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

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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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Further reading

    1. Cancer Biology
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    Replication Study

    As part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Phelps et al., 2016) that described how we intended to replicate selected experiments from the paper ‘Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs’ (Tay et al., 2011). Here, we report the results. We found depletion of putative PTEN competing endogenous mRNAs (ceRNAs) in DU145 cells did not impact PTEN 3’UTR regulation using a reporter, while the original study reported decreased activity when SERINC1, VAPA, and CNOT6L were depleted (Figure 3C; Tay et al., 2011). Using the same reporter, we found decreased activity when ceRNA 3’UTRs were overexpressed, while the original study reported increased activity (Figure 3D; Tay et al., 2011). In HCT116 cells, ceRNA depletion resulted in decreased PTEN protein levels, a result similar to the findings reported in the original study (Figure 3G,H; Tay et al., 2011); however, while the original study reported an attenuated ceRNA effect in microRNA deficient (DicerEx5) HCT116 cells, we observed increased PTEN protein levels. Further, we found depletion of the ceRNAs VAPA or CNOT6L did not statistically impact DU145, wild-type HCT116, or DicerEx5 HCT116 cell proliferation. The original study reported increased DU145 and wild-type HCT116 cell proliferation when these ceRNAs were depleted, which was attenuated in the DicerEx5 HCT116 cells (Figure 5B; Tay et al., 2011). Differences between the original study and this replication attempt, such as variance between biological repeats, are factors that might have influenced the results. Finally, we report meta-analyses for each result.