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.
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- 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.
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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.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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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.
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- 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
“Reductions in levels of HIF-1α protein and mRNA levels of some target genes were observed in two patients.”
§ 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
plaindirectn = 2- 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.
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
“Evaluable DCE-MRI data were available for only two patients.”
§ 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
plainn = 2- Asserted: passes — The authors put it forward as true.
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- 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
“Only one case of grade 1 anemia was observed”
§ 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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- 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
“Ten patients were enrolled, of whom all were evaluable for response”
§ 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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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“Even though our group has developed a validated assay to measure HIF-1α protein levels that provided reliable and reproducible results [15], quantifying HIF-1α protein in human tumor biopsy samples remained challenging.”
§ 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 [15] Park SR, Kinders RJ, Khin S, Hollingshead M, Parchment RE, Tomaszewski JE, Doroshow JH (2012) Validation and fitness testing of a quantitative immunoassay for HIF-1 alpha in biopsy specimens [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research, Chicago, Illinois. AACR, Philadelphia (PA), abstract nr 3616, 31 March–4 April 2012 source
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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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
“one patient with a duodenal neuroendocrine tumor had prolonged stabilization of disease (24 weeks)”
- Also stated in: § Patient demographics · plain
“One patient with low-grade neuroendocrine malignancy (Patient #2) had stable disease following 4 cycles of therapy (24 weeks)”
§ 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
plainSingle case- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- 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
“Patients #3 and 7 had decrease in levels of both 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- 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
“Six patients had paired pre- and post-dose biopsies for the assessment of HIF-1α mRNA levels (Patients #2, 3, 6, 7, 9, and 10; Fig. 1a)”
§ 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 = 6- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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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
“Both patients had progressive disease after one cycle (6 weeks).”
§ 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
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.
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
“Quantitative analysis of DCE-MRI from two patients revealed changes in Ktrans and kep.”
§ 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 = 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.
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
“High concentrations of HIF-1 are associated with poor prognosis and resistance to therapy in patients with numerous solid tumors, making HIF-1 an attractive target for cancer therapeutics [1–4].”
§ 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 [1] Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732 source
- Not checked — no full text of the sourcecites [2] Schindl M, Schoppmann SF, Samonigg H, Hausmaninger H, Kwasny W, Gnant M, Jakesz R, Kubista E, Birner P, Oberhuber G (2002) Overexpression of hypoxia-inducible factor 1α is associated with an unfavorable prognosis in lymph node-positive breast cancer. Clin Cancer Res 8:1831–1837
- Not checked — no full text of the sourcecites [3] Shibaji T, Nagao M, Ikeda N, Kanehiro H, Hisanaga M, Ko S et al (2003) Prognostic significance of HIF-1 alpha overexpression in human pancreatic cancer. Anticancer Res 23:4721–4727
- Not checked — no full text of the sourcecites [4] Swinson DEB, Jones JL, Cox G, Richardson D, Harris AL, O’Byrne KJ (2004) Hypoxia-inducible factor-1α in non small cell lung cancer: relation to growth factor, protease and apoptosis pathways. Int J Cancer 111:43–50 source
correlational- 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 claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“High concentrations of HIF-1 are associated with poor prognosis and resistance to therapy in patients with numerous solid tumors, making HIF-1 an attractive target for cancer therapeutics [1–4].”
§ 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 [1] Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732 source
- Not checked — no full text of the sourcecites [2] Schindl M, Schoppmann SF, Samonigg H, Hausmaninger H, Kwasny W, Gnant M, Jakesz R, Kubista E, Birner P, Oberhuber G (2002) Overexpression of hypoxia-inducible factor 1α is associated with an unfavorable prognosis in lymph node-positive breast cancer. Clin Cancer Res 8:1831–1837
- Not checked — no full text of the sourcecites [3] Shibaji T, Nagao M, Ikeda N, Kanehiro H, Hisanaga M, Ko S et al (2003) Prognostic significance of HIF-1 alpha overexpression in human pancreatic cancer. Anticancer Res 23:4721–4727
- Not checked — no full text of the sourcecites [4] Swinson DEB, Jones JL, Cox G, Richardson D, Harris AL, O’Byrne KJ (2004) Hypoxia-inducible factor-1α in non small cell lung cancer: relation to growth factor, protease and apoptosis pathways. Int J Cancer 111:43–50 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: unclear — It is unclear whether it could 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 claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Antisense oligonucleotides are an attractive therapeutic strategy because they can inhibit mRNA expression specifically [7, 8].”
