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

  • Elife. 2016 Jul 13;5:e15828. doi: 10.7554/eLife.15828.
James D Joseph  1 ,  Beatrice Darimont  1 ,  Wei Zhou  2 ,  Alfonso Arrazate  2 ,  Amy Young  2 ,  Ellen Ingalla  2 ,  Kimberly Walter  3 ,  Robert A Blake  4 ,  Jim Nonomiya  4 ,  Zhengyu Guan  2 ,  Lorna Kategaya  5 ,  Steven P Govek  6 ,  Andiliy G Lai  6 ,  Mehmet Kahraman  6 ,  Dan Brigham  1 ,  John Sensintaffar  1 ,  Nhin Lu  1 ,  Gang Shao  1 ,  Jing Qian  1 ,  Kate Grillot  1 ,  Michael Moon  1 ,  Rene Prudente  1 ,  Eric Bischoff  1 ,  Kyoung-Jin Lee  7 ,  Celine Bonnefous  6 ,  Karensa L Douglas  6 ,  Jackaline D Julien  6 ,  Johnny Y Nagasawa  6 ,  Anna Aparicio  7 ,  Josh Kaufman  7 ,  Benjamin Haley  8 ,  Jennifer M Giltnane  9 ,  Ingrid E Wertz  5 ,  Mark R Lackner  3 ,  Michelle A Nannini  2 ,  Deepak Sampath  2 ,  Luis Schwarz  10 ,  Henry Charles Manning  11 ,  Mohammed Noor Tantawy  11 ,  Carlos L Arteaga  10 ,  Richard A Heyman  1 ,  Peter J Rix  7 ,  Lori Friedman  2 ,  Nicholas D Smith  6 ,  Ciara Metcalfe  2 ,  Jeffrey H Hager  1
Affiliations
  • 1. Department of Biology, Seragon Pharmaceuticals, San Diego, United States.
  • 2. Department of Translational Oncology, Genentech, South San Francisco, United States.
  • 3. Department of Oncology Biomarker Development, Genentech, South San Francisco, United States.
  • 4. Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, United States.
  • 5. Departments of Discovery Oncology and Early Discovery Biochemistry, Genentech, South San Francisco, United States.
  • 6. Department of Chemistry, Seragon Pharmaceuticals, San Diego, United States.
  • 7. Department of Drug Safety and Disposition, Seragon Pharmaceuticals, San Diego, United States.
  • 8. Department of Molecular Biology, Genentech, South San Francisco, United States.
  • 9. Department of Pathology, Genentech, South San Francisco, United States.
  • 10. Department of Medicine and Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Nashville, United States.
  • 11. Vanderbilt University Institute of Imaging Science, Vanderbilt University, Nashville, United States.
PMID: 27410477 DOI: 10.7554/eLife.15828
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
GDC-0810; SERD; breast cancer; cancer biology; estrogen receptor; human; human biology; medicine.
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