The DOI matches its Crossref record; 21 of the 21 references it cites were found in a registry or an index; 7 of the 33 sources its claims cite were checked for support.
Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors
Open accessAbstract
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.
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Claims the paper makes
25 Own result · 13 No full text of the sources · 5 Own method · 4 Own interpretation · 3 Supported · 2 Partly supported · 2 Couldn’t confirm · 2 No basis given · 1 Not checked yet · accuracy not yet measured
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“GLUT-1, known to be targeted by both HIF-1α and HIF-2α, was only decreased in 2 patients [19].”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Discussion
What the sources say
- Could not verifycites [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 sourceExperimental — accuracy not yet measured
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)
plainn = 2- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Because preclinical biodistribution studies of EZN-2968 documented prolonged and preferential retention in the liver [11]”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Introduction > Patients and methods
What the sources say
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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.”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Discussion
What the sources say
- Supportedcites [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
Citation [19] is attached to the background description of VEGF as a HIF-1α and HIF-2α target, not to the citing authors’ observation that VEGF was unchanged in their samples. The source’s Therapy section links HIF-1α to VEGFA expression, and its “Assessing HIF1α and HIF2α function in tumor models” section reports increased VEGF expression with HIF-2α overexpression (page numbers unavailable). (LLM, conf=0.88)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Tumor growth inhibition was observed in xenograft models [11].”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Introduction
What the sources say
- Supportedcites [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 antitumor-effect results report significantly lower tumor weight in nude mice implanted with DU145 cells pretransfected with EZN-2968. The paper also notes that EZN-2968 given to mice without that pretransfection produced a small, statistically nonsignificant reduction; the claim is supported as an observation of tumor growth inhibition in a xenograft model, not as evidence that systemic treatment alone was effective. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“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].”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Discussion
What the sources say
- Could not verifycites [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 sourceExperimental — accuracy not yet measured
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)
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“EZN-2968 was generally well tolerated without significant toxicity (Table 2).”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Results > Toxicity
- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Five of the patients assessed had decreased HIF-1α mRNA copy numbers ranging from −7 to −94 % from baseline.”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Results > HIF-1α mRNA and protein levels
plainn = 5- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There were no new cases of hypertension in this study of EZN-2968”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The second, a patient with Hurthle cell thyroid carcinoma (Patient #3), had 35 and 14 % increases in Ktrans and kep values, respectively.”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Results > DCE-MRI
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Reduction in HIF-1α mRNA levels compared to baseline was demonstrated in 4 of 6 patients with paired tumor biopsies.”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Abstract > Results
boosteddirectn = 6- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 16
- Probably not a substantial claim. 8
Every source the paper cites for this claim was checked and supports it.
In the paper
“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].”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Introduction
What the sources say
- Supportedcites [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 Results (Biophysical Properties) describe EZN-2968 as an LNA/DNA oligonucleotide complementary to HIF-1α mRNA and report its high affinity for that RNA. The Results (Effect on HIF-1α mRNA and Protein Expression in Tumor Cells) report that HIF-1α protein was nearly absent after treatment of cultured cells. Page numbers were not supplied. (LLM, conf=0.92)
direct- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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].”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Discussion
What the sources say
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“five patients had paired biopsies for the assessment of HIF-1α protein levels (Patients #1, 2, 3, 6, and 7; Fig. 1b)”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Results > HIF-1α mRNA and protein levels
plainn = 5- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Patient #2 had a discordant 113 % increase in HIF-1α protein and 30 % decrease in HIF-1α mRNA.”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Results > HIF-1α mRNA and protein levels
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Discussion
plainn = 2- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Results > DCE-MRI
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We did not observe any cases of PTT prolongation, but one patient had a grade 2 infusion reaction attributed to complement activation.”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Discussion
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There were no differences in clinical response between these two groups of patients or across various sites of metastases.”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Ten patients were enrolled”
- Also stated in: § Patient demographics · plain
“A total of 10 patients were enrolled (Table 1)”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Abstract > Results
plainn = 10- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Also stated in: § Patient demographics · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Results > Expression of HIF-1α target genes
plain- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Discussion
plainSingle case- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Patient #6 had increase in level of HIF-1α protein and mRNA”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Results > HIF-1α mRNA and protein levels
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Four patients (Patients #2, 3, 6, and 7) had both HIF-1α protein and mRNA copy number assessed.”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Results > HIF-1α mRNA and protein levels
plainn = 4- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Results > HIF-1α mRNA and protein levels
plaindirectn = 3- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The enrollment goal was a total of 20 evaluable patients with paired biopsies and measurable HIF-1α protein levels.”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Introduction > Statistical analysis
plainn = 20- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“HIF-1 is frequently overexpressed in cancer cells, where it is involved in the upregulation of many genes necessary for survival.”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Abstract > Purpose
What the sources say
- Not checked — no full text of the sourcecites [1] Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732 source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Introduction > Statistical analysis
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim.
