title: HIF-1α activation mediates resistance to anti-angiogenic therapy in neuroblastoma xenografts.
abstract: BACKGROUND
  The anti-tumor activity of angiogenesis inhibitors is often limited by the development of resistance to these drugs. Here we establish HIF-1α as a major factor in the development of this resistance in neuroblastoma xenografts.
  
  
  METHODS
  Neuroblastoma xenografts were established by injecting unmodified SKNAS or NB-1691 cells (2 × 10(6) cells), or cells in which HIF-1α expression had been knocked down with shRNA, into the retroperitoneal space of SCID mice. Treatment of established tumors included bevacizumab (5mg/kg q2wk), sunitinib (40 mg/kg qd), or topotecan (0.5mg/kg qd) alone or in combination for a total of two weeks.
  
  
  RESULTS
  NB-1691 xenografts showed no difference in relative growth in HIF-1α knockdowns compared to control tumors (73.33 ± 7.90 vs 79.94 ± 6.15, p=0.528). However, HIF-1α knockdowns demonstrated relative final volumes that were significantly lower than unmodified tumors when both were treated with bevacizumab (35.88 ± 4.24 vs 53.57 ± 6.61, p=0.0544) or sunitinib (12.46 ± 2.59 vs 36.36 ± 4.82, p=0.0024). Monotherapy of unmodified xenografts with bevacizumab, sunitinib, or topotecan was largely ineffective. Relative final volumes of NB-1691 xenografts were significantly less in cohorts treated with sunitinib+topotecan (4.78 ± 0.77 vs 39.17 ± 2.44 [sunitinib alone], p=0.011) and bevacizumab+topotecan (13.63 ± 1.55 vs 48.16 ± 9.94 [bevacizumab alone], p=0.014).
  
  
  CONCLUSIONS
  Upregulation of HIF-1α appears to be a significant mechanism of resistance to antiangiogenic therapies in neuroblastoma. Suppressing HIF-1α with low-dose topotecan potentiates the effects of the antiangiogenic drugs in a mouse model.
authors: Department of Surgery, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Joseph
authors: J
authors: Hartwich
authors: W Shannon
authors: WS
authors: Orr
authors: Catherine Y
authors: CY
authors: Ng
authors: Yunyu
authors: Y
authors: Spence
authors: Christopher
authors: C
authors: Morton
authors: Andrew M
authors: AM
authors: Davidoff
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007211:Indoles / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D051379:Mice; D016513:Mice, SCID; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011758:Pyrroles / Q000008:administration & dosage; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077210:Sunitinib; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage; D019772:Topotecan / Q000008:administration & dosage; D016896:Treatment Outcome; D047368:Tumor Burden
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; D011758:Pyrroles; D059004:Topoisomerase I Inhibitors; D000068258:Bevacizumab; D019772:Topotecan; D000077210:Sunitinib