A new antiestrogen, 2-(4-hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol hydrochloride (ERA-923), inhibits the growth of tamoxifen-sensitive and -resistant tumors and is devoid of uterotropic effects in mice and rats

Purpose: Tamoxifen is an antiestrogen used in women who have estrogen recep tor (ER)-alpha -positive breast cancer. Unfortunately, resistance to tamoxi fen is common in women with metastatic disease and side effects, including increased risk of endometrial cancer, exist. Here we describe the activity of a new selective ER modulator, ERA-923, in preclinical models focused on these limitations. Experimental Design: The ability of ERA-923, 4-OH tamoxifen, or raloxifene to inhibit estrogen-stimulated growth was evaluated in cell-based and xenog raft assays with tumor cells that are sensitive or resistant to tamoxifen. Uterine effects of selective ER modulators were compared in rodents. Results: ERA-923 potently inhibits estrogen binding to ER-alpha (IC50, 14 n M). In ER-alpha -positive human MCF-7 breast carcinoma cells, ERA-923 inhib its estrogen-stimulated growth (IC50, 0.2 nM) associated with cytostasis. I n vitro, a MCF-7 variant with inherent resistance to tamoxifen (10-fold) or 4-OH tamoxifen (> 1000-fold) retains complete sensitivity to ERA-923. Part ial sensitivity to ERA-923 exists in MCF-7 variants that have acquired prof ound tamoxifen resistance. In tumor-bearing animals, ERA-923 (10 mg/kg/day given p.o.) inhibits 17 beta -estradiol-stimulated growth in human tumors d erived from MCF-7, EnCa-101 endometrial, or BG-1 ovarian carcinoma cells, i ncluding a MCF-7-variant that is inherently resistant to tamoxifen. Raloxif ene is inactive in the MCF-7 xenograft model. Unlike tamoxifen, droloxifene , or raloxifene, ERA-923 is not uterotropic in immature rats or ovariectomi zed mice. Consistent with this, tamoxifen, but not ERA-923, stimulates the growth of EnCa-101 tumors. Conclusions: In preclinical models, ERA-923 has an improved efficacy and sa fety compared with tamoxifen. Clinical trials with ERA-923 are in progress.