In the paper
“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].”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Discussion
What the sources say
- Not checked — no full text of the sourcecites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Introduction > Patients and methods
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“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].”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Discussion
What the sources say
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Safety and a recommended Phase 2 dose was determined, and preliminary evidence of activity observed in two Phase 1 clinical trials of EZN-2968.”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Introduction
What the sources say
- Not checked — no full text of the sourcecites [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
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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”
Claims other papers make about this one
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In the citing paper
“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
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measured
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Each contradiction between two passages listed here was confirmed by an independent check.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Abstract > Results
“Reduction in HIF-1α mRNA levels compared to baseline was demonstrated in 4 of 6 patients with paired tumor biopsies.”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Results > HIF-1α mRNA and protein levels
“Five of the patients assessed had decreased HIF-1α mRNA copy numbers ranging from −7 to −94 % from baseline.”
Citations
Cites
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)
Eisenhauer, E. A., Therasse, P., Bogaerts, J., Schwartz, L. H., Sargent, D., Ford, R., Dancey, J., Arbuck, S., Gwyther, S., Mooney, M., et al. (2009) · European Journal of Cancer · doi:10.1016/j.ejca.2008.10.026 · Cited by 29,534 · cited 1×
“1 [14].”
Targeting HIF-1 for cancer therapy
Semenza, G. L. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1187 · Cited by 6,717 · cited 1×
“Hypoxia-inducible factor-1 (HIF-1), a transcription factor, facilitates tissue adaptation to oxygen deprivation by inducing the expression of genes necessary for cell survival [1].”
Targeting Hypoxia-Inducible Factors for the Treatment of Anemia in Chronic Kidney Disease Patients
Locatelli, F., Fishbane, S. N., Block, G. A., & Macdougall, I. C. (2017) · American Journal of Nephrology · doi:10.1159/000455166 · Cited by 4,836
(1999) · PubMed · Cited by 2,204
HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression
Keith, B., Johnson, R. S., & Simon, M. C. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3183 · Cited by 1,693 · cited 2×
“Interestingly, the expression of VEGF, which is commonly considered a HIF-1α and HIF2α target gene [19], was unchanged in all of the samples examined.”
BackgroundTalks, K. L., Turley, H., Gatter, K. C., Maxwell, P. H., Pugh, C. W., Ratcliffe, P. J., & Harris, A. L. (2000) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)64554-3 · Cited by 1,312 · cited 1×
“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].”
BackgroundLNA (Locked Nucleic Acid): High-Affinity Targeting of Complementary RNA and DNA
Vester, B., & Wengel, J. (2004) · Biochemistry · doi:10.1021/bi0485732 · Cited by 727 · cited 1×
“Antisense oligonucleotides are an attractive therapeutic strategy because they can inhibit mRNA expression specifically [7, 8].”
BackgroundLevin, A. A. (1999) · Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression · doi:10.1016/s0167-4781(99)00140-2 · Cited by 438 · cited 2×
“One patient had a grade 2 infusion reaction that was attributed to complement activation, a known class effect of phosphorothioate-linked antisense oligodeoxynucleotides [16]; this toxicity resolved within a few hours after antihistamine and steroid treatment.”
Background(2002) · PubMed · Cited by 385
A RNA antagonist of hypoxia-inducible factor-1α, EZN-2968, inhibits tumor cell growth
Greenberger, L. M., Horak, I. D., Filpula, D., Sapra, P., Westergaard, M., Frydenlund, H. F., Albæk, C., Schrøder, H., & Ørum, H. (2008) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-08-0510 · Cited by 245 · cited 5×
“Tumor growth inhibition was observed in xenograft models [11].”
Influential
Cited by
Sorted by citations
Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer
Wigerup, C., Påhlman, S., & Bexell, D. (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2016.04.009 · Cited by 687
“Although the trial provided preliminary proof of concept for modulation of HIF-1α mRNA and protein expression in response to EZN-2968, the trial closed prematurely due to suspended development of the compound (Jeong et al., 2014).”
BackgroundBoon, R. A., Jaé, N., Holdt, L. M., & Dimmeler, S. (2016) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2015.12.051 · Cited by 525
“Gapmers against survivin and hypoxia-inducing factor 1a have been applied weekly over as long as 1 year without safety concerns (111,112).”
BackgroundPharmacologic Targeting of Hypoxia-Inducible Factors
Semenza, G. L. (2019) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010818-021637 · Cited by 288
Targeting hypoxia-inducible factors: therapeutic opportunities and challenges
Yuan, X., Ruan, W., Bobrow, B., Carmeliet, P., & Eltzschig, H. K. (2024) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00848-6 · Cited by 245
“The early effort to study HIF1A RNAi by ASO EZN-2968 in patients with refractory solid tumours was terminated prematurely owing to the loss of interest from the sponsoring agent 170 .”
