eLife (Jul 2016)
The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer
- James D Joseph,
- Beatrice Darimont,
- Wei Zhou,
- Alfonso Arrazate,
- Amy Young,
- Ellen Ingalla,
- Kimberly Walter,
- Robert A Blake,
- Jim Nonomiya,
- Zhengyu Guan,
- Lorna Kategaya,
- Steven P Govek,
- Andiliy G Lai,
- Mehmet Kahraman,
- Dan Brigham,
- John Sensintaffar,
- Nhin Lu,
- Gang Shao,
- Jing Qian,
- Kate Grillot,
- Michael Moon,
- Rene Prudente,
- Eric Bischoff,
- Kyoung-Jin Lee,
- Celine Bonnefous,
- Karensa L Douglas,
- Jackaline D Julien,
- Johnny Y Nagasawa,
- Anna Aparicio,
- Josh Kaufman,
- Benjamin Haley,
- Jennifer M Giltnane,
- Ingrid E Wertz,
- Mark R Lackner,
- Michelle A Nannini,
- Deepak Sampath,
- Luis Schwarz,
- Henry Charles Manning,
- Mohammed Noor Tantawy,
- Carlos L Arteaga,
- Richard A Heyman,
- Peter J Rix,
- Lori Friedman,
- Nicholas D Smith,
- Ciara Metcalfe,
- Jeffrey H Hager
Affiliations
- James D Joseph
- Department of Biology, Seragon Pharmaceuticals, San Diego, United States
- Beatrice Darimont
- Department of Biology, Seragon Pharmaceuticals, San Diego, United States
- Wei Zhou
- Department of Translational Oncology, Genentech, South San Francisco, United States
- Alfonso Arrazate
- Department of Translational Oncology, Genentech, South San Francisco, United States
- Amy Young
- Department of Translational Oncology, Genentech, South San Francisco, United States
- Ellen Ingalla
- Department of Translational Oncology, Genentech, South San Francisco, United States
- Kimberly Walter
- Department of Oncology Biomarker Development, Genentech, South San Francisco, United States
- Robert A Blake
- Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, United States
- Jim Nonomiya
- Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, United States
- Zhengyu Guan
- Department of Translational Oncology, Genentech, South San Francisco, United States
- Lorna Kategaya
- Departments of Discovery Oncology and Early Discovery Biochemistry, Genentech, South San Francisco, United States
- Steven P Govek
- Department of Chemistry, Seragon Pharmaceuticals, San Diego, United States
- Andiliy G Lai
- Department of Chemistry, Seragon Pharmaceuticals, San Diego, United States
- Mehmet Kahraman
- Department of Chemistry, Seragon Pharmaceuticals, San Diego, United States
- Dan Brigham
- Department of Biology, Seragon Pharmaceuticals, San Diego, United States
- John Sensintaffar
- Department of Biology, Seragon Pharmaceuticals, San Diego, United States
- Nhin Lu
- Department of Biology, Seragon Pharmaceuticals, San Diego, United States
- Gang Shao
- Department of Biology, Seragon Pharmaceuticals, San Diego, United States
- Jing Qian
- Department of Biology, Seragon Pharmaceuticals, San Diego, United States
- Kate Grillot
- Department of Biology, Seragon Pharmaceuticals, San Diego, United States
- Michael Moon
- Department of Biology, Seragon Pharmaceuticals, San Diego, United States
- Rene Prudente
- Department of Biology, Seragon Pharmaceuticals, San Diego, United States
- Eric Bischoff
- Department of Biology, Seragon Pharmaceuticals, San Diego, United States
- Kyoung-Jin Lee
- Department of Drug Safety and Disposition, Seragon Pharmaceuticals, San Diego, United States
- Celine Bonnefous
- Department of Chemistry, Seragon Pharmaceuticals, San Diego, United States
- Karensa L Douglas
- Department of Chemistry, Seragon Pharmaceuticals, San Diego, United States
- Jackaline D Julien
- Department of Chemistry, Seragon Pharmaceuticals, San Diego, United States
- Johnny Y Nagasawa
- Department of Chemistry, Seragon Pharmaceuticals, San Diego, United States
- Anna Aparicio
- Department of Drug Safety and Disposition, Seragon Pharmaceuticals, San Diego, United States
- Josh Kaufman
- Department of Drug Safety and Disposition, Seragon Pharmaceuticals, San Diego, United States
- Benjamin Haley
- Department of Molecular Biology, Genentech, South San Francisco, United States
- Jennifer M Giltnane
- Department of Pathology, Genentech, South San Francisco, United States
- Ingrid E Wertz
- Departments of Discovery Oncology and Early Discovery Biochemistry, Genentech, South San Francisco, United States
- Mark R Lackner
- Department of Oncology Biomarker Development, Genentech, South San Francisco, United States
- Michelle A Nannini
- Department of Translational Oncology, Genentech, South San Francisco, United States
- Deepak Sampath
- Department of Translational Oncology, Genentech, South San Francisco, United States
- Luis Schwarz
- Department of Medicine and Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Nashville, United States
- Henry Charles Manning
- Vanderbilt University Institute of Imaging Science, Vanderbilt University, Nashville, United States
- Mohammed Noor Tantawy
- Vanderbilt University Institute of Imaging Science, Vanderbilt University, Nashville, United States
- Carlos L Arteaga
- Department of Medicine and Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Nashville, United States
- Richard A Heyman
- Department of Biology, Seragon Pharmaceuticals, San Diego, United States
- Peter J Rix
- Department of Drug Safety and Disposition, Seragon Pharmaceuticals, San Diego, United States
- Lori Friedman
- Department of Translational Oncology, Genentech, South San Francisco, United States
- Nicholas D Smith
- Department of Chemistry, Seragon Pharmaceuticals, San Diego, United States
- Ciara Metcalfe
- ORCiD
- Department of Translational Oncology, Genentech, South San Francisco, United States
- Jeffrey H Hager
- Department of Biology, Seragon Pharmaceuticals, San Diego, United States
- DOI
- https://doi.org/10.7554/eLife.15828
- Journal volume & issue
-
Vol. 5
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 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.
Keywords
