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 Grillot; Michael 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

doi:10.7554/eLife.15828

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 journal › Article › peer-review

99 Scopus citations

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 language	English (US)
Article number	e15828
Journal	eLife
Volume	5
Issue number	2016JULY
DOIs	https://doi.org/10.7554/eLife.15828
State	Published - Jul 13 2016

ASJC Scopus subject areas

General Immunology and Microbiology
General Biochemistry, Genetics and Molecular Biology
General Neuroscience

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10.7554/eLife.15828

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Joseph, J. D., Darimont, B., Zhou, W., Arrazate, A., Young, A., Ingalla, E., Walter, K., Blake, R. A., Nonomiya, J., Guan, Z., Kategaya, L., Govek, S. P., Lai, A. G., Kahraman, M., Brigham, D., Sensintaffar, J., Lu, N., Shao, G., Qian, J., ... Hager, J. H. (2016). The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer. eLife, 5(2016JULY), Article e15828. https://doi.org/10.7554/eLife.15828

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

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

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.",

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

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AU - Joseph, James D.

AU - Darimont, Beatrice

AU - Zhou, Wei

AU - Arrazate, Alfonso

AU - Young, Amy

AU - Ingalla, Ellen

AU - Walter, Kimberly

AU - Blake, Robert A.

AU - Nonomiya, Jim

AU - Guan, Zhengyu

AU - Kategaya, Lorna

AU - Govek, Steven P.

AU - Lai, Andiliy G.

AU - Kahraman, Mehmet

AU - Brigham, Dan

AU - Sensintaffar, John

AU - Lu, Nhin

AU - Shao, Gang

AU - Qian, Jing

AU - Grillot, Kate

AU - Moon, Michael

AU - Prudente, Rene

AU - Bischoff, Eric

AU - Lee, Kyoung Jin

AU - Bonnefous, Celine

AU - Douglas, Karensa L.

AU - Julien, Jackaline D.

AU - Nagasawa, Johnny Y.

AU - Aparicio, Anna

AU - Kaufman, Josh

AU - Haley, Benjamin

AU - Giltnane, Jennifer M.

AU - Wertz, Ingrid E.

AU - Lackner, Mark R.

AU - Nannini, Michelle A.

AU - Sampath, Deepak

AU - Schwarz, Luis

AU - Manning, Henry Charles

AU - Tantawy, Mohammed Noor

AU - Arteaga, Carlos L.

AU - Heyman, Richard A.

AU - Rix, Peter J.

AU - Friedman, Lori

AU - Smith, Nicholas D.

AU - Metcalfe, Ciara

AU - Hager, Jeffrey H.

PY - 2016/7/13

Y1 - 2016/7/13

N2 - 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.

AB - 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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ER -

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

Abstract

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