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 GrillotMichael 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

Research output: Contribution to journalArticle

35 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere15828
JournaleLife
Volume5
Issue number2016JULY
DOIs
StatePublished - Jul 13 2016

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Estrogen Receptors
Tumors
Breast Neoplasms
Pharmacokinetics
Tamoxifen
Ports and harbors
Heterografts
Conformations
Cells
Degradation
Mutation
Therapeutics
Neoplasms
Recurrence
Cell Line
Mortality
3-(4-(2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Joseph, J. D., Darimont, B., Zhou, W., Arrazate, A., Young, A., Ingalla, E., ... Hager, J. H. (2016). The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer. eLife, 5(2016JULY), [e15828]. https://doi.org/10.7554/eLife.15828

The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer. / Joseph, James D.; Darimont, Beatrice; Zhou, Wei; Arrazate, Alfonso; Young, Amy; Ingalla, Ellen; Walter, Kimberly; Blake, Robert A.; Nonomiya, Jim; Guan, Zhengyu; Kategaya, Lorna; Govek, Steven P.; Lai, Andiliy G.; Kahraman, Mehmet; Brigham, Dan; Sensintaffar, John; Lu, Nhin; Shao, Gang; Qian, Jing; Grillot, Kate; Moon, Michael; Prudente, Rene; Bischoff, Eric; Lee, Kyoung Jin; Bonnefous, Celine; Douglas, Karensa L.; Julien, Jackaline D.; Nagasawa, Johnny Y.; Aparicio, Anna; Kaufman, Josh; Haley, Benjamin; Giltnane, Jennifer M.; Wertz, Ingrid E.; Lackner, Mark R.; Nannini, Michelle A.; Sampath, Deepak; Schwarz, Luis; Manning, Henry Charles; Tantawy, Mohammed Noor; Arteaga, Carlos L.; Heyman, Richard A.; Rix, Peter J.; Friedman, Lori; Smith, Nicholas D.; Metcalfe, Ciara; Hager, Jeffrey H.

In: eLife, Vol. 5, No. 2016JULY, e15828, 13.07.2016.

Research output: Contribution to journalArticle

Joseph, JD, Darimont, B, Zhou, W, Arrazate, A, Young, A, Ingalla, E, Walter, K, Blake, RA, Nonomiya, J, Guan, Z, Kategaya, L, Govek, SP, Lai, AG, Kahraman, M, Brigham, D, Sensintaffar, J, Lu, N, Shao, G, Qian, J, Grillot, K, Moon, M, Prudente, R, Bischoff, E, Lee, KJ, Bonnefous, C, Douglas, KL, Julien, JD, Nagasawa, JY, Aparicio, A, Kaufman, J, Haley, B, Giltnane, JM, Wertz, IE, Lackner, MR, Nannini, MA, Sampath, D, Schwarz, L, Manning, HC, Tantawy, MN, Arteaga, CL, Heyman, RA, Rix, PJ, Friedman, L, Smith, ND, Metcalfe, C & Hager, JH 2016, 'The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer', eLife, vol. 5, no. 2016JULY, e15828. https://doi.org/10.7554/eLife.15828
Joseph JD, Darimont B, Zhou W, Arrazate A, Young A, Ingalla E et al. The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer. eLife. 2016 Jul 13;5(2016JULY). e15828. https://doi.org/10.7554/eLife.15828
Joseph, James D. ; Darimont, Beatrice ; Zhou, Wei ; Arrazate, Alfonso ; Young, Amy ; Ingalla, Ellen ; Walter, Kimberly ; Blake, Robert A. ; Nonomiya, Jim ; Guan, Zhengyu ; Kategaya, Lorna ; Govek, Steven P. ; Lai, Andiliy G. ; Kahraman, Mehmet ; Brigham, Dan ; Sensintaffar, John ; Lu, Nhin ; Shao, Gang ; Qian, Jing ; Grillot, Kate ; Moon, Michael ; Prudente, Rene ; Bischoff, Eric ; Lee, Kyoung Jin ; Bonnefous, Celine ; Douglas, Karensa L. ; Julien, Jackaline D. ; Nagasawa, Johnny Y. ; Aparicio, Anna ; Kaufman, Josh ; Haley, Benjamin ; Giltnane, Jennifer M. ; Wertz, Ingrid E. ; Lackner, Mark R. ; Nannini, Michelle A. ; Sampath, Deepak ; Schwarz, Luis ; Manning, Henry Charles ; Tantawy, Mohammed Noor ; Arteaga, Carlos L. ; Heyman, Richard A. ; Rix, Peter J. ; Friedman, Lori ; Smith, Nicholas D. ; Metcalfe, Ciara ; Hager, Jeffrey H. / The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer. In: eLife. 2016 ; Vol. 5, No. 2016JULY.
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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.",
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AU - Ingalla, Ellen

AU - Walter, Kimberly

AU - Blake, Robert A.

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AU - Grillot, Kate

AU - Moon, Michael

AU - Prudente, Rene

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AU - Schwarz, Luis

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AU - Rix, Peter J.

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