Orally bioavailable selective estrogen receptor downregulators (SERDs) may offer greater systemic drug exposure, improved clinical efficacy, and more durable treatment outcome for breast cancer patients with disease progression following antiestrogen or aromatase inhibitor therapy. We report the design and synthesis of ZB716, a C-3 position boronic acid modified fulvestrant, which behaves as a steroidal SERD suitable for oral administration. ZB716 binds to ERa competitively at an IC50 of 4.1 nM as compared to 3.9 nM for fulvestrant, and it effectively downregulates ERa (IC50=12.7 nM) in both tamoxifen-sensitive (T47D) and tamoxifen-resistant (T47D/PKCa) breast cancer cells. It acts as an antiestrogen that exerts potent antiproliferative effects on tamoxifen-resistant breast cancer cells (MCF-7/TamR, T47D/PKCa, and T47D/Y537S). When orally administered to mice, rats, and Beagle dogs, ZB716 demonstrates superior oral bioavailability in all animal-based pharmacokinetic studies when compared to fulvestrant administered by subcutaneous injection. More importantly, orally administered ZB716 was found to potently inhibit xenograft tumor growth in mice. These pre-clinical data strongly suggest that ZB716 is a promising SERD drug that could offer significant improvement over existing SERD regimen of Faslodex. ZB716 is being prepared in an IND application for phase 1 clinical trial in ER+, HER2- advanced breast cancer patients. Citation Format: Wang G, Liu J, Zheng S, Miele L, Wiese T, Zhong Q, Guo S. An orally bioavailable selective estrogen receptor downregulator [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-08-11.
The CCAAT enhancer binding protein β (C/EBPβ) is overexpressed at late stages in carcinogenesis of prostate cancer (PCa), suggesting that it could potentially contribute to progression of PCa. Estrogen receptor beta (ERβ) is a tumor suppressor gene in PCa. However, whether C/EBPβ could regulate ERβ by promoter methylation is still poorly understood.In this study, expression levels of C/EBPβ and ERβ in two PC lines (LNCap and PC-3), prostatic epithelial cell line (RWPE-1), forty-eight paired non-cancerous and cancerous peripheral blood samples were examined via qRT-PCR, western blotting and methylation-specific PCR. In addition, PCa cell line was infected with pCDH-C/EBPβ and pLKO.1-C/EBPβ and expression levels of C/EBPβ, ERβ and DNA methyltransferases were detected. Finally, the role of C/EBPβ in proliferation and apoptosis of PCa cell lines was examined by MTT and flow cytometer assay. Our results show a higher frequency of promoter methylation of ERβ levels in blood samples from PCa patients (16 of 48 cases) compared with that from healthy controls (3 of 48). Besides, elevated expression levels of C/EBPβ were found in PCa patients and two PCa lines (LNCap and PC-3) compared to non-cancerous cases or prostatic epithelial cell line (RWPE-1), while opposite expression levels of ERβ were found. Overexpression of C/EBPβ could regulate ERβ expression, DNA methyltransferases expression, cell proliferation and apoptosis. Our results support the conclusion that C/EBPβ down-regulated ERβ expression through increasing its promoter methylation, and then regulated proliferation and apoptosis in PCa.
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