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.