title: Connectivity map identifies HDAC inhibition as a treatment option of high-risk hepatoblastoma.
abstract: Hepatoblastoma (HB) is the most common liver tumor of childhood, usually occurring in children under the age of 3 y. The prognosis of patients presenting with distant metastasis, vascular invasion and advanced tumor stages remains poor and children that do survive often face severe late effects from the aggressive chemotherapy regimen. To identify potential new therapeutics for high risk HB we used a 1,000-gene expression signature as input for a Connectivity Map (CMap) analysis, which predicted histone deacetylase (HDAC) inhibitors as a promising therapy option. Subsequent expression analysis of primary HB and HB cell lines revealed a general overexpression of HDAC1 and HDAC2, which has been suggested to be predictive for the efficacy of HDAC inhibition. Accordingly, treatment of HB cells with the HDAC inhibitors SAHA and MC1568 resulted in a potent reduction of cell viability, induction of apoptosis, reactivation of epigenetically suppressed tumor suppressor genes, and the reversion of the 16-gene HB classifier toward the more favorable expression signature. Most importantly, the combination of HDAC inhibitors and cisplatin - a major chemotherapeutic agent of HB treatment - revealed a strong synergistic effect, even at significantly reduced doses of cisplatin. Our findings suggest that HDAC inhibitors skew HB cells toward a more favorable prognostic phenotype through changes in gene expression, thus indicating a targeted molecular mechanism that seems to enhance the anti-proliferative effects of conventional chemotherapy. Thus, adding HDAC inhibitors to the treatment regimen of high risk HB could potentially improve outcomes and reduce severe late effects.
authors.affiliation: a Department of Pediatric Surgery, Dr. von Hauner Children's Hospital , Ludwig-Maximilians-University Munich , Munich , Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Beck
authors.affiliation: a Department of Pediatric Surgery, Dr. von Hauner Children's Hospital , Ludwig-Maximilians-University Munich , Munich , Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Eberherr
authors.affiliation: a Department of Pediatric Surgery, Dr. von Hauner Children's Hospital , Ludwig-Maximilians-University Munich , Munich , Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Hagemann
authors.affiliation: b XenTech , 4 rue Pierre Fontaine , Evry , France.|c University of Ferrara, LTTA Center, Department of Morphology , Surgery and Experimental Medicine, Via Fossato di Mortara , Ferrara , Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Cairo
authors.affiliation: a Department of Pediatric Surgery, Dr. von Hauner Children's Hospital , Ludwig-Maximilians-University Munich , Munich , Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Häberle
authors.affiliation: d Institute of Paidopathology, Pediatric Tumor Registry, Christian-Albrechts-University Kiel , Kiel , Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Vokuhl
authors.affiliation: a Department of Pediatric Surgery, Dr. von Hauner Children's Hospital , Ludwig-Maximilians-University Munich , Munich , Germany.
authors.forename: Dietrich
authors.initials: D
authors.lastname: von Schweinitz
authors.affiliation: a Department of Pediatric Surgery, Dr. von Hauner Children's Hospital , Ludwig-Maximilians-University Munich , Munich , Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Kappler
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D002675:Child, Preschool; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D056945:Hep G2 Cells; D018197:Hepatoblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000096:biosynthesis; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D012307:Risk Factors; D059467:Transcriptome
chemical_list: D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D002945:Cisplatin
keywords: Cisplatin; HDAC inhibitor; SAHA; connectivity map; hepatoblastoma; therapy