Hypoxia-Inducible Factor as an Angiogenic Master Switch
Hashimoto, T., & Shibasaki, F. (2015) · Frontiers in Pediatrics · doi:10.3389/fped.2015.00033 · Cited by 242
Ai, Z., Lü, Y., Qiu, S., & Fan, Z. (2016) · Cancer Letters · doi:10.1016/j.canlet.2016.01.009 · Cited by 196
Zheng, F., Chen, J., Zhang, X., Wang, Z., Chen, J., Lin, X., Huang, H., Fu, W., Liang, J., Wu, W., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-21535-3 · Cited by 199
Development of Inhibitors Targeting Hypoxia-Inducible Factor 1 and 2 for Cancer Therapy
Yu, T., Tang, B., & Sun, X. (2017) · Yonsei Medical Journal · doi:10.3349/ymj.2017.58.3.489 · Cited by 202
Metabolic and hypoxic adaptation to anti‐angiogenic therapy: a target for induced essentiality
McIntyre, A., & Harris, A. L. (2015) · EMBO Molecular Medicine · doi:10.15252/emmm.201404271 · Cited by 185
Interfering with Tumor Hypoxia for Radiotherapy Optimization
Telarović, I., Wenger, R. H., & Pruschy, M. N. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-02000-x · Cited by 203
Role of long non-coding RNAs in glucose metabolism in cancer
Fan, C., Tang, Y., Wang, J., Xiong, F., Guo, C. J., Wang, Y., Zhang, S., Gong, Z., Wei, F., Yang, L., et al. (2017) · Molecular Cancer · doi:10.1186/s12943-017-0699-3 · Cited by 182
“Survivin and HIF-1α gapmers have been used for one year without safety issues [116, 117].”
Hypoxia: The Cornerstone of Glioblastoma
Doménech, M., Hernández, A., Plaja, A., Martinez‐Balibrea, E., & Balañá, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222212608 · Cited by 187
“Drug Name Mechanism of Action Clinical Trial Phase Glioma Mod‐ els Ref EZN‐2208 Downregulation of HIF‐1 mRNA NCT01251926 Phase I Yes [115] Aminoflavone Blockage of HIF‐1α dimerization NCT0101552 Phase I No [104,105] EZN‐2698 Downregulation of HIF‐1 mRNA NCT01120288 Phase I Yes [106,107] KC7F2 Inhibition of HIF‐1 trans…”
BackgroundThe Epithelial–Mesenchymal Transition at the Crossroads between Metabolism and Tumor Progression
Fedele, M., Sgarra, R., Battista, S., Cerchia, L., & Manfioletti, G. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23020800 · Cited by 171
“Therefore, it may be targeted by HIF-1α inhibitors, such as the antisense oligonucleotide EZN-2968, which, in a pilot phase I clinical trial, has been shown to modulate HIF-1α and its target genes in biopsies of refractory solid tumors [211].”
BackgroundTumor hypoxia and radiotherapy: A major driver of resistance even for novel radiotherapy modalities
Beckers, C., Pruschy, M. N., & Vetrugno, I. (2023) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2023.11.006 · Cited by 182
Targeting cancer‐related inflammation in the era of immunotherapy
Nakamura, K., & Smyth, M. J. (2016) · Immunology and Cell Biology · doi:10.1038/icb.2016.126 · Cited by 164
Smith, S. F., Hosgood, S. A., & Nicholson, M. L. (2018) · Kidney International · doi:10.1016/j.kint.2018.10.009 · Cited by 164
Bui, B. P., Nguyen, P. L., Lee, K., & Cho, J. (2022) · Cancers · doi:10.3390/cancers14246054 · Cited by 171
The role of hypoxia in pancreatic cancer: a potential therapeutic target?
Erkan, M., Kurtoğlu, M., & Kleeff, J. H. (2015) · Expert Review of Gastroenterology & Hepatology · doi:10.1586/17474124.2016.1117386 · Cited by 156
Glycolysis inhibition as a cancer treatment and its role in an anti-tumour immune response
Gill, K. S., Fernandes, P., O’Donovan, T. R., McKenna, S. L., Doddakula, K., Power, D. G., Soden, D. M., & Forde, P. F. (2016) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2016.06.005 · Cited by 148
Morandi, A., Taddei, M. L., Chiarugi, P., & Giannoni, E. (2017) · Frontiers in Oncology · doi:10.3389/fonc.2017.00040 · Cited by 146
“Among the molecules described to be able to target HIF-1α (41), the compounds BAY87-2243, an inhibitor of its activity and stability, and the antisense oligonucleotide EZN-2968 entered phase I clinical trials (42).”
