ArticleClinical cancer research : an official journal of the American Association for Cancer Research2024
A First-in-Human Phase 1 Study of a Tumor-Directed RNA-Interference Drug against HIF2α in Patients with Advanced Clear Cell Renal Cell Carcinoma.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 18 citations in OpenAlex.
- HIFs: The central drivers of tumors and their role as molecular switches in targeted therapy?Acta pharmaceutica Sinica. B · 2026Review
- From Inflammatory RNAs to Therapeutic Silencing: Deciphering the RNA-Inflammation Axis in Cancer and Neurodegeneration.Biology · 2026Review
- The clinical landscape of HIF2α inhibitors in oncology.Nature reviews. Clinical oncology · 2026Review
- Review
- Hypoxic tumor microenvironment and immune cell dynamics: From metabolic reprogramming to therapeutic innovation.Iranian journal of basic medical sciences · 2026Review
- Detection of Unlabeled Oligonucleotides in FFPE Tissue Sections Using Automated miRNAscope Assays.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Smart Colloidal Systems as Drug Delivery and Therapeutic Modulation Platforms for Renal Cell Carcinoma.International journal of nanomedicine · 2026Review
- Targeted Delivery of Nucleic Acid Therapeutics: Emerging Carriers and Applications in Common Metabolic and Inflammatory Diseases.International journal of nanomedicine · 2026Review
- HIF-2-Dependent Regulation of PTHrP and Paraneoplastic Hypercalcemia in Aggressive Clear-Cell Renal Cell Carcinoma.Cancer discovery · 2025Article
- Article
- The HIF axes in cancer: angiogenesis, metabolism, and immune-modulation.Trends in biochemical sciences · 2025Review
- A Phase I Dose-Escalation Study of the HIF-2 Alpha Inhibitor DFF332 in Patients with Advanced Clear-Cell Renal Cell Carcinoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- Targeting Heat Shock Transcription Factor 4 Enhances the Efficacy of Cabozantinib and Immune Checkpoint Inhibitors in Renal Cell Carcinoma.International journal of molecular sciences · 2025Article
- Gene expression silencing therapy in tumors, focus on gastrointestinal and genitourinary tumors.Frontiers in immunology · 2025Review
Corrections and comments
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Authors and funding
12 authors at 7 institutions in 1 country.
Funding
Abstract
purposeARO-HIF2 is an siRNA drug designed to selectively target hypoxia-inducible factor-2α (HIF2α) interrupting downstream pro-oncogenic signaling in clear cell renal cell carcinoma (ccRCC). The aims of this Phase 1 study (AROHIF21001) were to evaluate safety, tolerability, pharmacokinetics, and establish a recommended Phase 2 dose. PATIENTS AND
methodsSubjects with ccRCC and progressive disease after at least 2 prior therapies that included VEGF and immune checkpoint inhibitors were progressively enrolled into dose-escalation cohorts of ARO-HIF2 administered intravenously at 225, 525, or 1,050 mg weekly.
resultsTwenty-six subjects received ARO-HIF2. The most common treatment emergent adverse events (AE) irrespective of causality were fatigue (50.0%), dizziness (26.9%), dyspnea (23.1%), and nausea (23.1%). Four subjects (15.4%) had treatment-related serious AEs. AEs of special interest included neuropathy, hypoxia, and dyspnea. ARO-HIF2 was almost completely cleared from plasma circulation within 48 hours with minimal renal clearance. Reductions in HIF2α were observed between pre- and post-dosing tumor biopsies, but the magnitude was quite variable. The objective response rate was 7.7% and the disease control rate was 38.5%. Responses were accompanied by ARO-HIF2 uptake in tumor cells, HIF2α downregulation, as well as rapid suppression of tumor produced erythropoietin (EPO) in a patient with paraneoplastic polycythemia.
conclusionsARO-HIF2 downregulated HIF2α in advanced ccRCC-inhibiting tumor growth in a subset of subjects. Further development was hampered by off-target neurotoxicity and low response rate. This study provides proof of concept that siRNA can target tumors in a specific manner.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.