H. Manning
Faculty Member
Last active: 3/22/2018

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

Joseph JD, Darimont B, Zhou W, Arrazate A, Young A, Ingalla E, Walter K, Blake RA, Nonomiya J, Guan Z, Kategaya L, Govek SP, Lai AG, Kahraman M, Brigham D, Sensintaffar J, Lu N, Shao G, Qian J, Grillot K, Moon M, Prudente R, Bischoff E, Lee KJ, Bonnefous C, Douglas KL, Julien JD, Nagasawa JY, Aparicio A, Kaufman J, Haley B, Giltnane JM, Wertz IE, Lackner MR, Nannini MA, Sampath D, Schwarz L, Manning HC, Tantawy MN, Arteaga CL, Heyman RA, Rix PJ, Friedman L, Smith ND, Metcalfe C, Hager JH
Elife. 2016 5

PMID: 27410477 · PMCID: PMC4961458 · DOI:10.7554/eLife.15828

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 (SERD), which was identified by prospectively optimizing ERα degradation, antagonism and pharmacokinetic properties. GDC-0810 induces a distinct ERα 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 ERα mutations. GDC-0810 is currently being evaluated in Phase II clinical studies in women with ER+ breast cancer.

MeSH Terms (14)

Animals Antineoplastic Agents Breast Neoplasms Cell Line, Tumor Cinnamates Disease Models, Animal Heterografts Humans Indazoles Mice Prospective Studies Rats Receptors, Estrogen Treatment Outcome

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