1. Antiestrogens in combination with immune checkpoint inhibitors in breast cancer immunotherapy
- Author
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Márquez-Garbán, Diana C, Deng, Gang, Comin-Anduix, Begonya, Garcia, Alejandro J, Xing, Yanpeng, Chen, Hsiao-Wang, Cheung-Lau, Gardenia, Hamilton, Nalo, Jung, Michael E, and Pietras, Richard J
- Subjects
Analytical Chemistry ,Biochemistry and Cell Biology ,Chemical Sciences ,Biological Sciences ,Women's Health ,Estrogen ,Vaccine Related ,Cancer ,Immunization ,Breast Cancer ,Immunotherapy ,5.1 Pharmaceuticals ,Animals ,Antineoplastic Agents ,Hormonal ,Antineoplastic Agents ,Immunological ,Antineoplastic Combined Chemotherapy Protocols ,Breast Neoplasms ,Cell Line ,Tumor ,Cell Proliferation ,Cytokines ,Estrogen Antagonists ,Female ,Fulvestrant ,Humans ,Lymphocytes ,Tumor-Infiltrating ,Mice ,Inbred BALB C ,Mice ,Nude ,Receptors ,Estrogen ,Selective estrogen receptor downregulator ,PD-L1 ,Myeloid-derived suppressor cells ,Breast cancer ,CD8+T-cells ,CD8+ T-cells ,Endocrinology & Metabolism ,Biochemistry and cell biology ,Analytical chemistry - Abstract
Breast cancers (BCs) with expression of estrogen receptor-alpha (ERα) occur in more than 70% of newly-diagnosed patients in the U.S. Endocrine therapy with antiestrogens or aromatase inhibitors is an important intervention for BCs that express ERα, and it remains one of the most effective targeted treatment strategies. However, a substantial proportion of patients with localized disease, and essentially all patients with metastatic BC, become resistant to current endocrine therapies. ERα is present in most resistant BCs, and in many of these its activity continues to regulate BC growth. Fulvestrant represents one class of ERα antagonists termed selective ER downregulators (SERDs). Treatment with fulvestrant causes ERα down-regulation, an event that helps overcome several resistance mechanisms. Unfortunately, full antitumor efficacy of fulvestrant is limited by its poor bioavailability in clinic. We have designed and tested a new generation of steroid-like SERDs. Using ERα-positive BC cells in vitro, we find that these compounds suppress ERα protein levels with efficacy similar to fulvestrant. Moreover, these new SERDs markedly inhibit ERα-positive BC cell transcription and proliferation in vitro even in the presence of estradiol-17β. In vivo, the SERD termed JD128 significantly inhibited tumor growth in MCF-7 xenograft models in a dose-dependent manner (P
- Published
- 2019