Estrogen Receptor Coregulator Binding Modulators (ERXs) Effectively Target Estrogen Receptor Positive Human Breast Cancers

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Abstract

The majority of human breast cancer is estrogen receptor alpha (ER) positive. While anti-estrogens/aromatase inhibitors are initially effective, resistance to these drugs commonly develops. Therapy-resistant tumors often retain ER signaling, via interaction with critical oncogenic coregulator proteins. To address these mechanisms of resistance, we have developed a novel ER coregulator binding modulator, ERX-11. ERX-11 interacts directly with ER and blocks the interaction between a subset of coregulators with both native and mutant forms of ER. ERX-11 effectively blocks ER-mediated oncogenic signaling and has potent anti-proliferative activity against therapy-sensitive and therapy-resistant human breast cancer cells. ERX-11 is orally bioavailable, with no overt signs of toxicity and potent activity in both murine xenograft and patient-derived breast tumor explant models. This first-in-class agent, with its novel mechanism of action of disrupting critical protein-protein interactions, overcomes the limitations of current therapies and may be clinically translatable for patients with therapy-sensitive and therapy-resistant breast cancers.

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Keywords

PELP1 protein, Tamoxifen, Estrogen Antagonists, Receptors, Estrogen, Breast—Cancer

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Cancer Prevention and Research Institute of Texas grant no. DP150096; Congressionally Directed Medical Research Programs grant no. W81XWH-12-1-0288, W81XWH-13-2-0093, W81XWH-16-1-0294; CPRIT grant # DP150096; DOD grant # W81XWH-12-1- 0288 and W81XWH-13-2-0093; Welch Foundation (AT-1595); UTH Cancer Center grant P30 CA-54174; NIH grant 1R01CA179120-01.

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CC BY 4.0 (Attribution), ©2017 The Authors

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