作者
Shripad V. Bhagwat,Cecilia Mur,Matthew VandeKopple,Baohui Zhao,Weihua Shen,Carlos Marugán,Andrew Capen,Lisa Kindler,Jennifer R. Stephens,Lysiane Huber,Mark Castanares,David Garcia-Tapia,J. Cohen,Jolie A. Bastian,Brian E. Mattioni,Eunice Yuen,Thomas K. Baker,Vivian Cruz,Dongling Fei,Jason R. Manro,Nicholas Pulliam,Michele Dowless,Maria Jesus. Ortiz Ruiz,Chunping Yu,Loredana Puca,Anke Klippel,F Bacchion,Roohi Ismail‐Khan,Vanessa Rodrik-Outmezguine,Sheng-Bin Peng,Marı́a José Lallena,Xueqian Gong,Alfonso de Dios
摘要
Targeting of the estrogen receptor (ER) by anti-estrogens is the standard-of-care for patients with ER+ HER2- advanced/metastatic breast cancer. While anti-estrogens that degrade ERα (fulvestrant) or block estrogen production (aromatase inhibitors) have improved patient outcomes, clinically important challenges remain related to drug administration, limited bioavailability, lack of brain exposure, and acquired resistance due to ESR1 mutations. These limitations indicate a need for more robust ER-targeted therapies. Here, we discovered and characterized imlunestrant, a next-generation potent, brain-penetrant oral selective estrogen receptor degrader (SERD). Imlunestrant degraded ERα and decreased ERα-mediated gene expression both in vitro and in vivo. Cell proliferation and tumor growth in ESR1 wildtype and mutant models were significantly inhibited by imlunestrant. Combining imlunestrant with abemaciclib (CDK4/6 inhibitor), alpelisib (PI3K inhibitor), or everolimus (mTOR inhibitor) further enhanced tumor growth inhibition, regardless of ESR1 mutational status. In an ER+ breast cancer intracranial tumor model, imlunestrant prolonged survival compared to vehicle or alternative SERD therapies. Together, these finding support the potential of imlunestrant to degrade ERα and suppress the growth of ESR1 wildtype and mutant breast cancer, including brain metastatic tumors.