BackgroundHypoxia-induced alternative splicing: the 11th Hallmark of Cancer
Farina, A. R., Cappabianca, L. A., Sebastiano, M., Zelli, V., Guadagni, S., & Mackay, A. R. (2020) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-020-01616-9 · Cited by 134
Zhang, J., Yao, M., Xia, S., Zeng, F., & Liu, Q. (2025) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-024-00682-7 · Cited by 145
Targeting Hypoxia-Inducible Factors for Antiangiogenic Cancer Therapy
Rey, S., Schito, L., Wouters, B. G., Eliasof, S. D., & Kerbel, R. S. (2017) · Trends in cancer · doi:10.1016/j.trecan.2017.05.002 · Cited by 118
Advances and challenges in targeting IRF5, a key regulator of inflammation
Almuttaqi, H., & Udalova, I. A. (2018) · FEBS Journal · doi:10.1111/febs.14654 · Cited by 116
Hypoxia-induced chemoresistance in cancer cells: The role of not only HIF-1
Doktorová, H., Hraběta, J., Khalil, M. A., & Eckschlager, T. (2015) · Biomedical Papers · doi:10.5507/bp.2015.025 · Cited by 122
Flavonoids Targeting HIF-1: Implications on Cancer Metabolism
Samec, M., Líšková, A., Koklesová, L., Meršaková, S., Strnádel, J., Kajo, K., Péč, M. J., Zhai, K., Šmejkal, K., Mirzaei, S., et al. (2021) · Cancers · doi:10.3390/cancers13010130 · Cited by 114
“EZN-2968 Regulation of HIF-1α mRNA expression [85] Topotecan Regulation of HIF-1α mRNA expression [86,87]”
BackgroundTargeting HIF-2 α in clear cell renal cell carcinoma: A promising therapeutic strategy
Martínez‐Sáez, O., Borau, P. G., Alonso‐Gordoa, T., Molina‐Cerrillo, J., & Grande, E. (2017) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2017.01.013 · Cited by 111
Belaïdi, E., Morand, J., Gras, E., Pépin, J., & Godin‐Ribuot, D. (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2016.07.010 · Cited by 116
“Antisense oligodeoxynucleotide HIF-1 α mRNA inhibitors, such as EZN-2968, have been shown to reduce the expression of its target genes in cell and animal models (Greenberger et al., 2008) as well as in cancer patients (Jeong et al., 2014).”
Zhang, J., Hu, Z., Horta, C. A., & Yang, J. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.12.002 · Cited by 106
Patients with obstructive sleep apnea present with chronic upregulation of serum HIF-1α protein
Gabryelska, A., Szmyd, B. M., Szemraj, J., Stawski, R. S., Sochal, M., & Białasiewicz, P. (2020) · Journal of Clinical Sleep Medicine · doi:10.5664/jcsm.8682 · Cited by 99
“43 Furthermore MiR-210 molecule has been described as a prognostic factor and therapeutic agent for both myocardial infarction and pulmonary hypertension.”
Hypoxia: Friend or Foe for drug delivery in Pancreatic Cancer
Shah, V. M., Sheppard, B. C., Sears, R. C., & Alani, A. W. G. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.07.041 · Cited by 101
Chambers, A. M., & Matosevic, S. (2019) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2019.00060 · Cited by 100
Пили, Р., Liu, G., Chintala, S., Verheul, H. M. W., Rehman, S., Attwood, K. M., Lodge, M. A., Wahl, R. L., Martin, J. I., Miles, K. M., et al. (2017) · British Journal of Cancer · doi:10.1038/bjc.2017.33 · Cited by 97
“Several strategies aimed to affect HIFs have been developed (Rapisarda et al, 2009; Kummar et al, 2011; Jeong et al, 2014).”
BackgroundProgress toward Overcoming Hypoxia-Induced Resistance to Solid Tumor Therapy
Reginato, M., & Karakashev, S. (2015) · Cancer Management and Research · doi:10.2147/cmar.s58285 · Cited by 95
“EZN-2968 has been shown to decrease HIF-1 levels in both animal models and patients with refractory advanced solid tumors including breast and colon carcinomas.(83) Inhibition of type I topoisomerase activity by topotecan was also shown to downregulate HIF-1 expression in glioma cells in vitro and in vivo.”
Hypoxia-mediated cancer stem cell resistance and targeted therapy
Sun, X., Lv, X., Yan, Y., Zhao, Y., Ma, R., He, M., & Wei, M. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110623 · Cited by 93
Hypoxia-inducible factor-1α: A promising therapeutic target for vasculopathy in diabetic retinopathy
Li, H.-Y., Yuan, Y., Fu, Y.-H., Wang, Y., & Gao, X.-Y. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.104924 · Cited by 88
Anti-angiogenesis in cancer therapeutics: the magic bullet
Oguntade, A. S., Al-Amodi, F., Alrumayh, A., Alobaida, M., & Bwalya, M. (2021) · Journal of the Egyptian National Cancer Institute · doi:10.1186/s43046-021-00072-6 · Cited by 86
Silva, V. L., & Al-Jamal, W. T. (2017) · Journal of Controlled Release · doi:10.1016/j.jconrel.2017.03.013 · Cited by 77
“del ivery In vitro s tudies in prostate cancer and glioblastoma showed [37-40] ACCEPTED MANUSCRIPT”
BackgroundPresent and future of cancer immunotherapy: A tumor microenvironmental perspective (Review)
Yu, Y., & Cui, J. (2018) · Oncology Letters · doi:10.3892/ol.2018.9219 · Cited by 78
“In a previous clinical trial, patients with refractory solid tumor types were treated with EZN-2968, a locked nucleic acid antisense oligonucleotide against HIF-1 α (73).”
