title: Evaluation of the pharmacological activities of RAD1901, a selective estrogen receptor degrader.
abstract: Endocrine therapy, using tamoxifen or an aromatase inhibitor, remains a first-line treatment for estrogen receptor 1 (ESR1) positive breast cancer. However, tumor resistance limits the duration of response. The clinical efficacy of fulvestrant, a selective ER degrader (SERD) that triggers receptor degradation, has confirmed that ESR1 often remains engaged in endocrine therapy resistant cancers. Recently developed, selective ER modulators (SERMs)/SERD hybrids (SSHs) that facilitate ESR1 degradation in breast cancer cells and reproductive tissues have been advanced as an alternative treatment for advanced breast cancer, particularly in the metastatic setting. RAD1901 is one SSH currently being evaluated clinically that is unique among ESR1 modulators in that it readily enters the brain, a common site of breast cancer metastasis. In this study, RAD1901 inhibited estrogen activation of ESR1 in vitro and in vivo, inhibited estrogen-dependent breast cancer cell proliferation and xenograft tumor growth, and mediated dose-dependent downregulation of ESR1 protein. However, doses of RAD1901 insufficient to induce ESR1 degradation were shown to result in the activation of ESR1 target genes and in the stimulation of xenograft tumor growth. RAD1901 is an SSH that exhibits complex pharmacology in breast cancer models, having dose-dependent agonist/antagonist activity displayed in a tissue-selective manner. It remains unclear how this unique pharmacology will impact the utility of RAD1901 for breast cancer treatment. However, being the only SERD currently known to access the brain, RAD1901 merits evaluation as a targeted therapy for the treatment of breast cancer brain metastases.
authors.affiliation: Department of Pharmacology and Cancer Biology Duke University School of Medicine, Box 3813, Durham, North Carolina 27710, USA.
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Wardell
authors.affiliation: Department of Pharmacology and Cancer Biology Duke University School of Medicine, Box 3813, Durham, North Carolina 27710, USA.
authors.forename: Erik R
authors.initials: ER
authors.lastname: Nelson
authors.affiliation: Department of Pharmacology and Cancer Biology Duke University School of Medicine, Box 3813, Durham, North Carolina 27710, USA.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Chao
authors.affiliation: Department of Pharmacology and Cancer Biology Duke University School of Medicine, Box 3813, Durham, North Carolina 27710, USA.
authors.forename: Holly M
authors.initials: HM
authors.lastname: Alley
authors.affiliation: Department of Pharmacology and Cancer Biology Duke University School of Medicine, Box 3813, Durham, North Carolina 27710, USA donald.mcdonnell@duke.edu.
authors.forename: Donald P
authors.initials: DP
authors.lastname: McDonnell
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D047628:Estrogen Receptor alpha; D012333:RNA, Messenger; D020845:Selective Estrogen Receptor Modulators
keywords: RAD1901; SERM; endocrine-resistant breast cancer; selective estrogen receptor degrader