Phase I Study of STX 64 (667 Coumate) in Breast Cancer Patients: The First Study of a Steroid Sulfatase Inhibitor

Abstract

Purpose: Inhibition of steroid sulfatase (STS), the enzyme responsible for the hydrolysis of steroid sulfates, represents a potential novel treatment for postmenopausal women with hormone-dependent breast cancer. Estrone and DHEA are formed by this sulfatase pathway and can be converted to steroids (estradiol and androstenediol, respectively), which have potent estrogenic properties. Experimental Design: STX64 (667 Coumate), a tricylic coumarin-based sulfamate that irreversibly inhibits STS activity, was selected for entry into the first phase I trial of a STS inhibitor in postmenopausal women with breast cancer. STX64 was administered orally (nine patients at 5 mg and five patients at 20 mg) as an initial dose followed 1week later by 3 Â 2 weekly cycles, with each cycle comprising daily dosing for 5 days followed by 9 days off treatment. Blood and tumor tissue samples were collected for the assessment of STS activity and serum was obtained for steroid hormone measurements before and after treatment. Results: The median inhibition of STS activity by STX64 was 98% in peripheral blood lymphocytes (PBL) and 99% in breast tumor tissue at the end of the 5-day dosing period. As expected, serum concentrations of estrone, estradiol, androstenediol, and DHEA all decreased significantly from pretreatment levels. Unexpectedly, androstenedione and testosterone concentrations also decreased. Four patients, all of whom had previously progressed on aromatase inhibitors, showed evidence of stable disease for 2.75 to 7 months. The drug was well tolerated with only minor drug-related adverse events recorded. Conclusion: STX64 is a potent, well-tolerated STS inhibitor. It inhibits STS activity in PBLs and tumor tissues and causes significant decreases in serum concentrations of steroids with estrogenic properties.

Sex steroid hormones in pairs of tumor and serum from breast cancer patients and pathobiological role of androstene‐3β, 17β‐diol

“…An STS inhibitor, 667 COU-MATE, has been developed, and a phase I trial has been completed. (13) Whether STS inhibitors are effective in treating patients resistant to AI warrants further study.…”

“…Aromatase inhibitors (AI) have been standardized for the treatment of postmenopausal patients with hormone receptor-positive breast cancers, (12) in the expectation of decreasing estrogens. Inhibitors of STS (13) or HSD-1 (14,15) have been also developed and expected as strategies against breast cancer.The importance of estrogens is well recognized, and their clinical relevance in breast cancer has been intensely studied; however, androstene-3b, 17b-diol (Aenediol) and 5a-androstane-3b, 17b-diol (Aanediol), androgen metabolites with estrogenic function, (16)(17)(18) produced by STS from DHEA-sulfate (DHEAS) via DHEA (Fig. 1), have been much less studied.…”

“…Aromatase inhibitors (AI) have been standardized for the treatment of postmenopausal patients with hormone receptor-positive breast cancers, (12) in the expectation of decreasing estrogens. Inhibitors of STS (13) or HSD-1 (14,15) have been also developed and expected as strategies against breast cancer.…”

Effects of mutations and glycosylations on STS activity: A site-directed mutagenesis study

“…These studies aid the understanding of how the new anti-cancer drug target, STS (Stanway et al, 2006), catalyses the conversion of inactive steroids, such as E1S, to active estrogens and may support further rational drug design. Indeed, several mechanisms of action for a sulphamatebased active site-directed steroid sulphatase inhibitor were proposed and sulphamates esters have been developed (Woo et al, 2000).…”

“…However, other selective sulphatase inhibitors showed promise as antiproliferative agents in hormone-dependent breast carcinoma (Purohit et al, 1999) and the recent phase I clinical studies testing STX64, a tricyclic coumarin sulphamate, in female breast cancer patients have shown very encouraging results (Stanway et al, 2006).…”