Hypoxia-Inducible Factors as an Alternative Source of Treatment Strategy for Cancer
Akanji, M. A., Rotimi, D. E., & Adeyemı, O. S. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/8547846 · Cited by 77
“This revealed a pilot proof of HIF-1α mRNA and protein expression modulation in response to EZN-2968 thereby indicating inhibition of HIF-1α mRNA has potential as a target for cancer therapy [60].”
BackgroundPulmonary arterial hypertension specific therapy: The old and the new
Zolty, R. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107576 · Cited by 75
Zhang, F., Duan, S., Tsai, Y., Keng, P. C., Chen, Y., Lee, S. O., & Chen, Y. (2016) · Cancer Science · doi:10.1111/cas.12937 · Cited by 73
An Overview of the Recent Development of Anticancer Agents Targeting the HIF-1 Transcription Factor
Shirai, Y., Chow, C. C. T., Kambe, G., Suwa, T., Kobayashi, M., Takahashi, I., Harada, H., & Nam, J. (2021) · Cancers · doi:10.3390/cancers13112813 · Cited by 75
Targeting immune cell metabolism in kidney diseases
Basso, P. J., Andrade‐Oliveira, V., & Câmara, N. O. S. (2021) · Nature Reviews Nephrology · doi:10.1038/s41581-021-00413-7 · Cited by 75
Warburg effect, lactate dehydrogenase, and radio/chemo-therapy efficacy
Koukourakis, M. I., & Giatromanolaki, A. N. (2018) · International Journal of Radiation Biology · doi:10.1080/09553002.2018.1490041 · Cited by 74
“EZN-2968 is a synthetic antisense oligodeoxynucleotide against the mRNA sequence of HIF1a (Jeong et al. 2014), with a weak inhibitory effect on HIF-2a expression.”
BackgroundTherapeutic Targets and Tumor Microenvironment in Colorectal Cancer
Gallo, G., Vescio, G., Paola, G. D., & Sammarco, G. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10112295 · Cited by 72
“Additionally, an antisense oligodeoxynucleotide targeting HIF-1α, EZN-2968, was recently developed [41] but still has a long way to go before becoming an approved therapy.”
BackgroundMissiaen, R., Lesner, N. P., & Simon, M. C. (2023) · The EMBO Journal · doi:10.15252/embj.2022112067 · Cited by 78
Hypoxia and cancer related pathology
Xiong, Q., Liu, B., Ding, M., Zhou, J., Yang, C., & Chen, Y. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.05.002 · Cited by 69
HIF-1 and HIF-2 in cancer: structure, regulation, and therapeutic prospects
Shi, Y., & Gilkes, D. M. (2025) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-024-05537-0 · Cited by 78
Control of the Antitumor Immune Response by Cancer Metabolism
Domblides, C., Lartigue, L., & Faustin, B. (2019) · Cells · doi:10.3390/cells8020104 · Cited by 63
“mRNA expressions can be blocked by using an antisense oligonucleotide, EZN-2968 [214].”
Understanding the Oxygen-Sensing Pathway and Its Therapeutic Implications in Diseases
Liao, C., & Zhang, Q. H. (2020) · American Journal Of Pathology · doi:10.1016/j.ajpath.2020.04.003 · Cited by 63
Can Metabolic Pathways Be Therapeutic Targets in Rheumatoid Arthritis?
Sánchez‐López, E., Cheng, A., & Gumá, M. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8050753 · Cited by 59
Targeting obesity-related dysfunction in hormonally driven cancers
Rubinstein, M. M. Z., Brown, K. A., & Iyengar, N. M. (2021) · British Journal of Cancer · doi:10.1038/s41416-021-01393-y · Cited by 61
Renal Cell Carcinoma: Molecular Aspects
Kumar, A., Kumari, N., Gupta, V., & Prasad, R. (2017) · Indian Journal of Clinical Biochemistry · doi:10.1007/s12291-017-0713-y · Cited by 58
Hypoxia signaling: Challenges and opportunities for cancer therapy
Ivan, M., Fishel, M. L., Tudoran, O. M., Pollok, K. E., Wu, X., & Smith, P. J. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.10.002 · Cited by 57
Therapeutic Targeting of Hypoxia-Inducible Factors in Cancer
Din, S. M. U., Streit, S., Huynh, B. T., Hana, C. K., Abraham, A. N. J., & Hussein, A. M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25042060 · Cited by 62
“Ten patients were enrolled; two showed reductions in HIF-1 α protein and mRNA levels, and one patient with a duodenal neuroendocrine tumor had prolonged stabilization of disease [54].”
