Evaluation of the pharmacological activities of RAD1901, a selective estrogen receptor degrader

Area of Science:

• Oncology
• Endocrinology
• Pharmacology

Background:

• Estrogen receptor 1 (ESR1) positive breast cancer is typically treated with endocrine therapy, but resistance limits efficacy.
• Selective estrogen receptor degraders (SERDs) like fulvestrant are effective, indicating ESR1 remains crucial in resistant cancers.
• Selective ER modulators/SERD hybrids (SSH) are emerging as a new treatment strategy for advanced and metastatic breast cancer.

Purpose of the Study:

• To evaluate the efficacy and pharmacology of RAD1901, a novel SSH, in preclinical models of breast cancer.
• To investigate RAD1901's ability to inhibit ESR1 activity, downregulate ESR1 protein, and affect tumor growth.
• To assess RAD1901's potential as a targeted therapy for breast cancer, particularly brain metastases, due to its brain penetrance.

Main Methods:

• In vitro and in vivo experiments to assess RAD1901's inhibition of estrogen-activated ESR1.
• Evaluation of RAD1901's effect on estrogen-dependent breast cancer cell proliferation and xenograft tumor growth.
• Dose-response studies to determine RAD1901's impact on ESR1 protein levels and target gene activation.

Main Results:

• RAD1901 effectively inhibited ESR1 activation, breast cancer cell proliferation, and xenograft tumor growth in vitro and in vivo.
• RAD1901 demonstrated dose-dependent downregulation of ESR1 protein.
• Sub-efficacious doses of RAD1901 led to ESR1 target gene activation and stimulated tumor growth, indicating complex pharmacology.

Conclusions:

• RAD1901 exhibits complex, dose-dependent, tissue-selective agonist/antagonist activity in breast cancer models.
• Despite complex pharmacology, RAD1901's unique ability to cross the blood-brain barrier warrants its investigation for treating breast cancer brain metastases.