Abstract LB-407: Down-modulation of mRNA by EZN-2968, an hypoxia-inducible factor-1α (HIF-1α) mRNA antagonist, administered in adult patients with advanced solid tumors
Abstract
Background: HIF-1 is a transcription factor that is a critical mediator of angiogenesis, cell proliferation, metabolism, survival, and adaptive responses to stress. Overexpression of HIF-1α is observed in many malignant tumors, and in some cases is associated with poor prognosis. Down-regulation of HIF-1α may impair tumor cell growth. EZN-2968 is a potent locked nucleic acid antisense oligonucleotide that down-modulates HIF-1α mRNA and protein in vitro (IC50 10% of pts were fatigue (29%) and headache (14%). Grade 3 drug-related AEs (fatigue [n=3], AST increase [n=3], ALT increase [n=2], and hyponatremia [n=1]) were reported for 7 patients (14%); no drug-related AE was Grade 4 or 5. PK data for all 49 patients will be presented. The current best response for EZN-2968 is stable disease (RECIST) in 16 pts; 7 pts were treated for >90 days. Objective tumor shrinkage was observed in several pts, including a pt with renal cell cancer. HIF-1α expression was evaluated pretreatment and on-treatment in tumor (n=6) and skin (n=41) samples. Tumor biopsy HIF-1α mRNA decreased in 4 pts, increased in 1 pt, and did not change in 1 pt. Skin biopsy HIF-1α mRNA decreased in 63% (26/41) of pts, remained the same in 10% (4/41) of pts, and increased in 27% (11/41) of pts. Conclusions: The MTD of EZN-2968 is 18 mg/kg given weekly for 4 of 6 weeks. EZN-2968 was generally well tolerated in previously treated pts with advanced tumors who received up to 10 cycles of EZN-2968. The best response was SD. E…
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Stable disease with tumor shrinkage occurred in 15% and 33% of patients in two Phase 1 trials.
“Stable disease with evidence of tumor shrinkage was reported in 15 % and 33 % of patients, respectively [12, 13].”
From Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors (2014) · cites this paper as [13]
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Jeong, W., Rapisarda, A., Park, S. R., Kinders, R. J., Chen, A., Melillo, G., Turkbey, B., Steinberg, S. M., Choyke, P., Doroshow, J. H., et al. (2014) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-013-2362-z · Cited by 159 · see citing works
Wu, J., Contratto, M., Shanbhogue, K. P., Manji, G. A., O’Neil, B. H., Noonan, A., Tudor, R., & Lee, R. (2019) · World Journal of Clinical Oncology · doi:10.5306/wjco.v10.i3.149 · Cited by 41 · see citing works
- Authors
- Cohen, R. B., Olszanski, A., Figueroa, J., Hurwitz, H., Lokiec, F. M., Rezaï, K., Berkowitz, N., & Buchbinder, A.
- Affiliations
- University of Pennsylvania (US)
- Fox Chase Cancer Center (US)
- 3Joe Arrington Cancer Research & Treatment Center, Lubbock, TX
- Duke University (US)
- Hôpital René Huguenin (FR)
- 5René Huguenin Hospital, Institut Curie, Saint-Cloud, France
- Enzon Pharmaceuticals (United States) (US)
- Venue
- Cancer Research
- Published
- 2011-04
- Volume
- 71
- Issue
- 8_Supplement
- Pages
- LB-407-LB-407
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2080237185
- Cited by
- 1
- References
- 0
- Citations by year
- 2019: 1
- Type
- conference abstract
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- HIF-1α, hypoxia-inducible factor-1α, advanced solid tumors, maximum tolerated dose, dose-limiting toxicity, intracerebral hemorrhage, pharmacokinetics, pharmacodynamics, tumor hypoxia, angiogenesis, cancer therapy
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