RAD1901: a novel, orally bioavailable selective estrogen receptor degrader that demonstrates antitumor activity in
Fiona Garner1, Maysoun Shomali, Dotty Paquin
1aRadius Health Inc., Waltham bPfizer, Andover, Massachusetts, USA.
Abstract:
Agents that inhibit estrogen production, such as aromatase inhibitors or those that directly block estrogen receptor (ER) activity, such as selective estrogen receptor modulators and selective estrogen receptor degraders, are routinely used in the treatment of ER-positive breast cancers. However, although initial treatment with these agents is often successful, many women eventually relapse with drug-resistant breast cancers. To overcome some of the challenges associated with current endocrine therapies and to combat the development of resistance, there is a need for more durable and more effective ER-targeted therapies. Here we describe and characterize a novel, orally bioavailable small-molecule selective estrogen receptor degrader, RAD1901, and evaluate its therapeutic potential for the treatment of breast cancer. RAD1901 selectively binds to and degrades the ER and is a potent antagonist of ER-positive breast cancer cell proliferation. Importantly, RAD1901 produced a robust and profound inhibition of tumor growth in MCF-7 xenograft models. In an intracranial MCF-7 model, RAD1901-treated animals survived longer than those treated with either control or fulvestrant, suggesting the potential benefit of RAD1901 in the treatment of ER-positive breast cancer that has metastasized to the brain. Finally, RAD1901 preserved ovariectomy-induced bone loss and prevented the uterotropic effects of E2, suggesting that it may act selectively as an agonist in bone but as an antagonist in breast and uterine tissues. RAD1901 is currently under clinical study in postmenopausal women with ER-positive advanced breast cancer.
Insights
A new drug, RAD1901, effectively targets estrogen receptor-positive breast cancer by degrading the estrogen receptor. This novel therapy shows promise in inhibiting tumor growth and improving survival, even in brain metastasis models.
Area of Science:
- Oncology
- Endocrinology
- Pharmacology
Background:
- Estrogen receptor (ER)-positive breast cancers are typically treated with endocrine therapies targeting estrogen production or ER activity.
- Many patients develop resistance to current treatments, necessitating the development of more effective ER-targeted therapies.
- Novel agents are needed to overcome resistance and provide more durable treatment outcomes for ER-positive breast cancer.
Purpose of the Study:
- To characterize a novel, orally bioavailable small-molecule selective estrogen receptor degrader, RAD1901.
- To evaluate the therapeutic potential of RAD1901 for treating ER-positive breast cancer, including metastatic disease.
- To assess RAD1901's efficacy and safety profile in preclinical models.
Main Methods:
- RAD1901 was characterized for its ability to bind and degrade the estrogen receptor (ER).
- The anti-proliferative effects of RAD1901 on ER-positive breast cancer cells were evaluated.
- Tumor growth inhibition was assessed in MCF-7 xenograft and intracranial models.
- Bone loss and uterotropic effects were evaluated to determine tissue selectivity.
Main Results:
- RAD1901 selectively binds to and degrades the ER, acting as a potent antagonist of ER-positive breast cancer cell proliferation.
- RAD1901 demonstrated robust inhibition of tumor growth in MCF-7 xenograft models.
- In an intracranial model, RAD1901 significantly improved survival compared to control or fulvestrant, suggesting efficacy in brain metastases.
- RAD1901 preserved bone density and prevented estrogen-induced uterine effects, indicating tissue-selective activity.
Conclusions:
- RAD1901 is a promising novel, orally bioavailable selective estrogen receptor degrader with significant therapeutic potential for ER-positive breast cancer.
- Its efficacy in preclinical models, including those with brain metastases, and its tissue-selective profile warrant further clinical investigation.
- RAD1901 is currently undergoing clinical trials for advanced ER-positive breast cancer.
