期刊
MOLECULAR CANCER THERAPEUTICS
卷 11, 期 7, 页码 1565-1575出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-11-0938
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类别
资金
- Merck
- Pfizer
- NIH [R01CA120196, R01CA129382]
- New York Community Trust
- Cancer Innovative Research
- Program of the Entertainment Industry Foundation [SU2C-AACR-IRG0409]
- ECOG tumor bank
- Leukemia & Lymphoma Society Scholar Award
T-cell acute lymphoblastic leukemias (T-ALL) and lymphomas are aggressive hematologic cancers frequently associated with activating mutations in NOTCH1. Early studies identified NOTCH1 as an attractive therapeutic target for the treatment of T-ALL through the use of gamma-secretase inhibitors (GSI). Here, we characterized the interaction between PF-03084014, a clinically relevant GSI, and dexamethasone in preclinical models of glucocorticoid-resistant T-ALL. Combination treatment of the GSI PF-03084014 with glucocorticoids induced a synergistic antileukemic effect in human T-ALL cell lines and primary human T-ALL patient samples. Mechanistically PF-03084014 plus glucocorticoid treatment induced increased transcriptional upregulation of the glucocorticoid receptor and glucocorticoid target genes. Treatment with PF-03084014 and glucocorticoids in combination was highly efficacious in vivo, with enhanced reduction of tumor burden in a xenograft model of T-ALL. Finally, glucocorticoid treatment effectively reversed PF-03084014-induced gastrointestinal toxicity via inhibition of goblet cell metaplasia. These results warrant the analysis of PF-03084014 and glucocorticoids in combination for the treatment of glucocorticoid-resistant T-ALL. Mol Cancer Ther; 11(7); 1565-75. (C)2012 AACR.
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