Breast cancer is the most frequent type of cancer diagnosed in women, with over 200,000 new cases diagnosed in the US each year. Treatment strategies are typically based on the tumors receptor status; that is, whether a tumor expresses estrogen receptor (ER), progesterone receptor (PR), or Her2. Estrogen receptor positive (ER+) breast cancers comprise approximately two-thirds of all breast cancers. For decades the approach to treat ER+ disease revolved around altering the ligand interactions with the receptor; either by preventing estrogen binding (e.g., tamoxifen) or preventing estrogen biosynthesis (aromatase inhibitors). While patients typically respond well to these agents, estrogen-independent ER activity and recurrent ER mutations are increasingly being reported as contributing factors to endocrine resistance and continue to be a clinical hurdle. Given this growing unmet medical need, selective estrogen receptor downregulators, or SERDs, have gained widespread attention as new therapeutic treatment strategies for ER + disease. Indeed, fulvestrant has been shown to downregulate ER and cause tumor growth inhibition in many ER+ breast cancer models. However, in the clinic fulvestrant appears to be limited by PK exposure properties and this, combined with its intramuscular route of administration, underscores the need for novel orally available SERDs. Here, we describe RAD1901, an orally administered SERD that binds ER and targets it for degradation in a dose-dependent manner. Biochemical affinity binding studies and cocrystallization experiments revealed insights into RAD1901 complexes with both wild-type and mutant forms of ER. In addition, RAD1901 treatment resulted in decreased cell proliferation in in vitro breast cancer cell lines and had profound single agent tumor growth inhibition in in vivo xenograft models. Consistent with these findings, RAD1901 treatment resulted in decreased expression levels of ER target genes. Interestingly, the extent of tumor growth inhibition induced by RAD1901 in vivo was dependent on ER expression levels, demonstrating the specificity of RAD1901 and predicting its activity in ER-driven cancers. Importantly, RAD1901 was also able to induce significant tumor growth inhibition in clinically relevant and representative patient-derived xenograft models, at a level similar to or greater than fulvestrant. In conclusion, our preclinical data demonstrate that RAD1901 is an orally available SERD, with potent single agent antitumor activity. RAD1901 is currently under clinical investigation in post-menopausal women with advanced ER+ disease.
Citation Format: Teeru Bihani, Jeffrey Brown, Gary Hattersley, Fiona Garner. RAD1901, an orally available selective estrogen receptor downregulator, has potent anti-tumor activity in in vitro and in vivo models of ER+ breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PR10.
- ©2015 American Association for Cancer Research.