Arzoxifene: the development and clinical outcome of an ideal SERM

Abstract

Hormone-sensitive tumours are among the most common cancers in women. Specific inhibition of the estrogen receptor by selective estrogen receptor downregulators or selective estrogen receptor modulators (SERMs) is effective for the treatment of breast and endometrial cancers and may be used for the prevention of breast cancer. Due to differential recruitment of co-activators and corepressors, SERMs are tissue specific and may have antiestrogenic effects in some tissues, with estrogen agonist activity in others. The ideal SERM would have antiestrogenic effects on the breast and endometrium, but pro-estrogenic effects on bone and lipids. The SERM, arzoxifene (LY-353381.HCl) meets all of these criteria. This review summarises the development, preclinical studies and the clinical outcome of arzoxifene and places it in context with other modalities in the treatment of hormone receptor-positive tumours.

A New Therapeutic Paradigm for Breast Cancer Exploiting Low Dose Estrogen-Induced Apoptosis

“…A recent genome-wide location analysis of AIB1 chromatin affinity sites in 17β-estradiol (E2) -treated MCF-7 cells demonstrated a significant overlap of AIB1 with FoxA1 binding sites in the breast cancer cell DNA (171). FoxA1 is another member of the forkhead family and a determining factor for estrogen receptor function and endocrine response (172). It would be interesting to investigate the portion of AIB1 genomic binding sites that are also engaged by FoxG1, and to determine whether such a population represent a subset of FoxG1-regulated genes.…”

“…Preclinical data has shown favorable estrogenic effects on bone and lipid metabolism, while exerting antiestrogen effects on breast and uterine tissue [174]. In fact, preclinical studies which compared equivalent doses of arzoxifene, tamoxifen, and raloxifene showed arzoxifene inhibits tumor growth to a greater extent than the other two agents [170,172,177,178].…”

“…Additionally, there is a protective methyl ether on one of the phenolic hydroxyls. These features lead to increased antiestrogen properties, greater bioavailability, and increased binding affinity for the ER compared with raloxifene [165][166][167][168][169][170][171][172][173][174][175][176][177]. Preclinical data has shown favorable estrogenic effects on bone and lipid metabolism, while exerting antiestrogen effects on breast and uterine tissue [174].…”

“…Preclinical data has shown favorable estrogenic effects on bone and lipid metabolism, while exerting antiestrogen effects on breast and uterine tissue [174]. In fact, preclinical studies which compared equivalent doses of arzoxifene, tamoxifen, and raloxifene showed arzoxifene inhibits tumor growth to a greater extent than the other two agents [170,172,177, 178].Phase I data has shown that in patients with metastatic breast cancer, arzoxifene at varying dosages (10, 20, 50 or 100 mg/day) was tolerated well, had no dose limiting toxicities, and was even found to decrease osteocalcin, which suggested a bone health benefit [179]. The drug was even tolerated well in women with liver disease, and the most common side effect was hot flashes, reported in 56% of women regardless of the dose taken.…”

“…In a study of patients with advanced hormone receptor positive endometrial cancer, 34% of women treated with arzoxifene 20mg daily showed favorable response with minimal toxicity [180]. Further, data from healthy volunteers showed doses as low as 10 mg/day is biologically active, and doses from 25 to 100 mg daily showed similar effects on bone markers, lipoprotein levels, and gonadotropin levels [172].In ovariectomized rats, long-term treatment with arzoxifene showed a protective effect on cancellous bone mass, architecture, and strength and did not stimulate endometrium proliferation [181]; in young rats, it entirely inhibited uterine growth [168]. At bone protective doses of 0.1 and 0.5 mg/kg/day, arzoxifene also exerts a positive effect on serum lipids [181].…”