CoChat
Sign Up
Cited by 159Cancer, Hypoxia, and MetabolismAngiogenesis and VEGF in CancerHepatocellular Carcinoma Treatment and Prognosis

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

Open access
Jeong, Woondong, Rapisarda, Annamaria, Park, Sook Ryun, Kinders, Robert J., Chen, Alice, Melillo, Giovanni, Turkbey, Baris, Steinberg, Seth M. +3 more·2014·Cancer Chemotherapy and Pharmacology
DOI 10.1007/s00280-013-2362-zPMC PMC8375568
Open this paper in CoChat — free account

Abstract

Ten patients with refractory solid tumors received EZN-2968 18 mg/kg weekly for 3 weeks in a 6-week cycle; one patient had prolonged stable disease for 24 weeks, and 4 of 6 paired biopsies showed reduced HIF-1α mRNA.

Integrity signals

Registry

Crossref · 10.1007/s00280-013-2362-z

Cites

21 of 21 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

7 of 33 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured

  • Findingcitation

    GLUT-1 was decreased in two patients.

    “GLUT-1, known to be targeted by both HIF-1α and HIF-2α, was only decreased in 2 patients [19].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] Keith B, Johnson RS, Simon MC (2012) HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer 12:9–22 source

      The passages from the review’s Acetylation and Differential stability sections discuss HIF activity and glucose transport, but do not report GLUT-1 decreasing in two patients. Searches for “GLUT-1,” “GLUT1,” and “two patients decreased expression” found no passage addressing that patient-level result. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
  • Premisecitation

    Preclinical biodistribution studies showed prolonged and preferential retention of EZN-2968 in the liver.

    “Because preclinical biodistribution studies of EZN-2968 documented prolonged and preferential retention in the liver [11]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [11] Greenberger LM, Horak ID, Filpula D, Sapra P, Westergaard M, Frydenlund HF, Albaek C, Schroder H, Orum H (2008) A RNA antagonist of hypoxia-inducible factor-1 alpha, EZN-2968, inhibits tumor cell growth. Mol Cancer Ther 7:3598–3608 source

      The Biodistribution and Tissue Half-life section reports prolonged retention in mice, with an estimated tissue half-life of about 200 hours, and identifies the liver as a major site of accumulation. It also reports broad distribution to several organs and similar half-lives across tissues, so it does not establish preferential retention in the liver. No page number is available in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Findingown data

    VEGF expression was unchanged in all samples examined.

    “Interestingly, the expression of VEGF, which is commonly considered a HIF-1α and HIF-2α target gene [19], was unchanged in all of the samples examined.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [19] Keith B, Johnson RS, Simon MC (2012) HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer 12:9–22 source
  • Premisecitation

    EZN-2968 inhibited tumor growth in xenograft models.

    “Tumor growth inhibition was observed in xenograft models [11].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [11] Greenberger LM, Horak ID, Filpula D, Sapra P, Westergaard M, Frydenlund HF, Albaek C, Schroder H, Orum H (2008) A RNA antagonist of hypoxia-inducible factor-1 alpha, EZN-2968, inhibits tumor cell growth. Mol Cancer Ther 7:3598–3608 source
  • Study design and conductcitation

    Because of the small number of patients and because the VEGF pathway was not interrogated, definitive conclusions about antiangiogenic effects of EZN-2968 in humans are difficult.

    “However, given the small number of patients on the trial and the fact that interrogation of the VEGF pathway was not part of the study, it is difficult to draw definitive conclusions about the antiangiogenic effects of EZN-2968 in humans [20].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [20] Jeong W, Doroshow JH, Kummar S (2013) United States Food and Drug Administration approved oral kinase inhibitors for the treatment of malignancies. Curr Probl Cancer 37:110–144 source

      Section 6 discusses VEGFR-inhibiting kinase inhibitors and their adverse reactions, but not EZN-2968. Searches for EZN-2968 and its antiangiogenic effects returned no passage about its trial, patient number, or whether the VEGF pathway was interrogated. Our copy therefore does not establish the attributed conclusion. (LLM, conf=0.77)

      Experimental — accuracy not yet measured
  • May combine two claims. 16
  • Classified as probably not a substantial claim. 8

  • May combine two claims.

    Premisecitation

    EZN-2968 is an LNA antisense oligodeoxynucleotide that hybridizes with HIF-1α mRNA and blocks HIF-1α protein expression in preclinical models.

