title: Preclinical Evaluation of Combined Targeted Approaches in Malignant Rhabdoid Tumors.
abstract: OBJECTIVE
  Rhabdoid tumors (RT) are aggressive pediatric tumors, which show poor prognosis despite use of multimodal intensive therapy. In these tumors, several different oncogenic pathways and epigenetic regulators (like CDK4/6-cyclinD-Rb-signaling, EZH2, histone deacetylases) are contemporaneously deregulated as a consequence of biallelic SMARCB1/SNF5/INI1 alterations. Since these tumors are highly resistant to current therapies, alternative treatment strategies are urgently required.
  
  
  METHODS
  In this study, we evaluated cytotoxic effects (by MTT tests) of small molecular compounds, which specifically target these deregulated pathways, using either single-drug or combined approaches. Half-maximal inhibitory concentration (IC50) and combined index (CI) were calculated.
  
  
  RESULTS
  All target-directed inhibitors blocked cell growth of three different rhabdoid tumor cell lines in vitro. Several combinations of those target-specific drugs synergistically inhibited cell proliferation of rhabdoid tumors.
  
  
  CONCLUSIONS
  Supporting earlier reports, combined target-directed approaches are a promising tool for the therapy of malignant rhabdoid tumors.
authors.affiliation: University Children's Hospital, Department of Hematology and Oncology, Münster, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Moreno
authors.affiliation: University Children's Hospital, Department of Hematology and Oncology, Münster, Germany kornelius.kerl@ukmuenster.de.
authors.forename: Kornelius
authors.initials: K
authors.lastname: Kerl
mesh_terms: D064096:Aurora Kinase A / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000069286:Bortezomib / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006655:Histone Deacetylases / Q000096:biosynthesis* / Q000187:drug effects; D006801:Humans; D058990:Molecular Targeted Therapy; D018335:Rhabdoid Tumor / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000071796:SMARCB1 Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D054852:Small Molecule Libraries / Q000008:administration & dosage
chemical_list: D056572:Histone Deacetylase Inhibitors; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D054852:Small Molecule Libraries; D000069286:Bortezomib; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C576917:AURKA protein, human; D064096:Aurora Kinase A; D006655:Histone Deacetylases
keywords: EZH2; HDAC; Rhabdoid tumors; aurora kinase; bortezomib; cyclin-D