Evaluation of a locked nucleic acid form of antisense oligo targeting HIF-1α in advanced hepatocellular carcinoma
Open accessAbstract
BACKGROUND: Hypoxia-inducible factor 1α (HIF-1α) is a gene that regulates tumor survival, neovascularization and invasion. Overexpression of HIF-1α correlates with poor prognosis in hepatocellular carcinoma (HCC). RO7070179 is a HIF-1α inhibitor that decreases HIF-1α mRNA and its downstream targets, it could be a potential treatment in HCC. AIM: To evaluate safety and preliminary activity of RO7070179 in patients with previously treated HCC, with focus on a patient with prolonged response to RO7070179. METHODS: In the preclinical study of RO7070179 in a HCC xenograft model, the mice were separated into 4 groups with each group received doses of 0, 3, 10 and 30 mg/kg for total 10 doses. HCC patients who failed at least one line of systemic treatment, received RO7070179 as a weekly infusion, each cycle is 6 wk. We evaluated the safety and HIF-1α mRNA levels of RO7070179. RESULTS: Preclinical evaluation of RO7070179 in orthotopic HCC xenograft model showed no significant differences in HCC tumor weight between the 3 and 10 mg/kg groups. However, dose of 10 mg/kg of RO7070179, has shown 76% reduction of the amount of HIF-1α mRNA in HCC tissue. In the phase 1b study of RO7070179 in previously treated HCC patients, 8 out of 9 were evaluable: 1 achieved PR and 1 SD. The patient with PR responded after 2 cycles treatments, which has been maintained for 12 cycles. This patient also showed reduction in perfusion of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) after 1 cycle of treatment. After 1 cycle of treatment, both patients with PR and SD showed decrease in HIF-1α mRNA at the root of biopsies (each biopsy was divided into 2 specimens, the tip and the root). CONCLUSION: RO7070179 can reduce HIF-1α mRNA level in HCC patients with SD or PR. It is well tolerated at 10 mg/kg, with transaminitis as the dose of increased toxicity. This study indicates that RO7070179 might benefit HCC patients, and an early signal for clinical benefit can potentially be predicted through changes in either mRNA level or DCE-MRI within 1 cycle of therapy.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
EZN-2968 is built on locked nucleic acid chemistry that enhances base-pairing affinity, nuclease resistance, and in vivo stability relative to conventional oligonucleotides.
“EZN-2968 is built on locked nucleic acid (LNA) chemistry, in which a methylene bridge between the 2′-oxygen and 4′-carbon of the ribose ring locks the sugar into a rigid conformation. This structural feature enhances base-pairing affinity, nuclease resistance, and in vivo stability relative to conventional oligonucleotides [[279], [280], [281]].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [279]
The Introduction (page unavailable) identifies EZN-2968 as a locked nucleic acid antisense oligonucleotide and says it is more resistant to degradation while maintaining binding specificity. It does not say that base-pairing affinity is enhanced, establish greater in vivo stability relative to conventional oligonucleotides, or describe the methylene-bridge structure. (LLM, conf=0.87)
Experimental — accuracy not yet measuredHIF-1α antisense inhibition (RO7070179/EZN-2968) has shown dose-dependent, reversible hepatotoxicity (ALT/AST elevations) in advanced hepatocellular carcinoma.
“In contrast, HIF-1α antisense inhibition (RO7070179/EZN-2968) has shown dose-dependent, reversible hepatotoxicity (ALT/AST elevations) in advanced hepatocellular carcinoma, likely exacerbated by limited hepatic reserve, and long-term safety data remain sparse [279].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [279]
The Results (Side effects; page unavailable) report ALT and AST elevations in patients with advanced HCC and less toxicity after the dose was reduced. The Discussion (Liver toxicity is dose dependent; page unavailable) reports dose-dependent AST/ALT increases in mice. Our copy does not establish that the hepatotoxicity in patients was reversible or directly demonstrate a dose-dependent pattern in those patients. (LLM, conf=0.86)
Experimental — accuracy not yet measuredA subsequent Phase I study of hepatocellular carcinoma did not confirm these effects, and the trial was discontinued early due to failure to achieve its primary endpoint of HIF1A suppression after one treatment cycle.
