CDA: combinatorial drug discovery using transcriptional response modules.
BACKGROUND
Anticancer therapies that target single signal transduction pathways often fail to prevent proliferation of cancer cells because of overlapping functions and cross-talk between different signaling pathways. Recent research has identified that balanced multi-component therapies might be more efficacious than highly specific single component therapies in certain cases. Ideally, synergistic combinations can provide 1) increased efficacy of the therapeutic effect 2) reduced toxicity as a result of decreased dosage providing equivalent or increased efficacy 3) the avoidance or delayed onset of drug resistance. Therefore, the interest in combinatorial drug discovery based on systems-oriented approaches has been increasing steadily in recent years.


METHODS
Here we describe the development of Combinatorial Drug Assembler (CDA), a genomics and bioinformatics system, whereby using gene expression profiling, multiple signaling pathways are targeted for combinatorial drug discovery. CDA performs expression pattern matching of signaling pathway components to compare genes expressed in an input cell line (or patient sample data), with expression patterns in cell lines treated with different small molecules. Then it detects best pattern matching combinatorial drug pairs across the input gene set-related signaling pathways to detect where gene expression patterns overlap and those predicted drug pairs could likely be applied as combination therapy. We carried out in vitro validations on non-small cell lung cancer cells and triple-negative breast cancer (TNBC) cells. We found two combinatorial drug pairs that showed synergistic effect on lung cancer cells. Furthermore, we also observed that halofantrine and vinblastine were synergistic on TNBC cells.


CONCLUSIONS
CDA provides a new way for rational drug combination. Together with phExplorer, CDA also provides functional insights into combinatorial drugs. CDA is freely available at http://cda.i-pharm.org.
Medicinal Bioconvergence Research Center, Seoul National University, Seoul, South Korea.
Ji-Hyun
JH
Lee
Dae Gyu
DG
Kim
Tae Jeong
TJ
Bae
Kyoohyoung
K
Rho
Ji-Tae
JT
Kim
Jong-Jun
JJ
Lee
Yeongjun
Y
Jang
Byung Cheol
BC
Kim
Kyoung Mii
KM
Park
Sunghoon
S
Kim
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D019295:Computational Biology / Q000379:methods; D055808:Drug Discovery / Q000379:methods*; D004351:Drug Resistance; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D015233:Models, Statistical; D010616:Phenanthrenes / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy; D015398:Signal Transduction; D014158:Transcription, Genetic; D014747:Vinblastine / Q000494:pharmacology
D010616:Phenanthrenes; D014747:Vinblastine; C023768:halofantrine