Candidate therapeutic agents for hepatocellular cancer can be identified from phenotype‐associated gene expression signatures

Abstract

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. Cancer 2009. © 2009 American Cancer Society.

NEDD4 Depletion Inhibits Hepatocellular Carcinoma Growth via Targeting PTEN

“…It has been shown that NEDD4 may act as an oncoprotein in colorectal cancer, gastric carcinomas, bladder cancer, and glioma as it participates in the malignant phenotype of cancer cells and is overexpressed in the aberrant tissues [31,36,37]. There are also reports indicating that NEDD4 may participate in the progress of HCC, yet the role of NEDD4 in HCC has not yet been investigated [3,38]. In this study, the expression levels of NEDD4 in 219 HCC tumors were assessed by immunohistochemical techniques, revealing correlations between NEDD4 expression and various clinical outcomes in HCC patients.…”

Galectin-1 and Its Involvement in Hepatocellular Carcinoma Aggressiveness

“…Molecular profiling of HCCs unraveled molecular subtypes of HCC associated with specific signalingpathway alterations (42,43). Moreover tumor-derived gene expression patterns have been associated with patient survival (44), and gene expression signatures of nontumoral liver tissue adjacent to the tumor have been shown to be associated with survival and late recurrence of HCC (45) and with vascular invasion (46). Although these results showed promise, they appeared rather inconsistent, possibly owing to differences in experimental platforms and/or the underlying biological heterogeneity of the disease.…”

Integrative and Functional Genomics of HCC

“…Recently, in an effort to identify candidate therapeutic agents capable of targeting the invasive phenotype in HCC, Braconi et al used a 73-gene signature that correlated with vascular invasion (Chen et al 2002) to screen a reference database of 453 genomic profiles associated with 164 bioactive small molecules. Using a connectivity map algorithm (Lamb et al 2006) resveratrol and 17-allylamino-geldanamycin were identified as attractive therapeutic candidates since both of these agents were able to reduce HCC cell invasion at noncytotoxic concentrations (Braconi et al 2009). …”