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Updated: Aug 26, 2025
In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice
Published on: August 23, 2019
HIF2 Inactivation and Tumor Suppression with a Tumor-Directed RNA-Silencing Drug in Mice and Humans
Yuanqing Ma1, Allison Joyce1, Olivia Brandenburg1
1Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas.
Purpose:
HIF2α is a key driver of kidney cancer. Using a belzutifan analogue (PT2399), we previously showed in tumorgrafts (TG) that ∼50% of clear cell renal cell carcinomas (ccRCC) are HIF2α dependent. However, prolonged treatment induced resistance mutations, which we also identified in humans. Here, we evaluated a tumor-directed, systemically delivered, siRNA drug (siHIF2) active against wild-type and resistant-mutant HIF2α.
Experimental Design:
Using our credentialed TG platform, we performed pharmacokinetic and pharmacodynamic analyses evaluating uptake, HIF2α silencing, target gene inactivation, and antitumor activity. Orthogonal RNA-sequencing studies of siHIF2 and PT2399 were pursued to define the HIF2 transcriptome. Analyses were extended to a TG line generated from a study biopsy of a siHIF2 phase I clinical trial (NCT04169711) participant and the corresponding patient, an extensively pretreated individual with rapidly progressive ccRCC and paraneoplastic polycythemia likely evidencing a HIF2 dependency.
Results:
siHIF2 was taken up by ccRCC TGs, effectively depleted HIF2α, deactivated orthogonally defined effector pathways (including Myc and novel E2F pathways), downregulated cell cycle genes, and inhibited tumor growth. Effects on the study subject TG mimicked those in the patient, where HIF2α was silenced in tumor biopsies, circulating erythropoietin was downregulated, polycythemia was suppressed, and a partial response was induced.
Conclusions:
To our knowledge, this is the first example of functional inactivation of an oncoprotein and tumor suppression with a systemic, tumor-directed, RNA-silencing drug. These studies provide a proof-of-principle of HIF2α inhibition by RNA-targeting drugs in ccRCC and establish a paradigm for tumor-directed RNA-based therapeutics in cancer.
Insights
A novel siRNA drug (siHIF2) effectively silenced HIF2α in kidney cancer models, inhibiting tumor growth and suppressing associated polycythemia. This demonstrates a new RNA-based therapeutic strategy for clear cell renal cell carcinoma (ccRCC).
Area of Science:
- Oncology
- Molecular Biology
- RNA Therapeutics
Background:
- HIF2α is a critical driver in clear cell renal cell carcinoma (ccRCC).
- Previous treatments with HIF2α inhibitors like belzutifan analogues (PT2399) showed efficacy but induced resistance mutations.
- A need exists for therapies targeting both wild-type and resistant HIF2α mutations in ccRCC.
Purpose of the Study:
- To evaluate a tumor-directed, systemically delivered siRNA drug (siHIF2) for its efficacy against HIF2α in ccRCC.
- To assess siHIF2's activity against both wild-type and resistance-mutant forms of HIF2α.
- To establish a proof-of-principle for RNA-targeting drugs in ccRCC treatment.
Main Methods:
- Utilized a tumorgraft (TG) platform for pharmacokinetic and pharmacodynamic analyses of siHIF2.
- Performed orthogonal RNA-sequencing to define the HIF2 transcriptome and identify effector pathways.
- Extended analyses to a TG line and patient from a siHIF2 phase I clinical trial (NCT04169711).
Main Results:
- siHIF2 demonstrated uptake in ccRCC TGs, leading to effective HIF2α depletion and inactivation of effector pathways (Myc, E2F).
- Treatment downregulated cell cycle genes and inhibited tumor growth.
- In a clinical trial participant, siHIF2 silenced tumor HIF2α, reduced erythropoietin, suppressed polycythemia, and induced a partial response.
Conclusions:
- This study presents the first functional inactivation of an oncoprotein and tumor suppression using a systemic, tumor-directed RNA-silencing drug.
- siHIF2 provides a viable strategy for HIF2α inhibition in ccRCC.
- These findings establish a paradigm for RNA-based therapeutics targeting tumors.
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