BackgroundClinically Evaluated Cancer Drugs Inhibiting Redox Signaling
Kirkpatrick, D. L., & Powis, G. (2016) · Antioxidants and Redox Signaling · doi:10.1089/ars.2016.6633 · Cited by 57
“EZN-2968, a locked nucleic acid antisense oligonucleotide inhibitor of HIF-1a that causes downregulation of HIF-1a mRNA and protein, was studied as a 2-h iv infusion in a pilot trial in patients with refractory solid tumors (NCT00466583) (49).”
MethodIkeda, H., & Kakeya, H. (2021) · The Journal of Antibiotics · doi:10.1038/s41429-021-00451-0 · Cited by 60
Antisense therapeutics in oncology: current status
Farooqı, A. A., Marwat, Z., & Muntané, J. (2014) · OncoTargets and Therapy · doi:10.2147/ott.s49652 · Cited by 55
“Four of six patients displayed a decrease in HIF-1α mRNA levels.(74) O nc oT ar ge ts a nd T he ra py d ow nl oa de d fr om h ttp s: //w w w .”
Pancreatic Cancer and Its Microenvironment—Recent Advances and Current Controversies
Stopa, K. B., Kusiak, A. A., Szopa, M. D., Ferdek, P. E., & Jakubowska, M. A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21093218 · Cited by 54
“However, despite a decreased level of HIF1α protein, expression of its target genes was not significantly reduced [165].”
BackgroundMethodNalwoga, H., Ahmed, L., Arnes, J. B., Wabinga, H., & Akslen, L. A. (2016) · PLoS ONE · doi:10.1371/journal.pone.0146823 · Cited by 55
“Our results, as well as previous studies [15, 18, 20, 40], support that HIF-1 factors promote major processes like tumor cell proliferation [6, 9] and support a hypothesis that Ki-67 proliferative rate might have a predictive role in classification of patients with VEGF positive high grade tumors for possible benefit…”
ResultThe HIF-1α as a Potent Inducer of the Hallmarks in Gastric Cancer
Metin, C. U., & Özcan, G. (2022) · Cancers · doi:10.3390/cancers14112711 · Cited by 56
Lee, H.-C., Tan, K.-L., Cheah, P.-S., & Ling, K. (2016) · Neural Plasticity · doi:10.1155/2016/7434191 · Cited by 53
Hypoxia in bone metastasis and osteolysis
Todd, V. M., & Johnson, R. W. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.06.004 · Cited by 50
HIF-1α Is a Rational Target for Future Ovarian Cancer Therapies
Wang, X., Du, Z., Xu, T., Wang, X., Li, W., Gao, J., Li, J., & Zhu, H. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.785111 · Cited by 50
Gan, E. S., & Ooi, E. E. (2020) · Virology Journal · doi:10.1186/s12985-020-01374-2 · Cited by 46
Harnessing Tumor Microenvironment for Nanoparticle‐Mediated Radiotherapy
Zhu, S., Gu, Z., & Zhao, Y. (2018) · Advanced Therapeutics · doi:10.1002/adtp.201800050 · Cited by 44
HIF-1 mediated metabolic reprogramming in cancer: Mechanisms and therapeutic implications
Taneja, N., Chauhan, A., Kulshreshtha, R., & Singh, S. K. (2024) · Life Sciences · doi:10.1016/j.lfs.2024.122890 · Cited by 56
Tumor aerobic glycolysis: new insights into therapeutic strategies with targeted delivery
Talekar, M., Boreddy, S. R., Singh, A., & Amiji, M. M. (2014) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2014.912270 · Cited by 42
The VHL/HIF Axis in the Development and Treatment of Pheochromocytoma/Paraganglioma
Song, P., Zhang, J., Tan, X., Huang, Y., Xu, J., Silk, N., Zhang, D., Liu, Q., & Jiang, J. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.586857 · Cited by 42
Up-regulation of hypoxia-inducible factor antisense as a novel approach to treat ovarian cancer
Lu, T., Tang, J., Shrestha, B., Heath, B. R., Li, H., Lei, Y. L., Ljungman, M. E., & Neamati, N. (2020) · Theranostics · doi:10.7150/thno.41792 · Cited by 40
“NCT00466583) and showed preliminary benefit in cancer patients, but the study was terminated [18, 75].”
