Drug and disease signature integration identifies synergistic combinations in glioblastoma

Vasileios Stathias, Anna M. Jermakowicz, Marie E. Maloof, Michele Forlin, Winston Walters, Robert K. Suter, Michael A. Durante, Sion L. Williams, J. William Harbour, Claude-Henry Volmar, Nicholas J. Lyons, Claes Wahlestedt, Regina M. Graham, Michael E. Ivan, Ricardo J. Komotar, Jann N. Sarkaria, Aravind Subramanian, Todd R. Golub, Stephan C. Schürer () and Nagi G. Ayad ()
Additional contact information
Vasileios Stathias: University of Miami Miller School of Medicine
Anna M. Jermakowicz: University of Miami Miller School of Medicine
Marie E. Maloof: University of Miami Miller School of Medicine
Michele Forlin: University of Miami Miller School of Medicine
Winston Walters: University of Miami Miller School of Medicine
Robert K. Suter: University of Miami Miller School of Medicine
Michael A. Durante: Bascom Palmer Eye Institute, Sylvester Comprehensive Cancer Center, Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine
Sion L. Williams: University of Miami Miller School of Medicine
J. William Harbour: Bascom Palmer Eye Institute, Sylvester Comprehensive Cancer Center, Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine
Claude-Henry Volmar: University of Miami Miller School of Medicine
Nicholas J. Lyons: Broad Institute of Harvard and MIT
Claes Wahlestedt: University of Miami Miller School of Medicine
Regina M. Graham: University of Miami Miller School of Medicine
Michael E. Ivan: University of Miami Miller School of Medicine
Ricardo J. Komotar: University of Miami Miller School of Medicine
Jann N. Sarkaria: Mayo Clinic
Aravind Subramanian: Broad Institute of Harvard and MIT
Todd R. Golub: Broad Institute of Harvard and MIT
Stephan C. Schürer: University of Miami Miller School of Medicine
Nagi G. Ayad: University of Miami Miller School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract Glioblastoma (GBM) is the most common primary adult brain tumor. Despite extensive efforts, the median survival for GBM patients is approximately 14 months. GBM therapy could benefit greatly from patient-specific targeted therapies that maximize treatment efficacy. Here we report a platform termed SynergySeq to identify drug combinations for the treatment of GBM by integrating information from The Cancer Genome Atlas (TCGA) and the Library of Integrated Network-Based Cellular Signatures (LINCS). We identify differentially expressed genes in GBM samples and devise a consensus gene expression signature for each compound using LINCS L1000 transcriptional profiling data. The SynergySeq platform computes disease discordance and drug concordance to identify combinations of FDA-approved drugs that induce a synergistic response in GBM. Collectively, our studies demonstrate that combining disease-specific gene expression signatures with LINCS small molecule perturbagen-response signatures can identify preclinical combinations for GBM, which can potentially be tested in humans.

Date: 2018
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DOI: 10.1038/s41467-018-07659-z

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