Selective Androgen Receptor Modulator RAD140 Inhibits the Growth of Androgen/Estrogen Receptor-Positive Breast Cancer...

Area of Science:

• Oncology
• Endocrinology
• Pharmacology

Background:

• Steroidal androgens have historically shown efficacy in treating androgen receptor and estrogen receptor positive (AR/ER+) breast cancer.
• There is a need for novel therapeutics targeting AR/ER+ breast cancer, a subtype influenced by androgen signaling.

Purpose of the Study:

• To evaluate the activity and efficacy of the oral selective androgen receptor (AR) modulator, RAD140.
• To assess RAD140 in preclinical models of AR/ER+ breast cancer, both as a single agent and in combination therapy.

Main Methods:

• In vitro assays determined RAD140's affinity for nuclear receptors and its tissue-selective AR activity.
• In vivo studies utilized AR/ER+ breast cancer patient-derived xenograft (PDX) models to assess RAD140's efficacy and pharmacodynamics.
• RAD140 was tested as monotherapy and in combination with palbociclib.

Main Results:

• RAD140 demonstrated high affinity and specificity for AR, acting as an agonist in breast cancer cells.
• Oral RAD140 significantly inhibited AR/ER+ breast cancer PDX growth, suppressing the estrogen receptor (ER) pathway and ESR1 gene.
• Combination therapy with RAD140 and palbociclib showed enhanced efficacy, suppressing AR-repressed genes involved in DNA replication.

Conclusions:

• RAD140 is a potent AR agonist with a unique mechanism, including AR-mediated repression of ESR1, in breast cancer.
• RAD140 effectively inhibits AR/ER+ breast cancer growth in preclinical models, both alone and with palbociclib.
• These findings support the further clinical investigation of RAD140 for AR/ER+ breast cancer patients.