BackgroundHypoxia-inducible factor 2α: a novel target in gliomas
Renfrow, J. J., Soike, M. H., Debinski, W., Ramkissoon, S. H., Mott, R. T., Frenkel, M. B., Sarkaria, J. N., Lesser, G. J., & Strowd, R. E. (2018) · Future Medicinal Chemistry · doi:10.4155/fmc-2018-0163 · Cited by 40
Recurrent Glioblastoma: Ongoing Clinical Challenges and Future Prospects
Pineda, E., Doménech, M., Hernández, A., Comas, S., & Balañá, C. (2023) · OncoTargets and Therapy · doi:10.2147/ott.s366371 · Cited by 44
“EZN-2698, a HIF-1 α inhibitor failed to demonstrate a clinical benefit in solid tumors.(102) Panobinostat and vorinostat effectively induced HIF-1 degradation,(103) but they inhibit all class I histone deacetylases, making them very non-specific.”
BackgroundEskandani, M., Vandghanooni, S., Barar, J., Nazemiyeh, H., & Omidi, Y. (2017) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2016.10.113 · Cited by 40
Hypoxia and viral infectious diseases
Huang, R., Huestis, M., Gan, E. S., Ooi, E. E., & Ohh, M. (2021) · JCI Insight · doi:10.1172/jci.insight.147190 · Cited by 37
“Small molecule inhibitors such as the antisense oligonucleotide EZN-2968 that target HIF-1α mRNA expression are ideal (55), as protein translation is a limiting factor for HIF-1α expression in response to hypoxia.”
BackgroundDual hypoxia-responsive supramolecular complex for cancer target therapy
Guo, J., Li, J., Wang, Z.-H., Liu, Y., Yue, Y., Li, H., Zhao, X., Sun, Y., Ding, Y., Ding, F., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-41388-2 · Cited by 39
“Although candidates targeting hypoxia-related proteins (HIF-1 α 15 – 18 or mTOR 19,20 ) or glycolysis 21,22 proved effective in laboratory investigations or early phase clinical studies, none of them has paved its way into the market as anti-PDAC drug to the best of our knowledge 13,14 .”
Kim, A., & Yeul, J. (2018) · International Journal of Oncology · doi:10.3892/ijo.2018.4479 · Cited by 36
“Consistent with these possibilities, inhibition of HIF-1 activity using an antisense oligonucleotide was an effective and safe treatment of metastatic cancer cells in Phase I clinical trials (40,41).”
Raguraman, P., Balachandran, A. A., Chen, S., Diermeier, S. D., & Veedu, R. N. (2021) · Cancers · doi:10.3390/cancers13215555 · Cited by 37
“Another phase I trial carried out in patients with refractory tumors revealed reduced levels of HIF-1α post treatment [119].”
BackgroundKunachowicz, D., Tomecka, P., Sędzik, M., Kalinin, J., Kuźnicki, J., & Rembiałkowska, N. (2025) · Cells · doi:10.3390/cells14141057 · Cited by 42
“In a study conducted by Jeong et al., administration of EZN-2968 at a dose of 18 mg/kg twice within a 6-week cycle resulted in disease stabilization in one patient with refractory solid tumors and a reduction in HIF-1 α protein levels in tumor biopsies from two patients [224].”
Dual Approaches in Oncology: The Promise of siRNA and Chemotherapy Combinations in Cancer Therapies
Sousa, C., & Videira, M. (2025) · Onco · doi:10.3390/onco5010002 · Cited by 39
“In 2013, a pilot trial investigated the use of EZN-2968, an antisense oligonucleotide targeting HIF-1 α , in patients with refractory solid tumors [134].”
Bad neighbours: hypoxia and genomic instability in prostate cancer
Ashton, J., & Bristow, R. G. (2020) · British Journal of Radiology · doi:10.1259/bjr.20200087 · Cited by 32
Arnason, T., & Harkness, T. A. A. (2015) · Cancers · doi:10.3390/cancers7040877 · Cited by 33
Cimmino, F., Pezone, L., Avitabile, M., Acierno, G., Andolfo, I., Capasso, M., & Iolascon, A. (2015) · Scientific Reports · doi:10.1038/srep11158 · Cited by 31
Phosphorylation of seryl-tRNA synthetase by ATM/ATR is essential for hypoxia-induced angiogenesis
Shi, Y., Liu, Z., Zhang, Q., Vallee, I., Mo, Z., Kishi, S., & Yang, X. (2020) · PLoS Biology · doi:10.1371/journal.pbio.3000991 · Cited by 31
“In a recent clinical trial of EZN-2968, the antisense oligonucleotide inhibitor of HIF-1α successfully down-regulated both mRNA and protein levels of HIF-1α but failed to reduce the expression of VEGFA in tumor biopsies [18].”
BackgroundThe Role of Imaging Biomarkers to Guide Pharmacological Interventions Targeting Tumor Hypoxia
Gallez, B. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.853568 · Cited by 35
“As HIFα mRNA is a limiting factor in the rate of protein synthesis, the antisense oligodeoxynucleotide EZN-2968 has been shown to downregulate the expression of HIF-1α protein in human biopsies of treated patients (Greenberger et al., 2008; Jeong et al., 2014).”
