclopedia ccle a. Cancer cell lines have a prominent role in the initial stages of drug discovery, facilitating highthroughput screening of potential drugs. Global microrna analysis of the nci60 cancer cell panel. Aug 31, 2017 a new cell culture system that provides a tool for preclinical cancer drug development and screening has been developed by american researchers.
News cancerrxgene genomics of drug sensitivity in cancer. R 2 values are from true cell line drug sensitivities versus crossvalidationbased predicted cell line sensitivities. Mar 29, 2012 image caption cells from a cancer line known as hela. Sep 15, 2016 for example, cell lines were used for the preclinical development of the smallmolecule egfr inhibitor gefitinib, which is approved for the treatment of egfrmutated nonsmall cell lung cancer 1, 2. Colorectal cancer cell line proteomes are representative. The increasing availability of in vitro sensitivity and cell line profiling data sets raises the question of whether this information could be used, and to which extent, to. Cancer cell lines predict drug response wellcome sanger. We assess whether drug sensitivity in cancer cell lines is able to discriminate tissue specificity. I am find an article where its opinion is against the cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity. This is why old cell growthbased assays didnt work and why cell deathbased assays do. The models were then tested in the excluded cell lines. Large cancer cell line based projects, such as nci60,7 cancer cell line encyclopedia ccle,2 and genomics of drug sensitivity in cancer gdsc,3 have used molecularly heterogeneous authors share co. D all cell lines belonging to the tumor type specified by the xaxis were excluded and the remaining cell lines used for building drug sensitivity models cross. The resulting collection encompasses 36 tumor types.
Thus, it is difficult to predict clinical anti cancer efficacy only by relying on the genomic information of cell lines i. Exploiting evolutionary steering to induce collateral drug. Sensitivity of drugs indicated for hormone receptor positive, triple negative and her2overexpressing breast cancer within 30 breast cancer cell lines representing the different subtypes. In order to test our theory on real dataset, we obtain gene expression and normalized area under the curve auc values for the cell lines tested on the drug 17aag from the cancer cell line encyclopedia ccle. Proteomic data tend to exhibit improved prediction of drug sensitivity as compared with genomic and transcriptomic profiles. Cancer cell lines predict drug response and accelerate. When coupled with pharmacologic profiles for 24 anticancer drugs across 479 of the lines, this collection allowed identification of genetic, lineage, and. The study concluded that the cell lines may provide representative genetic proxies for primary tumors in many cancer types. Methods and protocols, expert researchers describe in detail their most productive and uptodate methods for growing cancer cells in the laboratory. Mar 28, 2012 the cancer cell line encyclopedia presents the first results from a largescale screen of some 947 cancer cell lines with 24 anticancer drugs, with the aim of identifying specific genomic. The cancer types are those described by the cancer genome atlas tcga.
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