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Mar 29, 2012

Cancer Cell Line Encyclopedia Released to Aid Drug Discovery and Clinical Trials

  • Scientists have made a catalogue of genetic and molecular data on nearly 1,000 cancer cell lines publicly available. They hope it will aid the design of anticancer therapeutics and clinical trials. The Cancer Cell Line Encyclopedia (CCLE) has been drafted by a team led by researchers at the Broad Institute, Harvard Medical School, and the Novartis Institutes for Biomedical Research. It comprises a compilation of gene expression, chromosomal copy number, and massively parallel sequencing data from 947 human cancer cell lines used in drug research and development.

    The cell lines were acquired from commercial vendors in the U.S., Europe, Japan, and Korea and represent what the researchers say is a diverse picture of cancer as a disease by including subtypes of both common and rare forms of cancer. Each cell line has been genetically characterized through a series of high-throughput analyses at the Broad Institute, including global RNA-expression patterns and DNA sequence variations in about 1,600 cancer-associated genes. Pharmacologic profiling for several drugs was possible in about half of the cell lines. Algorithms were developed to predict drug responses based on the genetic and molecular makeup of cancer cells. 

    The Broad Institute’s Levi A. Garraway, Ph.D., and colleagues report on the CCLE in a paper in Nature titled “The CancerCell Line Encyclopedia enables predictive modeling of anticancer drug sensitivity.” The paper runs alongside another study, led by researchers at the Wellcome Trust Sanger Institute, Harvard Medical School, and Dana Farber Cancer Institute, which involved screening a panel of several hundred diverse cancer cell lines with 130 drugs under clinical and preclinical investigation to help identify new biomarkers of drug response. This paper is titled “Systematic identification of genomic markers of drug sensitivity in cancer cells.”

    Outlining their development of the CCLE, Dr. Garraway’s team describe proof-of-principal studies in which the resource was coupled with pharmacological profiles for 24 anticancer drugs to identify genetic, lineage, and gene-expression-based predictors of drug sensitivity. Interestingly, the results suggested that cell lineage is a major predictive feature for response of cells to a number of compounds, including that of hematological lineage cell lines to HDAC inhibitor panobinostat.

    The results similarly indicated that enhanced sensitivity of some NRAS-mutant cell lines to MEK inhibitors relates to a dependence on aryl hydrocarbon receptor (AHR) function and that in some instances elevated AHR may serve as a mechanistic biomarker for enhanced MEK inhibitor sensitivity. Further analyses indicated that multiple myeloma may respond to IGF1 receptor inhibitors, while SLFN11 expression was identified as the top correlate of sensitivity to irinotecan therapy. In fact all three Ewing’s sarcoma cell lines screened showed high SLFN11 expression and sensitivity to irinotecan.

    “Ewing’s sarcomas also exhibited the highest SLFN11 expression among 4,103 primary tumor samples spanning 39 lineages, suggesting that topoisomerase I inhibitors might offer an effective treatment option for this cancer type,” the authors write. “Towards this end, several ongoing trials in Ewing’s sarcoma are examining irinotecan-based combinations or the addition of topotecan to standard regimen.”

    The authors aim to build on the CCLE resource by adding in analyses based on deeper sequencing, metabolic activity profiles and epigenetic modifications. The current knowledge base represents what the authors claim is just the tip of the iceberg in terms of potential. “With this initial effort, we have taken some critical first steps,” comments co-author Todd Golub, Ph.D., director of the Broad Institute’s cancer program and Charles A. Dana Investigator in Human Cancer Genetics at the Dana-Farber Cancer Institute. “The challenge now is to greatly expand the number of compounds tested across the panel of cell lines.”  

    The published work by the Sanger Institute-led team separately identified a strong association between the EWS-FLI1 rearrangement characteristic of Ewing’s sarcoma tumors and sensitivity to the PARP inhibitor olaparib (AZD2281) and a structurally distint PARP inhibitor AG-014699. PARP inhibitors are known to be active against BRCA1- and BRCA2-mutant cancers, and the effectiveness of these drugs against the EWS-FLI1-carrying Ewing’s sarcoma cells was comparable to that in BRCA-deficient cells.

    “The observation of PARP inhibitor sensitivity by EWS-FLI1-positive Ewing’s sarcoma cell lines points to the likelihood of new potent gene-drug associations, as novel chemical and genomic space are explored,” write Massachusetts General Hospital Cancer Center lead author Cyril H. Benes, M.D., et. al. “By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.”


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