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

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

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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