“However, subsequent evaluation in a Phase I study of hepatocellular carcinoma did not confirm these effects, and the trial was discontinued early due to failure to achieve its primary endpoint of HIF1A suppression after one treatment cycle [279].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [279]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Sorafenib in advanced hepatocellular carcinoma
Llovet, J. M., Ricci, S., Mazzaferro, V., Hilgard, P., Gane, E., Blanc, J.-F., de Oliveira, A. C., Santoro, A., Raoul, J.-L., Forner, A., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0708857 · Cited by 13,097 · see citing works
A New Era of Systemic Therapy for Hepatocellular Carcinoma with Regorafenib and Lenvatinib
Kudo, M. (2017) · Liver Cancer · doi:10.1159/000462153 · Cited by 5,974 · see citing works
Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis
Carmeliet, P., Dor, Y., Herbert, J.-M., Fukumura, D., Brusselmans, K., Dewerchin, M., Neeman, M., Bono, F., Abramovitch, R., Maxwell, P., et al. (1998) · Nature · doi:10.1038/28867 · Cited by 2,502 · see citing works
Hypoxia, Clonal Selection, and the Role of HIF-1 in Tumor Progression
Semenza, G. L. (2000) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409230091169186 · Cited by 651 · see citing works
Jiang, B., Agani, F. H., Passaniti, A., & Semenza, G. L. (1997) · PubMed · Cited by 532 · see citing works
Regulation of angiogenesis by hypoxia-inducible factor 1
Hirota, K., & Semenza, G. L. (2006) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2005.12.003 · Cited by 466 · see citing works
Recent advances in hypoxia-inducible factor (HIF)-1 inhibitors
Xia, Y., Choi, H.-K., & Lee, K. (2012) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2012.01.033 · Cited by 278 · see citing works
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 · see citing works
Huang, G. (2005) · World Journal of Gastroenterology · doi:10.3748/wjg.v11.i11.1705 · Cited by 149 · see citing works
Yasuda, S., Arii, S., Mori, A. S., Isobe, N., Yang, W., Oe, H., Fujimoto, A., Yonenaga, Y., Sakashita, H., & Imamura, M. (2003) · Journal of Hepatology · doi:10.1016/s0168-8278(03)00503-8 · Cited by 142 · see citing works
Dai, C.-X., Gao, Q., Qiu, S., Ju, M., Cai, M., Xu, Y., Zhou, J., Zhang, B., & Fan, J. (2009) · BMC Cancer · doi:10.1186/1471-2407-9-418 · Cited by 133 · see citing works
Advances in Hypoxia-Mediated Mechanisms in Hepatocellular Carcinoma
Xiong, X., Qiu, X. Y., Hu, D. X., & Chen, X. (2017) · Molecular Pharmacology · doi:10.1124/mol.116.107706 · Cited by 118 · see citing works
Hsu, C., Shen, Y., Yu, C., Hsu, C., Hu, F., Hsu, C., Chen, B., Wei, S., Cheng, A., & Shih, T. T. (2011) · Journal of Hepatology · doi:10.1016/j.jhep.2011.01.032 · Cited by 118 · see citing works
Prognostic Significance of HIF-1α Expression in Hepatocellular Carcinoma: A Meta-Analysis
Zheng, S.-S., Chen, X.-H., Yin, X. H., & Zhang, B. (2013) · PLoS ONE · doi:10.1371/journal.pone.0065753 · Cited by 92 · see citing works
GL331 inhibits HIF-1α expression in a lung cancer model
Chang, H., Shyu, K., Lee, C.-C., Tsai, S.-C., Wang, B.-W., Lee, Y. H., & Lin, S. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(03)00111-6 · Cited by 66 · see citing works
Lei, D., Chen, X., Jing, K., Haiping, W., & Wanguang, Z. (2006) · Journal of Huazhong University of Science and Technology [Medical Sciences] · doi:10.1007/bf02828043 · Cited by 8 · see citing works
Cohen, R. B., Olszanski, A., Figueroa, J., Hurwitz, H., Lokiec, F. M., Rezaï, K., Berkowitz, N., & Buchbinder, A. (2011) · Cancer Research · doi:10.1158/1538-7445.am2011-lb-407 · Cited by 1 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Metabolic reprogramming in macrophage responses
Liu, Y., Xu, R., Gu, H., Zhang, E., Qu, J., Cao, W., Huang, X., Yan, H., He, J., & Cai, Z. (2021) · Biomarker Research · doi:10.1186/s40364-020-00251-y · Cited by 657 · see citing works
Hypoxia signaling in human health and diseases: implications and prospects for therapeutics
Luo, Z., Tian, M., Yang, G., Tan, Q., Chen, Y., Li, G., Zhang, Q., Li, Y., Wan, P., & Wu, J. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01080-1 · Cited by 499 · see citing works
