Phase I study of STX 64 (667 Coumate) in breast cancer patients: the first study of a steroid sulfatase inhibitor.
OBJECTIVE
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.


METHODS
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 1 week later by 3 x 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.


CONCLUSIONS
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.
Endocrinology and Metabolic Medicine and Sterix Ltd., UK.
Susannah J
SJ
Stanway
Atul
A
Purohit
L W Lawrence
LW
Woo
Saulat
S
Sufi
David
D
Vigushin
Rebecca
R
Ward
Richard H
RH
Wilson
Frank Z
FZ
Stanczyk
Nicola
N
Dobbs
Elena
E
Kulinskaya
Moira
M
Elliott
Barry V L
BV
Potter
Michael J
MJ
Reed
R Charles
RC
Coombes
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015114:Androstenediol / Q000097:blood; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D003374:Coumarins / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000097:blood; D004970:Estrone / Q000097:blood; D005260:Female; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000201:enzymology; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013449:Sulfonamides / Q000627:therapeutic use*; D013451:Sulfonic Acids; D013739:Testosterone / Q000097:blood
D003374:Coumarins; D013449:Sulfonamides; D013451:Sulfonic Acids; D004970:Estrone; C520511:irosustat; D013739:Testosterone; D004958:Estradiol; D015114:Androstenediol; D043266:Steryl-Sulfatase