BackgroundRole of prolyl hydroxylase/HIF-1 signaling in vascular calcification
Negri, A. L. (2022) · Clinical Kidney Journal · doi:10.1093/ckj/sfac224 · Cited by 31
“EZN-2968 is an antisense oligodeoxynucleotide that specifically targets HIF-1α [44], and could be a therapeutic alternative to treat vascular calci-”
BackgroundStresses in the metastatic cascade: molecular mechanisms and therapeutic opportunitiesPreprint
Shen, M., & Kang, Y. (2020) · Genes & Development · doi:10.1101/gad.343251.120 · Cited by 30
“EZN-2968, which is an antisense oligonucleotide againstHIF-1αmRNA expression, is currently under phase I clinical trial for refractory solid tumors (NCT01120288; Jeong et al. 2014).”
Fakhri, S., Moradi, S. Z., Faraji, F., Kooshki, L., Webber, K. J., & Bishayee, A. (2023) · Cancer and Metastasis Reviews · doi:10.1007/s10555-023-10136-9 · Cited by 31
DNA mechanocapsules for programmable piconewton responsive drug delivery
Velusamy, A., Sharma, R., Rashid, S. A., et al. (2024) · Nature Communications · doi:10.1038/s41467-023-44061-w · Cited by 30
Bae, J. E., Samur, M., Munshi, A., Hideshima, T., Keskin, D. B., Kimmelman, A. C., Lee, A., Dranoff, G., Anderson, K. C., & Munshi, N. C. (2014) · OncoImmunology · doi:10.4161/21624011.2014.970914 · Cited by 30
Tumor Hypoxia As an Enhancer of Inflammation-Mediated Metastasis: Emerging Therapeutic Strategies
DiGiacomo, J. W., & Gilkes, D. M. (2018) · Targeted Oncology · doi:10.1007/s11523-018-0555-4 · Cited by 29
Review of potential medical treatments for middle ear cholesteatoma
Schürmann, M., Goon, P. K. C., & Sudhoff, H. H. (2022) · Cell Communication and Signaling · doi:10.1186/s12964-022-00953-w · Cited by 31
Özcan, G. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1082057 · Cited by 29
“A pilot trial in patients with solid tumors refractory to treatment detected a decrease in the expression of HIF-1αmRNA in four of the six patients (Jeong et al., 2014).”
BackgroundTargeting energy metabolism to eliminate cancer cells
Shahruzaman, S. H., Fakurazi, S., & Maniam, S. (2018) · Cancer Management and Research · doi:10.2147/cmar.s167424 · Cited by 29
Mustonen, E.-K., Palomäki, T., & Pasanen, M. (2017) · Regulatory Toxicology and Pharmacology · doi:10.1016/j.yrtph.2017.09.028 · Cited by 28
An overview of biological research on hypoxia-inducible factors (HIFs)
Liu, Z., Wu, Z., Fan, Y., & Fang, Y. (2020) · Endokrynologia Polska · doi:10.5603/ep.a2020.0064 · Cited by 26
“MicroRNAs (miRNAs) can regulate the synthesis of HIF-a through interaction with HIF-a mRNA [82, 83].”
BackgroundKim, A., & Yeul, J. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.01455 · Cited by 26
“Agents targeting HIF-1α signaling such as EZN-2968 (HIF-1α antisense mRNA) and PX-478 (small molecule inhibitor of HIF1α) have been effective treatments for advanced solid tumors and lymphoma in phase I clinical trials (Jeong et al., 2014; Welsh et al., 2004).”
MethodMartin, A. R., Ronco, C., Demange, L., & Benhida, R. (2016) · MedChemComm · doi:10.1039/c6md00432f · Cited by 27
Focus on Hypoxia-Related Pathways in Pediatric Osteosarcomas and Their Druggability
Pierrevelcin, M., Fuchs, Q., Lhermitte, B., Messé, M., Guérin, É., Weingertner, N., Martin, S., Lelong-Rebel, I. H., Nazon, C., Dontenwill, M., et al. (2020) · Cells · doi:10.3390/cells9091998 · Cited by 28
Application of Antisense Conjugates for the Treatment of Myotonic Dystrophy Type 1
Stoodley, J., Vallejo-Bedia, F., Seoane-Miraz, D., Debasa‐Mouce, M., Wood, M. J. A., & Varela, M. A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032697 · Cited by 25
“Alternatively, LNA technology can also be used to synthesise all-LNA oligomers, capable of stably binding target DNA or RNA molecules without causing their endonucleolytic cleavage by RNase H [61,62].”
Background
Metadata
- 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
- Published
- 2013-11-30
- Volume
- 73
- Issue
- 2
- Pages
- 343-348
- ISSN
- 0344-5704 (ISSN-L)
- 1432-0843
- 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
- green
- www.ncbi.nlm.nih.gov
- 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
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