HIF2 Inactivation and Tumor Suppression with a Tumor-Directed RNA-Silencing Drug in Mice and Humans

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.