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

  1. James D Joseph
  2. Beatrice Darimont
  3. Wei Zhou
  4. Alfonso Arrazate
  5. Amy Young
  6. Ellen Ingalla
  7. Kimberly Walter
  8. Robert A Blake
  9. Jim Nonomiya
  10. Zhengyu Guan
  11. Lorna Kategaya
  12. Steven P Govek
  13. Andiliy G Lai
  14. Mehmet Kahraman
  15. Dan Brigham
  16. John Sensintaffar
  17. Nhin Lu
  18. Gang Shao
  19. Jing Qian
  20. Kate Grillot
  21. Michael Moon
  22. Rene Prudente
  23. Eric Bischoff
  24. Kyoung-Jin Lee
  25. Celine Bonnefous
  26. Karensa L Douglas
  27. Jackaline D Julien
  28. Johnny Y Nagasawa
  29. Anna Aparicio
  30. Josh Kaufman
  31. Benjamin Haley
  32. Jennifer M Giltnane
  33. Ingrid E Wertz
  34. Mark R Lackner
  35. Michelle A Nannini
  36. Deepak Sampath
  37. Luis Schwarz
  38. Henry Charles Manning
  39. Mohammed Noor Tantawy
  40. Carlos L Arteaga
  41. Richard A Heyman
  42. Peter J Rix
  43. Lori Friedman
  44. Nicholas D Smith
  45. Ciara Metcalfe  Is a corresponding author
  46. Jeffrey H Hager  Is a corresponding author
  1. Seragon Pharmaceuticals, United States
  2. Genentech, United States
  3. Vanderbilt-Ingram Cancer Center, United States
  4. Vanderbilt University, United States
Research Article
  • Cited 54
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Cite this article as: eLife 2016;5:e15828 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 ERα 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.

Article and author information

Author details

  1. James D Joseph

    Department of Biology, Seragon Pharmaceuticals, San Diego, United States
    Competing interests
    James D Joseph, Shareholder of Seragon.

  2. Beatrice Darimont

    Department of Biology, Seragon Pharmaceuticals, San Diego, United States
    Competing interests
    Beatrice Darimont, Shareholder of Seragon.

  3. Wei Zhou

    Department of Translational Oncology, Genentech, South San Francisco, United States
    Competing interests
    Wei Zhou, Employed by Genentech and own shares.

  4. Alfonso Arrazate

    Department of Translational Oncology, Genentech, South San Francisco, United States
    Competing interests
    Alfonso Arrazate, Shareholder of Seragon.

  5. Amy Young

    Department of Translational Oncology, Genentech, South San Francisco, United States
    Competing interests
    Amy Young, Employed by Genentech and own shares.

  6. Ellen Ingalla

    Department of Translational Oncology, Genentech, South San Francisco, United States
    Competing interests
    Ellen Ingalla, Employed by Genentech and own shares.

  7. Kimberly Walter

    Department of Oncology Biomarker Development, Genentech, South San Francisco, United States
    Competing interests
    Kimberly Walter, Employed by Genentech and own shares.

  8. Robert A Blake

    Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, United States
    Competing interests
    Robert A Blake, Employed by Genentech and own shares.

  9. Jim Nonomiya

    Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, United States
    Competing interests
    Jim Nonomiya, Employed by Genentech and own shares.

  10. Zhengyu Guan

    Department of Translational Oncology, Genentech, South San Francisco, United States
    Competing interests
    Zhengyu Guan, Employed by Genentech and own shares.

  11. Lorna Kategaya

    Department of Discovery Oncology, Genentech, South San Francisco, United States
    Competing interests
    Lorna Kategaya, Employed by Genentech and own shares.

  12. Steven P Govek

    Department of Chemistry, Seragon Pharmaceuticals, San Diego, United States
    Competing interests
    Steven P Govek, Shareholder of Seragon.

  13. Andiliy G Lai

    Department of Chemistry, Seragon Pharmaceuticals, San Diego, United States
    Competing interests
    Andiliy G Lai, Shareholder of Seragon.

