title: Synthetic lethal screen identifies NF-κB as a target for combination therapy with topotecan for patients with neuroblastoma.
abstract: BACKGROUND
  Despite aggressive multimodal treatments the overall survival of patients with high-risk neuroblastoma remains poor. The aim of this study was to identify novel combination chemotherapy to improve survival rate in patients with high-risk neuroblastoma.
  
  
  METHODS
  We took a synthetic lethal approach using a siRNA library targeting 418 apoptosis-related genes and identified genes and pathways whose inhibition synergized with topotecan. Microarray analyses of cells treated with topotecan were performed to identify if the same genes or pathways were altered by the drug. An inhibitor of this pathway was used in combination with topotecan to confirm synergism by in vitro and in vivo studies.
  
  
  RESULTS
  We found that there were nine genes whose suppression synergized with topotecan to enhance cell death, and the NF-κB signaling pathway was significantly enriched. Microarray analysis of cells treated with topotecan revealed a significant enrichment of NF-κB target genes among the differentially altered genes, suggesting that NF-κB pathway was activated in the treated cells. Combination of topotecan and known NF-κB inhibitors (NSC 676914 or bortezomib) significantly reduced cell growth and induced caspase 3 activity in vitro. Furthermore, in a neuroblastoma xenograft mouse model, combined treatment of topotecan and bortezomib significantly delayed tumor formation compared to single-drug treatments.
  
  
  CONCLUSIONS
  Synthetic lethal screening provides a rational approach for selecting drugs for use in combination therapy and warrants clinical evaluation of the efficacy of the combination of topotecan and bortezomib or other NF-κB inhibitors in patients with high risk neuroblastoma.
authors.affiliation: Oncogenomics Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Tsang
authors.forename: Adam T
authors.initials: AT
authors.lastname: Cheuk
authors.forename: Qing-Rong
authors.initials: QR
authors.lastname: Chen
authors.forename: Young K
authors.initials: YK
authors.lastname: Song
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Badgett
authors.forename: Jun S
authors.initials: JS
authors.lastname: Wei
authors.forename: Javed
authors.initials: J
authors.lastname: Khan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051379:Mice; D016513:Mice, SCID; D046228:Microarray Analysis; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism; D011719:Pyrazines / Q000008:administration & dosage; D034741:RNA, Small Interfering; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology*; D019772:Topotecan / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D016328:NF-kappa B; D011719:Pyrazines; D034741:RNA, Small Interfering; D059004:Topoisomerase I Inhibitors; D000069286:Bortezomib; D019772:Topotecan; D053148:Caspase 3