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

摘要: Fulvestrant is an estrogen receptor (ER) antagonist administered to breast cancer patients by monthly intramuscular injection. Given its present limitations of dosing and route administration, a more flexible orally available compound has been sought pursue the potential benefits this drug in with advanced metastatic disease. Here we report identification characterization AZD9496, nonsteroidal small-molecule inhibitor ERα, which potent selective downregulator ERα vitro vivo ER-positive models cancer. Significant tumor growth inhibition was observed as low 0.5 mg/kg dose estrogen-dependent MCF-7 xenograft model, where effect accompanied dose-dependent decrease PR protein levels, demonstrating activity. Combining AZD9496 PI3K pathway CDK4/6 inhibitors led further growth-inhibitory effects compared monotherapy alone. Tumor regressions were also seen long-term estrogen-deprived significant downregulation observed. bound downregulated clinically relevant ESR1 mutants inhibited ESR1-mutant patient-derived model that included D538G mutation. Collectively, pharmacologic evidence showed oral, nonsteroidal, ER(+) cells could provide meaningful benefit patients. currently being evaluated phase I clinical trial. Cancer Res; 76(11); 3307-18. ©2016 AACR.