  14. Mehmet Kahraman

    Department of Chemistry, Seragon Pharmaceuticals, San Diego, United States
    Competing interests
    Mehmet Kahraman, Shareholder of Seragon.

  15. Dan Brigham

    Department of Biology, Seragon Pharmaceuticals, San Diego, United States
    Competing interests
    Dan Brigham, Shareholder of Seragon.

  16. John Sensintaffar

    Department of Biology, Seragon Pharmaceuticals, San Diego, United States
    Competing interests
    John Sensintaffar, Shareholder of Seragon.

  17. Nhin Lu

    Department of Biology, Seragon Pharmaceuticals, San Diego, United States
    Competing interests
    Nhin Lu, Shareholder of Seragon.

  18. Gang Shao

    Department of Biology, Seragon Pharmaceuticals, San Diego, United States
    Competing interests
    Gang Shao, Shareholder of Seragon.

  19. Jing Qian

    Department of Biology, Seragon Pharmaceuticals, San Diego, United States
    Competing interests
    Jing Qian, Shareholder of Seragon.

  20. Kate Grillot

    Department of Biology, Seragon Pharmaceuticals, San Diego, United States
    Competing interests
    Kate Grillot, Shareholder of Seragon.

  21. Michael Moon

    Department of Biology, Seragon Pharmaceuticals, San Diego, United States
    Competing interests
    Michael Moon, Shareholder of Seragon.

  22. Rene Prudente

    Department of Biology, Seragon Pharmaceuticals, San Diego, United States
    Competing interests
    Rene Prudente, Shareholder of Seragon.

  23. Eric Bischoff

    Department of Biology, Seragon Pharmaceuticals, San Diego, United States
    Competing interests
    Eric Bischoff, Shareholder of Seragon.

  24. Kyoung-Jin Lee

    Department of Drug Safety and Disposition, Seragon Pharmaceuticals, San Diego, United States
    Competing interests
    Kyoung-Jin Lee, Shareholder of Seragon.

  25. Celine Bonnefous

    Department of Chemistry, Seragon Pharmaceuticals, San Diego, United States
    Competing interests
    Celine Bonnefous, Shareholder of Seragon.

  26. Karensa L Douglas

    Department of Chemistry, Seragon Pharmaceuticals, San Diego, United States
    Competing interests
    Karensa L Douglas, Shareholder of Seragon.

  27. Jackaline D Julien

    Department of Chemistry, Seragon Pharmaceuticals, San Diego, United States
    Competing interests
    Jackaline D Julien, Shareholder of Seragon.

  28. Johnny Y Nagasawa

    Department of Chemistry, Seragon Pharmaceuticals, San Diego, United States
    Competing interests
    Johnny Y Nagasawa, Shareholder of Seragon.

  29. Anna Aparicio

    Department of Drug Safety and Disposition, Seragon Pharmaceuticals, San Diego, United States
    Competing interests
    Anna Aparicio, Shareholder of Seragon.

  30. Josh Kaufman

    Department of Drug Safety and Disposition, Seragon Pharmaceuticals, San Diego, United States
    Competing interests
    Josh Kaufman, Shareholder of Seragon.

  31. Benjamin Haley

    Department of Molecular Biology, Genentech, South San Francisco, United States
    Competing interests
    Benjamin Haley, Employed by Genentech and own shares.

  32. Jennifer M Giltnane

    Department of Pathology, Genentech, South San Francisco, United States
    Competing interests
    No competing interests declared.

  33. Ingrid E Wertz

    Department of Discovery Oncology, Genentech, South San Francisco, United States
    Competing interests
    Ingrid E Wertz, Employed by Genentech and own shares.

  34. Mark R Lackner

    Department of Oncology Biomarker Development, Genentech, South San Francisco, United States
    Competing interests
    Mark R Lackner, Employed by Genentech and own shares.