    “EZN-2968 is an LNA antisense oligodeoxynucleotide that has been demonstrated to hybridize with HIF-1α mRNA and block HIF-1α protein expression in preclinical models [11].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [11] Greenberger LM, Horak ID, Filpula D, Sapra P, Westergaard M, Frydenlund HF, Albaek C, Schroder H, Orum H (2008) A RNA antagonist of hypoxia-inducible factor-1 alpha, EZN-2968, inhibits tumor cell growth. Mol Cancer Ther 7:3598–3608 source

  • May combine two claims.

    Premisecitation

    IC50 values for HIF-2α, with which EZN-2968 has a 3-base-pair mismatch, were five times higher than for HIF-1α in all cell lines tested, supporting relative selectivity of EZN-2968 for HIF-1α.

    “IC50 values for the HIF-2α isoform, with which EZN-2968 has a 3-base-pair mismatch, were 5 times higher in all cell lines tested compared to IC50 values for HIF-1α, supporting the relative selectivity of EZN-2968 for HIF-1α [11].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [11] Greenberger LM, Horak ID, Filpula D, Sapra P, Westergaard M, Frydenlund HF, Albaek C, Schroder H, Orum H (2008) A RNA antagonist of hypoxia-inducible factor-1 alpha, EZN-2968, inhibits tumor cell growth. Mol Cancer Ther 7:3598–3608 source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Five patients had paired biopsies for HIF-1α protein assessment.

    “five patients had paired biopsies for the assessment of HIF-1α protein levels (Patients #1, 2, 3, 6, and 7; Fig. 1b)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Patient #2 had a 113% increase in HIF-1α protein and a 30% decrease in HIF-1α mRNA.

    “Patient #2 had a discordant 113 % increase in HIF-1α protein and 30 % decrease in HIF-1α mRNA.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Two patients had decreases in both HIF-1α mRNA and protein after EZN-2968, but no corresponding decrease in the four HIF-1-targeted genes evaluated.

    “Two patients had a decrease in levels of both HIF-1α mRNA and protein following EZN-2968 treatment, yet there was no corresponding decrease in the expression of the four HIF-1-targeted genes evaluated.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    EZN-2968 was well tolerated at the dose and schedule; most toxicities were grade 1 or 2 and no unexpected toxicities occurred.

    “EZN-2968 was well tolerated at the dose and schedule described; most of the toxicities were grade 1 or 2, and there were no unexpected toxicities.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Patient #1 with rectal adenocarcinoma had a 48% decrease in Ktrans and a 33% decrease in kep.

    “The first, a patient with rectal adenocarcinoma (Patient #1), had a 48 % decrease in Ktrans value and a 33 % decrease in kep value between baseline and post-treatment DCE-MRI.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    No PTT prolongation was observed, but one patient had a grade 2 infusion reaction attributed to complement activation.

    “We did not observe any cases of PTT prolongation, but one patient had a grade 2 infusion reaction attributed to complement activation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There were no differences in clinical response between liver-predominant and widespread disease groups or across metastatic sites.

    “There were no differences in clinical response between these two groups of patients or across various sites of metastases.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Ten patients were enrolled.

    “Ten patients were enrolled”
    • Also stated in: § Patient demographics · plain
      “A total of 10 patients were enrolled (Table 1)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the limited samples, there were no clear patterns of decreased HIF-1α target gene expression after EZN-2968 or overall associations with HIF-1α protein or mRNA changes.

    “In the limited number of patient samples available for analysis, there were no clear patterns of decreased expression as a result of EZN-2968 therapy, or overall associations with changes in either HIF-1α protein or mRNA levels.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Only one patient met the predefined >50% decrease in HIF-1α mRNA criterion, and sufficient biopsy material for protein analysis was not available for that patient.

    “Only one patient met the predefined study criteria of a greater than 50 % decrease in HIF-1α mRNA; however, sufficient tumor biopsy material was not available to perform protein analysis for this patient.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Patient #6 had increases in both HIF-1α protein and mRNA.

    “Patient #6 had increase in level of HIF-1α protein and mRNA”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Four patients had both HIF-1α protein and mRNA copy number assessed.

    “Four patients (Patients #2, 3, 6, and 7) had both HIF-1α protein and mRNA copy number assessed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Three patients had decreased HIF-1α protein levels after EZN-2968, with two showing >50% decrease.

    “Three patients had decreased HIF-1α protein levels following EZN-2968 treatment, of which two (Patients #1 and #7) had a greater than 50 % decrease.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The enrollment goal was 20 evaluable patients with paired biopsies and measurable HIF-1α protein.

    “The enrollment goal was a total of 20 evaluable patients with paired biopsies and measurable HIF-1α protein levels.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    HIF-1 is often overexpressed in cancer cells and drives many genes needed for survival.

