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

by Selleckchem | Jul 30 2023

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.

Comments:

The purpose of the study you mentioned was to investigate the effectiveness of a siRNA drug called siHIF2 in targeting and inhibiting HIF2α, a key driver of kidney cancer, particularly clear cell renal cell carcinomas (ccRCC). The researchers previously demonstrated that approximately 50% of ccRCCs are dependent on HIF2α for growth using a belzutifan analogue called PT2399. However, prolonged treatment with PT2399 led to the development of resistance mutations, which were also identified in human patients.

In this experimental design, the researchers utilized a tumorgraft (TG) platform to assess the pharmacokinetics and pharmacodynamics of siHIF2. They evaluated the uptake of siHIF2, its ability to silence HIF2α expression, its impact on downstream target genes, and its antitumor activity. They also conducted RNA-sequencing studies to compare the transcriptome of siHIF2 with PT2399 to better understand the HIF2-dependent pathways. Furthermore, they extended their analyses to include a TG line derived from a biopsy of a participant in a phase I clinical trial (NCT04169711) involving siHIF2. This patient had advanced ccRCC and paraneoplastic polycythemia, likely indicating a dependence on HIF2.

The results of the study showed that siHIF2 was taken up by ccRCC TGs and effectively depleted HIF2α expression. It also deactivated other pathways influenced by HIF2α, such as the Myc pathway and novel E2F pathways. Treatment with siHIF2 resulted in the downregulation of cell cycle genes and inhibited tumor growth. These effects were observed not only in the TG model but also in the patient derived from the clinical trial, where siHIF2 silenced HIF2α in tumor biopsies, decreased circulating erythropoietin (a hormone associated with polycythemia), suppressed polycythemia, and induced a partial response in the tumor.

The study findings represent a significant advancement in the field, as they demonstrate functional inactivation of an oncoprotein (HIF2α) and tumor suppression using a systemic, tumor-directed, RNA-silencing drug (siHIF2). This research establishes the potential of RNA-targeting drugs for HIF2α inhibition in ccRCC and serves as a model for future tumor-directed RNA-based therapeutics in cancer.