Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors

Woondong Jeong, Annamaria Rapisarda, Sook Ryun Park, Robert J. Kinders, Alice Chen, Giovanni Melillo, Baris Turkbey, Seth M. Steinberg, Peter Choyke, James H. Doroshow, Shivaani Kummar

Research output: Contribution to journalArticlepeer-review

72 Scopus citations

Abstract

Purpose: 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)343-348
Number of pages6
JournalCancer Chemotherapy and Pharmacology
Volume73
Issue number2
DOIs
StatePublished - Feb 2014
Externally publishedYes

Keywords

  • Antiangiogenesis
  • HIF mRNA
  • Pharmacodynamics-driven trials
  • Synthetic locked nucleic acid (LNA) oligodeoxynucleotide

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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