    “HIF-1 is frequently overexpressed in cancer cells, where it is involved in the upregulation of many genes necessary for survival.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732 source

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The primary endpoint for sample size determination was the proportion of patients with a ≥50% decrease in HIF-1α mRNA in tumor biopsy from baseline.

    “For purposes of sample size determination, the primary endpoint was the proportion of patients in whom expression of HIF-1α mRNA in a tumor biopsy decreased by 50 % compared to baseline.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Hepatic and renal toxicities, complement activation, and PTT prolongation have been reported with phosphorothioate antisense oligonucleotides.

    “Hepatic and renal toxicities have been reported previously with the administration of phosphorothioate antisense oligonucleotides, as have complement activation and prolongation of PTT due to interaction with complement and coagulation factor [16].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Levin AA (1999) A review of the issues in the pharmacokinetics and toxicology of phosphorothioate antisense oligonucleotides. Biochim Biophys Acta 1489:69–84 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The trial was conducted under an NCI-sponsored IND with IRB approval and followed applicable regulations.

    “This trial was conducted under a National Cancer Institute (NCI)-sponsored IND with Institutional Review Board approval. The protocol design and conduct followed all applicable regulations, guidance, and local policies (ClinicalTrials.gov Identifier: NCT01120288).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Literature reports show clusters of HIF-1α-positive cells at tumor margins, around necrotic regions, and areas of neovascularization by immunohistochemistry.

    “Reports in the literature demonstrate clusters of HIF-1α-positive cells at the edge of tumor margins, around necrotic regions and areas of neovascularization using immunohistochemical analysis [17, 18].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW (1999) Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases. Cancer Res 59:5830–5835
    • cites [18] Talks KL, Turley H, Gatter KC, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL (2000) The expression and distribution of the hypoxia-inducible factors HIF-1α and HIF-2α in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol 157:411–421 source

  • May combine two claims.

    Premisecitation

    Phase 1 trials of EZN-2968 established safety and a recommended Phase 2 dose and showed preliminary activity.

    “Safety and a recommended Phase 2 dose was determined, and preliminary evidence of activity observed in two Phase 1 clinical trials of EZN-2968.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] Patnaik A, Chiorean EG, Tolcher A, Papadopoulos K, Beeram M, Kee D, Waddell M, Gilles E, Buchbinder A (2009) EZN-2968, a novel hypoxia-inducible factor-1 (HIF-1) messenger ribonucleic acid (mRNA) antagonist: results of a phase I, pharmacokinetic (PK), dose-escalation study of daily administration in patients (pts) with advanced malignancies. J Clin Oncol 27:2564 source
    • cites [13] Cohen RB, Olszanski A, Figueroa J, Hurwitz H, Lokiec FM, Rezaï K, Berkowitz N, Buchbinder A (2011) Down-modulation of messenger ribonucleic acid (mRNA) by EZN-2968, an hypoxia-inducible factor-1(HIF-1α) mRNA antagonist, administered in adult patients with advanced solid tumors [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research, Orlando, Florida. AACR, Philadelphia (PA), abstract nr LB-407, 2–6 April 2011

      Not checked in the free run.

22 of 22

  • The paper relies on this without support.

    Changes in HIF-1α mRNA and protein levels in tumor biopsies are attributable to EZN-2968 rather than to other factors.

    “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.”

  • The paper relies on this without support.

    HIF-1 is a heterodimer of an oxygen-inducible HIF-1α subunit and a constitutively expressed HIF-1β subunit.

    “HIF-1 is a heterodimer consisting of the HIF-1α subunit, inducible by tissue hypoxia, and the HIF-1β subunit, which is constitutively expressed.”

  • The paper relies on this without support.

    Preclinical biodistribution findings in animals predict human liver delivery and target modulation.

    “Because preclinical biodistribution studies of EZN-2968 documented prolonged and preferential retention in the liver [11], we initially restricted enrollment to patients with advanced solid tumors where the liver involvement represented the predominant disease burden to optimize our ability to demonstrate target modulation and provide clinical benefit (2 patients).”

  • The paper relies on this without support.

    Anemia is a sensitive marker of erythropoietin suppression by EZN-2968.

    “Only one case of grade 1 anemia was observed, which suggests that EZN-2968 did not suppress erythropoietin production in the kidney”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Results from one phase I trial of EZN-2968 showed reduced HIF-1α mRNA in post-treatment biopsies from 4 out of 6 patients with paired tumor biopsies, and HIF-1α protein and mRNA levels of target genes were reduced in biopsies from two patients.

