Journal
ELIFE
Volume 5, Issue -, Pages -Publisher
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.15828
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Funding
- Vanderbilt-Ingram Cancer Center [P30 CA68485]
- Susan G. Komen for the Cure [SAC100013]
- Breast Cancer Specialized Program of Research Excellence [P50 CA098131]
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ER-targeted therapeutics provide valuable treatment options for patients with ER+ breast cancer, however, current relapse and mortality rates emphasize the need for improved therapeutic strategies. The recent discovery of prevalent ESR1 mutations in relapsed tumors underscores a sustained reliance of advanced tumors on ER alpha signaling, and provides a strong rationale for continued targeting of ER alpha. Here we describe GDC-0810, a novel, non-steroidal, orally bioavailable selective ER downregulator (SERD), which was identified by prospectively optimizing ER alpha degradation, antagonism and pharmacokinetic properties. GDC-0810 induces a distinct ER alpha conformation, relative to that induced by currently approved therapeutics, suggesting a unique mechanism of action. GDC-0810 has robust in vitro and in vivo activity against a variety of human breast cancer cell lines and patient derived xenografts, including a tamoxifen-resistant model and those that harbor ER alpha mutations. GDC-0810 is currently being evaluated in Phase II clinical studies in women with ER+ breast cancer.
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