Candidate therapeutic agents for hepatocellular cancer can be identified from phenotype-associated gene expression signatures.
BACKGROUND
The presence of vascular invasion in hepatocellular cancer (HCC) correlates with prognosis, and is a critical determinant of both the therapeutic approach and the recurrence or intrahepatic metastases. The authors sought to identify candidate therapeutic agents capable of targeting the invasive phenotype in HCC.


METHODS
A gene expression signature associated with vascular invasion derived from 81 human cases of HCC was used to screen a database of 453 genomic profiles associated with 164 bioactive molecules using the connectivity map. Candidate agents were identified by their inverse correlation to the query gene signature. The efficacy of the candidate agents to target invasion was experimentally verified in PLC/PRF-5 and HepG2 HCC cells.


RESULTS
The gene signature associated with vascular invasion in HCC comprised of 47 up-regulated and 26 down-regulated genes. Computational bioinformatics analysis revealed several putative candidates, including resveratrol and 17-allylamino-geldanamycin (17-AAG). Both of these agents reduced HCC cell invasion at noncytotoxic concentrations. 17-AAG, a heat shock protein 90 (HSP-90) inhibitor, was shown to modulate the expression of several diverse cancer-associated genes, including ADAMTS1, part of the query signature, and maspin, an HSP-90-associated protein with a tumor suppressor role in HCC.


CONCLUSIONS
Candidates for further evaluation as therapies to limit invasion in HCC have been identified using a computational bioinformatics analysis of phenotype-associated gene expression. Phenotype targeting using genomic profiling is a rational approach for drug discovery. Therapeutic strategies targeting a defined cancer-associated phenotype can be identified without a detailed knowledge of individual downstream targets.
Braconi
Chiara
C
Department of Internal Medicine, College of Medicine, Ohio State University, Columbus, OH, USA.
Meng
Fanyin
F
Swenson
Erica
E
Khrapenko
Lyudmyla
L
Huang
Nianyuan
N
Patel
Tushar
T
D016227:Benzoquinones / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D019295:Computational Biology; D055808:Drug Discovery; D005240:Feasibility Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047029:Lactams, Macrocyclic / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics*; D010641:Phenotype
D016227:Benzoquinones; D047029:Lactams, Macrocyclic; C112765:tanespimycin