    “EZN-2968 has also been evaluated in two phase I clinical trials: results from one trial showed reduced HIF-1α mRNA in post-treatment biopsies from 4 out of 6 patients with paired tumor biopsies, and HIF-1α protein and mRNA levels of target genes were reduced in biopsies from two patients.”

    From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Jeong et al., 2014

    Split into 2 atoms — 1 confirmed, 0 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • EZN-2968 binds specifically to HIF1A mRNA, promoting transcript degradation and inhibiting translation.

    “EZN-2968 binds specifically to HIF1A mRNA, promoting transcript degradation and inhibiting translation [280,281].”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [280]

    The Introduction reports that EZN-2968 hybridizes with HIF-1α mRNA and blocks HIF-1α protein expression in preclinical models. The Results report reduced mRNA levels in some treated patients, but the paper does not establish transcript degradation as the mechanism or directly demonstrate inhibition of translation. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • In phase I clinical trials in lymphoma and advanced solid tumors with liver metastases, EZN-2968 reduced HIF1A expression in 4 of 6 evaluable patients based on paired biopsies, with concomitant suppression of HIF-1 target genes in two cases, and was generally well tolerated.

    “In these studies, EZN-2968 reduced HIF1A expression in 4 of 6 evaluable patients based on paired biopsies, with concomitant suppression of HIF-1 target genes in two cases and was generally well tolerated [39,280].”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [280]

    The Results sections report reduced HIF-1α mRNA in paired biopsies and describe EZN-2968 as generally well tolerated. But the detailed Results count five of six patients with decreased mRNA, not four, and report no clear pattern of HIF-1 target-gene suppression associated with HIF-1α changes. This pilot trial enrolled patients with refractory solid tumors, not lymphoma patients. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • EZN-2968 is built on locked nucleic acid chemistry that enhances base-pairing affinity, nuclease resistance, and in vivo stability relative to conventional oligonucleotides.

    “EZN-2968 is built on locked nucleic acid (LNA) chemistry, in which a methylene bridge between the 2′-oxygen and 4′-carbon of the ribose ring locks the sugar into a rigid conformation. This structural feature enhances base-pairing affinity, nuclease resistance, and in vivo stability relative to conventional oligonucleotides [[279], [280], [281]].”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [280]

    The Introduction (page not specified) identifies EZN-2968 as an LNA antisense oligodeoxynucleotide and says LNA oligonucleotides have higher affinity and resistance to degradation than other oligonucleotides. Our copy does not describe the methylene-bridge structure or establish enhanced in vivo stability relative to conventional oligonucleotides. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting counts of patients with reduced HIF-1α mRNA

    Major

    The abstract reports reduced HIF-1α mRNA in four of six patients with paired biopsies, but the Results section reports five patients with decreased mRNA copy numbers. These are different counts for the same outcome.

1 of 1

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Jeong, W., Rapisarda, A., Park, S. R., Kinders, R. J., Chen, A., Melillo, G., Turkbey, B., Steinberg, S. M., Choyke, P., Doroshow, J. H., & Kummar, S.
Affiliations
  • National Cancer Institute (US)
  • Frederick National Laboratory for Cancer Research (US)
Corresponding author
Kummar, Shivaani
ORCID
Venue
Cancer Chemotherapy and Pharmacology
Publisher
Springer Science and Business Media LLC
Published
2013-11-30
Volume
73
Issue
2
Pages
343-348
ISSN
  • 0344-5704 (ISSN-L)
  • 1432-0843
DOI
10.1007/s00280-013-2362-z
PMC
PMC8375568
OpenAlex
W1986912321
Cited by
159
References
20
Citations by year
2026: 8 · 2025: 10 · 2024: 9 · 2023: 18 · 2022: 14 · 2021: 19 · 2020: 22 · 2019: 8 · 2018: 13 · 2017: 12 · 2016: 12 · 2015: 9 · 2014: 5
FWCI
3.04
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Cancer Chemotherapy and Pharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (HHSN261200800001C)
  • National Cancer Institute (HHSN261200800001E), Z01BC010714, ZIABC011078)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
Keywords
antisense oligonucleotides, hypoxia-inducible factor-1α, HIF-1α inhibition, refractory solid tumors, tumor hypoxia, HIF-1 target genes, tumor biopsy, dynamic contrast-enhanced MRI, duodenal neuroendocrine tumor
MeSH terms
Aged, Biopsy, Female, Humans, Infusions, Intravenous, Male, Middle Aged, Neoplasms, Oligonucleotides, Pilot Projects, RNA, Messenger, Oligonucleotides, Antisense, Cell Line, Tumor, Hypoxia-Inducible Factor 1

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review