  35. Michelle A Nannini

    Department of Translational Oncology, Genentech, South San Francisco, United States
    Competing interests
    Michelle A Nannini, Employed by Genentech and own shares.

  36. Deepak Sampath

    Department of Translational Oncology, Genentech, South San Francisco, United States
    Competing interests
    Deepak Sampath, Employed by Genentech and own shares.

  37. Luis Schwarz

    Department of Medicine and Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Nashville, United States
    Competing interests
    No competing interests declared.

  38. Henry Charles Manning

    Vanderbilt University Institute of Imaging Sciences, Vanderbilt University, Nashville, United States
    Competing interests
    No competing interests declared.

  39. Mohammed Noor Tantawy

    Vanderbilt University Institute of Imaging Sciences, Vanderbilt University, Nashville, United States
    Competing interests
    No competing interests declared.

  40. Carlos L Arteaga

    Department of Medicine and Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Nashville, United States
    Competing interests
    No competing interests declared.

  41. Richard A Heyman

    Department of Biology, Seragon Pharmaceuticals, San Diego, United States
    Competing interests
    Richard A Heyman, Shareholder of Seragon.

  42. Peter J Rix

    Department of Drug Safety and Disposition, Seragon Pharmaceuticals, San Diego, United States
    Competing interests
    Peter J Rix, Shareholder of Seragon.

  43. Lori Friedman

    Department of Translational Oncology, Genentech, South San Francisco, United States
    Competing interests
    Lori Friedman, Employed by Genentech and own shares.

  44. Nicholas D Smith

    Department of Chemistry, Seragon Pharmaceuticals, San Diego, United States
    Competing interests
    Nicholas D Smith, Shareholder of Seragon.

  45. Ciara Metcalfe

    Department of Translational Oncology, Genentech, South San Francisco, United States
    For correspondence
    metcalfe.ciara@gene.com
    Competing interests
    Ciara Metcalfe, Employed by Genentech and own shares.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7233-661X

  46. Jeffrey H Hager

    Department of Biology, Seragon Pharmaceuticals, San Diego, United States
    For correspondence
    jeff.hager@icloud.com
    Competing interests
    Jeffrey H Hager, Shareholder of Seragon.

Ethics

Animal experimentation: Animal studies were conducted in accordance with the Guide for the Care and Use of Laboratory Animals, National Academy Press (2006), conforming to California State legal and ethical practices and approved by the Institutional Animal Care and Use Committee (IACUC, Seragon and/or Genentech).

Reviewing Editor

  1. John A Katzenellenbogen, University of Illinois at Urbana-Champaign, United States

Publication history

  1. Received: March 7, 2016
  2. Accepted: July 9, 2016
  3. Accepted Manuscript published: July 13, 2016 (version 1)
  4. Version of Record published: July 26, 2016 (version 2)
  5. Version of Record updated: January 7, 2019 (version 3)

Copyright

© 2016, Joseph et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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Research organism

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    Estrogen receptor alpha in the brain mediates tamoxifen-induced changes in physiology in mice

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    Research Article

    Adjuvant tamoxifen therapy improves survival in breast cancer patients. Unfortunately, long-term treatment comes with side effects that impact health and quality of life, including hot flashes, changes in bone density, and fatigue. Partly due to a lack of proven animal models, the tissues and cells that mediate these negative side effects are unclear. Here, we show that mice undergoing tamoxifen treatment experience changes in temperature, bone, and movement. Single-cell RNA sequencing reveals that tamoxifen treatment induces widespread gene expression changes in the hypothalamus and preoptic area (hypothalamus-POA). These expression changes are dependent on estrogen receptor alpha (ERα), as conditional knockout of ERα in the hypothalamus-POA ablates or reverses tamoxifen-induced gene expression. Accordingly, ERα-deficient mice do not exhibit tamoxifen-induced changes in temperature, bone, or movement. These findings provide mechanistic insight into the effects of tamoxifen on the hypothalamus-POA and indicate that ERα mediates several physiological effects of tamoxifen treatment in mice.