Abstract A002: Targeting hypoxia inducible factor (HIF)-2α with AB521, a novel and potent small molecule HIF-2α inhibitor, for the treatment of clear cell renal cell carcinoma

Abstract

Abstract Cells in the solid tumor microenvironment are frequently exposed to hypoxic or pseudohypoxic conditions, necessitating molecular adaptations such as induction of transcriptional programs for survival. HIF-2α is a transcriptional regulator of hypoxia-induced genes that is regulated post-translationally in an oxygen-dependent manner via hydroxylation by prolyl hydroxylase enzymes - a modification required for recognition by pVHL for subsequent degradation. Therefore, under hypoxic conditions or in the case of pVHL inactivation (pseudohypoxia), HIF-2α is stabilized and translocates to the nucleus where it forms a heterodimer with ARNT to initiate transcription of its target genes. HIF-2α has been shown to be an oncogenic driver in clear cell renal cell carcinoma (ccRCC) where VHL mutations occur frequently, resulting in a pseudohypoxic state and stable HIF-2α expression. There is both preclinical and clinical evidence in ccRCC demonstrating that inhibiting HIF-2α is a valid therapeutic approach in blocking tumor progression. AB521 is a clinical-stage novel and potent small-molecule HIF-2α inhibitor. In vitro, AB521 effectively inhibits transcription of pro-tumorigenic HIF-2α target genes in multiple human cell types relevant to the tumor microenvironment, including cancer cells, primary endothelial cells, and pro-tumorigenic M2-polarized macrophages. AB521 also blocks HIF-2α-mediated gene transcription in vivo, as detected using both intratumoral and peripheral markers, an activity that is accompanied by a marked reduction in tumor burden in two VHL-mutant ccRCC xenograft models. Supporting a potential combinatorial treatment approach for HIF-2α inhibition in ccRCC, AB521 combines favorably with standard-of-care tyrosine kinase inhibitor cabozantinib in mouse models, further enhancing tumor efficacy in VHL-mutant ccRCC compared to either single agent alone. In healthy human volunteers, AB521 exhibits favorable pharmacokinetic (PK) and pharmacodynamic (PD) properties including a half-life of 18-24 hours, supportive of once-daily dosing, dose-dependent reductions in serum erythropoietin (EPO) following a single dose of 10 to 100 mg, and sustained EPO reduction after multiple daily dosing. In summary, AB521 is a potent and selective HIF-2α inhibitor that has been thoroughly characterized in a suite of in vitro assays, reduces tumor burden in ccRCC xenografts both as a single agent and in combination with cabozantinib, and exhibits favorable PK/PD properties in human healthy volunteers. Phase I clinical evaluation of AB521 in subjects with ccRCC and other solid tumors has been initiated and is currently ongoing (NCT05536141). Citation Format: Dana Piovesan, Soonweng Cho, Kenneth V. Lawson, Kai H. Liao, Paul G. Foster, Tzuling Cheng, Matthew J. Walters, Kelsey E. Sivick Gauthier. Targeting hypoxia inducible factor (HIF)-2α with AB521, a novel and potent small molecule HIF-2α inhibitor, for the treatment of clear cell renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr A002.