title: Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors.
abstract: OBJECTIVE
  Hypoxia-inducible factor-1 (HIF-1) facilitates the adaptation of normal and tumor tissues to oxygen deprivation. HIF-1 is frequently overexpressed in cancer cells, where it is involved in the upregulation of many genes necessary for survival. EZN-2968 is an antisense oligodeoxynucleotide that specifically targets HIF-1α, one of the subunits of HIF-1. We conducted a trial of EZN-2968 in patients with refractory solid tumors to evaluate antitumor response and to measure modulation of HIF-1α mRNA and protein levels as well as HIF-1 target genes.
  
  
  METHODS
  Adult patients with refractory advanced solid tumors were administered EZN-2968 as a 2-h IV infusion at a dose of 18 mg/kg once a week for three consecutive weeks followed by 3-week off; in a 6-week cycle. Tumor biopsies and dynamic contrast enhanced MRI (DCE-MRI) were performed at baseline and after the third dose.
  
  
  RESULTS
  Ten patients were enrolled, of whom all were evaluable for response; one patient with a duodenal neuroendocrine tumor had prolonged stabilization of disease (24 weeks). Reduction in HIF-1α mRNA levels compared to baseline was demonstrated in 4 of 6 patients with paired tumor biopsies. Reductions in levels of HIF-1α protein and mRNA levels of some target genes were observed in two patients. Quantitative analysis of DCE-MRI from two patients revealed changes in K (trans) and k ep. The trial was closed prematurely when the sponsor suspended development of this agent.
  
  
  CONCLUSIONS
  This trial provides preliminary proof of concept for modulation of HIF-1α mRNA and protein expression and target genes in tumor biopsies following the administration of EZN-2968.
authors.affiliation: Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, 20892, USA.
authors.forename: Woondong
authors.initials: W
authors.lastname: Jeong
authors.forename: Annamaria
authors.initials: A
authors.lastname: Rapisarda
authors.forename: Sook Ryun
authors.initials: SR
authors.lastname: Park
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kinders
authors.forename: Alice
authors.initials: A
authors.lastname: Chen
authors.forename: Giovanni
authors.initials: G
authors.lastname: Melillo
authors.forename: Baris
authors.initials: B
authors.lastname: Turkbey
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: Peter
authors.initials: P
authors.lastname: Choyke
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
authors.forename: Shivaani
authors.initials: S
authors.lastname: Kummar
mesh_terms: D000368:Aged; D001706:Biopsy; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000009:adverse effects; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000009:adverse effects; D010865:Pilot Projects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: C533794:EZN 2968; D051793:Hypoxia-Inducible Factor 1; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger