AZD9496: An Oral Estrogen Receptor Inhibitor That Blocks the Growth of ER-Positive and ESR1-Mutant Breast Tumors in...

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Fulvestrant, an estrogen receptor (ER) antagonist, is administered via intramuscular injection for breast cancer treatment.
• Limitations in fulvestrant's dosing and administration route necessitate the development of orally available alternatives.
• Estrogen receptor-positive (ER+) breast cancer remains a significant challenge, driving research for novel therapeutic agents.

Purpose of the Study:

• To identify and characterize AZD9496, a novel nonsteroidal small-molecule inhibitor of ERα.
• To evaluate the efficacy of AZD9496 as a potent and selective ERα antagonist and downregulator in preclinical models of ER+ breast cancer.
• To assess the potential of AZD9496 as an orally available therapeutic option for advanced metastatic breast cancer.

Main Methods:

• In vitro and in vivo studies using ER-positive breast cancer models, including MCF-7 xenografts and estrogen-deprived models.
• Assessment of tumor growth inhibition, progesterone receptor (PR) protein levels, and ERα protein downregulation.
• Evaluation of AZD9496 in combination with PI3K pathway and CDK4/6 inhibitors.
• In vitro characterization of AZD9496 binding and downregulation of clinically relevant ESR1 mutants, including D538G.
• Testing in an ESR1-mutant patient-derived xenograft model.

Main Results:

• AZD9496 demonstrated significant tumor growth inhibition at low doses (0.5 mg/kg) in the MCF-7 xenograft model.
• A dose-dependent decrease in PR protein levels confirmed potent antagonist activity.
• Combination therapy with AZD9496 and PI3K or CDK4/6 inhibitors yielded enhanced growth inhibition compared to monotherapy.
• Tumor regressions and significant ERα protein downregulation were observed in an estrogen-deprived model.
• AZD9496 effectively bound and downregulated ESR1 mutants and inhibited tumor growth in an ESR1-mutant xenograft model.

Conclusions:

• AZD9496 is a potent, selective, oral, nonsteroidal ER antagonist and downregulator with significant preclinical efficacy in ER+ breast cancer models.
• The drug demonstrated activity against wild-type and mutant ESR1, suggesting broad applicability.
• AZD9496 has the potential to offer meaningful clinical benefit to patients with ER+ breast cancer, including those with ESR1 mutations.
• AZD9496 is currently under evaluation in a Phase I clinical trial.