Self-citationBai, R., Li, Y., Jian, L., Yue-hui, Y., Zhao, L., & Wei, M. (2022) · Molecular Cancer · doi:10.1186/s12943-022-01645-2 · Cited by 282 · see citing works
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 · see citing works
The von Hippel-Lindau Tumor Suppressor Gene
Elias, R. M., Zhang, Q. H., & Brugarolas, J. (2020) · The Cancer Journal · doi:10.1097/ppo.0000000000000480 · Cited by 209 · see citing works
Metabolic Reprogramming Induces Macrophage Polarization in the Tumor Microenvironment
Wang, S., Liu, G., Li, Y., & Pan, Y. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.840029 · Cited by 194 · see citing works
Hypoxia-inducible factors and innate immunity in liver cancer
Yuen, V. W., & Wong, C. C. (2020) · Journal of Clinical Investigation · doi:10.1172/jci137553 · Cited by 182 · see citing works
Transcription Factors in Cancer Development and Therapy
Vishnoi, K., Viswakarma, N., Rana, A., & Rana, B. (2020) · Cancers · doi:10.3390/cancers12082296 · Cited by 167 · see citing works
Zhang, J., Yao, M., Xia, S., Zeng, F., & Liu, Q. (2025) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-024-00682-7 · Cited by 139 · see citing works
Hypoxia‑inducible factors in hepatocellular carcinoma (Review)
Guo, Y., Xiao, Z., Liu, Y., Gao, Y., Zhu, Q., Hu, L., Huang, D., & Xu, Q. (2019) · Oncology Reports · doi:10.3892/or.2019.7397 · Cited by 92 · see citing works
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 91 · see citing works
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 74 · see citing works
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 70 · see citing works
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 62 · see citing works
Hypoxia signaling in hepatocellular carcinoma: Challenges and therapeutic opportunities
Sin, Q. S., Mohan, C. D., Goh, R. M., You, M., Nayak, S. C., Chen, L., Sethi, G., Rangappa, K. S., & Wang, L. (2022) · Cancer and Metastasis Reviews · doi:10.1007/s10555-022-10071-1 · Cited by 56 · see citing works
Locked nucleic acid (LNA): A modern approach to cancer diagnosis and treatment
Kamali, M. J., Salehi, M., Fatemi, S., Moradi, F., Khoshghiafeh, A., & Ahmadifard, M. (2022) · Experimental Cell Research · doi:10.1016/j.yexcr.2022.113442 · Cited by 54 · see citing works
The 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 53 · see citing works
Chen, Y., Zhao, D., Xiao, F., Li, X., Li, J., Su, Z., & Jiang, X. (2023) · Advanced Materials · doi:10.1002/adma.202209672 · Cited by 47 · see citing works
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 46 · see citing works
Raguraman, P., Balachandran, A. A., Chen, S., Diermeier, S. D., & Veedu, R. N. (2021) · Cancers · doi:10.3390/cancers13215555 · Cited by 36 · see citing works
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 30 · see citing works
Targeting Metabolic Pathways of Myeloid Cells Improves Cancer Immunotherapy
Li, J., Bolyard, C. M., Xin, G., & Li, Z. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.747863 · Cited by 29 · see citing works
Özcan, G. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1082057 · Cited by 29 · see citing works
Hepatocellular carcinoma: an update on investigational drugs in phase I and II clinical trials
Noonan, A. M., & Pawlik, T. M. (2019) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2019.1677606 · Cited by 27 · see citing works
Self-citationPandey, M., Ojha, D., Bansal, S., Rode, A. B., & Chawla, G. (2021) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2021.101003 · Cited by 23 · see citing works
Von Hippel-Lindau tumor suppressor pathways & corresponding therapeutics in kidney cancer
Shulman, M., Shi, R., & Zhang, Q. H. (2021) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2021.05.016 · Cited by 23 · see citing works
Li, Z., Zhao, M., Qi, X., Tang, Y., & Cheng, S. (2023) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.17808 · Cited by 21 · see citing works
Hypoxia Pathway in Osteoporosis: Laboratory Data for Clinical Prospects
Wang, J., Zhao, B., Che, J., & Shang, P. (2023) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph20043129 · Cited by 13 · see citing works
