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Cancer Chemotherapy and Pharmacology

, Volume 73, Issue 2, pp 343–348 | Cite as

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
Original Article

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.

Keywords

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

Notes

Acknowledgments

We thank Drs. Yvonne, A. Evrard, and Andrea Voth for editorial assistance. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

Conflict of interest

None declared.

Supplementary material

280_2013_2362_MOESM1_ESM.doc (63 kb)
Supplementary material 1 (DOC 63 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg (outside the USA) 2013

Authors and Affiliations

  • Woondong Jeong
    • 1
  • Annamaria Rapisarda
    • 2
  • Sook Ryun Park
    • 1
  • Robert J. Kinders
    • 2
  • Alice Chen
    • 1
  • Giovanni Melillo
    • 2
  • Baris Turkbey
    • 3
  • Seth M. Steinberg
    • 3
  • Peter Choyke
    • 3
  • James H. Doroshow
    • 1
    • 3
  • Shivaani Kummar
    • 1
    • 3
  1. 1.Division of Cancer Treatment and DiagnosisNational Cancer InstituteBethesdaUSA
  2. 2.Leidos Biomedical Research, Inc.Frederick National Laboratory for Cancer ResearchFrederickUSA
  3. 3.Center for Cancer ResearchNational Cancer InstituteBethesdaUSA

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