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The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer.


ABSTRACT: 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? signaling, and provides a strong rationale for continued targeting of ER?. Here we describe GDC-0810, a novel, non-steroidal, orally bioavailable selective ER downregulator (SERD), which was identified by prospectively optimizing ER? degradation, antagonism and pharmacokinetic properties. GDC-0810 induces a distinct ER? 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? mutations. GDC-0810 is currently being evaluated in Phase II clinical studies in women with ER+ breast cancer.

SUBMITTER: Joseph JD 

PROVIDER: S-EPMC4961458 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer.

Joseph James D JD   Darimont Beatrice B   Zhou Wei W   Arrazate Alfonso A   Young Amy A   Ingalla Ellen E   Walter Kimberly K   Blake Robert A RA   Nonomiya Jim J   Guan Zhengyu Z   Kategaya Lorna L   Govek Steven P SP   Lai Andiliy G AG   Kahraman Mehmet M   Brigham Dan D   Sensintaffar John J   Lu Nhin N   Shao Gang G   Qian Jing J   Grillot Kate K   Moon Michael M   Prudente Rene R   Bischoff Eric E   Lee Kyoung-Jin KJ   Bonnefous Celine C   Douglas Karensa L KL   Julien Jackaline D JD   Nagasawa Johnny Y JY   Aparicio Anna A   Kaufman Josh J   Haley Benjamin B   Giltnane Jennifer M JM   Wertz Ingrid E IE   Lackner Mark R MR   Nannini Michelle A MA   Sampath Deepak D   Schwarz Luis L   Manning Henry Charles HC   Tantawy Mohammed Noor MN   Arteaga Carlos L CL   Heyman Richard A RA   Rix Peter J PJ   Friedman Lori L   Smith Nicholas D ND   Metcalfe Ciara C   Hager Jeffrey H JH  

eLife 20160713


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 ERα signaling, and provides a strong rationale for continued targeting of ERα. Here we describe GDC-0810, a novel, non-steroidal, orally bioavailable selective ER downregulator (S  ...[more]

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