Cancer stem cells in hepatocellular carcinoma: therapy resistance and emerging treatments
Yadav, D. K., Yadav, R. K., Singh, A., Huang, Y., Bao, D., Yang, Z., Huang, H., Jiang, Y., Wang, P., Lin, S., et al. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1704868 · Cited by 12 · see citing works
Sartorius, K., Antwi, S. O., Chuturgoon, A. A., Roberts, L. R., & Kramvis, A. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.891812 · Cited by 12 · see citing works
Roig-Carles, D., Jackson, H., Loveson, K. F., Mackay, A. G., Mather, R. L., Waters, E. V., Manzo, M., Alborelli, I., Golding, J. P., Jones, C., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179165 · Cited by 7 · see citing works
Pechenkina, K., Fan, W., & Luo, X. (2019) · International Journal of Paleopathology · doi:10.1016/j.ijpp.2019.06.003 · Cited by 6 · see citing works
Jensen, C. C., & Warfel, N. A. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-820472-6.00039-6 · Cited by 5 · see citing works
Nucleic Acid Drugs in Radiotherapy
Yang, Y., Cai, Y., Deng, K., Xiao, Y., Liu, X., & Du, Z. H. (2025) · ChemBioChem · doi:10.1002/cbic.202400854 · Cited by 3 · see citing works
HIF inhibition: Current strategies and clinical challenges
Więch-Walów, A., Bartoszewska, S., Barton, A., Czechowicz, P., Dudzik, J., Wielockx, B., Collawn, J. F., & Bartoszewski, R. (2026) · Redox biology · doi:10.1016/j.redox.2026.104220 · Cited by 3 · see citing works
“However, subsequent evaluation in a Phase I study of hepatocellular carcinoma did not confirm these effects, and the trial was discontinued early due to failure to achieve its primary endpoint of HIF1A suppression after one treatment cycle [279].”
Hypoxia‐Inducible Factors as Guardians of Cancer Stem Cell Fate: Implications for Novel Therapies
Abuhassan, Q., Al‐Ameer, H. J., Ahmed, H. M., Rizaev, J. A., Togaev, A., Salih, R. M., & Adil, M. (2026) · IUBMB Life · doi:10.1002/iub.70092 · Cited by 3 · see citing works
Chi, Z.-C. (2025) · World Chinese Journal of Digestology · doi:10.11569/wcjd.v33.i1.11 · Cited by 1 · see citing works
Hypoxia-inducible Factors: Molecular Basis and Clinical Implications
Assi, M. H. (2023) · Mustansiriya Medical Journal · doi:10.4103/mj.mj_38_23 · Cited by 1 · see citing works
Bardaweel, S. K., Banihani, S. A., & Al-Barghouthy, E. (2024) · Springer eBooks · doi:10.1007/978-3-031-69962-7_13
Xu, L., Zhang, X., Zhu, H., Niu, D., Zhu, X., & Jin, C. (2026) · Frontiers in Bioscience-Landmark · doi:10.31083/fbl45415
Drug resistance in cancer radiotherapy: From mechanisms to overcoming strategies
Chen, Y., Cai, C., Xu, X.-C., Yang, Z., Li, J., Pan, Q., Wang, L., Luo, W., Chen, Z., Zeng, L., et al. (2026) · Pharmacological Research · doi:10.1016/j.phrs.2026.108380
- Authors
- Wu, J., Contratto, M., Shanbhogue, K. P., Manji, G. A., O’Neil, B. H., Noonan, A., Tudor, R., & Lee, R.
- Affiliations
- NYU Langone’s Laura and Isaac Perlmutter Cancer Center (US)
- New York University (US)
- Columbia University Irving Medical Center (US)
- Indiana University Indianapolis (US)
- The Ohio State University Wexner Medical Center (US)
- Venue
- World Journal of Clinical Oncology
- Publisher
- Baishideng Publishing Group Inc.
- Published
- 2019-03-24
- Volume
- 10
- Issue
- 3
- Pages
- 149-160
- ISSN
- 2218-4333 (ISSN-L)
- PMC
- PMC6441661
- OpenAlex
- W2923306121
- Cited by
- 41
- References
- 17
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 1 · 2023: 7 · 2022: 7 · 2021: 9 · 2020: 5 · 2019: 3
- FWCI
- 3.83
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by-nc
- Locations
- World Journal of Clinical Oncology (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by-nc-nd)
- Funders
- York University
- School of Medicine, New York University
- Topics
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- HIF-1α, hepatocellular carcinoma, antisense oligonucleotides, locked nucleic acid, HIF-1α inhibitors, advanced hepatocellular carcinoma, xenograft models, drug safety, elevated liver enzymes, tumor hypoxia
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