§ 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 [7] Aboul-Fadl T (2005) Antisense oligonucleotides: the state of the art. Curr Med Chem 12:2193–2214 source
- Not checked — no full text of the sourcecites [8] Vester B, Wengel J (2004) LNA (locked nucleic acid): high-affinity targeting of complementary RNA and DNA. Biochemistry 43:13233–13241 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.
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
“Various inhibitors of HIF-1α have been described, but they lack specificity [5, 6].”
§ 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 [5] Hu Y, Liu J, Huang H (2013) Recent agents targeting HIF-1 alpha for cancer therapy. J Cell Biochem 114:498–509 source
- Not checked — no full text of the sourcecites [6] Melillo G (2007) Targeting hypoxia cell signaling for cancer therapy. Cancer Metastasis Rev 26:341–352 source
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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In the paper
“Hypoxia-inducible factor-1 (HIF-1) facilitates the adaptation of normal and tumor tissues to oxygen deprivation.”
- Also stated in: § Introduction · plain
“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].”
§ 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.
- 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.
- Also stated in: § Introduction · plain
A conclusion the paper draws from its own results — 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 case of grade 1 anemia was observed, which suggests that EZN-2968 did not suppress erythropoietin production in the kidney, despite the fact that erythropoietin is a target gene of HIF-2α.”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Discussion
hedgedSingle case- 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.
- Rests on an assumption: Anemia is a sensitive marker of erythropoietin suppression by EZN-2968.
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 trial was closed prematurely when the sponsor suspended development of this agent.”
- Also stated in: § Patient demographics · plain
“the study was closed prematurely when further clinical development of EZN-2968 was suspended by the pharmaceutical sponsor.”
§ 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
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- Also stated in: § Patient demographics · plain
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Conclusive evidence demonstrating modulation of HIF-1α mRNA, protein and target genes in tumor tissue following EZN-2968 treatment was not obtained in this study due to the small numbers of patients entered as a consequence of the study’s premature closure.”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Discussion
boosted- Asserted: passes — The authors put it forward as true.
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In the paper
“Levels of HIF-1 can be modulated by targeting HIF-1α transcription, protein translation, DNA binding, or protein degradation [5].”
§ 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 [5] Hu Y, Liu J, Huang H (2013) Recent agents targeting HIF-1 alpha for cancer therapy. J Cell Biochem 114:498–509 source
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.
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
“Synthetic locked nucleic acid (LNA) antisense oligodeoxynucleotides are a new class of nucleic acid analog that have demonstrated higher affinity, specificity, and resistance to degradation compared to other oligonucleotides [9, 10].”
§ 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 [9] Raunak, Ravindra Babu B, Sorensen MD, Parmar VS, Harrit NH, Wengel J (2004) Oligodeoxynucleotides containing alpha-L-ribo configured LNA-type C-aryl nucleotides. Org Biomol Chem 2:80–89 source
- Not checked — no full text of the sourcecites [10] Nimesh S, Gupta N, Chandra R (2011) Cationic polymer based nanocarriers for delivery of therapeutic nucleic acids. J Biomed Nanotechnol 7:504–520 source
boosted- 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.
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
“A validated assay was developed to measure modulation of HIF-1α in human samples”
§ 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 conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors > Abstract > Conclusion
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.
- Rests on an assumption: Changes in HIF-1α mRNA and protein levels in tumor biopsies are attributable to EZN-2968 rather than to other factors.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“however, statistically significant modulation of target was not demonstrated due to the small sample size and the heterogeneous nature of the target.”
§ 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 claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Stable disease with evidence of tumor shrinkage was reported in 15 % and 33 % of patients, respectively [12, 13].”
§ 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 — no full text of the sourcecites [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 source
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.
In the paper
“Methods for specimen collection to preserve HIF-1α in 18-gauge tumor needle biopsies and an assay to quantitatively measure HIF-1α levels in human tissue biopsy were validated (Supplementary Data section, online only) [15].”
§ 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
- Not checked — no full text of the sourcecites [15] Park SR, Kinders RJ, Khin S, Hollingshead M, Parchment RE, Tomaszewski JE, Doroshow JH (2012) Validation and fitness testing of a quantitative immunoassay for HIF-1 alpha in biopsy specimens [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research, Chicago, Illinois. AACR, Philadelphia (PA), abstract nr 3616, 31 March–4 April 2012 source
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. 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.
- 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.
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.
- 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
“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.
- 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.
- 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.
- 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
“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.
- 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
“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.
- 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.
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.
- 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.
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.
- 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.
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.
- 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.
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.
- 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.
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.
- 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. 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.
- 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. 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.
- 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.
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
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source doesn’t support the claim as written.
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
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.
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
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
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.
A language model drew the claims from the paper on 2026-09-28, under version 3 of the claim definition (prompt extract-v3).
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Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
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