Background: SR16157 is a novel dual-acting antiestrogen with promise as a treatment for breast and other estrogen-modulated cancers. SR16157 inhibits the hydrolysis of estrone sulfate to estrone, and is cleaved by estrone sulfatase (ES) to SR16137, a tissue-selective estrogen receptor modulator, with potent antiestrogen effects in breast and uterus and protective estrogen-like agonist effects on bone and cardiovascular systems. Steroid sulfatase (STS) is much higher than aromatase activity in breast cancer, and high levels of STS mRNA expression in tumors is associated with a poor prognosis. Using in vitro and xenograft MCF-7 breast cancer models, we demonstrated that SR16157 inhibited STS activity, cell growth, and estrogenic functions and that SR16137 reduced expression of estrogen-regulated genes with greater potency than tamoxifen.Methods: We conducted preclinical toxicity and pharmacokinetic evaluations of SR16157 as part of an investigational new drug application. SR16157 was administered to female Sprague-Dawley rats or beagle dogs by oral gavage or capsule. In rats, the maximum tolerated dose (MTD; highest dose that did not cause lethality, but produced toxicity) was 33 mg/kg/day (198 mg/m2/day), and the no observed adverse effect level (NOAEL) was <10 mg/kg/day (60 mg/m2/day). In dogs, the MTD was estimated to be >10 mg/kg/day (200 mg/m2/day), and the NOAEL was estimated to be ≥2.5 mg/kg/day (50 mg/m2/day). In a GLP toxicity study, female dogs received SR16157 by oral capsule for 28 days at 0.5, 2.5, or 10 mpk (10, 50, 200 mpm2) with 14 days recovery (Day 42). ES activity was determined in peripheral blood mononuclear cells (PBMC) before and during the study, and in liver at necropsy. Plasma drug levels and urinary metabolites were evaluated by LC-MS/MS.Results: All dogs survived to scheduled sacrifice with no test article-related clinical observations or body weight changes. Reversible changes related to white blood cells were observed in SR16157-treated dogs, including reduced white blood cell count, absolute lymphocytes, absolute eosinophils, and absolute monocytes. Mean thymus weights for high dose dogs were decreased 30% compared with controls at Day 29 and remained 20% lower at Day 42. Tissues showed no drug-related findings. Hepatic ES activity was completely inhibited in SR16157 groups by Day 29. PBMC ES activity was completely inhibited by Day 6, remained low through Day 29, and increased by Day 42. SR16137 levels were highest in plasma samples that also contained higher concentrations of SR16157.Discussion: SR16157 has excellent bioavailability and a favorable safety profile. Daily oral administration of SR16157 for 28 days in dogs was not associated with toxicologically significant effects that would limit clinical use. ES inhibition in PBMC is a sensitive indicator of the pharmacologic action of SR16157 and a potential biomarker of efficacy in humans. Based on these results, the recommended Phase I starting dose of SR16157 given orally once daily for 28 days is 20 mg/m2/day, which is 10% of the MTD in the more sensitive preclinical species (the rat). This work was supported by NCI Contract N01-CM-42203.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5124.