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Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 3/2020

Open Access 01-04-2020 | Breast Cancer | Preclinical study

G1T48, an oral selective estrogen receptor degrader, and the CDK4/6 inhibitor lerociclib inhibit tumor growth in animal models of endocrine-resistant breast cancer

Authors: Kaitlyn J. Andreano, Suzanne E. Wardell, Jennifer G. Baker, Taylor K. Desautels, Robert Baldi, Christina A. Chao, Kendall A. Heetderks, Yeeun Bae, Rui Xiong, Debra A. Tonetti, Lauren M. Gutgesell, Jiong Zhao, Jessica A. Sorrentino, Delita A. Thompson, John E. Bisi, Jay C. Strum, Gregory R. J. Thatcher, John D. Norris

Published in: Breast Cancer Research and Treatment | Issue 3/2020

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Abstract

Purpose

The combination of targeting the CDK4/6 and estrogen receptor (ER) signaling pathways with palbociclib and fulvestrant is a proven therapeutic strategy for the treatment of ER-positive breast cancer. However, the poor physicochemical properties of fulvestrant require monthly intramuscular injections to patients, which limit the pharmacokinetic and pharmacodynamic activity of the compound. Therefore, an orally available compound that more rapidly reaches steady state may lead to a better clinical response in patients. Here, we report the identification of G1T48, a novel orally bioavailable, non-steroidal small molecule antagonist of ER.

Methods

The pharmacological effects and the antineoplastic mechanism of action of G1T48 on tumors was evaluated using human breast cancer cells (in vitro) and xenograft efficacy models (in vivo).

Results

G1T48 is a potent and efficacious inhibitor of estrogen-mediated transcription and proliferation in ER-positive breast cancer cells, similar to the pure antiestrogen fulvestrant. In addition, G1T48 can effectively suppress ER activity in multiple models of endocrine therapy resistance including those harboring ER mutations and growth factor activation. In vivo, G1T48 has robust antitumor activity in a model of estrogen-dependent breast cancer (MCF7) and significantly inhibited the growth of tamoxifen-resistant (TamR), long-term estrogen-deprived (LTED) and patient-derived xenograft tumors with an increased response being observed with the combination of G1T48 and the CDK4/6 inhibitor lerociclib.

Conclusions

These data show that G1T48 has the potential to be an efficacious oral antineoplastic agent in ER-positive breast cancer.
Appendix
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Metadata
Title
G1T48, an oral selective estrogen receptor degrader, and the CDK4/6 inhibitor lerociclib inhibit tumor growth in animal models of endocrine-resistant breast cancer
Authors
Kaitlyn J. Andreano
Suzanne E. Wardell
Jennifer G. Baker
Taylor K. Desautels
Robert Baldi
Christina A. Chao
Kendall A. Heetderks
Yeeun Bae
Rui Xiong
Debra A. Tonetti
Lauren M. Gutgesell
Jiong Zhao
Jessica A. Sorrentino
Delita A. Thompson
John E. Bisi
Jay C. Strum
Gregory R. J. Thatcher
John D. Norris
Publication date
01-04-2020
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 3/2020
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-020-05575-9

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