Combination therapy for treating breast cancer using antiestrogen, ERA-923, and the mammalian target of rapamycin inhibitor, temsirolimus.
The effect of combinations of a mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, and an estrogen receptor-alpha (ERalpha) antagonist, ERA-923, on breast carcinoma in culture and in a xenograft model has been studied. Phase III trials are underway using temsirolimus for several cancers. ERA-923 was studied in a phase I trial for tamoxifen refractory metastatic breast cancer and was shown to have good safety profiles. Combination of noninhibitory doses of temsirolimus with suboptimal doses of ERA-923 synergistically inhibited the growth of MCF-7 cells. Synergy was found across a wide range of doses and could also be achieved by combining temsirolimus with other antiestrogens such as raloxifene and 4-hydroxytamoxifen. In vivo combination of temsirolimus and ERA-923 at certain doses and schedules completely inhibited tumor growth, while individual agents were only partially effective. Although the mechanism underlying the synergism remains to be understood, the results were associated with the ability of temsirolimus to block the transcriptional activity mediated by ERalpha as well as an increase in G1 arrest when it was combined with ERA-923. Results demonstrated for the first time that the combination of temsirolimus and a pure antiestrogen has excellent anticancer activity in preclinical models and, therefore, may have clinical use in treating hormone-dependent tumors.
Sadler
T M
TM
Department of Oncology, Wyeth Research, 401 North Middle Town Road, Pearl River, New York, New York 10965, USA.
Gavriil
M
M
Annable
T
T
Frost
P
P
Greenberger
L M
LM
Zhang
Y
Y
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D020847:Estrogen Receptor Modulators / Q000008:administration & dosage; D005260:Female; D005819:Genetic Markers; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D051379:Mice; D008819:Mice, Nude; D010052:Ovariectomy; D010880:Piperidines / Q000008:administration & dosage; D016133:Polymerase Chain Reaction; D015183:Restriction Mapping; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D013934:Thymectomy; D014162:Transfection
C439584:2-(4-hydroxyphenyl)-3-methyl-1-(4-(2-piperidin-1-yl-ethoxy)-benzyl)-1H-indol-5-ol; D020847:Estrogen Receptor Modulators; D005819:Genetic Markers; D007211:Indoles; D010880:Piperidines; C401859:temsirolimus; D020123:Sirolimus