期刊
CLINICAL LYMPHOMA & MYELOMA
卷 9, 期 -, 页码 S205-S210出版社
CIG MEDIA GROUP, LP
DOI: 10.3816/CLM.2009.s.013
关键词
c-MYC; FBXW7; gamma-secretase inhibitors; PTEN; Targeted therapy
类别
资金
- NCI NIH HHS [R01CA120196, R01 CA120196-03, R01 CA129382, R01 CA129382-02, R01CA129382, R01 CA120196] Funding Source: Medline
The recent identification of activating mutations in NOTCH1 in the majority of T-cell acute lymphoblastic leukemias (T-ALLs) has brought major interest toward targeting the NOTCH signaling pathway in this disease. Small-molecule gamma-secretase inhibitors (GSIs), which block a critical proteolytic step required for NOTCH1 activation, can effectively block the activity of NOTCH1 mutant alleles. However, the clinical development of GSIs has been hampered by their low cytotoxicity against human T-ALL and the development of significant gastrointestinal toxicity derived from the inhibition of NOTCH signaling in the gut. Improved understanding of the oncogenic mechanisms of NOTCH1 and the effects of NOTCH inhibition in leukemic cells and the intestinal epithelium are required for the design of effective anti-NOTCH1 therapies in T-ALL.
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