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

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Jeong W, Rapisarda A, Park SR, Kinders RJ, Chen A, Melillo G, Turkbey B, Steinberg SM, Choyke P, Doroshow JH, Kummar S

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

Cancer Chemother Pharmacol. 2014 Feb;73(2):343-8. doi: 10.1007/s00280-013-2362-z. Epub 2013 Nov 30.

PubMed ID
24292632 [ View in PubMed
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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-1alpha, 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-1alpha 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-1alpha mRNA levels compared to baseline was demonstrated in 4 of 6 patients with paired tumor biopsies. Reductions in levels of HIF-1alpha 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-1alpha mRNA and protein expression and target genes in tumor biopsies following the administration of EZN-2968.

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