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

Breast Cancer Research and Treatment
Kaitlyn J AndreanoJohn D Norris

Abstract

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. 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). 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 e...Continue Reading

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Citations

Apr 15, 2020·Cancer Cell·Ariella B HankerCarlos L Arteaga
Aug 8, 2021·International Journal of Molecular Sciences·Cristina HernandoJuan Miguel Cejalvo
Aug 17, 2021·Breast Cancer Research : BCR·Jamie O BrettSeth A Wander
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Oct 26, 2021·Expert Opinion on Investigational Drugs·Ya-Chi ChenXiaojing Wang

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Methods Mentioned

BETA
pharmacotherapy
xenograft
PCR
immunoprecipitation
xenografts

Clinical Trials Mentioned

NCT02422615
NCT02107703

Software Mentioned

SAS
JMP

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